Chapter 45. Principles of Antimicrobial Therapy and the Clinical Pharmacology of Antimicrobial Drugs

• Rational antibiotic use requires the most specific diagnosis that can be made, knowledge of commonly used antimicrobial agents, and appropriate monitoring of therapy.
• Antimicrobial prophylaxis against bacterial infections is indicated in selected patients undergoing surgical procedures and in those with cardiac valvular disease.
• When suspected infection threatens life or major organ function, antimicrobial therapy should be directed at all infectious possibilities of more than trivial probability until the results of definitive investigations are available.
• Knowledge of the clinical pharmacology of antibiotics commonly prescribed in the intensive care unit is essential for the intensivist.

The importance of antimicrobial drugs in the management of patients admitted to the intensive care unit (ICU) is beyond question. The prevention and treatment of infections in ICU patients pose formidable challenges despite advances in our understanding of the pathophysiology of specific infections, the availability of more rapid, sensitive, and specific diagnostic tests, and an array of potent antimicrobial agents.

Prophylaxis of Infectious Diseases in ICU Patients

The efficacy of short-term systemic antibacterial administration to prevent operative site infections after surgery is well established. Effective prophylaxis requires that the antibacterial agent inhibit specific pathogenic agents that cause the infection and be present at therapeutic concentrations in the operative site at the time the incision is made. It is imperative that surgical wound prophylaxis be prescribed, when appropriate, in the management of ICU patients. Recommended drugs, doses, and duration of prophylaxis for some specific surgical procedures are listed in Table 45-1.1

Unlike perioperative antimicrobial prophylaxis for the prevention of wound infection, the efficacy of antibiotics to prevent bacterial endocarditis has not been established by controlled trials. Nevertheless, to prevent bacterial endocarditis, it is recommended that patients with valvulopathy (congenital or acquired) or prosthetic valves (bioprosthetic and homograft valves) be given antimicrobial prophylaxis.2 Table 45-2 lists the cardiac conditions for which endocarditis prophylaxis is recommended, Table 45-3 presents the surgical procedures for which antibacterial prophylaxis is recommended, and Table 45-4 lists the recommended injectable drugs and doses, all of which were adapted with permission from Dajani and associates.3

In contrast, the usefulness of antimicrobial agents to prevent infections other than endocarditis and infections related to surgery remains limited or controversial. Two general approaches have been evaluated. In one, antibiotics are applied to sterile sites or clean skin wounds to prevent local infection; in the other, antibiotics are used to selectively eradicate the potentially pathogenic bacteria of the gastrointestinal tract and simultaneously preserve the anaerobic “nonpathogenic'' flora. The former approach includes endotracheal administration of nonabsorbable antibacterial drugs, such as the aminoglycosides, instillation of antibiotics into the urinary bladder, and the covering of wounds by creams mixed with antibacterial agents. With the exception of topical use of sulfonamide creams in the management of burned patients, these methods have been associated with inconsistent prophylactic effects and a high incidence of relapse, resistance, and superinfection that renders this strategy unacceptable.

The second approach is referred to as selective decontamination of the digestive tract (SDD).4 The strategy of SDD is based on the hypothesis that eradication of selected components of the bacterial and fungal flora of the oropharyngeal or gastrointestinal tract can decrease the risk of infection and maintain the natural defense of these mucosal surfaces conferred by the anaerobic flora. SDD studies include various systematic antimicrobial agents plus oral administration of nonabsorbable agents such as polymyxin E, tobramycin, plus amphotericin B, but other regimens use only nonadsorbable drugs. The antibiotics are administered for the entire duration of the critical illness; in this respect, SDD differs from short-term perioperative surgical prophylaxis. The technique has received intensive investigative attention over the past decade and evidence that SDD is effective in decreasing ICU mortality but the relative importance of antibiotic resistance varies among institutions so that SDD cannot be recommended for routine use.5

Therapy of Infectious Diseases in ICU Patients

Rational antibiotic use requires a systematic approach to the assessment of suspected infection, knowledge of commonly used agents, and appropriate selection and monitoring of drugs.

Regardless of whether infection is suspected in an ICU patient because of the development of florid symptoms and signs of inflammation (rubor, calor, dolor, tumor, or functio laesa) or of subtle deterioration in the level of consciousness or gas exchange, the same thorough, systematic evaluation is recommended: The first question to be addressed is whether infection can be reasonably inferred to be present. Does the history show systemic or local symptoms of inflammation? Are signs of inflammation present? Can other causes of inflammation such as tissue injury due to drugs, immunologic diseases, and physical agents (thermal energy or electromagnetic irradiation) be excluded? Is there laboratory evidence of inflammation—visible pus or polymorphonuclear leukocytes in microscopic examinations of body fluids?

The second question for the intensivist is: What is the infectious disease that is occurring? Is this meningitis, pneumonitis, intraabdominal sepsis, intravascular, catheter-related bacteremia, or some other process? This question must be answered as specifically as possible, because an accurate diagnosis will logically lead to collection of the appropriate specimens for microbiologic testing before antibiotic therapy is initiated, and an appropriate working conclusion about the probable etiologic agents involved.

An outline of the investigation of particular infections is beyond the scope of this chapter and is detailed elsewhere in the text. Contemporary intensivists have access to a wide range of noninvasive radiologic imaging techniques that have been invaluable in confirming the diagnosis of deep visceral infections and assisting in their repeated evaluation during treatment. Occasionally, however, the patient will be too ill to tolerate the most appropriate diagnostic evaluation. This may limit the accuracy of the initial assessment, but the initiation of antimicrobial therapy must not be delayed. It is axiomatic in the critically ill patient that initial antimicrobial therapy be directed at all infectious possibilities of more than trivial probability until the results of definitive investigations are available.

Ideally, the choice of antibiotic agent(s) for the treatment of a specific infectious disease in a given host in the ICU should be based on unequivocal results from rigorous, controlled clinical trials. With a few exceptions, such data do not exist. Therefore, the selection of the proper antimicrobial agent depends on careful consideration of the known or likely susceptibility patterns of the putative pathogen in this specific type of patient at this particular institution, the natural history of the infection, and the spectrum of agents likely or known to be effective for treatment of this type of infection. The two former areas are reviewed in other sections of this book and are not elaborated on here. This chapter emphasizes the importance of knowledge of the clinical pharmacology of antibiotics as one critical element in the rational use of drugs for treatment of infectious disease in the ICU patient.

The selection of the proper drug is essential to minimize toxicity and maximize efficacy. The following key steps relative to knowledge of the antimicrobial agents in humans should be systematically considered in the selection process. These steps are essential to the rational use of any drug.

1. Individualize the treatment by considering the following in choosing drugs and designing dosage regimens.

   1. Processes that alter the pharmacokinetics of the drug

      1. Physiologic

         • Extremes of age

         • Pregnancy

         • Barriers to drug penetration (e.g., blood-brain barrier, intraocular fluid)

      2. Disease induced

         • Barriers to drug penetration (avascular abscess wall, infarcts, burn eschar, wet gangrene, etc.)

         • Changes in drug clearance because of hepatic, renal, or other disease (e.g., enhanced aminoglycoside clearance in burned patients, penicillins in cystic fibrosis patients)

      3. Drugs administered concurrently

         • Chemical interaction (e.g., penicillins inactivate aminoglycosides in azotemic plasma)

         • Enhanced metabolism

         • Competitive inhibition of renal or metabolic clearance in the kidney or liver

         • Displacement of highly bound drug from plasma protein

   2. Processes that alter the pharmacodynamics of the drug

      1. Allergy to the drug

      2. Other (e.g., reduced seizure threshold)

2. Select and monitor therapeutic end points.

   1. Clinical symptoms and signs of infection

   2. Laboratory measures of

      1. Efficacy (e.g., leukocyte concentration, erythrocyte sedimentation rate, serial imaging results such as brain abscess shrinkage on serial computed tomographic scans)

      2. Toxicity (e.g., creatinine concentration and urinalysis in patients receiving aminoglycosides)

   3. Microbiologic (e.g., serial cultures, serum bactericidal titers)

   4. Pharmacologic—serum concentrations of drugs

Selecting the proper antimicrobial agent, skillfully individualizing the dose regimen, and choosing the appropriate parameters to monitor for beneficial and adverse effects of drugs are closely related to knowledge of the pharmacologic effects of antimicrobial agents in humans. The remainder of this chapter reviews these aspects of many classes of antimicrobial agent from the intensivist's perspective.

This section reviews selected aspects of commonly used groups of antimicrobial agents likely to be prescribed by intensivists, with an emphasis on the clinical pharmacology of the drugs rather than on their molecular pharmacology and mechanisms of action.

Penicillins

Mechanism of Action

The penicillins are natural and semisynthetic compounds that have in common a thiazolidine ring connected to a β-lactam ring to which is attached a side chain of variable composition. The composition of the side chain affects the antibacterial spectrum of the molecule. The integrity of the β-lactam ring is essential for the antibacterial activity of the penicillins. Hence, its enzymatic hydrolysis by β-lactamases is the most important mechanism of bacterial resistance to penicillins.

Penicillins are generally bactericidal. The antibacterial effect of penicillins involves binding to penicillin binding proteins (PBPs), which are peptidases in the cell wall of susceptible bacteria.6 The types of PBPs found in different bacterial species vary. High activity of penicillins against susceptible bacteria correlates with high affinity binding to certain PBPs, especially PBPs 1, 2, and 4. Modifications in the penicillin side chain of some semisynthetic penicillins have enhanced their antibacterial activity against gram-negative bacteria by increasing their ability to pass through the lipopolysaccharide outer layer to reach PBP ligands in the peptidoglycan layer and, less importantly, by increasing their resistance to β-lactamase, which these organisms all contain in small amounts in the periplasmic space between the inner and outer membranes.

Penicillin binding to PBPs inhibits peptidoglycan assembly and cross-linking. Cell death is usually the result of activation of endogenous autolysins (peptidoglycan hydrolases), which cause structural defects, resulting in cell lysis. Occasionally, stable round forms develop that continue to grow for several generations before lysis ultimately occurs.7 Hence, although different penicillins, carbapenems, and cephalosporins may have different molecular sites of action, combining two or more of these agents to achieve additive or synergistic antibacterial effects is of unproven value.

The antibacterial effect of the penicillins when susceptible organisms are exposed to intermittent doses of the drugs is determined by composite events occurring during three periods: the time during which the antibacterial drug exerts its maximal effect, the time during which the drug is present at concentrations that have a definite but lesser bactericidal effect, and the period after which concentrations have decreased to levels that are not bactericidal but during which some bacteria continue to die at a faster rate than the surviving cells can multiply (now known as the period of the postantibiotic effect [PAE]).8

Bacterial killing during exposure to penicillins in vitro occurs most rapidly when exposure occurs during the logarithmic phase of bacterial growth. The killing effect of penicillins during this phase shows little dependence on concentration in excess of minimal inhibitory levels. The PAE of the penicillins usually lasts 1 to 3 hours against gram-positive coccal bacteria and 1 hour against susceptible Enterobacteriaceae and other enteric gram-negative bacteria. The duration of the PAE is more closely related to the duration of exposure to inhibitory concentrations of penicillin than to concentration per se. Beyond these facts, the relation between penicillin concentration and bacterial killing is complex even in vitro and more so in patients in whom host factors contribute to the antibacterial effect. It has been difficult to use these observations to optimize the way we give penicillins to patients—by intermittent administration or continuous infusion.9 Morever, because the concentrations at the site of infection cannot be predicted, it is conventional to administer penicillins in relatively large doses at frequent intervals, or else continuously, to ensure the maximal antibacterial effect.10 The effectiveness of this strategy depends more on the duration that penicillin concentrations exceed the inhibitory level than on the absolute concentration of drug. Extremely high peak concentrations may only increase the frequency of concentration-related adverse effects of penicillins (see below).

Mechanisms of Resistance

Enzymatic hydrolysis of the β-lactam bond by β-lactamase is the most important mechanism of bacterial resistance to penicillins. Many gram-negative bacteria are inherently insusceptible to penicillins because the penicillins cannot diffuse through the lipopolysaccharide layer to interact with PBPs. In other bacteria, mutations in genes encoding PBPs may yield altered transpeptidases that no longer bind penicillins. Mutant streptococci have been described in which exposure to penicillins triggers synthesis of inhibitors of autolysins.

Classification

The penicillins can be divided into five classes based on their clinically most important antibacterial activity, notwithstanding substantial degrees of overlap demonstrable in vitro.

Natural Penicillins

Penicillin G, the prototypical member of this group, is the drug of choice for infections caused by susceptible streptococci, staphylococci, Clostridia and Neisseria species, and oral anaerobes including Bacteroides melaninogenicus.

Aminopenicillins

Ampicillin is the only member of this group, which includes amoxicillin and bacampicillin among others, that can be administered parenterally. It is the drug of initial choice for the treatment of community-acquired meningitis in adults, in addition to a third-generation cephalosporin and, when combined with an aminoglycoside, for the therapy of subacute bacterial endocarditis in individuals with native valves and pyelonephritis suspected to be or caused by E. faecalis. Although ampicillin was widely used for treatment for Haemophilus influenzae infections, 19% to 24% of H. influenzae type B bacteria causing respiratory infection in adults are now resistant to ampicillin, usually by virtue of producing β-lactamase.11 Accordingly, in the seriously ill patients in whom H. influenzae is a potential pathogen, it is prudent to use a drug other than ampicillin until the organism can be shown to lack β-lactamase by in vitro testing.

Penicillinase-Resistant Penicillins

These penicillins, such as cloxacillin and nafcillin, are the antibacterial drugs of choice for therapy of Staphylococcus aureus infection suspected or known to be susceptible (collectively referred to as methicillin-sensitive S. aureus [MSSA].

Antipseudomonal Penicillins

Ticarcillin has been superseded by the extended-spectrum penicillins (see below) for treatment of patients with suspected or proven infection caused by Pseudomonas aeruginosa. The activity of ticarcillin against Proteus vulgaris, Proteus rettgeri, and Morganella morganii exceeds that of ampicillin, but against other enteric aerobic gram-negative bacilli its potency is similar to that of ampicillin and inferior to the extended-spectrum penicillins. In addition, ticarcillin and carbenicillin may interfere more with platelet function, an undesirable side effect in critically ill patients with thrombocytopenia or other potential causes of hemorrhage (e.g., stress ulcers). Because development of resistance during therapy can be a problem, ticarcillin is generally used with an aminoglycoside when P. aeruginosa sepsis is suspected or diagnosed.

Extended-Spectrum Penicillins

Piperacillin and mezlocillin inhibit P. aeruginosa in a manner similar to the antipseudomonal penicillins but also have considerably more clinically useful activity against a number of other enteric gram-negative aerobic and anaerobic organisms. Mezlocillin is more active than ticarcillin against most Enterobacteriaceae, but many strains are resistant through production of β-lactamase. Mezlocillin is active against oropharyngeal gram-negative anaerobic bacilli, but Bacteroides fragilis group organisms are not uniformly susceptible. Mezlocillin is highly active against H. influenzae, meningococci and gonococci, Streptococci (including S. faecalis), and penicillin-sensitive S. aureus strains. Because of its greater potency against P. aeruginosa in vitro, piperacillin is the antipseudomonal penicillin of choice.

Combining piperacillin with the β-lacatamase inhibitor tazobactam (or ticarcillin with clavulanate) extends the spectrum of piperacillin to include a number of β-lactamase–producing bacteria, including S. aureus, and some gram-negative bacilli such as Serratia species, Acinetobacter species, and B. fragilis. Thus, piperacillin/tazobactam and ticarcillin/ clavulanate have utility in the ICU as broad-spectrum antibiotics in patients in whom P. aeruginosa is also a significant concern as an etiologic agent (see section on β-lactamases).

Clinical Pharmacology

The absorption of orally administered penicillins is sufficiently variable among even ambulatory patients that, for this reason alone, these drugs are administered only intravenously in the critically ill patient. The range of doses of some penicillins recommended for adult patients with moderate to severe infection, with normal or impaired renal function, and dialysis-dependent kidney disease are presented in Table 45-5.

In the circulation, penicillins are bound to plasma proteins, chiefly albumin, to different degrees, ranging from 18% for ampicillin to 96% for dicloxacillin. This affects the apparent volume of distribution (AVD), the theoretical calculated volume in which a drug must be uniformly distributed if present at the concentration measured in plasma12 expressed as liters per kg of body weight. The AVD of penicillins is approximately inversely related to the degree of protein binding, ranging from 9% of body weight for dicloxacillin to 41% for ampicillin. Although protein-bound antibiotic is not pharmacologically active, serum protein binding of penicillins has not proved to be clinically important because the binding is loose and rapidly reversible in vivo, and the doses used in clinical practice greatly exceed the capacity of the plasma proteins to bind drug. The clinical relevance of coadministering drugs that compete for the same albumin binding sites as penicillins is unclear but unlikely, with an interaction due to altered protein becoming likely only when binding exceeds 90%.13

Penicillins are largely eliminated from the body as unchanged drug by renal proximal tubular secretion and glomerular filtration, but some metabolic transformation occurs and can compensate for diminished renal clearance of some penicillins. For example, in anuric patients, the plasma elimination half-life (t½) of penicillin G is increased from 0.5 to 10.0 hours, and doses must be reduced to obviate dose-related toxic effects (see below). However, the serum elimination t½ of cloxacillin increases only threefold, to 1.5 hours, and no dose reduction is required.

Probenecid, an organic acid like the penicillins, competitively inhibits renal tubular secretion of penicillins. Coadministration results in an array of pharmacokinetic effects including increased plasma concentrations (double in the case of penicillin G), higher concentrations in the cerebrospinal fluid (CSF) because of inhibition of penicillin secretion from CSF into blood by the choroid plexus, and higher free drug concentrations in plasma because of displacement from albumin. The magnitude of these effects is greatest for those penicillins primarily eliminated by renal proximal tubular secretion.

Various other organic acids also compete with penicillins for secretion by renal tubular cells and produce probenecid-like effects on penicillin disposition. These acids include aspirin, phenylbutazone, sulfonamides, indomethacin, thiazide diuretics, furosemide, and ethacrynic acid. The clinical importance of concurrent administration of these drugs on the antibacterial effects of penicillin is not known but is unlikely to be significant.

Adverse Drug Reactions

Adverse drug reactions (ADRs) include all unwanted effects of drugs. They are classified into those that are immunologically mediated (hypersensitivity or allergic reactions) and those that are dose or concentration related. For antibiotics, the latter class also includes all unwanted or undesired complications arising from perturbations in the normal microbiologic flora (e.g., pseudomembranous colitis and yeast vaginitis) and from superinfections caused by agents resistant to the antibiotics being administered to the patient. A third class comprises ADRs for which the mechanism is not understood. This includes anaphylactoid reactions (similar clinically to anaphylaxis but without a demonstrated immunologic basis) and idiosyncratic effects. ADRs to penicillins mostly are of the first two classes. Although they may rarely be fatal (1 per 100,000 cases treated), hypersensitivity reactions are much more important than dose-related penicillin ADR in the ICU, because such intolerance precludes the use of this useful class of drugs. Allergic reactions to penicillins are not uncommon.14 The overall incidence in different studies ranges from 0.7% to 10.0%. In order of decreasing frequency, hypersensitivity reactions to penicillins include urticaria, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, and anaphylaxis. Hypersensitivity reactions may be induced by any member of this group, and cross-reactions must be anticipated. Anaphylaxis has been reported more commonly with penicillin G than with other members of the penicillin group, but this probably reflects the frequency of its use. Anaphylaxis and accelerated urticarial reactions, rash, and serum sickness are triggered by immunobinding of penicillin antigens to immunoglobulin (Ig) E, IgM, and IgG antibodies, respectively.15 Atopic individuals are not more prone to have allergic reactions to penicillins. Approximately 75% of persons without medical exposure to penicillins have IgM antibody to penicilloyl, the most important penicillin antigen produced by breakage of the β-lactam ring. It acts as a hapten by covalently binding to plasma proteins. The formation of two other antigens, penicilloic acid and penicillanic acid, are increased by high and low pH, respectively. Together, penicilloic and penicillanic acids are known as major determinants because 95% of tissue-bound penicillin is in the form of penicilloyl and penicillanic acid conjugates with body proteins. IgG and IgM antibodies to these moieties occur in most patients treated with penicillins, but the allergic reactions that occasionally result are generally limited to skin rash rather than accelerated, systemic reactions. The term penicillin minor determinants, however, refers to benzylpenicillin itself, sodium benzyl penicilloate, and penilloate. IgE-mediated reactions to minor determinants are responsible for most anaphylactic reactions due to penicillins.

Interstitial nephritis associated with methicillin may be a delayed-type hypersensitivity reaction in which the drug induces autoimmunity to renal tubular basement membranes. This unusual immunologically mediated ADR is most commonly seen in patients treated with methicillin for extended periods in large doses, but it has been reported after therapy with most other penicillins and some cephalosporins.

The most important aspect of management of patients with hypersensitivity to penicillins is avoidance. A reliable story of anaphylaxis or an accelerated reaction to any member of this group of drugs (or a cephalosporin or carbapenem) is an absolute contraindication to their use. A history of any other form of hypersensitivity reaction should be given appropriate weight in the therapeutic decision-making process and, in particular, should be balanced against the fact that, perhaps, apart from the treatment of syphilis in the pregnant woman, there are no infectious diseases for which penicillins are absolutely the only effective antibacterial available. If it is decided to administer penicillins to a person with a history of a hypersensitivity reaction, skin testing is advised to identify those with severe hypersensitivity. Testing should be done with major and minor determinant mixtures.16,17 The reagents themselves appear safe: 1% of patients with a history of penicillin allergy developed reactions to the skin test reagents, mostly urticaria. Negative results of skin testing with both preparations have a high negative predictive value in individuals despite a history of penicillin allergy. Ninety-seven percent to 99% did not experience any reaction on administration of penicillin. However, two (22%) of nine patients with positive skin tests to major or minor determinant mixture given penicillin experienced reactions compatible with IgE-mediated or accelerated penicillin allergy, indicating the positive predictive value of such testing.

Even if no reaction to a skin test reagent is observed, it is prudent to administer the first dose with epinephrine and resuscitation equipment at hand and to inject only a fraction of the initial dose. If none occurs after 15 to 30 min, the remainder of the initial dose may be administered. If a reaction occurs during skin testing, penicillin should, in general, be avoided, although in selected cases consultation with a clinical immunologist to effect desensitization may be appropriate.

Rashes caused by ampicillin should be distinguished from those caused by other penicillins. The rashes occur in 7% to 8% of patients, an incidence three times greater than with all other penicillins, and are not considered to be immunologically mediated. Certain patients are more prone to experience ampicillin-induced skin reactions: females, hyperuricemic patients receiving allopurinol, individuals with acute mononucleosis caused by Epstein-Barr virus (EBV) or cytomegalovirus (CMV), and those with lymphocytic leukemia, reticulosarcoma, and other lymphomas. The rashes typically are morbilliform, appear 4 to 5 days after initiation of therapy, are not accompanied by other signs of allergy, and usually subside during continued therapy. Skin testing with ampicillin and major and minor penicillin determinants will be negative. Such rashes should not be considered a contraindication to subsequent therapy with one of the other penicillins.

A few adverse reactions to penicillins are neither immunologically mediated nor dose related. Neutropenia occurs in about 15% of patients treated with methicillin and somewhat less commonly with other penicillins. Neutropenia generally occurs 10 to 20 days after initiation of therapy and resolves rapidly on discontinuation of therapy. Reversible thrombocytopenia and bone marrow suppression have also been described in patients receiving penicillins. Hypokalemia has been described in up to 81% of patients without significant renal dysfunction who were treated with methicillin or carbenicillin. The mechanism of this ADR is unclear. Although these two penicillins likely behave like a nonabsorbable anion in the distal renal tubule, increasing passive potassium urinary excretion, some have proposed that the hypokalemia may instead be caused by an intracellular shift of potassium because of a membrane-altering effect.

Four dose-related side effects of the penicillins are uncommon but may be clinically important. First, undesirable augmentation of body sodium or potassium content can occur in patients with salt and water overload (e.g., congestive heart failure or renal failure) who are treated with large doses of penicillins because the penicillins are formulated for injection as salts of one of these cations (Table 45-6).

Second, penicillins may cause neurotoxic effects including seizures. This is related to an innate pharmacologic effect of the molecule and, hence, to the concentration of drug in the body. Penicillin G is the most inherently epileptogenic of the group. Seizures usually will be seen only in patients with impaired renal function given large doses. Impairment of the blood-brain barrier due to meningeal inflammation, uremia, and cardiopulmonary bypass may contribute to the effect, as may hyponatremia or concomitant probenecid therapy that blocks penicillin excretion from the CSF. Neurotoxicity will progress from muscular irritability with choreiform, involuntary twitching, or myoclonic jerking to a depressed level of consciousness and, ultimately, seizures, unless penicillin administration is halted. Penicillin concentrations in lumbar sac CSF in excess of 5 mg/L have been associated with seizures,18 but the critical concentration in the CSF contiguous with cortical neurons has not been described. This toxic effect of penicillins will resolve with discontinuation of therapy and elimination of penicillin. Unfortunately, in those most predisposed to this ADR (patients with severe renal failure),19 penicillin clearance will be slower than in those with normal renal function.

A third dose-related side effect of penicillins is impaired platelet aggregation that may lead to clinically important bleeding. Ticarcillin is the most potent in this regard, although piperacillin, mezlocillin, and penicillin G can induce this defect.20 The effect is caused by a concentration-dependent blocking of receptor sites on platelet membranes, thereby interfering with adenosine-induced aggregation. The defect may persist for up to 12 days after drug discontinuation, suggesting an effect on megakaryocytes and circulating platelets. Impaired platelet aggregation can be avoided by limiting dose size and avoiding these agents in patients with conditions predisposing to hemorrhage, such as thrombocytopenia or severe hepatic dysfunction.

A fourth category of ADR caused by penicillin is that related to suppression of endogenous bacterial flora. The most important example is Clostridium difficile toxin-induced pseudomembranous colitis or diarrhea. As a group, the penicillins (and cephalosporins) rank close behind clindamycin as the most common antibacterials causing this undesirable and potentially life-threatening complication.

Cephalosporins

The cephalosporins resemble the penicillins structurally and in their mode of action, versatility, and general lack of toxicity. They possess a β-lactam structure in which the thiazolidine ring characteristic of penicillins is replaced by a six-member dihydrothiazine ring. Modification in the side chains at the 3 and 7 positions of the nucleus has yielded molecules with different pharmacokinetic and pharmacodynamic characteristics, respectively.21 Side chain modifications at position 7 alter and extend the spectrum of antibacterial activity but, in some cases, also cause unusual adverse pharmacologic effects such as inhibition of vitamin K–dependent hepatocyte synthesis of clotting factors II, VII, IX, and X and induction of reactions to disulfiram (Antabuse) in individuals ingesting or being treated with alcohol concurrently.

The potency of third-generation cephalosporins against a wide range of clinically important bacteria and a general lack of serious toxicity have led to an emerging consensus that certain members of this group are drugs of first choice for a number of severe bacterial infections, especially nosocomial ones, including meningitis, pneumonitis, bacteremia, and urinary tract infections.22 This is particularly true for infection caused by increasingly resistant organisms and for initial, empirical therapy in the ICU setting. The first- and second-generation cephalosporins, however, are not drugs of first choice for any acute life-threatening infectious disease that might be seen in ICU patients, although they continue to be important first-line drugs for a variety of less severe infections such as cellulitis and community-acquired pneumonia.

Mechanism of Action

The mechanism of action of the cephalosporins is identical to that of the penicillins and involves binding to, and inactivation of, PBPs in the inner aspect of the cell wall of susceptible bacteria.

Mechanism of Resistance

Resistance to cephalosporin antibiotics is also mediated by mechanisms that confer resistance to penicillins. Cephalosporins may not penetrate through the lipopolysaccharide cell wall to the site of the PBPs. The cephalosporin may be inactivated by β-lactamase. Substantial evidence indicates that exposure to some third-generation cephalosporins may induce synthesis of large amounts of β-lactamase with high affinity for the cephalosporins. As a result, the antibiotic is avidly bound by the enzyme and unable to interact with PBPs.23 This is hypothesized to be the mechanism of resistance observed in Enterobacter, Serratia, Citrobacter, and Pseudomonas species exposed to third-generation cephalosporins.

Classification

Cephalosporins are arbitrarily classified as belonging to one of three generations. This classification is based solely on the spectrum of antibacterial activity. None of the cephalosporins is useful for infections caused by Streptococcus faecalis or methicillin-resistant Staphylococcus epidermidis and S. aureus (MRSA). However, cephalosporins are useful antibacterials for treatment of a wide range of infections and for surgical prophylaxis (Table 45-1).

The first-generation cephalosporins are potent inhibitors of aerobic gram-positive cocci such as S. aureus and S. pneumoniae, with moderate activity against a limited number of aerobic gram-negative bacilli including Escherichia coli, Klebsiella pneumoniae, and indole-negative proteus. They are active against some anaerobic gram-positive and gram-negative oropharyngeal organisms, as is penicillin G, but are not consistently effective against B. fragilis group and other fecal anaerobic organisms. Cefazolin is the prototypical agent of this group, which contains the most active cephalosporins against susceptible aerobic gram-positive cocci.

The second-generation cephalosporins as a group exhibit enhanced potency against E. coli, K. pneumoniae, and indole-negative proteus, compared with first-generation agents. Individual members of this class have clinically important antibacterial activity against β-lactamase–producing H. influenzae (cefamandole, cefuroxime, and cefotetan), B. fragilis group organisms (cefoxitin, cefotetan), Neisseria meningitidis and N. gonorrhoeae, and some species of enteric gram-negative bacilli. However, activity against the last group of organisms is sufficiently variable so that it is more appropriate to initially prescribe a third-generation cephalosporin, aminoglycoside, or perhaps fluoroquinolone. The extended spectrum of some of these second-generation agents has made them drugs of importance, albeit not first choice, in some serious infections: mixed aerobic and anaerobic pulmonary, gastrointestinal, genital tract, and skin and soft tissue infections, such as aspiration pneumonia, intra-abdominal and pelvic peritonitis, pelvic inflammatory disease, and diabetic foot infection (cefoxitin), respectively. For pneumonia caused by an exacerbation of chronic bronchitis, cefuroxime is commonly prescribed.

The third-generation cephalosporins are particularly noteworthy for their potency against aerobic gram-negative bacilli, which they inhibit in concentrations 10 to 100 times less than required for aminoglycosides. These cephalosporins inhibit a wide range of this group of bacteria that are resistant to first- and second-generation cephalosporins, extended-spectrum penicillins, and aminoglycosides. The lack of inherent toxicity of third-generation cephalosporins is another advantage in treating ICU patients with multisystem dysfunction, especially renal failure. Two of the third-generation cephalosporins, cefoperazone and, particularly, ceftazidime, have clinically useful activity against most strains of P. aeruginosa, although susceptibility may differ substantially across institutions. Third-generation cephalosporins are not more resistant to penicillinase produced by S. aureus, nor are they more active against this organism than are the penicillinase-resistant penicillins or first-generation cephalosporins, which are preferred for therapy of such infections.

Recommended intravenous doses of selected cephalosporins for adult patients with moderate to severe infection and normal or impaired renal function or undergoing dialysis are presented in Table 45-7.

Clinical Pharmacology

Like the penicillins, the cephalosporins are variably bound to plasma proteins; the range is 15% (cephalexin) to 84% (cefazolin) with AVDs of 0.10 (cefoxitin) to 0.30 (cefuroxime) L/kg. These characteristics are independent of the generation to which the agent belongs. They differ from the penicillin group pharmacokinetically:

1. Hepatic biotransformation is a significant route of elimination for some members of this group. Moreover, cefotaxime hepatic biotransformation yields metabolites with antibacterial activity that contribute to the overall antibacterial effect, although their precise contribution is unclear.

2. Some have prolonged plasma t½ in patients with normal renal function. For example, the extended plasma t½ of 8 hours for ceftriaxone has made once- to twice-daily dosing feasible without a loss in efficacy.

3. The third-generation drugs readily cross the blood-brain barrier. Therefore, unlike the first- and second-generation cephalosporins, the third-generation ones predictably attain therapeutic concentrations in the CSF and are efficacious for treatment of meningitis. However, therapeutic concentrations of cephalosporins are attained in the vitreous and aqueous humors of the eye only by sub-Tenon or intraocular injection or topical administration of antibiotic, respectively.

Probenecid inhibits renal proximal tubule secretion of cephalosporins just as for penicillins. Moderate to severe renal dysfunction necessitates reduction in the doses of some of the cephalosporins (see Table 45-7). Hemodialysis or peritoneal dialysis may remove sufficient drug (see Table 45-7) to necessitate additional postdialysis doses. Only cefoperazone doses must be reduced in patients with moderate to severe hepatic dysfunction.

Adverse Drug Reactions

Hypersensitivity reactions to the cephalosporins qualitatively similar to those produced by penicillins are the most common adverse effects.15 They are no more common with any single cephalosporin or generation of cephalosporins and likely are related to the shared bicyclic nuclear structure. However, cephalosporins lose both their ring structures when exposed to β-lactamases, in contrast to penicillin degradation. Thus, molecules unique to cephalosporins that may function as haptens are generated. This probably accounts for the lack of predictable cross-allergenicity between penicillins and cephalosporins. Haptenic activity of acyl side chains at position 7 of the β-lactam ring further complicates the predicting of reactions induced by cephalosporins in individuals with a history of penicillin intolerance. Cross-reactions do occur in penicillin-sensitive patients treated with cephalosporins.24 However, the frequency of such cross-reactions is minimally, if at all, increased in patients with penicillin allergy. Nevertheless, a history of penicillin allergy of the immediate or accelerated type precludes use of cephalosporins. No established testing methods identify cephalosporin allergy.

Dose-related side effects of cephalosporins are generally less marked than those induced by penicillins. The likelihood of cation overloading even with large doses of cephalosporins is small. Although they are mostly sodium salts containing up to 3.6 mEq Na1/g (Ceftriaxone), the total sodium load administered even with very large doses is unlikely to be clinically important except in rare patients with severe sodium and water overload. The epileptogenic potential of the cephalosporins is less than that of the penicillins. All cephalosporins in high concentration except cephaloridine are similar to penicillins in interfering with platelet aggregation.

Modifications induced by altering the side chain on the dihydrothiazine ring at position 3 have yielded cephalosporins with unusual pharmacologic side effects: cefamandole, cefoperazone, cefotetan, and moxalactam have a methyltetrazolethiol side chain that provokes a disulfiram-like reaction in patients ingesting or receiving ethanol. Inhibition of hepatic aldehyde dehydrogenase with accumulation of acetaldehyde during metabolism of alcohol is the presumed mechanism. These four agents may also predispose the patient to bleeding because of interference with synthesis of vitamin K–dependent clotting factors25 in addition to their inhibition of platelet aggregation. Bleeding may only occur in patients whose oral intake of vitamin K and synthesis of endogenous vitamin K by colonic flora are impaired concomitantly. As a consequence, cefamandole, cefoperazone, and moxalactam are no longer widely used.

Superinfections are surprisingly uncommon given the wide antibacterial spectrum of third-generation cephalosporins, with occurrences from 1% of cefotaxime recipients up to 3% to 5% for cefoperazone-treated patients.26 Superinfections in patients treated with moxalactam have been observed to frequently be caused by S. faecalis. Otherwise, superinfection caused by resistant aerobic enteric gram-negative bacilli, Clostridia species, and yeast has been the most common.

Adverse effects of cephalosporins on the kidney are rare with two exceptions: cephaloridine in doses of 4 to 6 g/d causes acute tubular necrosis, and cephalothin appears to enhance the nephrotoxic effect (but not vestibular or cochlear toxic effects) of gentamicin and tobramycin.

Other β-Lactam Drugs

Carbapenems and monobactams are two new classes of β-lactam antibiotics of importance to intensivists (Table 45-8).

Carbapenems

Carbapenems possess novel stereochemical characteristics that distinguish them from the other bicyclic β-lactams, the penicillins, and cephalosporins. Imipenem, meropenem, and ertapenem are currently licensed carbapenems.

Imipenem and meropenem have the widest spectrum of any β-lactam antibiotic studied to date. They are potent inhibitors of nearly all common bacterial pathogens, including those resistant to aminoglycosides and newer cephalosporins, in concentrations as low as, or lower than, any other β-lactams. Imipenem binds primarily to PBP-2 and is not hydrolyzed by most β-lactamases, penicillinases, or cephalosporinases. The wide spectrum of activity appears to be related to the ability of this relatively compact β-lactam molecule to diffuse readily through porin channels of gram-negative enteric bacilli, in addition to the β-lactamase resistance conferred on the molecule by the unusual transconformation related to the hydroxyethyl side chain. Tolerance is not observed when bacteria are exposed to imipenem (i.e., there is no major discrepancy between inhibitory and bactericidal concentrations), and, unique among β-lactams, imipenem exerts a marked PAE on gram-positive and gram-negative bacteria. Imipenem inhibits gram-positive cocci other than E. faecium and MRSA, most Enterobacteriaceae, and gram-negative bacilli including P. aeruginosa but excluding most Pseudomonas cepacia and S. maltophilia strains, and all oral and most fecal anaerobic bacteria. There is no cross-resistance between imipenem and other β-lactams.

Meropenem differs from imipenem in possessing slightly greater activity against gram-negative bacteria due to more rapid penetration through the cell wall. Thus, it inhibits some P. aeruginosa strains resistant to imipenem.27

Ertapenem has a narrower spectrum of activity than does imipenem or meropenem. It is more similar to meropenem than to imipenem against Enterbacteriaceae including most anaerobes. However, unlike imipenem and meropenem, it possesses no activity against P. aeruginosa or Acinetobacter species.28

The place of the carbapenems in the therapy of infection in ICU patients continues to evolve. Clinical experience suggests that meropenem and imipenem are therapeutically equivalent.29 For treatment of lower respiratory tract infection in patients in the ICU, meropenem is more effective than ceftazidime.30Ertapenem has been demonstrated to be comparable to piperacillin/tazobactam in patients with intra-abdominal, skin and skin structure, and pelvic infections;31 its efficacy compared with imipenem and meropenem has not been described. For treatment of patients with meningitis, meropenem is the carbapenem of choice (imipenem use is associated with a significant risk of seizures and ertapenem has not been studied in patients with meningitis).

Overall, imipenem and meropenem are appropriate as monotherapy for treatment of serious nosocomial and community-acquired infections due to aerobic and/or anaerobic bacteria. Ertapenem may be as efficacious, but data are not available to support that conclusion and ertapenem should not be administered where P. aeruginosa is a probable or proven cause of infection. In general, they are appropriate for indications such as those for which extended-spectrum cephalosporins would be used. As monotherapy, they are probably as effective as clindamycin combined with an aminoglycoside for treatment of seriously ill patients with intra-abdominal infections.32 Imipenem and meropenem should not be used as monotherapy of P. aeruginosa infections because of the risk of resistance, and ertapenem should not be used at all. The greatest value of the carbapenems may be that their broad spectrum permits their use conveniently in place of multiple-drug regimens for polymicrobial infections, with an attendant reduction in the risk of adverse reactions. Recommended intravenous doses of the carbapenems for adult patients with moderate to severe infections and variable renal function are listed in Table 45-8.

Clinical Pharmacology

The carbapenems are not absorbed after oral administration and therefore are available only in parenteral formulations. Imipenem and meropenem are only 2% to 20% protein bound, whereas ertapenem is highly bound. They penetrate into a wide variety of tissues and brain cells but poorly into other cells. These characteristics make them unsuitable for treatment of infections caused by bacteria that are primarily intracellular pathogens and may account in part for the epileptogenic potential of imipenem in particular.

The carbapenems are eliminated from plasma by a first-order process primarily by glomerular filtration, with a mean t½ of 1 hour for imipenem and meropenem; the t½ for ertapenem is 4 hours, due in part to its high protein binding. Renal tubular secretion is minimal.

Renal handling of filtered carbapenems differs markedly. Imipenem is remarkably stable to bacterial β-lactamase but its β-lactam ring structure is susceptible to metabolic degradation in humans, primarily by peptidases in the brush border of renal tubular epithelial cells. Inhibition of these enzymes (by cilastatin, see below) increases urinary recovery of undegraded imipenem from 7% to 38% up to 70% to 85%. Meropenem and ertapenem are not degraded by renal tubular peptidase and, unlike imipenem, therefore are formulated without cilastatin.

Like cephaloridine, imipenem is toxic to proximal renal tubule epithelial cells. The toxic moiety appears to be a hydrolysis product, the formation of which can be safely blocked by coadministration of cilastatin, which inhibits the catalytic effect of dehydropeptidase I in the brush border and completely eliminates renal tubular damage without affecting the plasma t½ of imipenem. A ratio of 1:1 for imipenem to cilastatin is optimal, and imipenem is marketed in this fixed combination.33

Adverse Drug Reactions

The carbapenems are generally well tolerated, like other β-lactams. Major adverse effects such as diarrhea, superinfection, or pseudomembranous colitis are infrequent. Allergic reactions, including rashes and drug fever, occur in 2% to 3% of subjects, and cross-allergenicity to penicillins has been observed. The relatively high incidence of seizures, 0.2% in series of patients treated with imipenem,34 is unique among β-lactam antibiotics and also not seen with meropenem or ertapenem. Pre-existing central nervous system (CNS) disease, advanced age, and renal insufficiency predispose patients to this serious but reversible side effect. Seizures ought to be preventable by appropriate dose reductions in patients with renal disease, a maneuver of particular importance in patients with CNS disease.

Monobactams

Aztreonam is the first marketed member of a new completely synthetic class of monocyclic β-lactam antibiotics called monobactams. Aztreonam has no clinically important activity against gram-positive or anaerobic bacteria because of failure to bind to PBPs of these organisms. Aztreonam binds primarily to PBP 3 in Enterbacteriaceae, P. aeruginosa, and other gram-negative aerobic bacteria and, hence, has a bactericidal effect; its narrow spectrum of activity most resembles that of the aminoglycosides. When combined with other β-lactam antibiotics to treat gram-negative aerobic bacterial infections, the net effect is unpredictable. Aztreonam is more predictably synergistic, or at least additive, with aminoglycosides.35 Lack of susceptibility is caused by failure of aztreonam to cross the outer cell wall and failure to bind to PBPs. Aztreonam is stable in the presence of a wide variety of β lactamases,36 so inactivation by this process is less important as a mechanism of bacterial resistance than for other β-lactam antibacterial agents.

The exact niche of aztreonam in the treatment of gram-negative aerobic bacterial infections in ICU patients is unclear at present. The most logical, albeit rare, circumstance for which it could be used would be in treating patients with significant allergy to β-lactam antibiotics (see below) in whom its combination with another agent, such as an aminoglycoside to obtain a synergistic or additive effect, is deemed necessary. Aztreonam also may be used alone in such patients if an aminoglycoside is considered contraindicated, but its relative utility compared with aminoglycosides and other alternatives such as fluoroquinolones and trimethoprim-sulfamethoxazole (TMP-SMX) has not been evaluated in controlled trials.

Clinical Pharmacology

Aztreonam is poorly absorbed after enteral administration because of intragastric hydrolysis and, hence, must be administered intramuscularly or intravenously. After such injection, aztreonam distributes widely and achieves therapeutic concentrations in all body tissues and fluids except perhaps the vitreous humor. Metabolism has a minimal effect on aztreonam clearance. Aztreonam is eliminated primarily by renal filtration and tubular secretion, but some excretion in bile into the gut occurs.37 Elimination is a first-order process with a plasma t½ of 1.7 hours that is inversely related to glomerular filtration rate and increases to 6 hours in anephric patients. The usual dose, 1 to 2 g every 6 to 12 hours (maximum, 8 g/d), should be reduced in patients with renal insufficiency. The drug is removed by hemodialysis and peritoneal dialysis, but alternative schedules for such patients (see Table 45-8) have not been established.

Adverse Drug Reactions

Aztreonam shares the general safety profile of other β-lactam antibiotics. Up to 7% of patients experience rash, diarrhea, nausea, or vomiting, and isolated elevations of serum transaminase concentrations. Aztreonam is unique among β-lactams in being weakly immunogenic and not cross-allergenic with other penicillins or cephalosporins.15 Aztreonam has been administered safely to penicillin-allergic patients, including those with positive skin test results. This unique property appears to result from the fact that aztreonam lacks the allergenic bicyclic nuclear structure of penicillins, cephalosporins, and carbapenem β-lactam antibiotics.

β-Lactamase Inhibitors

Clavulanate, sulbactam, and tazobactam are β-lactam compounds that possess weak, insignificant antibacterial activity but are clinically useful because they extend the spectrum of activity of many β-lactam antibiotics by inhibiting β-lactamases. The three compounds differ in their potency and the range of lactamases they inhibit.38 Tazobactam inhibits a wider range of plasmid- and chromosome-encoded lactamases than clavulanate and sulbactam. This fact and the greater intrinsic antibacterial effect of piperacillin in comparison with ticarcillin or amoxicillin/ampicillin account for the wider antibacterial spectrum and greater potency of piperacillin-tazobactam than the other two combinations of drugs. Thus, although injectable formulations of ampicillin-sulbactam and ticarcillin-clavulanate exist, piperacillin-tazobactam has largely supplanted the other two compounds. Moreover, the combination of tazobactam with piperacillin makes the combination an effective inhibitor of MSSA, thereby converting piperacillin into a broad-spectrum antimicrobial with attendant added utility for ICU patients.

The efficacy and safety of piperacillin-tazobactam compared with standard therapy has been demonstrated in controlled trials of patients with intra-abdominal infection, postpartum endometritis or pelvic inflammatory disease, community-acquired pneumonia, and skin and skin-structure infections.39,40 The usual dose is 3 g piperacillin with 375 mg tazobactam every 6 hours, but for patients seriously ill with proven or suspected Pseudomonas species infection, 4 g plus 500 mg for every 4 hours with another drug is recommended. Studies suggest that piperacillin-tazobactam combined with amikacin is more efficacious (61% efficacy) than ceftazidime with amikacin (54%) for treatment for febrile episodes in neutropenic cancer patients.41

The value of piperacillin-tazobactam compared with piperacillin alone for treatment of serious infection caused by Pseudomonas species is unclear39 because most lactamase-mediated resistance of Pseudomonas species is a result of the production of inhibitor-insusceptible enzymes. Therefore, for the treatment of serious Pseudomonas infections, Sanders and Sanders recommend piperacillin-tazobactam (4 g/0.5 g) every 4 hours with an additional agent such as an aminoglycoside.39

Clinical Pharmacology

Clavulanate, sulbactam, and tazobactam share many clinical pharmacologic characteristics common to β-lactam antibiotics. Only the characteristics of tazobactam combined with piperacillin are discussed here; the characteristics of amoxicillin-clavulanate,42ampicillin-sulbactam,43 and ticarcillin-clavulanate44 have been reviewed elsewhere.

When piperacillin and tazobactam are administered together in a ratio of 8:1, the pharmacokinetic activities of piperacillin are unaffected. However, the pharmacokinetic characteristics of tazobactam are significantly affected, largely owing to competitive inhibition of renal proximal tubular secretion of tazobactam by the much larger quantity of piperacillin. When the peak plasma concentration of tazobactam was increased by about 30% and the plasma t½ by about 100% from a mean of 0.45 to 0.94 hours, renal clearance was reduced approximately 25%.45

Piperacillin and tazobactam are eliminated primarily into urine by glomerular filtration and tubular secretion. Less than 1% of piperacillin and no tazobactam are secreted into bile. In patients with renal impairment, the renal clearances of piperacillin and tazobactam are proportionately reduced. Dose reductions are recommended for patients with creatinine clearances lower than 40 mL/min (see Table 45-8). Hemodialysis removes approximately 35% of piperacillin-tazobactam and peritoneal dialysis removes approximately 20% of piperacillin-tazobactam. Hence, the supplementary doses recommended after the two types of dialysis are different (see Table 45-8).

In patients with hepatic cirrhosis, the elimination t½ of piperacillin and tazobactam increases by about 20%, but no dose reductions are recommended in such patients.

Adverse Drug Reactions

Adverse effects of piperacillin-tazobactam have been generally mild to moderate in severity.34 Gastrointestinal complaints, mostly diarrhea, were noted in 4.6% of patients, but with a range from 0% to 32%; skin rash occurred in 0% to 12% of subjects. In their review, Sanders and Sanders concluded that, overall, the rates and character of adverse reactions are comparable to, or less than, those reported for piperacillin alone, ticarcillin-clavulanate, ampicillin-sulbactam, and imipenem-cilastin.39

Aminoglycoside Antibiotics

One or more of the aminoglycoside antibiotics (streptomycin, kanamycin, gentamicin, tobramycin, netilmicin, amikacin, and neomycin) has been a mainstay of our antibacterial armamentarium since the discovery of streptomycin in 1943. Streptomycin currently is limited to use in the combination therapy of tuberculosis and for treatment of Francisella, Yersinia pestis infection, and brucellosis. Neomycin is too toxic for systemic use but is still administered orally for the treatment of portosystemic encephalopathy (see Chaps. 83 and 84). The remaining agents—kanamycin, gentamicin, tobramycin, netilmicin, and amikacin—are first-line drugs for the treatment of serious infection caused by Enterobacteriaceae and Pseudomonas and Serratia species. The importance of these bacterial species as causes of nosocomial infection has progressively increased in the antibacterial era, and the importance of the aminoglycosides has increased in parallel. Kanamycin utility has been limited by widespread resistance among many Enterobacteriaceae and innate inefficacy against P. aeruginosa. Gentamicin, tobramycin, amikacin, and netilmicin share similar spectra of activity with the following caveats. Tobramycin is twice as potent as gentamicin or netilmicin in inhibiting P. aeruginosa in vitro, although the clinical relevance of this superiority is not clear. Netilmicin is the most potent inhibitor of S. epidermidis. Amikacin is the most resistant to aminoglycoside-inactivating enzymes. As a result, many enteric bacilli resistant to kanamycin, gentamicin, and netilmicin remain susceptible to amikacin.

Unfortunately, the utility of these agents in the therapy of patients with significant infection in the ICU has been limited by their inherent toxic effects on the proximal tubule epithelial cells of the kidney and the hair cells of the cochlea, saccule, and utricle and by the emergence of resistance.

Mechanisms of Action

The aminoglycosides are rapidly bactericidal in contrast to β-lactam antibacterial drugs, which cause bacterial cell death only after a lag period.9 Although their mode of action has been extensively studied,46 the precise mechanism(s) of their lethal effect remains unclear. It is generally accepted that aminoglycosides interfere with bacterial protein synthesis by binding to the 30S subunit of bacterial ribosomes, resulting in misreading of mRNA codons and synthesis of faulty bacterial proteins, but the resulting alterations in protein molecules are not considered sufficient by themselves to cause cell death. Aminoglycoside uptake by bacteria depends in part on energy derived from aerobic metabolism. Thus, all of these agents are inactive under anaerobic conditions. In vitro, aminoglycosides cause bacterial cell death in a concentration-dependent manner,47 and this effect is little affected by inoculum size.48 This pharmacologic effect underlies, in part, the attractiveness of once-daily aminoglycoside dosing to attain greater efficacy (and less toxicity) than is achieved with multiple doses each day. Moreover, these agents consistently produce a concentration- and time-dependent PAE on gram-positive and gram-negative aerobic bacteria.49 The PAE persists longer (usually longer than 3 hours) for gram-negative aerobic bacilli than for gram-positive aerobic bacteria (usually less than 2 hours). The mechanism of the PAE of aminoglycosides is likely related to the time required for organisms to resynthesize proteins essential for replication.

Mechanisms of Resistance

Aminoglycoside resistance of aerobic organisms is mediated primarily by aminoglycoside-inactivating enzymes.50 Less commonly, ribosomal mutation and diminished permeability of bacterial cells to aminoglycoside molecules account for resistance. Different enzymes may acetylate, adenylate, or phosphorylate aminoglycosides and, by these changes, preclude binding of the drug to ribosomes. The aminoglycosides differ considerably in their susceptibility to enzymatic modification. For example, gentamicin is susceptible to modification by at least five different enzymes elaborated by gram-negative bacilli, but amikacin is susceptible only to an acetyltransferase found in some P. aeruginosa and Acinetobacter species strains. The genes encoding aminoglycoside-modifying enzymes are most commonly acquired on plasmids. This usually occurs in the setting of heavy and widespread use of these agents (antibiotic selection pressure).50 As a result, gentamicin resistance emerging under antibiotic selection pressure in institutions is more common than resistance of bacteria to amikacin; resistance of bacteria to tobramycin, netilmicin, and kanamycin is of intermediate prevalence. Although aminoglycoside resistance is to some extent a function of use, this association is not entirely predictable because other factors are probably involved.52

Clinical Pharmacology

The aminoglycosides are poly-cations whose polarity is responsible in part for many of their shared clinical pharmacokinetic characteristics. They are poorly absorbed after oral administration, have an AVD that is mathematically similar to the extracellular fluid volume, are excluded from the normal subarachnoid space, vitreous humor, and prostatic fluid, and are eliminated almost exclusively by the kidney.53

After intramuscular administration, the aminoglycosides are rapidly and completely absorbed. Their AVD is equal to 25% to 30% of ideal body weight. The AVD is approximately 25% less in obese than in nonobese individuals and approximately 20% greater in patients with protein-calorie malnutrition. This information must be used to calculate the initial dose, which is a function of the desired plasma concentration multiplied by the AVD. For gentamicin, tobramycin, and netilmicin, the minimal inhibitory concentration (MIC) of most susceptible aerobic enteric gram-negative bacilli is 2 to 4 mg/L, and toxicity has been shown to increase at peak concentrations in excess of 10 mg/L. It is therefore conventional to prescribe an initial dose to attain a serum concentration (Cs) of 7 mg/L, which for a 70-kg adult would be 7 mg/kg × 70 kg × 0.25, or approximately 120 mg. For kanamycin and amikacin, for which desired Cs values are 25 to 30 mg/L, the initial dose, similarly calculated, would be 500 mg.

Aminoglycosides are actively concentrated in the endolymph of the cochlea, saccule, and utricle and in epithelial cells of the proximal renal tubule, a fact important in the production of aminoglycoside toxicity54 (see below). Less than 1% of an injected dose appears in the feces and none in saliva.

Aminoglycosides are eliminated exclusively by glomerular filtration. An inverse relation exists between plasma t½ and creatinine clearance as a measure of glomerular filtration rate. At creatinine clearance rates of 100 mL/min, the plasma t½ averages 2 hours.55 As the creatinine clearance declines, the plasma t½ increases. In the presence of renal disease, it is possible to prescribe maintenance doses by repeating the initial dose at intervals equal to three times the estimated t½ of the drug. However, it has been found to be more practical to maintain the interval at the conventional 8 or 12 hours but to reduce the dose administered proportionate to renal function (e.g., if estimated remaining renal function is 50% of normal, one can administer 50% of the dose at 8-hour intervals51); such a dose regimen will result in a lower peak plasma aminoglycoside concentration but in trough plasma concentrations comparable to those achieved by maintaining the dose (milligrams per kilogram) constant and increasing the dose interval. The efficacy and safety of these two approaches has not been compared in patients with renal insufficiency. Maderazo and colleagues confirmed the utility of the following formulas for adjusting the dosing regimen for aminoglycosides (and other drugs eliminated almost wholly by glomerular filtration).56

A. To reduce the dose and maintain the same interval as in a person with normal renal function, use this formula:

B. To maintain the dose but decrease the dose frequency, use this formula:

where the creatinine clearance (milliliters per minute) is calculated from the formula of Cockcroft and Gault57 and n represents dose (milligrams) and u represents the dose interval (hours) in a person with normal renal function.

If possible, it is preferable to use antibiotics other than aminoglycosides in patients with significant renal insufficiency. If aminoglycosides must be used, serum aminoglycoside measurements should be used to maximize efficacy and minimize toxicity (see below). The importance of serum aminoglycoside measurements is greater when renal function is fluctuating or when disease or other drugs may be affecting aminoglycoside disposition. For example, in burned and febrile patients, aminoglycoside pharmacokinetic characteristics are altered, and larger doses will be required. In patients with renal failure given aminoglycosides and penicillins in large doses, aminoglycosides are inactivated. The rate and extent of the inactivation depend on the concentration of the penicillin. Kanamycin, gentamicin, and tobramycin are most susceptible to inactivation in this manner, and amikacin the least with netilmicin of intermediate susceptibility.

The concentration in plasma (Cp)-versus-time curve after intravenous administration of an aminoglycoside dose is affected by the pre-existing Cp, the dose administered, and the method of administration (intramuscular or intravenous injection, bolus, or infusion and the rate of infusion). These variables particularly affect the time and magnitude of peak Cp. Trough Cp is less affected by these factors. This variability has made it more difficult to define the relation between post-dose aminoglycoside concentration and therapeutic effect than that between trough Cp and toxic effects. Although incontrovertible data do not exist, some data demonstrate that Cp measured 60 minutes after intramuscular or 15 minutes after an intravenous infusion of the aminoglycoside is related to efficacy. For gentamicin, a post-dose Cp of 8 mg/L or larger is associated with a better outcome than lower Cp in patients being treated for gram-negative aerobic bacillary pneumonia, whereas concentrations of at least 5 mg/L are associated with a better outcome in patients being treated for non-pneumonia, non-CNS, gram-negative aerobic bacillary infections.58 It is assumed that the same relation holds for netilmicin and tobramycin. For amikacin and kanamycin, post-dose Cp values of 20 to 40 mg/L are desirable.

A direct relation between predose or trough aminoglycosides Cp and toxicity was first demonstrated in 1950 for streptomycin.59 Trough Cp higher than 3 mg/L during once-daily intramuscular administration of streptomycin for therapy of tuberculosis was associated with an increased risk of dizziness, presumably owing to vestibulotoxicity. Old age was also a factor. At other times Cp values were much more variable, and often higher, but did not correlate with this toxic effect. Subsequent studies have suggested an increased risk of gentamicin nephrotoxicity, demonstrated by a rise in serum creatinine concentration, when trough gentamicin Cp exceeds 2 mg/L.60 This interpretation is supported by studies in animals.

Compelling in vitro and correlative in vivo data provide strong support for the current practice of administering aminoglycosides intermittently rather than by constant infusion to optimize efficacy and minimize toxicity. Extrapolating further, some have argued for once-daily dosing in individuals with normal renal function.49 These expectations are based on in vitro observations including a concentration-dependent aminoglycoside antibacterial effect over a wide range of concentrations beginning at the MIC and extending beyond tolerable serum concentrations in patients, and concentration-dependent PAE. Moreover, these observations have been supported by studies in animals with experimental infection and provide the rationale for dosing to achieve high aminoglycoside concentrations in plasma and at the site of infection. However, clinical trials comparing conventional multiple-daily doses with once-daily administration of aminoglycosides have demonstrated little or no advantage of this practice over traditional 8- or 12-hour administration in terms of efficacy or safety.61,62 It may only be more convenient than dosing two or three times daily.

The methodologically best-designed controlled trials included almost exclusively immunocompetent adults with normal renal function; a few had mildly impaired renal function (serum creatinine <300 mmol/L).63 Controversy exists concerning virtually all other aspects of the practice. This includes the question of whether it is appropriate to prescribe aminoglycosides once daily to infected patients with neutropenia, sepsis syndrome, and moderate to severe renal insufficiency.64 Additional subgroups for whom few or no data are available to support once-daily aminoglycoside use include pediatric patients and patients with severe burns, endocarditis, pregnancy, or ascites. Moreover, uncertainty exists about optimal dose size65 and the rationale for, and specifics of, serum aminoglycoside concentration measurement for monitoring.66 Despite these limitations of the available data, as early as 1993, 19% of a random sample of 336 acute care hospitals in the United States reported that aminoglycosides were being prescribed once daily in their institutions, albeit with the anticipated variability in practice expected given the incomplete database.67

Until definitive data become available to guide the practice of once-daily administration of aminoglycosides, the following guidelines are recommended:

1. Restrict the practice to the prescription of netilmicin, gentamicin, tobramycin, and amikacin.

2. Once-daily administration is acceptable to treat adult patients with normal or mildly impaired renal function (serum creatinine <300 mmol/L or estimated creatinine clearance >30 mL/min). Patients should not be pregnant; endocarditis, neutropenia, severe burns, or sepsis and moderate or severe renal impairment are relative contraindications.

3. Doses: netilmicin 6 mg/kg; gentamicin and tobramycin 4 mg/kg; and amikacin 15 mg/kg.

4. Infuse the drug over 60 min, preferably by a pump, to permit interpretation of the peak serum concentration result as described by Moore and colleagues.68

5. Measure aminoglycoside Cp:

   1. To enhance efficacy, measure the Cp 60 minutes after the end of the infusion “peak.''68 If the peak Cp is below 5 mg/L for netilmicin, gentamicin, or tobramycin, increase the dose proportionately (e.g., if Cp = 4 mg/L, increase the dose by at least 20%).

   2. To minimize toxicity, measure the Cp just before the dose. If the Cp is above 2 mg/L for netilmicin, gentamicin, or tobramycin or above 10 mg/L for amikacin, reduce the dose proportionately.

6. Measure aminoglycoside Cp at the peak and trough every 3 days if renal function (serum creatinine concentration) is stable and more frequently if it is not.

Adverse Drug Reactions

All aminoglycosides share three dose-related, largely reversible toxic effects, although quantitative differences exist among members of this family. These are neuromuscular paralysis, nephrotoxicity, and cochleovestibular toxicity. The mechanisms of the unwanted effects are not well characterized, but an interaction of the cationic aminoglycoside molecule with calcium, magnesium, and membrane phospholipids69 may be common to all. These effects of aminoglycosides are a result of their inherent pharmacologic properties occurring at doses close to those required for treatment. As such, the effects are not likely completely avoidable.

Neuromuscular paralysis of clinical consequence is likely to be seen only in patients receiving neuromuscular blocking drugs or with diseases such as botulism or myasthenia gravis. Aminoglycoside-induced skeletal muscle paralysis involves inhibition of acetylcholine release and blockage of acetylcholine receptors. The postsynaptic inhibitory effect is directly related to high concentrations of aminoglycoside at the neuromuscular end plate as seen when the antibiotic is injected rapidly as a bolus or when large quantities of aminoglycoside are administered and absorbed (e.g., by injection in the pleural or peritoneal cavity). The effect can be avoided by slow intravenous administration over 30 to 60 minutes or intramuscular injection and mitigated by calcium injection.

Aminoglycoside nephrotoxicity spans a wide spectrum, ranging from asymptomatic increased urinary excretion of renal tubular epithelial cell brush border enzymes to renal failure necessitating dialysis. In between is diminished creatinine clearance demonstrated by elevated serum creatinine concentration. Enzymuria is almost universally demonstrable in patients receiving therapeutic doses of aminoglycosides, whereas oliguric renal failure is rare. Elevated serum creatinine concentration is observed in 5% to 25% of treated patients.

The nephrotoxic effect is associated with accumulation of aminoglycoside in renal proximal tubule epithelial cells with resultant cell damage and, possibly, inhibition of synthesis of vasodilatory prostaglandins resulting in renal afferent arteriolar vasoconstriction and diminished glomerular filtration. Renal injury manifest as elevations in serum creatinine concentration usually occurs several days after initiation of therapy and is largely reversible because of epithelial cell regeneration. Animal and clinical studies have indicated that neomycin is the most nephrotoxic and amikacin the least nephrotoxic of currently used aminoglycosides. Gentamicin is more nephrotoxic than tobramycin.70

The nephrotoxic effect of aminoglycosides in animal studies is related directly to the height of the trough serum aminoglycoside concentration and the area under the serum concentration-time curve, which in turn are the important determinants of aminoglycoside uptake and sequestration in proximal tubule epithelial cells. This leads to the recommendation that trough serum aminoglycoside concentrations should be as low as possible.61 For gentamicin, levels below 3 mg/L at trough are recommended.62 Intuitively, the same level would seem to be appropriate for tobramycin and netilmicin, which have similar pharmacokinetic properties and antibacterial potency to gentamicin. The appropriate trough Cp for amikacin is 5 to 10 mg/L.

Additional risk factors for nephrotoxicity include older age, female sex, concomitant liver disease, hypotension, and concomitant drug therapy with cephalothin, cisplatin, amphotericin B, and cyclosporine.

Ototoxic effects of aminoglycosides include hearing loss caused by cochlear injury and vertigo caused by vestibular damage. Neither has been as well studied as nephrotoxicity because of difficulties in assessing cochlear and vestibular functions in critically ill patients. Nevertheless, available data suggest that all the injected aminoglycosides can cause both types of injury. Tobramycin is more ototoxic than netilmicin.71

The incidence of clinically detectable hearing loss ranges from 0.5% to 5.0% and that of vestibular dysfunction causing vertigo or nystagmus ranges from 0.4% to 4.0%. Auditory toxicity is caused by selective destruction of the outer hair cells of the organ of Corti, especially at the basal turn, with subsequent retrograde degeneration of the associated fibers of the auditory nerve. The vestibular toxicity is caused by similar injury to hair cells of the ampullae cristae. Because these are highly differentiated cells that do not regenerate if destroyed, ototoxicity is irreversible. Animal and some clinical data suggest that ototoxic effects are related to selective concentration and trapping of the cation aminoglycoside molecules in the perilymph and endolymph of the cochlea and vestibular apparatus and this in turn to high trough serum aminoglycoside concentrations,59,72 although other data show no relation.73 Renal insufficiency is the most important risk factor,73 but dose is important in patients with normal renal function; duration of therapy and older age are of variable pertinence. Concomitant ethacrynic acid, but not furosemide therapy, increases the risk of ototoxicity.

Other adverse effects of aminoglycosides are uncommon.These include pseudomembranous colitis due to C. difficile toxin and hypersensitivity reactions such as rash, fever, Stevens-Johnson syndrome, and delirium.

Although dose-related toxic effects of aminoglycosides may be unavoidable despite assiduous attention to dose selection plus monitoring of serum concentrations, the small risk of toxic effects that are generally reversible should not engender use of small, potentially inefficacious doses of these drugs in critically ill ICU patients.

Polymyxins B and E (Colistin)

The polymyxins are a group of basic polypeptide antibiotics that inhibit only aerobic gram-negative bacteria. Their antimicrobial action is mediated by binding to phospholipids in the cytoplasmic membrane, with disruption of membrane permeability, macromolecular and ion disequilibria, and cell lysis. Intrinsic resistance is caused in part by inability of the drug to gain access to the cytoplasmic membrane; acquired resistance is rarely observed. The potency and spectrum of activity of polymyxin are similar to those of the aminoglycosides. However, because of more marked nephrotoxicity, only polymyxins B and E (colistin) are used clinically. Polymyxin B continues to be used in topical or oral formulations from which it cannot be absorbed. Thus, polymyxin B has been administered orally to suppress aerobic gram-negative bacterial intestinal flora in immunocompromised patients. Polymyxin E (colistin) alone, or combined with another antibiotic, has a limited role as a parenteral agent for the treatment of infection caused by multiply resistant, nosocomial pathogens for which no alternative agents are available. Polymyxin E has been administered with rifampicin to treat multiresistant nosocomial S. marcesens infection74 and with cotrimoxazole, to treat P. cepacia and S. marcescens infections.75,76 It is unaffected by enzymes that degrade β-lactam and aminoglycoside antibiotics.

Clinical Pharmacology

Like aminoglycosides, polymyxins are eliminated unchanged by glomerular filtration. The plasma elimination t½ of colistin is 1.6 to 3.0 hours. No reliable data exist on the relation between serum concentrations and therapeutic or toxic effects. Accordingly, when polymyxin E is administered parenterally, avoidance of drug toxicity depends solely on clinical evaluation, urinalysis, and measurement of changes in glomerular filtration rate. In the critically ill ICU patient, the confounding effect of concurrent changes owing to disease and other drugs makes this more difficult than usual.

The usual dose of polymyxin E is 2.5 to 5.0 mg/kg per day as two or four divided intramuscular or intravenous doses or a continuous intravenous infusion at a rate of 5 to 6 mg/h. Polymyxin E accumulates in patients with renal failure so that the total daily dose should be reduced:

Adverse Drug Reactions

Adverse reactions after topical or oral administration are uncommon, although nausea, vomiting, and diarrhea are caused by administration of large doses (≥600 mg) by mouth. After parenteral administration, side effects are similar to those caused by aminoglycosides. Reversible dizziness, paresthesias especially affecting the face, incoordination caused by vestibulotoxicity and proteinuria, microscopic hematuria, and progressive azotemia or acute tubular necrosis may occur. Respiratory paralysis owing to neuromuscular blockade occurs rarely; unlike that owing to aminoglycosides, respiratory paralysis cannot be reversed by neostigmine.

A recent report described the nephrotoxicity of polymyxin B in 80 patients with nosocomial multidrug-resistant gram-negative bacterial infections.77 Mortality rate was 20%; the organism was cleared in 88% of patients. Nephrotoxicity, defined as a doubling in serum creatinine occurred in 14% of patients, all of whom had normal baseline creatinine levels. Older age was the only predictor of nephrotoxicity; neither total dose nor duration of polymyxin B therapy was a significant predictive factor. This study is encouraging in demonstrating that this drug, which is often active against multidrug-resistant gram-negative nosocomial bacteria, can be used, if necessary, with a reasonable therapeutic-to-toxic index.

Glycopeptide Antibiotics

Vancomycin and teicoplanin are structurally and functionally related members of the glycopeptide family of antibacterial drugs.

Vancomycin

The antibacterial activity of vancomycin is essentially restricted to gram-positive bacteria. It is the drug of first choice for initial therapy of MRSA and S. epidermidis infection.22 It is a significant alternative agent for treatment of enterococcal infection as ampicillin resistance continues to increase. Staphylococcus aureus, S. epidermidis, streptococci, and Corynebacterium and Clostridium species are almost uniformly sensitive to vancomycin. However, strains of vancomycin-resistant S. aureus (MIC >32 mg/L) are being reported.78 Fortunately, their prevalence has not yet significantly compromised the utility of vancomycin as initial therapy for infections suspected to be caused by these organisms. In combination with gentamicin or tobramycin, vancomycin synergically inhibits S. aureus strains, including those resistant to methicillin and nearly all strains of S. faecalis. A major crisis in antimicrobial therapeutics is looming with the emergence of vancomycin-resistant enterococci (VRE), which are often resistant to all other available antibiotics.

Mechanisms of Action and Resistance

Vancomycin is bactericidal by inhibiting an early stage in the formation of the peptidoglycan of the cell wall. Resistance to it, at least in enterococci, is associated with synthesis of a plasmid-encoded ligase that results in synthesis of cell wall precursors that will not bind vancomycin but can still be cross-linked by enterococcal transpeptidases to form a normal cell wall. Concern is increasing that this vancomycin resistance may be transferred to MRSA, because this can be effected readily in vitro. This appears to have occurred in a case of vancomycin-resistant S. aureus78 in which vancomycin resistance was mediated by acquisition of the Van A gene.

Clinical Pharmacology

Vancomycin is poorly absorbed after oral administration. For systemic therapy, it must be injected intravenously because intramuscular injection causes marked discomfort and possibly tissue necrosis. It is 30% to 55% protein bound and distributes widely into inflamed tissues and spaces in effective concentrations, including the subarachnoid space in patients with meningitis and the peritoneal cavity in patients with renal failure and peritonitis complicating chronic peritoneal dialysis. The AVD is approximately 40% of total body weight. It may be 50% less on average in morbidly obese patients, but the implication of this for dose calculation is unclear. The drug is eliminated primarily unchanged by glomerular filtration. The plasma elimination t½ varies widely, with a range of 3 to 13 hours (average, 6 hours) even in patients with normal renal function. Plasma t½ is prolonged with renal insufficiency and may be as long as 17 days in anuric patients. In patients with liver disease without concomitant renal dysfunction, plasma t½ is also increased and has been reported to be as long as 37 hours. This observation and the incomplete recovery of injected vancomycin in urine collections from healthy volunteers indicate that vancomycin is partly eliminated by a nonrenal, presumably hepatic, route.

Vancomycin Cp is directly proportional to dose. The Cp 2 hours after infusion of 0.5, 1.0, and 2.0 g in adult volunteers averages 2 to 10, 25, and 45 mg/L, respectively. The mean Cp 6 hours after infusion of 0.5 g is 6 mg/L and that 12 hours after infusion of 1.0 g is 5 mg/L.

The usual adult dose of vancomycin is 6.5 to 8.0 mg/kg administered every 6 hours or 15 mg/kg every 12 hours, given in a relatively dilute solution infused over 60 min. More rapid infusion is frequently associated with the occurrence of the red-man syndrome, an important adverse reaction (see below). In adults with impaired renal function, dose reductions are recommended to avoid ototoxic and, purportedly, nephrotoxic side effects (see below). One nomogram that permits calculation of the appropriate dose interval is shown in Fig. 45-1.79

In patients with fluctuating renal function and those with clinically important liver disease, dose intervals should be based on vancomycin concentrations in serum after the usual initial dose. Although the data demonstrating a relation between vancomycin Cp and beneficial or toxic effects are not robust80 and lack consensus in some countries,81 avoiding maximum concentrations of 30 mg/L is conventional after the distribution phase is complete (30 minutes after the end of infusion) to obviate ototoxicity and perhaps the red-man syndrome, as is avoiding trough concentrations above 10 mg/L, to minimize nephrotoxicity. However, in patients with gram-positive bacteremia receiving vancomycin alone, peak serum vancomycin above 20 mg/L and trough concentrations above 10 mg/L were associated with an “improved outcome.''82 If a continuous infusion of vancomycin is administered, the target Cp should be 15 mg/L.

In functionally anephric patients who are being dialyzed, 1 g vancomycin infused weekly yields maximum Cp values of 40 to 50 mg/L that are usually well tolerated and remain therapeutic after 7 days (Cp 5 to 7 mg/L). Thus, once-weekly vancomycin infusions are a practical and convenient method for treating serious infection in patients requiring dialysis. Hemodialysis does not remove significant amounts of vancomycin so that no supplemental doses need be administered after completion of dialysis.

Vancomycin administered by mouth is effective for therapy of pseudomembranous colitis.83 It is considered the drug of choice for severe cases, whereas metronidazole is no less effective for mild to moderately severe disease.84 The recommended dose is 125 mg administered four times per day; the maximum dose is 500 mg administered four times per day. In patients with adynamic ileus, the optimal therapy for pseudomembranous colitis is unknown. Some experts recommend vancomycin administration intravenously and by nasogastric tube. When cholestyramine is administered by mouth for treatment of pseudomembranous colitis, coadministration of vancomycin should be avoided because it will be inactivated by binding to the resin. In patients with severe pseudomembranous colitis and moderate to severe renal dysfunction treated with vancomycin by mouth, vancomycin Cp values have been reported to reach peak concentrations as high as 13 mg/L depending on the dose given.85 It was estimated that only an average of 4.0% of oral doses were absorbed and that the accumulation of vancomycin in serum was primarily a function of concurrent renal insufficiency in those patients. Monitoring of vancomycin Cp values has been recommended if such therapy is prolonged (>28 days) or involves higher than conventional doses (>2 g/d).

Vancomycin administered intraperitoneally in dialysis fluid is the preferred mode for treatment of gram-positive coccal peritonitis complicating peritoneal dialysis. This choice is predicated on the knowledge that peritonitis in such patients is a superficial and localized infection of the serosal surface of the peritoneum. Absence of fever in 80% to 90% of milder cases and the rarity of bacteremia support this view. Vancomycin moves readily bidirectionally across the inflamed peritoneal lining into the blood stream, and vice versa. Accordingly, the Cp ultimately attained approaches that in the peritoneal fluid. One vancomycin treatment schedule for peritonitis begins with a dose of 1 g in the initial dialysate, followed by 50-mg maintenance doses in subsequent exchanges. On such therapy, mean vancomycin Cp rises to 9 mg/L at 5 hours and averages 6 to 9 mg/L during subsequent dwell periods. In patients with severe peritonitis, it is not certain that concomitant intravenous therapy alters the outcome, but vancomycin may be administered by both routes. In such patients, the need for frequent measurement of vancomycin Cp to avoid excessively high levels becomes more acute.

Adverse Drug Reactions

The red man syndrome is the most important immediate adverse effect of vancomycin infusion. It appears to be caused by histamine release. The reaction may begin within minutes of starting the infusion or shortly after its completion and definitely occurs more commonly with rapid infusions. In general, tingling and flushing of the neck, face, and thorax develop during the course of a rapid infusion, sometimes with progression to hypotension and shock. The flushed appearance usually resolves over several hours. Antihistamines can prevent vancomycin-induced hypotension in humans,86 but the value of antihistamines for treating hypotension after the onset of the reaction is unclear. Nevertheless, treatment with fluid administration, antihistamines, and steroids has been advocated for severe reactions. Many, but not all, occurrences of the syndrome can be prevented by following the manufacturer's strong recommendation that vancomycin be infused over at least 60 min. A maximum rate of administration of 10 mg/min may further reduce the risk of hypotension, as demonstrated in a study in volunteers.87

A maculopapular rash (sometimes accompanied by pruritus, fever, and rigors), not dissimilar to the cutaneous flushing seen as a component of the red man syndrome, may occur in up to 3% of patients treated with vancomycin. This adverse effect appears to be an allergic reaction, so intensivists may have to decide whether to risk readministration of the antibiotic in such patients. In those in whom the reaction is part of a typical red man syndrome, continued therapy with cautious, slower administration has been advocated; however, if allergy is diagnosed, use of alternative agents is more prudent.

Ototoxicity owing to vancomycin does not appear to be common, but definitive data are lacking.88 In one prospective study, reversible tinnitus and dizziness occurred in 2 of 34 patients.89 However, tinnitus may herald high-frequency hearing loss and deafness that will progress despite discontinuation of vancomycin therapy. Ototoxicity is probably caused by injury to the hair cells of the cochlea, a toxic effect identical to that caused by aminoglycoside antibiotics. It is therefore not surprising that vancomycin ototoxicity is more likely when aminoglycosides are administered concomitantly. Ototoxicity is also more frequent in elderly patients and those with renal failure. It is associated with peak vancomycin Cp above 80 mg/L but is infrequent if drug is administered so the peak and trough Cp values are below 30 mg/L and below 10 mg/L, respectively.

The nephrotoxic potential of vancomycin administered alone or in combination with an aminoglycoside is not clear despite several careful prospective observational studies. Nephrotoxicity demonstrated by a rise in creatinine Cp values has been reported in 5% to 75% of patients treated with vancomycin alone and in 0% to 22% of patients treated with vancomycin plus an aminoglycoside. In one study, trough vancomycin Cp values above 30 mg/L were associated with nephrotoxicity,80 but others could not identify such an association.80 Renal dysfunction developing during vancomycin therapy is usually mild and reversible, but as many as 9% of patients may have persisting evidence of diminished renal function.89

Even though the nephrotoxicity of vancomycin and the relevance of monitoring serum vancomycin concentration are debated, until the issue is clarified serum creatinine levels should be monitored in patients being treated with vancomycin and doses should be adjusted to obtain peak and trough Cp values below 30 mg/L and below 10 mg/L, respectively. Combination therapy with an aminoglycoside plus vancomycin requires even more careful attention to these measures.90

Teicoplanin

Teicoplanin is, like vancomycin, a glycopeptide antibiotic. It is produced by Actinoplanes teichomyceticus and is formulated as a complex mixture of six closely related molecules.91

Teicoplanin, like vancomycin, inhibits a wide range of gram-positive aerobic and anaerobic bacteria ranging from MRSA to Clostridia species. It is indicated for treatment of infections caused by susceptible gram-positive bacteria including MRSA and VRE. In the ICU, it probably represents an alternative to vancomycin. Administered orally, teicoplanin may be an alternative to metronidazole or vancomycin for the treatment of C. difficile toxin diarrhea and colitis.

The usual dose is 400 mg infused intravenously over 30 minutes or by intramuscular injection (unlike vancomycin) once daily or as often as every 12 hours for treatment of more severe infection.

Mechanism of Action

Teicoplanin is bactericidal like vancomycin, presumably through its inhibition of peptidoglycan synthesis and, hence, the cell wall of daughter cells. It binds to the alanine residue of the terminal portion of the muramyl pentapeptide, resulting in inhibition of the transglycosylation reaction and cell wall biosynthesis.

Compared with vancomycin, it contains more fatty acid chains that, it is hypothesized, facilitate penetration through the bacterial cell wall and result in greater potency and a longer biological t½. These fatty acids also may account for its solubility at pH 7.4, which permits good local tolerance and rapid absorption after intramuscular injection.

Mechanism of Resistance

Some bacteria are inherently insensitive to glycopeptide antibiotics; these include Leuconostic, Pediococcus, Lactobacillus, and Erysipelothrix species. Of greater clinical importance are strains that are differentially inhibited by teicoplanin and vancomycin. Enterococcus faecalis and E. faecium strains expressing the Van A gene exhibit high-level resistance to both drugs. Resistance is transferable by conjugation and inducible by the glycopeptides. Enterococcus faecium strains with the Van B phenotype exhibit susceptibility to teicoplanin but moderate resistance to vancomycin. Differential susceptibility of S. epidermidis or S. haemolyticus to the two glycopeptides has been observed. In vitro selection of stepwise resistance to teicoplanin has been observed in coagulase-negative staphylococci and S. aureus strains with heterogeneous patterns of β-lactam susceptibility.

Overall, these data suggest that teicoplanin may be an alternative to vancomycin for some vancomycin-resistant infections.

Clinical Pharmacology

Absorption after intramuscular injection is equivalent in extent to intravenous injection. The AVD is 0.8 to 1.62 L/kg body weight. The drug does not penetrate into the CSF. Elimination from plasma is almost wholly by renal mechanisms; only 3% of teicoplanin is metabolized. The elimination t½ is 155 to 168 hours.

Renal and total body clearance correlate with creatinine clearance, and doses must be reduced in patients with impaired renal function. Dose reductions are recommended to begin after the fourth day of treatment. For patients with creatinine clearance 40 to 60 ml/min, maintenance doses should be halved by administering one-half the dose daily or the usual dose every 2 days. For those with creatinine clearance slower than 40 mL/min and in patients on hemodialysis (teicoplanin is not removed by dialysis), the maintenance dose should be one-third the usual dose by administering one-third the usual dose daily or the full dose every 3 days.

For treatment of peritonitis due to susceptible patients on continuous ambulatory peritoneal dialysis (CAPD), a loading dose of 400 mg intravenously or intramuscularly should be accompanied by addition of teicoplanin to yield 20 mg/mL in the dialysate for the first week and then 20 mg/mL on alternate days in the second week and then in each bag in the third week.

Adverse Drug Reactions

Teicoplanin is generally well tolerated. In a large trial in Europe, 10.3% of 3377 patients treated with teicoplanin had an adverse reaction: allergic-type reactions in 2.6%, local intolerance in 1.7%, fever in 6.8%, and ototoxicity in 0.3%. Abnormal liver and renal function tests developed in 1.7% and 0.6% of patients, respectively.

Anaphylactoid reactions to vancomycin, described as “red man syndrome,'' have seldom been reported in patients treated with teicoplanin. The extent of cross-allergenicity to teicoplanin in patients allergic to vancomycin is uncertain, but some reactions have been reported.

Nephrotoxicity due to teicoplanin appears to be very uncommon, including a lesser propensity than with vancomycin to increase creatinine concentration when administered with an aminoglycoside.

Overall, based on a lesser likelihood than vancomycin of causing nephrotoxicity when coadministered with an aminoglycoside and greater ease of administration intravenously or intramuscularly once daily, with probable equal efficacy, teicoplanin may be a preferred alternative to vancomycin for initial broad-spectrum therapy of nosocomial infection, especially when the prevalence of MRSA and VRE is of any concern. Conversely, the lack of availability of a serum teicoplanin assay and knowledge of levels associated with safety and efficacy makes it more complicated to administer teicoplanin than vancomycin. More data from head-to-head comparative trials are needed.

Sulfonamides

The discovery of the antibacterial action of sulfonamides in the 1930s and the administration of these agents systemically to prevent and cure bacterial infections represented a revolutionary breakthrough in medicine and opened the chemotherapeutic era. When first introduced for general use, this group of antibiotics was effective against a wide range of infections caused by aerobic gram-positive and gram-negative bacteria, actinomycetes (Nocardia and Actinomyces), protozoa (Pneumocystis carinii, Toxoplasma gondii, and malarial parasites), and Chlamydia trachomatis. Since that time, their usefulness has declined markedly because of a number of factors: the advent of a wide range of alternative agents, the frequent emergence of resistance to sulfonamides in many formerly susceptible microorganisms, an awareness of the frequency and severity of ADR caused by some sulfonamides, and the relative unavailability of parenteral formulations.

Classification

Sulfonamides may be classified as follows:

1. Sulfonamides rapidly absorbed and eliminated after oral administration. Sulfisoxazole is the prototypical agent; sulfamethoxazole and sulfadiazine are other widely used members of this class.

2. Poor absorption of orally administered sulfonamide.Sulfasalazine is used to treat ulcerative colitis and Crohn's disease. About 20% of an oral dose is absorbed in the small intestine, a small portion (∼10%) of which is excreted into urine, and the rest is secreted in bile and enters the enterohepatic circulation.92 This portion plus unabsorbed drug passes into the colon, where it is split into two metabolites, sulfapyridine and 5-aminosalicylic acid, which accounts for the therapeutic effect of sulfasalazine in inflammatory bowel disease.

3. Sulfonamides for topical use.Sulfacetamide is approximately 90 times more soluble in aqueous solution than is sulfadiazine at neutral pH and is nonirritating to the eye. It is formulated as 30% and 10% ophthalmic solutions and a 10% ointment. Ocular fluids and tissues are thus exposed to high concentrations of antibiotic during topical ophthalmic application. However, topical ophthalmic use is associated with a risk of sensitization, and this consideration plus the insensitivity of most nosocomial bacteria to sulfonamides limit the usefulness of sulfacetamide for treatment of bacterial conjunctivitis and keratitis.

   Two sulfonamides have an established place in the ICU for the topical therapy of patients with second- and third-degree burns. Silver sulfadiazine is relatively insoluble. It reacts with chloride and protein components of tissue exudate to form silver chloride, silver protein complexes, and sodium sulfadiazine. The relative contributions of each of these products to the potent inhibitory effect of silver sulfadiazine on the growth of a broad spectrum of microorganisms is unclear, but inhibition of growth of bacteria, including some species resistant to sulfonamides and fungi,93 is observed. This suggests that inhibition other than by interference with folate synthesis (see below) contributes to the antibiotic effect.

   Mafenide is a sulfonamide marketed as 8.5% cream. Like silver sulfadiazine, it is effective for the prevention of colonization of burns by a large variety of gram-negative and gram-positive bacteria, including some anaerobes. However, Candida species are not inhibited as they are by silver sulfadiazine. Mafenide is rapidly absorbed and converted to a nontoxic metabolite, p-carboxy-benzene-sulfonamide, which is excreted in urine. Unlike all other sulfonamides, mafenide is active in the presence of blood, pus, and serum.

4. Long-acting sulfonamides. Sulfadoxine has a singularly long t½ of 7 to 9 days. This has made it an attractive choice for malaria prophylaxis in combination with pyrimethamine (Fansidar) for the prevention and treatment of illness owing to chloroquine-resistant strains of Plasmodium falciparum. It has no uses as an antibacterial agent.

Mechanism of Action

Sulfonamides are structural analogues of para-aminobenzoic acid. They exert a bacteriostatic effect by competitively inhibiting dihydropteroate synthetase. This enzyme catalyzes the synthesis of dihydropteroic acid, the immediate precursor of folic acid, from para-aminobenzoic acid. Folic acid is required for 1-carbon transfer reactions for purine synthesis. Most bacterial cells are impermeable to folic acid, in contrast to mammalian cells. These facts concerning the mechanism of action of sulfonamides on susceptible cells account for the selective toxicity of sulfonamides for bacterial but not for mammalian cells, the mechanism of bacterial resistance to sulfonamides, inhibition of sulfonamide action in sites of tissue necrosis, and, as will be discussed later, synergistic inhibition of some bacteria by combination with dihydrofolate reductase inhibitors such as trimethoprim (TMP) or pyrimethamine.

Because mammalian cells are permeable to folic acid, sulfonamides do not cause dose-related or concentration-related adverse effects on cellular metabolism in humans. Side effects are predominantly idiosyncratic or allergic (see below).

Mechanisms of Resistance

Acquired bacterial resistance to sulfonamides arises by random mutation and selection or by transfer of resistance by plasmids. Such resistance is a stable characteristic whose cumulative prevalence currently limits the use of sulfonamides as initial therapy to a few infections such as brucellosis and nocardiosis. Sulfonamide resistance may be mediated by an alteration in the affinity of dihydrofolate reductase for sulfonamide, use of alternative pathways for purine and pyrimidine synthesis, and compensatory overproduction of the natural substrate, para-aminobenzoic acid. Acquired resistance to silver sulfadiazine cream in burn units has been reported and necessitated use of alternative therapy such as silver nitrate and chlorhexidine cream.94

Clinical Pharmacology

Most orally administered sulfonamides are rapidly absorbed from the stomach and small intestine, but the efficiency of this process in acutely ill patients has not been described. Absorbed sulfonamides bind to serum proteins, in particular albumin, from 20% to more than 90% and affect disposition. High protein binding of sulfadoxine (97%) accounts in part for its long disappearance t½ from plasma. High protein binding of other sulfonamides administered to neonates can contribute to the development of kernicterus. This is hypothesized to be due to displacement of bilirubin from albumin binding sites, although this is disputed.95 The lipid-soluble sulfonamides diffuse readily into inflamed and noninflamed tissues and body fluids including pleural, peritoneal, and ocular fluids, and the CSF. They readily cross the placenta and enter the fetal circulation in sufficient concentration to exert antibacterial and toxic effects.

A varying proportion of sulfonamide is acetylated in the liver or inactivated by other metabolic pathways. The rate of acetylation is genetically determined, and slow acetylators are more likely to experience certain side effects than are rapid acetylators (see below). Unchanged non–protein-bound sulfonamides and metabolites are excreted mainly by glomerular filtration into urine. Different agents are reabsorbed to different degrees in the renal tubules. In the case of sulfadoxine, resorption is so extensive and efficient that this contributes to its long t½ of 7 to 9 days.

The pH of the urine influences urinary excretion of sulfonamides because they are weak acids. Thus, their clearance is enhanced in the presence of alkaline urine. In general, however, sufficient free drug reaches the urine to make sulfonamides effective agents for therapy of urinary tract infections caused by susceptible organisms. In patients with significant renal insufficiency, too little sulfonamide reaches the urine to be effective. Doses must be reduced if they are used to treat nonrenal or nonurinary infection. In burned patients with renal failure, mafenide should be used with caution (see below).

Adverse Drug Reactions

Overall, sulfonamides cause ADR in about 5% of recipients. The types and severity of ADR are quite varied. They are due largely to allergy and only occasionally to direct dose-related toxic effects.

The best understood dose-related toxic effects include renal colic, urethral pain, hematuria and obstruction due to crystalluria, and hemolysis in patients (and fetuses) with glucose-6-phosphate dehydrogenase deficient erythrocytes. Pseudocyanosis owing to methemoglobinemia or sulfhemoglobinemia was seen with earlier sulfonamide formulations; it is rarely seen now. Mafenide causes a unique dose-related toxic effect. Mafenide and its metabolite inhibit carbonic anhydrase, which results in a metabolic acidosis usually compensated for by hyperventilation. In patients with significant renal dysfunction, high concentrations of mafenide and its metabolite will accumulate and exaggerate this effect. The absorption of silver from silver sulfadiazine and its deposition in different organs has recently been identified as a possible cause of ocular injury and of leucopenia and renal, hepatic, and neurologic toxicities.96,97

The slow acetylator phenotype is associated with severe, delayed hypersensitivity reactions to sulfonamides in patients with98 and without99 the human immunodeficiency virus. These reactions occur much less commonly than do typical exanthematous or urticarial rashes caused by sulfonamides, which resolve rapidly on discontinuation of therapy. The reactions occur late in the course of sulfonamide therapy and are typically heralded by the onset of high fever followed by development of a skin rash such as erythema multiforme. Patients with the slow acetylator phenotype are postulated to have more parent sulfonamide available for oxidative metabolism to intermediates that have been shown to mediate those adverse reactions.100 The slow acetylator phenotype is also associated with the common side effects of sulfasalazine therapy: nausea, vomiting, anorexia, and headache are related to serum sulfapyridine concentrations above 20 mg/L,92 which are more commonly observed in slow acetylators given the standard dose of sulfasalazine.

Sulfonamides may also cause ADR because of interactions with other drugs being administered concurrently. Sulfadiazine, sulfamethizole, and sulfaphenazole may impair hepatic metabolism of phenytoin and warfarin. Cotrimoxazole may cause an exaggerated hypoprothrombinemic effect in patients taking warfarin if their warfarin dose requirements are high and the plasma albumin level is low (see below).

Allergic and idiosyncratic reactions to sulfonamides are relatively common, occasionally may be severe, and rarely are fatal. Skin rashes are fairly frequent, usually occur after treatment of approximately 1 week, and may be maculopapular or urticarial. Erythema nodosum, erythema multiforme, and, rarely, Stevens-Johnson syndrome may occur. The risk of developing Stevens-Johnson syndrome is increased by prior sulfonamide therapy (because of the risk of sensitization) and administration of long-acting sulfonamides. Cross-allergy between sulfonamides makes it unwise to administer another agent from this group. Moreover, cross-allergy with other non-antibacterial sulfonamide drugs may occur: diuretics (acetazolamide, thiazides, bumetanide, and furosemide), oral sulfonylurea hypoglycemic agents, and antithyroid drugs (propylthiouracil). There is no skin test for sulfonamide allergy.

Idiosyncratic reactions include acute agranulocytosis. This rare reaction may be reversible on cessation of administration. However, leukopenia is seen in as many as 3% to 5% of burned patients treated with silver sulfadiazine, usually within 2 to 4 days of initiation of therapy. It is usually self-limiting even with continued use of the drug. Fatal aplastic anemia has been described with sulfonamides but less commonly than with chloramphenicol; megaloblastic anemia responsive to folic acid in patients with inflammatory bowel disease treated with sulfasalazine and thrombocytopenia has been reported.

Hepatotoxicity is a rare idiosyncratic hypersensitivity reaction to sulfasalazine administration. The toxic effect appears to be caused by sulfapyridine, the major absorbed metabolite of sulfasalazine breakdown by colonic bacteria. That this reaction is a result of hypersensitivity is suggested by additional features such as rash, lymphadenopathy, arthralgia, and eosinophilia often observed concurrently 2 to 4 weeks after initiation of therapy.

Drug interactions involving sulfonamides may cause ADR because of interference with hepatic metabolism of the concomitantly administered drug by sulfonamide and displacement of drug from plasma protein by highly bound sulfonamides. For example, tolbutamide, phenytoin, and warfarin metabolism is inhibited by usual therapeutic doses of sulfaphenazole, sulfadiazine, and sulfamethizole. Sulfamethoxazole may displace warfarin from plasma albumin and predispose the patient to an exaggerated anticoagulant effect (however, interference with hepatic metabolism of warfarin is more important).

Trimethoprim Combined with Sulfamethoxazole

TMP is marketed commercially alone and in combination with SMX in oral and parenteral formulations in a fixed ratio of 1:5. Due to its greater lipid solubility, TMP distributes more rapidly and widely than the sulfonamide, yielding a plasma TMP:SMX ratio of approximately 1:20 throughout the dose interval, the optimal ratio for in vitro synergistic antibacterial effects. This ratio is maintained relatively constant because the two agents have similar elimination t½ values of about 10 hours in persons with normal renal function.

Mechanism of Action

TMP inhibits dihydrofolate reductase of bacteria about 50,000 times more efficiently than that of mammalian cells. It interferes with purine synthesis in the same pathway that sulfonamides act. The combination, therefore, produces synergistic inhibition of replication in certain bacteria.

TMP is more active than sulfonamide against many bacterial species except Nocardia, Neisseria, and Brucella species. The net inhibitory effect of the combination of TMP-SMX against bacteria is not consistently predictable. However, a synergistic effect is likely when a bacterium is sensitive to both agents. Moreover, when synergy is demonstrable in vitro, the net antibacterial effect may be bactericidal, although the component agents alone are only bacteriostatic.

The clinical advantage of prescribing TMP-SMX together to achieve a synergistic therapeutic effect or to minimize the emergence of resistant isolates during therapy is not well supported by clinical studies. For example, in urinary tract infection, the activity of TMP greatly exceeds that of SMX, and the potential synergy expected is not observed.101 Resistance to TMP is increased by TMP use, but its administration with SMX has not been shown to substantially decrease this occurrence.102

TMP enhances the antibacterial activity of antibiotics other than sulfonamides. It enhances the inhibitory effect of rifampin against H. influenzae and Brucella species. In combination with carbenicillin and rifampicin, TMP is often synergistic against S. maltophilia, a frequently multiply-resistant nosocomial pathogen.103 The potential utility of these combination therapies in critically ill patients with resistant infections should not be overlooked, but appropriate in vitro testing will be necessary to permit confident administration of these combinations.

Mechanisms of Resistance

Resistance to TMP is most commonly associated with acquisition of a plasmid that codes for an altered dihydrofolate reductase enzyme. Some species have acquired resistance as a result of the selection of mutants that do not use the tetrahydrofolate pathway to synthesize thymidine. It is not uncommon for 30% to 40% of aerobic gram-negative enteric bacteria in hospitals to be resistant to TMP and, usually, also SMX.

Clinical Pharmacology

TMP is a lipid-soluble, weak base. Its AVD, 1.8 L/kg body weight, greatly exceeds that of SMX, 0.24 L/kg body weight. It diffuses freely into most tissues and body fluids and concentrates in prostatic and vaginal fluids, which are more acidic than plasma. TMP is eliminated primarily by glomerular filtration as unchanged drug, with a small amount eliminated with bile. Approximately 10% of drug in the urine is inactive metabolites formed in the liver. The elimination t½ of TMP from plasma is approximately 10 hours in patients with normal renal function but increases with diminished renal function. In severe renal failure, the serum t½ of SMX is increased slightly more than that of TMP, to ranges of 22 to 50 hours and 14 to 46 hours, respectively. This is attributable to the more efficient clearance of TMP than of SMX by nonrenal mechanisms.

The usual adult doses for those with normal renal function are 160 to 240 mg of TMP and 800 to 1200 mg of SMX infused intravenously every 6, 8, or 12 hours, depending on the severity of the infection. The dose should be diluted to minimize phlebitis: each 5-mL ampule (TMP 80 mg and SMX 400 mg) should be diluted in a minimum of 75 mL of 5% dextrose, 0.15 M NaCl, or Ringer solution. Extravasation causes local irritation and inflammation. In patients with renal dysfunction, a modified dose is advised: for patients with creatinine clearance faster than 25 mL/min, there is no reduction in the standard dose; for those with creatinine clearance of 15 to 24 mL/min, one-half the usual dose is given; for those with creatinine clearance slower than 15 mL/min, use is not recommended.

For P. carinii infection, it has been recommended that TMP-SMX doses should be adjusted to achieve TMP concentrations 1.5 to 2 hours after administration of 3 to 10 mg/L (or SMX concentrations of 100 to 150 mg/L).104 These concentrations are usually achieved with oral or intravenous doses of TMP and SMX of 20 and 100 mg/kg per day in three to four divided doses, respectively, using the fixed-dose formulation of TMP with SMX. However, in one trial, only 32% of SMX levels were in the desired range after dose adjustments.104 Thus, although no beneficial clinical effect on the therapeutic outcome or side effects was observed, this trial was not able to answer the question of whether sustained maintenance of SMX levels in the target range would be beneficial.

Adverse Drug Reactions

In many cases, it is difficult to separate side effects caused by the components of TMP-SMX. TMP causes fewer reactions than the combination, but it is not known whether the combination causes a “synergistic'' increase in adverse effects.

Although interference with folic acid metabolism and, hence, erythropoiesis can be demonstrated with high TMP concentrations in normal human bone marrow cells cultured in vitro, concentrations observed during therapy in humans do not attain these levels and do not produce such impairment, and this is corroborated by clinical experience. However, in individuals with pre-existing megaloblastic anemia, TMP can aggravate neutropenia and thrombocytopenia and interfere with the therapeutic response to vitamin B12 or folic acid. Therefore, the drug is relatively contraindicated in patients with megaloblastic anemia or in those who may be predisposed to it: pregnant women, patients on anticonvulsant drugs (phenytoin, primidone, or barbiturates), and those with macrocytic erythrocytes. For these individuals, regular blood cell counts are advised if prolonged therapy is prescribed.

Combination TMP-SMX may cause an apparent dose-related impairment of renal function in renal transplant patients or individuals with pre-existing renal insufficiency, especially if inappropriately high doses of TMP-SMX are used. TMP-SMX should be prescribed cautiously to such patients. TMP-SMX administration may cause a temporary rise in serum creatinine concentration not due to a reduction in glomerular filtration rate. This has been attributed to TMP competitive inhibition of creatinine secretion by the renal tubular cation transport system.

Gastrointestinal reactions are the most common side effects of oral TMP-SMX therapy: 3% of recipients experience nausea, vomiting, and anorexia and approximately 0.5% experience diarrhea. Clostridium difficile toxin-induced diarrhea and pseudomembranous colitis have been reported in patients treated with these agents.

Skin rashes occur in 1.6% to 8% of patients treated with TMP-SMX. Most of these are probably caused by the sulfonamide, but TMP occasionally causes rashes when administered alone. The rashes usually present as morbilliform eruptions and less frequently as urticarial or vasculitic processes.

Quinolones

The quinolone antibiotics comprise three relatively distinct generations of drugs.105,106 The first-generation quinolones, nalidixic acid, oxolinic acid, and cinoxacin, achieve effective concentrations only in urine, thus limiting their usefulness to the oral therapy of uncomplicated urinary tract infection and, hence, are not discussed further. The second-generation quinolones are 4-fluorinated analogues of nalidixic acid: norfloxacin, ciprofloxacin, pefloxacin, ofloxacin, and enoxacin. They have enhanced potency against enteric bacteria compared with the first-generation agents but have inconsistent inhibitory activity against gram-positive cocci including streptococci of groups A, B, C, and G, S. pneumoniae, viridans group streptococci, Streptococci, or E. faecalis. Ciprofloxacin is distinguished by its potency against P. aeruginosa, for which it is the most useful fluoroquinolone for systemic therapy, although, for P. aeruginosa urine infection, some of the other members of this group achieve therapeutic concentrations in urine. All members of this group, apart from norfloxacin, exhibit sufficient oral bioavailability to make them useful to treat systemic infection. Only 26% to 32% of a norfloxacin dose is recovered in the urine over 24 hours compared with 75% to 95% for the other agents.

A third generation of fluoroquinolones consists of levofloxacin, moxifloxacin, and gatifloxacin. This group is characterized by clinically useful antibacterial activity against Chlamydia, Legionella, and Mycoplasma species and by streptococcal and staphylococcal pathogens and, hence, is also referred to as respiratory fluoroquinolones; they possess variable activity against E. faecalis. They inhibit penicillin-sensitive and penicillin-resistant pneumococci. Moxifloxacin and gatifloxacin are the only fluoroquinolones that inhibit B. fragilis species.

In the ICU setting, ciprofloxacin is particularly useful as therapy for systemic P. aeruginosa infection. All the second- and third-generation fluoroquinolones are effective for most enteric bacterial infections, especially as less toxic alternatives to aminoglycosides, as are third-generation cephalosporins, carbapenems, and extended-spectrum β-lactams. The respiratory quinolones are alternatives to the macrolide agents for treatment of atypical pneumonia caused by Chlamydia, Mycoplasma, and Legionella species. Thus, the third-generation fluoroquinolones can be administered as broad-spectrum agents for nosocomial infection and for a wide range of community-acquired respiratory and genitourinary infections.

Mechanisms of Action

The quinolones exert a bactericidal effect by selectively inhibiting two type II DNA topoisomerase enzymes, DNA gyrase and topoisomerase IV, but not the analogous cellular enzyme, topoisomerase; both normally cut segments of replicating bacterial DNA strands to prevent tangling.

Mechanisms of Resistance

Resistance among gram-negative enteric bacteria including P. aeruginosa and S. aureus, although varying in prevalence in different countries, has emerged since widespread use of ciprofloxacin began in 1984.107 Such strains are usually completely cross-resistant to other quinolones. Resistance arises due to chromosomal mutations in the DNA gyrase and topoisomerase IV and, to a lesser extent, to reduced drug accumulation in the bacterial cell due to active efflux of the agents by antibiotic efflux pumps.108

Clinical Pharmacology

The oral bioavailability of the fluoroquinolones, apart from norfloxacin, exceeds 75%; however, for the ill patient in the ICU, intravenous administration is recommended. Ciprofloxacin, levofloxacin, and gatifloxacin are formulated for intravenous and oral administrations, and the plasma t½ values in patients with normal renal function are 4.0, 6.0, and 8.4 hours, respectively; therefore, for levofloxacin and gatifloxacin, once-daily dosing is adequate. The usual doses are 400 mg every 12 hours and 500 and 400 mg once daily, respectively. Renal elimination accounts for 60%, 95%, and 90% of the drug clearance, so t½ is not unexpectedly inversely related to creatinine clearance. When creatinine clearance declines to 50 mL/min, doses should be halved. Hemodialysis patients should receive 50% of the standard dose supplemented by 200 mg every 12 hours, no extra doses, and 200 mg every 24 hours after dialysis for the three drugs, respectively.

Dose reductions are generally unnecessary for healthy elderly patients or patients with mild to moderately severe hepatic disease (Child-Pugh class B).

Adverse Drug Effects

Quinolones and fluorinated quinolones are generally well tolerated. Gastrointestinal symptoms including nausea, anorexia, vomiting, and diarrhea occur in fewer than 5% of patients. First- and second-generation quinolones on the market cause neurologic symptoms whose pathogenesis is unclear. Dizziness and headache are the most common, being reported in 2% of patients. Giddiness, excitation or depression, visual disturbances, lethargy, agitation, somnolence, syncope, and, rarely, convulsions and acute psychosis have been reported with the first-generation quinolones and norfloxacin but not with ciprofloxacin. These effects may be more common in patients given larger doses in the presence of renal dysfunction. Some quinolones interfere with the inhibitory neurotransmitter γ-aminobutyric acid, but no clear relation exists between this characteristic of the quinolones and their propensity to cause neurotoxic symptoms. Nevertheless, the quinolones should be used with caution in patients with CNS disease or renal impairment.

Hypersensitivity reactions are uncommon; urticarial rash with eosinophilia has been reported in 0.5% to 1.0% of patients.

Rare side effects observed with nalidixic acid that may occur with second-generation quinolones include intracranial hypertension, lactic acidosis, and hemolytic anemia.

Quinolones interfere with cartilage formation in young animals and are therefore relatively contraindicated in prepubertal patients. In addition, fluoroquinolones appear to double the risk of tendinopathy compared with other antibiotics.109 This appears to be a class effect, although pefloxacin is the most commonly associated agent (up to 68% of cases). Achilles tendon rupture is the most common and dramatic manifestation and can manifest after only 1 to 2 days of fluoroquinolone therapy. The mechanism is unknown, and the pathology is nonspecific. Concomitant renal dysfunction may predispose the patient to this adverse effect.

Drug interactions include enhancement of warfarin activity because of displacement from albumin by nalidixic acid, elevated plasma theophylline concentrations caused by impairment of metabolism by ciprofloxacin, and increased risk of CNS toxic effects in patients given nonsteroidal anti-inflammatory drugs and ciprofloxacin concurrently.

Fluoroquinolones as a class effect can increase QTc intervals. QTc prolongation can result in torsade de pointes, which can lead to ventricular fibrillation and sudden death. Thus, ciprofloxacin, levofloxacin, and gatifloxacin should not be given in excess of recommended doses and should be avoided in patients with known QTc prolongation and hypokalemia and those receiving class Ia (e.g., quinidine and procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. These fluoroquinolones also should be given with caution concurrently with other drugs that prolong QTc intervals including cisapride, erythromycin, cotrimoxazole, astemizole, terfenadine, haloperidol, phenothiazine, tricyclic antidepressants, and vasopressin.106

Anaphylactoid reactions reported after administration of ciprofloxacin, pefloxacin, and norfloxacin may be another adverse class effect of the fluoroquinolones.110 Hypotension, shock, asthma, laryngeal edema and urticaria, and angioedema have been reported as manifestations of these reactions. Having the acquired immunodeficiency syndrome (AIDS) may predispose to the reaction. It has been reported within 5 minutes after a first dose in individuals previously unexposed to fluoroquinolones. Although life-threatening, no deaths have been reported. The exact incidence is not known, but the adverse reaction is one with which intensivists need to be aware.

Hypoglycemia has been reported in diabetic patients receiving insulin or glyburide plus fluoroquinolone, so their coadministration must be undertaken with care.

Metronidazole

Metronidazole is one of a group of 5-nitroimidazoles, including tinidazole, nimorazole, carnidazole, and sulnidazole, that possesses a broad spectrum of antiprotozoal and antibacterial activities. Only metronidazole is available in North America. The following comments pertain to metronidazole only and its antibacterial action.

The clinically important antibacterial activity of metronidazole is restricted to obligate anaerobic bacteria. In vitro, metronidazole is a potent bactericidal antimicrobial against anaerobic gram-negative and gram-positive organisms. More than 99% of 341 blood culture isolates of B. fragilis from U.S. patients collected from 1987 to 1999 were susceptible to metronidazole, whereas 22% were not susceptible to clindamycin. Thus, metronidazole continues to be a potentially, uniformly efficacious, antimicrobial agent for initial treatment of B. fragilis infection before susceptibility test results can be available.111 Resistant anaerobic organisms include Proprionobacterium species, many strains of Bifidobacterium, Actinomyces, and Arachnia. Lactobacillus species and aerobic and microaerophilic streptococci are also resistant.

Oral metronidazole is the drug of choice for C. difficile toxin-associated diarrhea and colitis.84 When administered with penicillin, metronidazole is the drug of choice for the treatment of brain abscess complicating paranasal sinusitis, caused primarily by aerobic streptococci, in particular Streptococcus milleri, together with β-lactamase–producing Bacteroides species. Metronidazole is used similarly in the combined therapy of temporal lobe brain abscesses of otitic origin commonly caused by anaerobic bacteria, in particular B. fragilis and aerobic enteric bacilli. Metronidazole combined with an aminoglycoside is efficacious therapy for mixed aerobic and anaerobic bacterial infections of the peritoneal cavity and female genital tract. In general, this combination is not different in efficacy from clindamycin, ticarcillin, cefoxitin, or chloramphenicol combined with the aminoglycoside.32 Advantages arise from differences in the frequency, nature, and severity of adverse effects.

Mechanism of Action

Metronidazole is rapidly bactericidal by an immediate inhibition of DNA synthesis, but the mechanism of this action has not been fully elucidated.

Mechanism of Resistance

Acquired resistance to metronidazole occurs extremely rarely.111 Isolated reports have documented resistance to metronidazole associated with clinical failure in B. fragilis strains. Resistance appeared to be related to a decreased rate of metronidazole uptake and to an insufficiently low intracellular redox potential to reduce metronidazole to its active form.

Clinical Pharmacology

The clinical pharmacology of metronidazole and its two principal metabolites has been studied extensively.112 It can be administered intravenously, orally, and rectally as a suppository to treat bacterial infection. The absolute bioavailability of orally administered metronidazole approaches 100%. After intravenous administration of 500 mg over 20 min, the mean metronidazole Cp 30 minutes after the completion of infusion was 27 mg/L and the trough concentration was 16 mg/L.112 After rectal administration of a 500-mg suppository, mean peak Cs after about 3 hours was 19 mg/L, with the level remaining at approximately 10 mg/L over the next 8 hours.113 These data suggest that rectal administration may be effective in those who cannot take the drug orally. The drug diffuses widely throughout the body: concentrations in saliva and breast milk are comparable to those in the serum; CSF concentrations in normal volunteers average 43% of the simultaneous Cp and are therapeutic; urine concentrations range from 76 to 115 mg/L after a 500-mg dose. Only about 14% of an oral dose of metronidazole is excreted in the feces, but concentrations attained in feces are much greater than the MIC of metronidazole for C. difficile, which is 4 mg/L or lower.

Metronidazole undergoes extensive metabolism, probably in the liver, to two oxidation products, an “alcohol'' metabolite and a “hydroxy'' metabolite.112 The latter is produced in larger amounts, can be readily detected in the plasma of patients with normal renal function, and accumulates in the plasma of those with renal insufficiency. The metabolites possess 5% and 30%, respectively, of the antibacterial activity of the parent compound, so that they probably contribute in part to the therapeutic effect of metronidazole, particularly in patients with renal failure. Of 500 mg of metronidazole administered intravenously to healthy volunteers, 44% was recovered in the urine, consisting of parent drug (8%) and the hydroxy (24%) and alcohol (12%) metabolites. The mean plasma t½ of metronidazole is 8.5 hours.

In patients with renal insufficiency, metabolites accumulate, but the parent compound does not. It is conventional not to reduce the dose of metronidazole for such patients, including those undergoing peritoneal dialysis or hemodialysis. Severe hepatic disease would be expected to reduce the metabolism of metronidazole, but its disposition in such patients and a need for dose reduction have not been described.

Interactions of metronidazole have been described in adults ingesting phenytoin and barbiturates, which induce its metabolism. Phenobarbital decreased the plasma t½ of metronidazole to 3.5 hours.

Adverse Drug Effects

In experimental nonhuman systems, metronidazole is teratogenic, mutagenic, and carcinogenic. Comparable effects have not been demonstrated in humans, but avoiding its use during the period of organogenesis in the first trimester of pregnancy is considered prudent. Metronidazole is generally well tolerated. Gastrointestinal side effects occur occasionally. These include a metallic taste, furred tongue, and nausea. Paradoxically, two confirmed reports of pseudomembranous colitis have been described in patients receiving only metronidazole. In one, this side effect appeared to be caused by a metronidazole-resistant strain of C. difficile,114 but in the other, the organism was susceptible. Transient reversible leukopenia occurs infrequently, but it is the most common hematologic side effect. Peripheral sensory neuropathy has been described in patients receiving large doses for prolonged periods. The cause is not known. One child developed seizures during metronidazole therapy that ultimately resolved completely.

Interactions of metronidazole with a few other drugs are well documented; it can produce an Antabuse-like reaction after alcohol ingestion. This is probably caused by inhibition of hepatic alcohol metabolism resulting in accumulation of acetaldehyde, which causes the adverse symptoms. Metronidazole augments the hypoprothrombinemic effect of warfarin sodium (Coumadin) owing to a stereoselective inhibition of the S(2)-moiety (levo warfarin).

Macrolides, Lincosamides, and Ketolides

Erythromycin, Clarithromycin, Azithromycin, Clindamycin, Lincomycin, and Telithromycin

These six antibiotics are considered together because they share similar mechanisms of action and resistance spectra of antibacterial activity, and clinical pharmacologic properties. Structurally, they comprise three groups, macrolides (erythromycin, clarithromycin, and azithromycin), lincosamides (lincomycin and clindamycin), and ketolides (telithromycin).

Erythromycin

Erythromycin is produced by Streptomyces erythreus. It is a member of the macrolide group of antibacterial compounds, which also includes spiramycin (used in Europe to treat T. gondii infection), azithromycin, and clarithromycin.

Erythromycin base is poorly soluble in water, has a pKa of 8.8, and is rapidly inactivated by gastric acid. Many alternative oral formulations have therefore been developed to enhance oral bioavailability over that of the base. Two water-soluble salts, erythromycin-gluceptate and erythromycin-lactobionate, have been developed for intravenous administration. In ICU patients, only the intravenous formulation can ensure adequate systemic delivery of drug, so this discussion does not include the characteristics of the oral products.

In vitro, erythromycin has a broad spectrum of antimicrobial activity that includes bacteria (including chlamydia), mycoplasma, spirochetes (Treponema pallidum), Ureaplasma, and some strains of rickettsias. Its useful antibacterial activity includes gram-positive organisms (S. aureus, S. pyogenes, S. pneumoniae, and viridans group streptococci, Cornyebacterium diphtheriae, Clostridium perfringens, and Listeria monocytogenes). Unfortunately, increased use of macrolides over a long duration has resulted in the emergence of substantial levels of resistance to macrolides in S. pneumoniae. Macrolide resistance increased from 13% to 23%, from 9% to 11%, from 15% to 25%, and from 34% to 41%, between 1997 and 1999 in the United States, Canada, Europe, and the Asia-Pacific region, respectively.115 Some gram-negative organisms (B. pertussis, H. influenzae, N. gonorrhoeae, N. meningitidis, and B. catarrhalis), Legionella pneumophila, Mycoplasma pneumoniae, Ureaplasma urealyticum, and C. trachomatis are susceptible.

Clinically, erythromycin is used to treat M. pneumoniae and L. pneumophila infections. It is the alternative drug of choice for C. trachomatis infection of pregnant women and children who cannot be treated with tetracycline and for C. diphtheriae infection in penicillin-allergic patients. Although formerly used as the alternative to penicillin in allergic patients with T. pallidum, M. catarrhalis, and L. monocytogenes infections, erythromycin use in these infections has been largely superseded by other agents.

Mechanism of Action

Erythromycin and the other macrolide antibiotics inhibit bacterial growth by interfering with protein synthesis. Erythromycin binds specifically to the 50S subunit of the ribosome. The precise molecular mechanism is not known but is hypothesized to interfere with the translocation reaction. This reaction, catalyzed by the enzyme translocase, involves the movement of the growing peptide chain, with its tRNA, from the acceptor to the donor site on the ribosome. Erythromycin is thought to bind to the donor site and thereby interfere with translocation of the peptide chain from the acceptor to the donor site. In humans, erythromycin is likely only bacteriostatic.

Mechanism of Resistance

Gram-negative enteric bacilli are uniformly resistant to erythromycin. This is probably a result of the inability of the drug to penetrate the cell wall to reach the ribosomal site of action. In certain other resistant bacteria, a plasmid-mediated mutational change in the 50S subunit, resulting in methylation of the tRNA erythromycin receptor, precludes erythromycin binding. Two other plasmid-mediated mechanisms confer erythromycin resistance: diminished permeability of the cell envelope of gram-positive bacteria as occurs with S. epidermidis and production of an esterase that hydrolyzes erythromycin in some Enterobacteriaceae.

Overall, the prevalence of erythromycin resistance among important pathogens such as S. pneumoniae currently limits the utility of these agents as first-line antimicrobials for some serious infections such as community-acquired pneumonia.

Clinical Pharmacology

Therapeutic concentrations are attained in all sites except the brain and subarachnoid space. Although inflammation enhances erythromycin penetration into brain tissue and CSF, this effect is unpredictable, and erythromycin is thus relatively contraindicated for therapy of brain abscess and meningitis. Disappearance from plasma is first order with t½ of 1.6 hours. Approximately 15% of an injected dose appears as unchanged drug in the urine; high concentrations of drug are observed in bile, but the overall contribution of this route of drug clearance to erythromycin elimination is not known. A large proportion of injected erythromycin cannot be accounted for by drug in urine or bile, so extensive biotransformation, probably in the liver, is hypothesized.

The normal plasma t½ of 1.6 hours is prolonged to 4.8 to 5.8 hours in anuric patients. In patients with alcoholic liver disease and ascites, plasma t½ was increased to an average of 1.6 hours as opposed to 1.3 hours in concurrently studied healthy controls.116 In both groups, no dose reduction was necessary in view of the low risk of dose-related ADR. In patients with more severe liver disease, dose reduction would appear prudent. However, no explicit guidelines for such patients have been proposed or validated.

Adverse Drug Effects

Erythromycin is one of the safest antibacterial agents in clinical use, but tolerance is limited by the frequent occurrence of irritating side effects. First, abdominal cramps, dyspepsia, nausea, vomiting, and diarrhea occur, which result, in part, from a direct smooth muscle–stimulating effect of erythromycin.117 They are observed after oral and intravenous administrations. Although the smooth muscle–stimulating effect can be inhibited in vitro by the antimuscarinic agent atropine, this strategy has not been studied in humans. Second, intravenous administration predictably causes phlebitis, which can be ameliorated only partly by slow infusion of drug diluted in large volumes of intravenous fluid.

Tinnitus and reversible severe deafness occur after large intravenous doses of erythromycin.118 Old age, renal failure, and hepatic insufficiency appear to predispose to this unusual adverse effect. The mechanism of this reaction is not known. Pseudomembranous colitis has been reported. Hypersensitivity reactions such as skin rash, fever, and eosinophilia are rare.

Cholestatic jaundice caused by erythromycin estolate (and rarely by the stearate) appears to be specifically related to the propionyl ester linkage of the 29 position so that cross-sensitivity is said not to occur.119 Thus, a history of cholestatic jaundice during therapy with oral erythromycin estolate is not an absolute contraindication to intravenous therapy with erythromycin gluceptate or lactobionate.

In some individuals, erythromycin can inhibit elimination of astemizole, terfenadine, methylprednisolone, theophylline, carbamazepine, warfarin, and cyclosporine, with significant clinical consequences.

Clarithromycin and Azithromycin

Clarithromycin and azithromycin are recently approved analogues of erythromycin.120,121 They differ in several respects, but few of these differences are clinically important, particularly for the intensivist.

In vitro, both drugs differ qualitatively from erythromycin in their potent inhibitory effect on Mycobacterium avium intracellulare. They differ quantitatively from erythromycin in being up to 10-fold more potent against C. trachomatis, H. pylori, M. catarrhalis, N. gonorrhoeae, and H. ducreyi.

Bacteria resistant to erythromycin are cross-resistant to clarithromycin and azithromycin.

Clinical Pharmacology

Only azithromycin is available in a parenteral formulation. Clarithromycin and azithromycin are well absorbed after oral administration, although bioavailability has not been assessed in critically ill patients. Their good oral bioavailability is attributable in part to the changes in the lactone ring that prevent acid degradation. Reduced acid degradation, moreover, decreases the formation of ketal products that have prokinetic effects on the gastrointestinal smooth muscle, thereby decreasing the frequency of adverse gastrointestinal effects of clarithromycin and azithromycin compared with erythromycin (see Adverse Effects, below). Clarithromycin undergoes first-pass hepatic metabolism, with 20% of an oral dose being converted to a 14-hydroxymetabolite that possesses antibacterial properties similar to those of the parent molecule. Like erythromycin, these two newer macrolides have a low degree of ionization at physiologic pH and are lipid soluble, so they distribute extensively in body fluids and tissues. The AVD of clarithromycin is 2 to 3 L/kg versus 0.6 L/kg for erythromycin. Azithromycin is distributed even more widely, with an AVD of 23 L/kg.

Clarithromycin is primarily eliminated by hepatic oxidation and hydrolysis. Metabolism is characterized by a disproportionate 13-fold increase in clearance when the dose is increased from 150 to 1200 mg. Elimination t½ increases from 4.4 to 11.3 hours over the same dose range. Unchanged clarithromycin increases from 18% to 30% of the dose over the 250- to 1200-mg dose range. Doses should be reduced by one-half when creatinine clearance is less than 30 mL/min; dose adjustments in the presence of hepatic disease are likely necessary but as yet remain undefined.

Azithromycin kinetic characteristics are distinguished by low Cp values and a prolonged elimination t½ that reflects extensive tissue sequestration. The liposomal phospholipid complex of azithromycin is mainly excreted unchanged in the feces, with a polyphasic serum t½ of 10 to 57 hours, depending on the dose and the sampling intervals. Azithromycin doses need not be adjusted in the elderly or in the presence of mild renal or mild to moderate hepatic impairment.

Clarithromycin, unlike erythromycin or azithromycin, is embryolethal and has induced congenital anomalies (cardiovascular) in preclinical studies. Its use in pregnant patients is relatively contraindicated because of uncertainty about the relevance of these data to humans.

Azithromycin appears less likely than clarithromycin or erythromycin to interact with drugs that are metabolized by hepatic cytochrome P450 enzymes. Elevated theophylline, carbamazepine, and terfenadine plasma concentrations have been demonstrated during concurrent administration of clarithromycin. These have not been observed during concomitant administration with azithromycin, but careful observation during combined therapy is recommended by the manufacturer.

The following agents interact adversely with erythromycin and warrant prudence during coadministration with clarithromycin and azithromycin: cyclosporin, valproic acid, and phenytoin.

Adverse Drug Effects

Like erythromycin, clarithromycin and azithromycin are well tolerated. Overall, side effects are observed in 20% to 10% of recipients of clarithromycin and azithromycin, respectively; 80% to 90% of these adverse symptoms are mild to moderate in severity. Gastrointestinal side effects are the most common adverse symptoms with both drugs but occur half as often as with erythromycin. Like erythromycin, azithromycin administration has been associated with transient deafness.122

A uniquely prolonged adverse effect observed with azithromycin is noteworthy: rare patients have developed serious allergic reactions including angioedema and anaphylaxis. Despite successful initial symptomatic therapy, allergic symptoms reappeared when therapy was discontinued, even without further azithromycin exposure, presumably owing to the slow clearance of azithromycin from the body. Thus, intensivists should be aware of the possible risk of protracted serious allergic reactions even after discontinuation of azithromycin therapy.

In summary, clarithromycin and azithromycin are new macrolide antibiotics that broaden the therapeutic spectrum of this class of drugs and decrease the incidence of gastrointestinal side effects but may not offer any solution to the problem observed with the prototype, erythromycin, of adverse interactions with other drugs given concomitantly.123 The usual dose of clarithromycin for serious infection is 250 to 500 mg twice daily. A loading dose of 500 mg azithromycin is recommended, followed by 250 mg once daily; for single-dose therapy of C. trachomatis infection, a 1-g dose is administered.

Clindamycin and Lincomycin

Lincomycin was marketed only for oral administration. Chemical modification of lincomycin led to the development of clindamycin, which is superior in activity to lincomycin and is available for oral administration as the hydrochloride salt and for intravenous injection as the phosphate ester. This characteristic has led to the exclusive use of clindamycin in critically ill patients. Accordingly, only clindamycin is reviewed here.

In vitro, the antibacterial spectrum of clindamycin exceeds that of erythromycin as follows: resistance of S. aureus to clindamycin tends to be less common than to erythromycin, but resistance levels can range from 5% to 20% depending on the region. Many of these clindamycin-resistant S. aureus strains are also resistant to multiple other antibiotics, including methicillin. Clindamycin is much more potent than erythromycin against species of the B. fragilis group, although up to 22% of B. fragilis strains111 and up to 15% of Bacteroides vulgatus strains are relatively resistant to clindamycin. Nevertheless, this degree of activity against enteric gram-negative anaerobic bacilli is exceeded only by metronidazole. Clostridium difficile strains are resistant, but other species such as Clostridium welchii and Clostridium tetani are sensitive. Mycoplasma pneumoniae, H. influenzae, and N. meningitidis are resistant.

Clindamycin in combination with an aminoglycoside is arguably the antibiotic of first choice for the therapy of serious mixed aerobic and anaerobic enteric bacterial infection of the abdomen and pelvis.32 A meta-analysis has suggested that the dose of 900 mg every 8 hours may be more efficacious than 600 mg every 8 hours for treatment of intra-abdominal infection (although results of treating female pelvic infection with either dose are similar).125 In similar infections of the soft tissues and skin of the feet of diabetic patients, this combination is also highly efficacious. Clindamycin alone is superior to penicillin as a single agent for treatment of serious anaerobic lung infection,124 but their combined use for treatment of such infections is currently recommended. Clindamycin is also considered to be as effective as penicillins for the therapy of non-endocarditis infections caused by S. aureus, S. pyogenes, and S. pneumoniae and as effective as a single injection of benzathine penicillin in eradicating C. diphtheriae from the nasopharynx of asymptomatic carriers. Clindamycin is an acceptable alternative to penicillin for treatment of cervicofacial actinomycosis. Incidentally, clindamycin and quinine sulfate are effective for treatment of Falciparum malaria infection.

In summary, clindamycin is a valuable alternative to penicillin in patients who are allergic to the β-lactam agents and is a first-line agent, when combined with an aminoglycoside, for intra-abdominal and pelvic infections, and with penicillin, for mixed anaerobic and aerobic lung infection.

Mechanism of Action

The mechanism of action of clindamycin is identical to that of erythromycin, and both are bacteriostatic.

Mechanism of Resistance

Resistance is caused by modification of the ribosomal target of clindamycin. Clindamycin-resistant S. aureus strains are usually resistant to erythromycin. Clindamycin resistance in B. fragilis group organisms is caused by at least two different mechanisms, one of which is plasmid mediated.

Clinical Pharmacology

After intravenous injection, clindamycin distribution is analogous to that of erythromycin. Clindamycin does not predictably attain therapeutic concentrations in the fluids of the eye, the cavity or wall of brain abscess, or the CSF even in patients with meningitis. High concentrations are demonstrable in bone, but the relevance of this observation to treatment of osteomyelitis is not clear. High concentrations are attained in polymorphonuclear leukocytes, which may contribute to enhanced killing of phagocytosed bacteria.

The elimination of clindamycin is incompletely understood but probably similar to that of lincomycin, which has been more extensively documented. After intravenous injection, approximately 30% appears in urine and 5% to 15% in feces as unchanged drug and metabolites (N-dimethyl clindamycin, clindamycin sulfoxide, and others). The remainder is hypothesized to be metabolized to inactive compounds. The mean plasma t½ is normally 3 hours. Severe renal failure is associated with a doubling of peak Cp, and, on this basis, halving of the usual dose is recommended. Neither hemodialysis nor peritoneal dialysis enhances its clearance from plasma. The effect of liver disease on the clinical pharmacokinetics of clindamycin is not clear; increases in plasma t½ from 40% to 500% have been described. It would seem reasonable to reduce clindamycin doses in patients with severe liver disease, but no clear guidelines have been tested or validated. The usual dose for adults with moderate to severe infection is 900 to 2400 mg/d in two or three divided equal intravenous doses.125

Adverse Drug Effects

Intravenous clindamycin commonly causes local phlebitis, which can be reduced by slow infusion of dilute solutions. The manufacturer recommends dilution to a concentration of 12 mg/L or lower and infusion longer than 10 minutes (preferably >25 min).

The most important adverse effect of clindamycin administration is diarrhea. This occurs in 2% to 20% of patients treated intravenously or by mouth and varies in severity. Clindamycin is the most common antibiotic cause of diarrhea. The precise pathogenesis of diarrhea associated with clindamycin is not known. However, in that subgroup of patients in whom diarrhea and, in florid cases, pseudomembranous colitis is associated with production of enterotoxin by C. difficile in the colon, a direct toxic effect on the colonic mucosa is responsible. Continuation of clindamycin will intensify the severity of the colitis. When clindamycin cannot be discontinued, concomitant oral administration of metronidazole or vancomycin may permit safe continuation of the clindamycin.

Hypersensitivity reactions caused by clindamycin occur occasionally. In one study, rash occurred in 10% of patients. Drug fever and eosinophilia have also been reported.

It is worth reiterating that no cross-allergenicity exists between clindamycin and penicillin.

Unlike erythromycin, clindamycin does not cause clinically important interactions with other drugs.

Telithromycin

Telithromycin is the first ketolide antibiotic to be licensed. Ketolides are analogues of the macrolide class, molecularly modified specifically to inhibit respiratory tract bacterial pathogens that have acquired resistance to the macrolide agents.126

In vitro, the spectrum of activity of telithromycin is comparable to that of other macrolides except it is a potent inhibitor of S. pneumoniae and S. pyogenes strains that are resistant to macrolides by virtue of the erm B–resistance genotype. It does not inhibit erythromycin-resistant S. aureus strains.

It is available only for oral administration. The usual dose is 800 mg once daily. Clinical trials comparing telithromycin with conventional treatments for community-acquired pneumonia and exacerbations of chronic obstructive airway disease and acute sinusitis have generally demonstrated comparable efficacy and good tolerance. Limited data suggest very good efficacy in patients with macrolide-resistant S. pneumoniae infection. Based on the limited published data, the availability of other antibiotics to treat macrolide-resistant S. pneumoniae infection, and the lack of a parenteral formulation, a role for telithromycin in the ICU remains undefined.

Mechanism of Action

Like erythromycin from which it is synthesized, telithromycin is bacteriostatic by inhibiting protein synthesis by binding near the peptidyl transfer site on the bacterial 50S ribosomal subunit.

Mechanism of Resistance

Resistance to macrolides is mediated most commonly by mef-encoded efflux and erm A- and B-encoded methylation of 23srRNA. Bacterial strains possessing mef and erm A genotypes are susceptible to telithromycin (see above). In vitro and in vivo experiments have demonstrated that streptococci exposed to ketolides are less likely to develop such resistance genotypes than are those exposed to macrolides.

Clinical Pharmacology

The oral bioavailability is approximately 60% under controlled conditions in healthy volunteers; fractional absorption in ill ICU patients is not known and may be less. Telithromycin distributes widely throughout the body; of note is active transport into polymorphonuclear cells, which may contribute to its clinical efficacy in infections caused by intracellular pathogens such as Chlamydia. Approximately 70% of a telithromycin dose is metabolized (33% presystemic and 37% systemic) primarily by cytochrome P450, specifically CYP 3A4, hepatic enzymes. Elimination is a first-order process with t½ of 9.5 hours, mediated by hepatic biotransformation and biliary and renal excretion.

The doses should be halved in patients with severe renal insufficiency. No dose adjustment is recommended in the presence of mild, moderate, or severe hepatic impairment.

Adverse Drug Effects

Available data suggest that telithromycin is well tolerated, with a tolerance profile similar to those of clarithromycin and azithromycin. Gastrointestinal symptoms were the most common adverse symptoms (diarrhea in 13%, nausea in 8%, and vomiting in 2%). Most (69%) of these symptoms were mild in severity.

Less common (0.4%) but more severe side effects included hepatitis, pseudomembranous colitis, and erythema multiforme.

Laboratory abnormality, specifically elevated liver enzymes in comparative trials, occurred with similar frequency in groups treated with other conventional antibiotics. Fewer than 1.0% of telithromycin recipients had elevated liver enzymes.

Telithromycin may prolong the QT interval when large doses are administered (see below).

Drug interactions due to competitive metabolism of telithromycin by CYP 3A4 and other drugs administered concurrently have demonstrated inhibition of simvastatin, cisapride, itraconazole, ketoconazole, and theophylline. No interaction with concomitant warfarin has been demonstrated.

Streptogramins

Quinupristin and dalfopristin are streptogramin antibacterial drugs recently licensed for the treatment of vancomycin-resistant E. faecium infection and complicated skin and skin-structure infection caused by S. pyogenes and MSSA. The drugs are formulated as a 30:70 mixture for intravenous injection. The standard dose is 7.5 mg/kg infused over 60 minutes every 8 to 12 hours in 5% dextrose in water; it is incompatible with saline.127

Mechanism of Action

Quinupristin and dalfopristin inhibit susceptible gram-positive bacteria including E. faecium, MSSA, MRSA, S. pyogenes, and S. pneumoniae by binding to the 50S ribosome. The two streptogramins produce a synergistic effect. Against Staphylococcus, including MRSA, quinupristin and dalfopristin are bactericidal; against E. faecium, the effect is generally bacteriostatic. The locus of ribosomal binding is near to, but different from that of, the macrolides.

A prolonged PAE of 9 to 10 hours from S. aureus and S. pneumoniae permits dosing every 8 or 12 hours despite a short elimination t½.

Mechanism of Resistance

The macrolide antibiotics, lincosamide, and streptogramin antimicrobial agents have a common mechanism of action so that shared resistance is common. However, quinupristin and dalfopristin bind to a proximate but different locus on the 70S ribosome, so that cross-resistance with the aforementioned agent is uncommon as is resistance to quinupristin or dalfopristin.

Clinical Pharmacology

Only a parenteral formulation is available. Dose and peak plasma concentrations are linearly related over the dose range of 1.4 to 29.4 mg/kg, suggesting indirectly that the apparent volume of distribution is constant. The mean plasma t½ is similar for both drugs and ranges from 30 to 50 min. Protein bindings range from 11% to 26% for dalfopristin and from 55% to 78% for quinupristin.

Quinupristin and dalfopristin are eliminated primarily (about 75%) by hepatic biotransformation, followed by secretion into the bile and elimination in feces; 15% to 20% is eliminated as metabolite into urine.

Plasma concentrations are significantly increased in patients with hepatic insufficiency (Child-Pugh classes A and B). Dose reduction in such patients is appropriate, but precise regimens have not been formulated or validated.

Severe renal dysfunction (creatinine clearance 6 to 28 mL/min) did not significantly alter quinupristin and dalfopristin kinetics.

Pharmacokinetic studies in elderly (69 to 74 years) adults or obese patients did not yield clinically important differences from values in healthy male volunteers.

Quinupristin and dalfopristin inhibit CYP 3A4 and, at doses in excess of 10 mg/kg, prolong QT intervals. Thus, this combination must be given with care to patients receiving other drugs primarily metabolized by the CYP 3A4 P450 isozyme and with a narrow therapeutic window, particularly those that can prolong the QT interval (cisapride, lidocaine, quinidine, and disopyramide), and other drugs such as cyclosporine and tacrolimus, some antiretroviral drugs (delavirdine, neviapine, indinavir, and ritonavir), antineoplastic agents (vinca alkaloids, docetaxel, and paclitaxel), benzodiazepines (midazolam and diazepam), calcium channel blockers (dihydropyrines, verapamil, and diltiazem), antiepileptics (carbamazepine), and cholesterol-lowering drugs (statins).

Adverse Drug Effects

Local pain and inflammation with edema and phlebitis are common during quinupristin or dalfopristin intravenous infusion, being observed in almost 50% of treated patients. Arthralgia, myalgia, and/or nausea resulted in treatment discontinuation in 22% of 90 treated patients with MRSA infection.

The major adverse effect of quinupristin and dalfopristin is phlebitis. This may be ameliorated by increasing the volume of the diluent, slowing the infusion rate even more, and delivering the drugs through a central venous catheter rather than a peripheral one.

Conjugated hyperbilirubinemia has been reported in 9% of treated patients, possibly related to competition for hepatocyte biliary secretion.

Oxazolidinone

Linezolid is a synthetic, recently licensed member of a new class of antibiotics, the oxazolidinones.128 It has a unique mechanism of action on susceptible bacterial ribosomes that differs from that of the macrolides, aminoglycosides, streptogramins, and lincosamides, making cross-resistance unlikely.

Linezolid is indicated for a wide range of gram-positive coccal infections in adult patients: VRE faecium infection; nosocomial pneumonia caused by MSSA, MRSA, and S. pneumoniae (penicillin-susceptible strains only); complicated skin and skin-structure infection due to MSSA, MRSA, S. pyogenes, or S. agalactiae; and uncomplicated skin and soft tissue infection caused by MSSA or S. pyogenes; and community-acquired pneumonia (CAP) due to penicillin-susceptible S. pneumoniae or MSSA.

Linezolid is formulated as oral tablets or for intravenous injection. The usual adult dose is 600 mg every 12 hours (400 mg every 12 hours for uncomplicated skin infection).

Mechanism of Action

The precise molecular mechanism of action is not known, but linezolid inhibits bacterial protein synthesis. It is hypothesized to do so by interfering with the interaction of tRNA with the 50S ribosomal subunit during the initiation phase.

Mechanism of Resistance

Resistance of S. aureus and S. epidermidis, including methicillin-resistant strains, has been difficult to induce during serial passage in vitro in the presence of linezolid. A few E. faecium clinical isolates resistant to linezolid have been observed in a compassionate-use treatment program.129

Clinical Pharmacology

Linezolid is 100% orally bioavailable in volunteers, but it is not known whether the same completeness of absorption can be confidently expected in critically ill patients; for such patients, intravenous administration is preferable. It is metabolized principally by oxidation to a biologically inactive form and excreted in urine as metabolites (70%) and unchanged drug (30%). The plasma t½ is 4.6 to 5.4 hours.

Pharmacokinetic studies in volunteers with different degrees of renal dysfunction have indicated that linezolid doses need not be adjusted in persons with creatinine clearance faster than 10 mL/min. However, hemodialysis removes 38% of a dose, so the drug should be given after a hemodialysis treatment or an additional 200-mg dose can be given at the end of dialysis.

Linezolid pharmacokinetic characteristics in subjects with mild to moderate hepatic dysfunction did not differ from those in controls.

Adverse Drug Reactions

Linezolid can cause two unusual, clinically important adverse effects, myelosuppression and drug–drug interactions with adrenergic and serotonergic drugs.

Linezolid causes dose- and time-dependent myelosuppressions in 2% to 10% of patients at therapeutic doses; most commonly, thrombocytopenia is observed. The effect appears to be generally reversible on discontinuation of therapy; no irreversible blood dyscrasias have been reported. Complete blood counts at weekly intervals are recommended during therapy to facilitate early detection of this adverse effect.

Linezolid is a mild, reversible, competitive inhibitor of monoamine oxidase; therefore, in patients in the ICU, concomitant administration of linezolid with indirectly acting adrenergic or dopaminergic drugs including serotonin reuptake inhibitors may cause exaggerated sympathomimetic effects and occasionally signs and symptoms of the serotonin syndrome (e.g., hyperpyrexia and cognitive dysfunction). This adverse effect was expected but not observed in controlled clinical trials of linezolid in part because patients treated concurrently with dopaminergic and adrenergic drugs were excluded and because the monoamine oxidase inhibitory effect of linezolid is a relatively weak one.

In comparative clinical trials, linezolid was more likely than control comparator antibiotics to cause diarrhea (8.3% vs. 6.3% for comparators), nausea (6.2% vs. 4.6%), vomiting (3.7% vs. 2.0%), and insomnia (2.5% vs. 1.7%). Linezolid caused thrombopenia in 2.4% of recipients of linezolid versus 1.5% in recipients of comparative antibiotics. Bleeding effects were not observed in those randomized trials but were observed during open-label compassionate use.

Overall, in the ICU, linezolid may become a valuable niche agent with particular utility for treatment of infection caused by nosocomial drug-resistant pathogens such as MRSA and VRE faecium.

Community-acquired and nosocomial viral infections may cause acute organ dysfunction or failure that necessitates admission of adult patients to the ICU or may complicate their management. A moderate number of different drugs are currently available that specifically and selectively inhibit virus replication and have an established role in the management of selected, serious, acute infections caused by DNA and RNA viruses in immunocompetent and immunocompromised hosts. The following agents are discussed in more detail: acyclovir, valacyclovir, famciclovir, foscarnet, ganciclovir, amantadine, rimantadine, zanamivir, oseltamivir, ribavirin, and some of the 16 currently licensed HIV-1 inhibitor drugs.

All these agents are virustatic only, which partly explains their limited value or failure in patients with defective immune responses.

Vidarabine

Vidarabine (ara-A) was the first antiviral drug administered parenterally to humans whose efficacy was demonstrated unequivocally in a controlled trial (in patients with Herpes simplex virus [HSV] encephalitis).130

Ara-A has been approved for the treatment of HSV-1 encephalitis. Controlled trials have demonstrated that it is efficacious for the therapy of otherwise healthy neonates with HSV infection (mostly HSV-2) and immunocompromised patients with chickenpox, mucocutaneous HSV infection, and localized herpes zoster with a duration shorter than 72 hours. Acyclovir has replaced it for these indications, owing to greater ease of administration and better tolerance.131 Ara-A is no longer marketed and is not further discussed.

Acyclovir

Acyclovir is a synthetic, acyclic, purine nucleoside analogue of guanine in which the deoxyribose moiety has been replaced by a hydroxy-ethoxy-methyl substituent. In vitro, acyclovir inhibits HSV-1 and HSV-2 equally in concentrations 10 to 100 times less than are required with ara-A. Varicella zoster virus (VSV) is 10 times less sensitive than HSV, and the susceptibility of VZV to ara-A and acyclovir is similar. EBV is 10 to 20 times less sensitive than VZV, and CMV is 10 times less sensitive than EBV, to acyclovir.

Acyclovir is approved for the treatment of initial and recurrent mucocutaneous HSV infections in immunocompromised children and adults and for initial episodes of genital herpes in the normal host. It is the drug of choice for treatment of HSV encephalitis131 and perinatal HSV infection.131a In neonates, it is no more effective than ara-A, but it is more acceptable because it can be administered in smaller volumes of intravenous fluid. It is also the drug of choice for the treatment of chickenpox132 in normal and immunocompromised hosts and for recurrent VZV skin infections133 in immunocompromised patients. In these patients, acyclovir accelerates resolution of the cutaneous eruption and prevents cutaneous and visceral dissemination. Acyclovir efficacy for other serious, non-neurologic HSV infections such as esophagitis and hepatitis in normal and immunodeficient hosts has been suggested in case reports.

CMV infections do not respond in a predictable manner to acyclovir because of the relative insusceptibility of CMV to acyclovir and the host immunodeficiency commonly present. To treat CMV infection, ganciclovir is currently recommended (see below). However, therapeutic and limited antiviral effects with acyclovir treatment were observed in renal transplant recipients with CMV pneumonia, enteritis, hepatitis, nephritis, and retinitis,134 bone marrow transplant recipients with CMV pneumonitis,135 and children with congenital CMV infection.

Infectious mononucleosis in normal hosts is favorably affected by acyclovir,136 but steroids are more likely to be useful to treat oropharyngeal airway obstruction owing to lymphatic hyperplasia and hypertrophy. The usefulness of intravenous acyclovir to treat life-threatening EBV complications such as hepatitis or polyclonal B-cell lymphoproliferative disease in immunodeficient individuals (X-linked lymphoproliferative syndrome, renal transplantation, severe combined immunodeficiency, and ataxia telangiectasia) is unclear, although some favorable effects have been observed.

Herpesvirus simiae, also called herpes B virus, commonly causes infection in Old World monkeys. In rare instances, infection has been transmitted to monkey handlers and laboratory workers manipulating simian tissue. Infection usually results in severe, fatal encephalomyelitis. If an animal handler is scratched or bitten by a monkey suspected or known to be carrying B virus, an experimental study has suggested that intravenous, but not topical, acyclovir can prevent infection.137 Its value in patients with established neurologic infection is less clear, but its use would seem reasonable.138

Mechanism of Action

Acyclovir inhibits HSV with low toxicity for uninfected host cells. Its therapeutic:toxic ratio in vitro is 30 to 300:1. Acyclovir acts as a prodrug that diffuses freely into and out of host cells. In HSV-infected cells, viral thymidine kinase phosphorylates acyclovir to a monophosphate nucleotide. This conversion selectively traps the drug and contributes to its lack of toxicity for uninfected cells. Cellular enzymes convert the monophosphate form to di- and triphosphate nucleotides. Acyclovir triphosphate mediates the antiviral effect by inhibiting viral DNA polymerase and by inserting into DNA, precluding further addition of bases to the DNA strand, a process known as chain termination.

Because EBV possesses little thymidine kinase and CMV possesses none, acyclovir lacks a similar potent inhibitory effect on these two herpesvirus strains.

Mechanism of Resistance

Strains of HSV relatively resistant to acyclovir exist in nature and may comprise up to 10% of HSV viruses.139 In addition, acyclovir-resistant strains of HSV and VZV may be selected in vitro and in patients during therapy. In patients, acyclovir inefficacy associated with emergence of resistant strains is almost exclusively observed in immunocompromised hosts.139 Acyclovir-resistant strains of HSV and VZV remain susceptible to ara-A and foscarnet in vitro, and these agents have been reported to be effective when acyclovir is not.140

Acyclovir resistance in HSV and VZV is mediated by genetic alterations that result in production of thymidine kinase–defective mutants (mostly) and DNA polymerase-insusceptible mutants (less commonly).141

Clinical Pharmacology142

Acyclovir is available in topical, oral, and intravenous formulations. Although it is freely soluble in water, solutions have a high pH of 9 to 11, so it is not recommended for intramuscular or subcutaneous injection because it causes tissue inflammation and pain. After intravenous injection, concentrations in CSF and aqueous humor are 35% to 50% of those in the plasma. Binding to plasma proteins is relatively low (9% to 22%), so adverse interactions owing to displacement by other drugs have not been described.

The elimination t½ of acyclovir from plasma is directly related to renal function because acyclovir is eliminated by glomerular filtration and renal tubular secretion. The latter mechanism is dominant as demonstrated by a mean acyclovir clearance rate that is four to six times greater than the creatinine clearance rate and by elevated Cp and prolonged t½ values in patients given probenecid concurrently. The plasma elimination t½ ranges from 2.5 hours in adults with normal renal function to 18 hours in those who are anuric. Nonrenal elimination of acyclovir contributes minimally to acyclovir clearance except in the presence of severe renal insufficiency. Up to 14% of a dose is eliminated as a glucuronide metabolite in urine, and less than 2% appears in feces.

Mean acyclovir plasma t½ during hemodialysis is approximately 5 hours, which reflects removal of about 50% of drug during 6 hours of dialysis.

The usual doses of acyclovir are 5 mg/kg for patients with mucocutaneous HSV infection and 10 mg/kg for patients with HSV encephalitis or VZV infection. The dose is repeated at intervals inversely related to creatinine clearance:

Hemodialysis patients should be given a standard initial dose that is repeated every 48 hours and after each dialysis.

Adverse Drug Reactions

Acyclovir is relatively free of serious toxicity. Crystalluria with renal tubular obstruction and elevated serum creatinine concentration can be avoided by not exceeding the recommended doses and by not administering a dose in less than 60 min. Phlebitis can be avoided by infusing acyclovir in concentrations below 10 mg/mL. Tissue inflammation will develop if drug extravasates during infusion.

Neurotoxic symptoms of lethargy, agitation, tremor, disorientation, or transient paraesthesias have been observed in bone marrow transplant recipients during prolonged intravenous acyclovir therapy.143 These symptoms resolved on withdrawal of therapy, but their relation to acyclovir dose, duration of therapy, or plasma or CSF concentrations remains unknown. Psychiatric side effects including hallucinations and depression have been observed in patients with renal failure given doses in excess of those currently recommended, suggesting a dose-related effect. Delirium has been reported as a side effect of acyclovir in a hemodialysis patient receiving appropriately reduced doses,144 and coma has been reported, beginning 24 to 48 hours after development of peak acyclovir serum concentration after a severe overdose.145 Based on pharmacokinetic calculations, a loading oral dose of 400 mg followed by 200 mg twice daily with a supplemental oral dose of 400 mg has been proposed for oral doses to minimize neurotoxicity.146 However, the utility of these calculated doses has not been validated prospectively.

Serious neurotoxic effects of acyclovir are likely to occur primarily in individuals with renal insufficiency in whom these effects can largely be avoided by careful attention to dose, frequency, and rate of administration; it has been suggested that the adverse effects can be treated by hemodialysis.146

Valacyclovir and Famciclovir

Valacyclovir is the ester oral prodrug of acyclovir.147 Esterification increases oral bioavailability of acyclovir approximately twofold, from 15% to 30% to 55%. Famciclovir is a well-absorbed (77% oral bioavailability) analogue of acyclovir.148

Neither of these oral agents offers any unique advantage over intravenous acyclovir for treatment of ICU patients and they are not discussed further.

Ganciclovir149

Ganciclovir is a synthetic, acyclic, nucleoside analogue of guanine that differs from acyclovir in possessing a hydroxymethyl group on the ribose remnant. This modest structural alteration nevertheless profoundly affects its antiviral potency and its cellular toxicity. Compared with acyclovir, ganciclovir in vitro is on average three times less potent against HSV-1 and HSV-2, 10 times less potent against VZV, similarly potent against EBV, and 10 to 100 times more potent against CMV (0.2 to 2.8 mg/L is inhibitory). Ganciclovir concentrations of approximately 0.6 mg/L are toxic to human bone marrow progenitor cells compared with concentrations in excess of 20 mg/L for acyclovir. The clinically important feature of ganciclovir is its antiviral effect against CMV, but its therapeutic:toxic ratio is 1 or less.

In addition to its low therapeutic:toxic ratio, ganciclovir is mutagenic, teratogenic, and carcinogenic in laboratory animals. Accordingly, its use is limited to patients with serious CMV infections, almost all of whom are immuno-incompetent owing to iatrogenic factors, such as immunosuppressive drug therapy in transplant recipients, or disease, such as HIV infection. Controlled clinical trials have demonstrated ganciclovir efficacy for treatment of CMV retinitis in HIV-infected individuals.150 Less substantive data suggest that ganciclovir produces improvement in 65% of HIV-infected patients with CMV enteritis, esophagitis, wasting illness, and, possibly, pneumonitis.151 Ganciclovir for 3 weeks is effective to suppress CMV-emia in allogeneic bone marrow recipients.152 However, controlled trials in bone marrow transplant recipients with CMV pneumonitis have demonstrated that ganciclovir is inefficacious when administered alone or in combination with corticosteroids but decreases mortality rate when administered with CMV hyperimmune globulin.153

Intravitreal ganciclovir appears to be effective for treatment of CMV retinitis in HIV-infected patients and to obviate the toxicity observed with intravenous therapy.

Mechanisms of Action

Ganciclovir inhibits viral DNA replication after intracellular conversion to the triphosphate nucleotide form. Phosphorylation is catalyzed by the virus-encoded enzyme UL97. Ganciclovir triphosphate acts like acyclovir triphosphate in selectively inhibiting viral DNA polymerase; its incorporation into viral DNA causes a slowing of DNA chain elongation and ultimately effects chain termination of the viral DNA strand. However, because it possesses two hydroxyl groups on the acyclic side chain, ganciclovir can be incorporated into host and viral DNA without abruptly interfering with chain elongation the way acyclovir triphosphate does.

Mechanism of Resistance

Ganciclovir-resistant CMV strains have been selected during serial passage of virus in the laboratory in the presence of the drug. Resistance associated with failure of ganciclovir therapy has been reported in immunocompromised patients. Foscarnet was effective in two such patients. Resistance was associated with reduced intracellular accumulation of ganciclovir in infected cells mediated by one or more specific point mutations in the UL97 gene.154 The presence of the mutation can be demonstrated by direct sequencing of CMV DNA in the patient's plasma.

Clinical Pharmacology

Oral and intravenous formulations of ganciclovir are available. There are two oral formulations, ganciclovir in capsules, which is 3% to 6% bioavailable, and valganciclovir in tablets, a prodrug that increases systemic ganciclovir availability to 61% of injected drug.155 Valganciclovir increases ganciclovir oral bioavailability 10-fold, likely due to recognition of valganciclovir as a substrate by intestinal peptide transporters.

Oral ganciclovir capsules in large doses (3000 mg/d) deliver sufficient ganciclovir systemically to maintain CMV suppression achieved initially by intravenous drug. Thus, it is efficacious for suppressing CMV retinitis in HIV patients. Oral valganciclovir will replace oral ganciclovir capsules because of its more favorable bioavailability. It also likely will be a stepdown alternative to intravenous ganciclovir, which remains the recommended mode of administration for ill patients.

Ganciclovir diffuses readily into lungs, liver, aqueous and vitreous humors, and CSF. Elimination from plasma is by a first-order process with a t½ of 2.5 to 3.6 hours that is inversely related to creatinine clearance. Ganciclovir is excreted into urine as unaltered drug.

The recommended dose of intravenous ganciclovir for adults with normal renal function is 5 mg/kg infused intravenously over 1 hour every 12 hours. Oral valganciclovir, 900 mg in a single dose, yields a serum area under the plasma-concentration versus time curve (AUC) of 0 to 24 hours similar to that observed after a single ganciclovir intravenous infusion of 5 mg/kg (41.7 vs. 48.2 mg/L per hour). For patients with impaired renal function, the dose or interval for intravenous ganciclovir scheduling should be adjusted as follows:

Hemodialysis for 4 hours removes an average of 53% of the body load of ganciclovir; one-half (2.5 mg/kg body weight) the standard dose should be administered after each dialysis.

Adverse Drug Reactions

Primarily because of incorporation in replicating host DNA, ganciclovir causes significant toxic effects in rapidly proliferating tissues and organs. Thus, in laboratory animals, ganciclovir causes hematopoietic, gonadal, and gastrointestinal toxicities.

In humans, hematopoietic toxicity has been the most common adverse side effect observed. Neutropenia and thrombocytopenia have been observed in 40% and 20%, respectively, of HIV-infected patients, and anemia has been noted less frequently. Concomitant administration of zidovudine and ganciclovir increases the frequency of neutropenia. Neutropenia and thrombocytopenia are almost always promptly reversible when ganciclovir is discontinued. In up to 15% of patients, ganciclovir, similar to the antiviral nucleosides acyclovir and ara-A, causes CNS toxicity, with manifestations ranging from headaches to behavioral changes, psychosis, convulsions, and coma. The mechanism is not known. Ganciclovir CNS toxicity may be difficult to differentiate from CNS dysfunction owing to concurrent disease and other drug therapy in seriously ill patients.

Oral ganciclovir capsules, oral valganciclovir, and intravenous ganciclovir in clinically equivalent doses caused diarrhea in 13%, 42%, and 7%, respectively, of patients; nausea in 7%, 28%, and 13%, respectively; anemia in 7%, 25%, and 14%, respectively; and leucopenia in 22%, 36%, and 25%, respectively.

Foscarnet156

Foscarnet (trisodium phosphonoformate hexahydrate) is a relatively insoluble (aqueous solubility 5% [wt/wt]) antiviral drug. In vitro, foscarnet inhibits several DNA and RNA viruses at concentrations from 6 to 120 mg/L, but cellular cytotoxicity is observed at concentrations of 150 to 300 mg/L, yielding toxic:therapeutic ratios ranging from 1 to 7:1.

Intravenous foscarnet is licensed only for treatment of CMV retinitis in AIDS patients. However, studies have suggested that foscarnet may have value for a wider range of CMV infections (pneumonitis and encephalitis) in immunocompromised patients (HIV-infected patients and renal and bone marrow transplant recipients). Foscarnet is effective for therapy of acyclovir-resistant HSV or VZV and ganciclovir-resistant CMV infections. Six patients with fulminant hepatitis caused by hepatitis B or concomitant Delta virus infection survived in association with intravenous foscarnet therapy. Although the number of patients studied was small and historical controls were used to analyze therapeutic benefit, foscarnet may have a role in fulminant hepatitis B infection because no other specific treatment for this infection is currently available.

Foscarnet is the drug of choice for the treatment of CMV infections in individuals unable to tolerate ganciclovir, for patients with acyclovir-resistant HSV and VZV infection, and for those with ganciclovir-resistant CMV infections.

Mechanism of Action

Foscarnet is an analogue of pyrophosphate, a metabolite of nucleic acid synthesis. Foscarnet acts by inhibiting DNA and RNA polymerases, including HIV reverse transcriptase. Foscarnet inhibits DNA polymerase activity noncompetitively by binding at the pyrophosphate binding site.

Mechanisms of Resistance

Naturally occurring foscarnet-resistant HSV strains seem uncommon (1 of 41 HSV isolates in one study). Foscarnet-resistant mutants of HSV-1 and HSV-2 and non-HIV retroviruses can be cultivated in in vitro experimental systems. These mutants possess DNA polymerase resistant to foscarnet. However, resistance development has not been observed during foscarnet therapy of experimental HSV infection in laboratory animals or during clinical trials in patients with HSV or CMV infection.

Resistance appears to be mediated by a mutation in the foscarnet binding site on the DNA polymerase. Some, but not all, of these foscarnet-resistant strains exhibit diminished susceptibility to nucleoside analogues such as ara-A, suggesting that the mutational alteration affected a binding site on the enzyme common to both drugs. In addition, an acyclovir-resistant HSV-1 strain with intact thymidine kinase but mutated DNA polymerase exhibited increased sensitivity to foscarnet and ara-A, suggesting that a change in the acyclovir triphosphate binding site affects the interaction of foscarnet and the ara-A triphosphate metabolite with the polymerase.

Clinical Pharmacology156

Foscarnet oral bioavailability is low, with only 12% to 22% of oral doses being absorbed. The combination of poor oral bioavailability and the large doses required (100 to 200 mg/kg per day) even when foscarnet is given intravenously make oral therapy impractical. Intravenous regimens used to treat CMV infections consist of an initial dose of 20 mg/kg over 30 minutes followed by continuous infusion of 230 mg/kg per day or 60 mg/kg three times per day to achieve a target Cp of 45 to 135 mg/L. Infusion requires several hours because the maximum concentration of drug recommended for intravenous administration is 2000 mg/L. Steady-state plasma foscarnet concentrations range from 40 to 400 mg/L (mean, 100) with a peak Cp of approximately 150 mg/L.

After intravenous administration, the drug disappears from plasma in a tri-exponential manner, with t½ values of 0.5, 3, and 18 hours. The long terminal t½ probably reflects the slow release of foscarnet from bone. The kinetic AVD is about 0.6 to 0.7 L/kg. Plasma protein binding is 17%. CSF concentrations average 43% (range, 13% to 68%) of simultaneous Cp. Penetration into the retina seems sufficient to inhibit CMV replication and ameliorate retinitis. Knowledge of foscarnet distribution in humans is otherwise incomplete. In animals, foscarnet, being a phosphate analogue, is incorporated into the mineral matrix of bone. Foscarnet does not undergo metabolic transformation. It is eliminated unchanged into the urine. Renal clearance averages 130 to 175 mL/min per 1.73 m2 of surface area, suggesting that renal tubular secretion and glomerular filtration contribute to foscarnet elimination.

The kinetic characteristics of foscarnet in patients undergoing dialysis require further study. Available data indicate that the Cp of foscarnet declines rapidly during hemodialysis. This is consistent with the knowledge that foscarnet is a small molecule (molecular weight, 300 kd) that is minimally protein bound. Tissue binding of foscarnet likely will preclude extensive removal by dialysis. This facet of foscarnet disposition and its implications for dosing require further study. However, one recommendation suggests reducing the foscarnet dose by 30 mg/kg per day for each 20 mmol/L increase in creatinine concentration above 70 mmol/L.157

Adverse Drug Effects

Although foscarnet commonly causes biochemical evidence of toxicity (anemia, leukopenia, thrombocytopenia, and elevation in serum creatinine, etc.), symptomatic toxicity is uncommon. Hallucinations and a flapping tremor, temporally directly related to foscarnet therapy, were associated with a relatively high Cp of 449 mg/L for foscarnet and disappeared when foscarnet was discontinued; these were therefore considered to represent direct toxic effects of the drug.

Anemia without alterations in white blood cell count or platelet concentration and mild elevations in the serum creatinine level occurs in 15% to 50% of patients, but the contributions of concurrent other drugs (e.g., cyclosporine) and underlying disease have been difficult to exclude. Hypercalcemia occurs in about 20% of patients and abnormal transaminase in 5% to 10%. Local phlebitis is uncommon. Adverse interactions of foscarnet with other drugs have not been described.

Amantadine

Amantadine is a synthetic, tricyclic, basic amine antiviral agent with antimicrobial utility limited to the prevention and treatment of influenza A virus infection.

In vitro, amantadine inhibits influenza A viruses in low concentrations of 0.2 to 0.4 mg/L. This effect has been uniformly demonstrable against all three major pandemic strains of influenza A virus and their subtypes.

Amantadine is approved for the prevention and treatment of influenza A virus infection. It has been demonstrated to be efficacious in preventing nosocomial influenza A infection in patients in acute general hospital wards, and it should be similarly effective in ICU patients, although no data exist on this issue.158 Treatment of otherwise healthy, young adults with uncomplicated influenza illness accelerates resolution of systemic symptoms and some respiratory tract symptoms by 50% and hastens the resolution of increased peripheral airways resistance that is presumably related to inflammatory narrowing of small and medium bronchioles. In addition, treatment decreases the frequency and duration of virus shedding. Unfortunately, no data demonstrate that similar beneficial effects can be achieved by amantadine therapy in ICU patients with influenza A infection complicating severe obstructive airways disease or other severe underlying parenchymal lung disease, or with primary influenza A pneumonia in the absence of pre-existing lung disease.

For outbreak control, amantadine should be administered to all patients if epidemic influenza A infection is suspected or documented in the institution. When amantadine is used for outbreak control, it should be administered to all patients regardless of whether they received influenza vaccine recently and to unvaccinated staff. All unimmunized staff and patients given prophylactic amantadine should be offered immunization with the current vaccine simultaneously if the epidemic strain(s) is identical to, or closely related to, the vaccine strain(s). Amantadine prophylaxis should be continued until the outbreak is over, that is, until an interval equivalent to two incubation periods, 48 and 72 hours, after the period of communicability of the last case in the institution (about 5 to 6 days after onset) has passed.

Mechanism of Action

Amantadine inhibits replication of influenza A virus by interfering with uncoating of the virus and release of the RNA genome in lysosomes. This effect requires that drug be present continuously in the extracellular milieu. Thus, the prophylactic or therapeutic effect is rapidly lost as drug is excreted from the body after discontinuation of drug administration.

Mechanism of Resistance

Susceptibility to the antiviral effect of amantadine is influenced by the virion M2 protein in the influenza virion envelope. Even single changes of amino acid in M2 decrease susceptibility to amantadine. Resistance to amantadine is readily selected for in vitro, during passage in mice experimentally infected with influenza A virus, and during amantadine treatment in patients. More studies are required to define the precise clinical relevance of these observations.

Clinical Pharmacology159

Amantadine is highly water soluble with a pKa of 11. Its utility in the ICU setting is limited by its availability only in enteral forms as capsules of 100 mg or a syrup containing 10 mg/mL. Although data from studies in experimentally infected mice and patients with severe natural infection suggest that inhalation of amantadine as an aerosol may be more effective for influenza therapy than administration enterally, no formulation suitable for aerosol administration is available. For healthy adults 65 years of age, the recommended amantadine dose is 200 mg/d; for those older than 65 years, the dose is 100 mg/d.

In healthy adults including the elderly, amantadine is slowly (time to peak Cp, 6 to 12 hours after ingestion) but virtually completely absorbed, but no data have confirmed that similar results occur in acutely ill ICU patients. It is widely distributed with a mean AVD of 6.6L/kg that probably decreases with advanced age. As expected, there are two consequences of this pharmacokinetic characteristic. First, Cp values are low, averaging 0.5 to 0.8 mg/L at peak and 0.3 mg/L at trough at steady state, in young, healthy adults ingesting 200 mg/d and elderly men with normal creatinine Cp ingesting 100 mg/d. Second, negligible amounts are removed by hemodialysis. Amantadine is found in highest concentration in the brain, liver, lung, and kidneys in treated animals; a similar localization in humans may explain the propensity of this drug to cause CNS side effects (and, in part, ameliorate symptoms of Parkinson disease). Nasal mucus concentrations of amantadine only approximate concurrent Cp. This may explain the superiority of administration of amantadine as an aerosol for therapy of influenza A in experimentally infected mice and volunteers because aerosol administration of amantadine resulted in a mean nasal washing fluid (and presumably mucus and respiratory epithelial cell) concentration of 66,658 mg/L after long-term oral ingestion of 200 mg/d and 30,300 to 111,300 mg/L after inhalation of aerosol generated from a reservoir containing 10 g/L amantadine in volunteers.

Elimination is a first-order process, with a plasma t½ averaging 14 hours in healthy, young adults and 28 hours in healthy, elderly men (and, presumably, women). Renal clearance exceeds creatinine clearance by approximately three times, implying significant renal tubular secretion of amantadine in addition to elimination by glomerular filtration. The plasma t½ is inversely related to creatinine clearance, and this fact led to the following recommendation for dose modification in patients with stable renal dysfunction:

In patients on hemodialysis, a single 200-mg loading dose should be sufficient. The plasma t½ of amantadine may be as long as 30 days in such individuals.

Adverse Drug Reactions

Amantadine is generally well tolerated. Mild, amphetamine-like adverse symptoms occur in 1% to 10% of young adults, manifesting as insomnia, difficulty concentrating, nightmares, jitteriness, and depression. These symptoms are rapidly reversible on discontinuation of drug administration. Rarely, severe neurotoxic adverse symptoms ranging from seizures (in those with underlying convulsive disorders), psychosis, to convulsions occur. These generally occur in patients given excessive doses or with renal insufficiency. Amantadine Cp values are usually above 1 mg/L in these individuals.

Isolated instances of congestive heart failure, vision loss, and urinary retention have been reported. Livedo reticularis and peripheral edema during chronic therapy have been described.

Anticholinergic and antihistamine drugs may increase adverse effects caused by amantadine. A diuretic containing triamterene and hydrochlorothiazide was associated with neurotoxicity and increased amantadine Cp owing to reduced renal clearance. Because amantadine is a cationic drug, its renal tubular secretion would be expected to be decreased by concurrent administration of other basic drugs such as quinidine, nicotine, and trimethoprim. The possibility of such concomitant therapy increasing the frequency or severity of amantadine side effects requires further study.

Rimantadine

Rimantadine, a methylated analogue of amantadine, is approved in the United States as an oral agent for prophylaxis of influenza A infection in children and adults and for the treatment of influenza A infection in adults. Rimantadine thus may be used to prevent infection in ICU patients and personnel during an outbreak. Rimantadine was better tolerated than amantadine in a comparative trial in young adults but no more efficacious than amantadine at the same dose, 200 mg/d. An experimental formulation of rimantadine was administered as aerosol to volunteers with influenza A infection. Aerosolized rimantadine caused mild nasal irritation but was as effective as a small oral dose (150 mg/d) of rimantadine and more effective than placebo. The value of such treatment in intubated, ventilated patients with severe influenzal illness in the ICU has not been described. No injectable formulation is available.

Mechanisms of Action and Resistance

See mechanism of action of amantadine (above). Rimantadine is more potent in vitro than amantadine, with 50% inhibitory concentrations being two to eight times less than for amantadine; the clinical importance of this difference is uncertain.

Mechanism of Resistance

Resistance emerges as readily during therapy with rimantadine as during therapy with amantadine, being demonstrable in 30% of recipients after 2 to 3 days of treatment. The mechanism of rimantadine resistance is identical to that for amantadine resistance. Cross-resistance is complete.

Clinical Pharmacology160

Rimantadine is available only as tablets or syrup for oral administration. Some clinical pharmacokinetic characteristics of rimantadine differ substantially from those of amantadine. Rimantadine is absorbed as well and completely (>90%) as amantadine. The AVD is similar to that of amantadine, about 10 L/kg. Greater than 75% of a rimantadine dose is metabolized compared with less than 10% of an amantadine dose. Rimantadine undergoes hydroxylation, conjugation, and glucuronidation. A 2-OH metabolite has 10% the activity of the parent compound; the others are devoid of antiviral activity. The metabolites are eliminated into urine. Rimantadine clearance, averaging 350 mL/min, is not affected by age in otherwise healthy adults. The elimination serum t½ of rimantadine averages 25 to 37 hours, approximately twice as long as that of amantadine. The recommended dose for healthy adults younger than 65 years is 200 mg/d. Based on the incomplete pharmacokinetic data, a reduced dose of 100 mg/d is recommended for prophylaxis and treatment of adults with severe renal dysfunction (creatinine clearance <10 mL/min) or hepatic dysfunction and of elderly nursing home patients. In patients with mild or moderate renal insufficiency, the standard dose should be administered and patients closely observed for adverse reactions. In patients with end-stage renal failure, mean elimination t½ is 44 hours. A 50% reduction in dose is recommended. Rimantadine is not removed by hemodialysis. In patients with mild or moderate liver disease (no ascites, normal albumin, total bilirubin <46 mmol), rimantadine kinetics were not different from those in normal subjects.

Adverse Drug Reactions

Comparative trials have demonstrated that rimantadine, like amantadine, is generally well tolerated. It causes a lower incidence of adverse symptoms than does amantadine, and, unlike that drug, it causes predominantly gastrointestinal ADR (nausea, anorexia, dry mouth, abdominal pain, and diarrhea). Rimantadine enters the brain, but CNS toxic symptoms are less commonly seen with it than with amantadine.

No clinically important interactions of rimantadine with other drugs have been reported.

There are no trials comparing the efficacy or safety of amantadine or rimantadine used to treat patients in the ICU, but the differences in pharmacokinetic characteristics are important to note in selecting one or the other in patients with severe renal or hepatic insufficiency.

Zanamivir and Oseltamivir

These drugs have recently been approved for the prevention and treatment of influenza A and B infections.161,162Zanamivir is administered as an orally inhaled powder, whereas oseltamivir is administered as oral capsules; no intravenous formulations are available commercially, although intravenous zanamivir was well tolerated and effective in preventing experimental influenza A infection in volunteers.

These agents differ from the M2 ion channel inhibitors, amantadine and rimantadine, in three characteristics. First, zanamivir and oseltamivir inhibit influenza A and B viruses, whereas the M2 ion channel inhibitors only inhibit influenza A strains. Second, these agents do not cause dose-related side effects of consequence (oseltamivir causes mild nausea and/or vomiting after initial doses in 10% to 15% of subjects vs. 5% to 8% of placebo recipients and zanamivir rarely causes bronchospasm in those with underlying obstructive airways disease). Third, these agents do not seem to share the propensity of amantadine and rimantadine to engender the emergence of drug-resistant virus. Amantadine- and rimantadine-resistant influenza A viruses would be expected to be susceptible to zanamivir and oseltamivir.

Zanamivir and oseltamivir are effective for the prevention of influenza A and B, and the treatment of uncomplicated influenzal illness. Neither drug appears more efficacious than the other or more efficacious than amantadine or rimantadine. No available data demonstrate that either of these agents is effective for treatment of established primary influenza pneumonia.

Mechanism of Action

Zanamivir and oseltamivir inhibit influenza virus replication by inhibiting the virus-encoded enzyme neuraminidase, which is essential for release of daughter virions from infected cells. Human neuraminidase is 106 to 107 times less susceptible to inhibition by these drugs.163

Mechanism of Resistance

Resistance evolves in two steps. Initially, mutational changes in the viral hemagglutinin enzymatic pocket result in diminished affinity of the hemagglutinin for sialic acid, resulting in decreased dependency on the neuraminidase for virus elution. Such viruses would be less susceptible to the inhibitory effect of these drugs. Subsequently, resistance arises due to mutations in the enzymatic pocket of the neuraminidase itself, which impairs the ability of the drugs to interfere with the neuraminidase-mediated catalytic function.

Clinical Pharmacology

Orally inhaled zanamivir is administered in a dose of two puffs (10 mg) once (for prophylaxis) or twice (for treatment) each day. The recommended dose of oseltamivir is 75 mg once or twice a day for prevention or treatment of influenza, respectively. From 4% to 17% of a zanamivir dose is absorbed, mostly through the lungs. Oseltamivir is 80% orally bioavailable, although this has not been confirmed in seriously ill patients in the ICU.

Both drugs exhibit low levels of protein binding (<5%). Inhaled zanamivir distributes through the upper and lower airways, whereas oseltamivir distributes throughout the body, with an AVD equivalent to about 36% of total body weight; the anatomic correlate is not known.

Both drugs are eliminated from the body largely unchanged by glomerular filtration and by renal tubular secretion by a first-order process, with a serum t½ of 1.8 hours in persons with normal renal function. Renal clearance is decreased by renal dysfunction and dose reductions by half are recommended for oseltamivir in patients with creatinine clearance slower than 30 mL/min. Systemic exposure to zanamivir after oral inhalation is so low and the tolerance of zanamivir sufficiently high that dose reduction of zanamivir is not needed in patients with renal dysfunction.

Drug Interactions

In both cases, low protein binding and systemic clearance as unchanged drug without significant metabolism suggest that drug interactions due to alterations in binding or competitive inhibition of metabolism will not affect other drugs administered concurrently. Animal studies and limited human studies have confirmed these predictions. Oseltamivir, which is secreted by a renal tubular anionic transporter, might interfere with the renal secretion of other anionic drugs such as probenecid. A clinical study confirmed that such an interaction could occur; probenecid clearance was reduced 50%.

Adverse Drug Reactions

Zanamivir rarely can cause worsening of airway obstruction in patients with severe or decompensated chronic pulmonary or airway disease or asthma, and the manufacturer recommends against its use in these patients.

Oseltamivir causes nausea and/or vomiting, usually after only the initial dose, in 5% to 10% of oseltamivir recipients in excess of rates in concurrent placebo recipients. No serious or fatal drug-related adverse events have been observed in oseltamivir recipients.

In conclusion, these two new anti-influenza drugs have substantial advantages over amantadine and rimantadine as agents for preventing and treating influenza A and B infections in the ICU. Unfortunately and of primary concern, no studies have demonstrated their efficacy for treating patients with influenza pneumonia.

Ribavirin

Ribavirin is a synthetic analogue of guanosine. In vitro, it inhibits the replication of a wide range of RNA and DNA viruses. Clinically, its value in the management of ICU patients is limited to the treatment of individuals with influenza A or B or respiratory syncytial virus respiratory tract infection with aerosolized drug and the intravenous therapy of patients with Lassa fever, an enzootic infection of rodents in West Africa that may be imported in returning travelers and be transmitted from patients to health care workers.

In clinical trials, ribavirin has been efficacious when administered as an aerosol to children and adults with respiratory syncytial virus infection and otherwise healthy adults with uncomplicated influenza A or B virus infection. Intravenous ribavirin decreases mortality rate in patients with Lassa fever and it is likely effective, although incompletely studied, for some other viral hemorrhagic fevers.164 A rigorous evaluation failed to demonstrate any beneficial effect of intravenous plus intracerebroventricular ribavirin in an adult with symptomatic rabies encephalomyelopathy. An uncontrolled study suggested efficacy when given intravenously to three patients with severe lower respiratory tract infection with influenza or parainfluenza viruses.165 The utility of ribavirin for therapy of alphavirus encephalitides caused by Eastern, Western, or Venezuelan equine encephalitis viruses that are susceptible in vitro has not been reported.

Recently, ribavirin combined with pegylated interferon α2b has been licensed for the treatment of chronic hepatitis C infection. The recommended dose is 200 mg, or five capsules per day for patients weighing less than 75 kg or six capsules per day for those weighing more than 75 kg, plus 3 million U interferon α2b injected subcutaneously three times per week, for 24 to 48 weeks.

Mechanism of Action

The precise molecular basis of the antiviral effects of ribavirin is not known. Multiple mechanisms probably are involved with differences between RNA and DNA viruses and virus-specific differences within each of these two groups.

Within cells, ribavirin behaves in part like an adenosine analogue, being phosphorylated to its mono-, di-, and triphosphate nucleotide forms by cellular adenosine kinase. Ribavirin-5′-phosphate seems to be the principal metabolite mediating the antiviral effect of ribavirin on influenza replication by inhibition of cellular inosine monophosphate dehydrogenase resulting in guanosine depletion and inhibition of viral RNA synthesis. This antiviral effect can be reversed by exogenous guanosine. However, ribavirin-5′-triphosphate also selectively inhibits influenza RNA polymerase, suggesting another locus for the antiviral effect of ribavirin on influenza replication. The multiple modes of action of ribavirin may account for the absence of reports of ribavirin resistance in clinical isolates.

Clinical Pharmacology

Ribavirin is a water-soluble agent that has been administered to patients by aerosol, mouth, and intravenous injection.

For aerosol administration to patients with viral pulmonary infection, the drug has been prepared as a solution containing 20 g/L, which must be aerosolized in a special generator to yield particles of about 1.4 μm in diameter that will reach terminal airways and alveoli. Oral ribavirin is approximately 45% bioavailable due to substantial first-pass metabolism. Intravenous administration yields Cp values of 17 and 24 mg/L after doses of 500 and 1000 mg, respectively. These are approximately 10-fold higher than after comparable oral doses. Ribavirin distributes widely throughout the body. It accumulates within erythrocytes owing to trapping by phosphorylation. CSF concentrations average 50% to 65% of concurrent plasma levels. The drug undergoes extensive hepatic biotransformation as demonstrated by recovery of only 24% of an intravenous dose as unchanged drug in urine. Elimination from plasma is a triphasic process, with t½ values of 0.2, 2, and 36 hours. Attainment of plateau concentrations in plasma will take 1 to 2 weeks.

The effect of concomitant hepatic or renal disease or other drugs on ribavirin disposition remains largely unstudied.

Adverse Drug Reactions

After administration by aerosol, ribavirin is generally well tolerated except for mild conjunctival irritation. Wheezing and cough have been observed in patients with asthma or mild chronic obstructive airway disease. These adverse effects were reversible by discontinuation of aerosol therapy or administration of aerosolized β agonist.166 When administered to intubated patients by mechanical ventilator, ribavirin aerosol droplets deposit on the tubing and hoses, absorb water owing to their hygroscopic nature, and thereby interfere with efficient ventilation. The use of in-line filters, modified circuitry, and careful attention to pressure build-up can minimize deleterious effects on pulmonary gas exchange.

Ribavirin given intravenously for Lassa fever therapy only caused reversible anemia, which did not require transfusion, as a side effect.

Chronic oral ribavirin therapy causes CNS and gastrointestinal complaints including headache, lethargy, fatigue, insomnia, and anorexia. A dose-dependent macrocytic hemolytic anemia with a contribution from myelosuppression in those receiving larger doses commonly occurs. During treatment of chronic active hepatitis C infection, 10% of patients developed hemolysis resulting in hemoglobin levels below 10 g/dL.

Adverse interactions of ribavirin with other drugs or diseases have not been described.

In view of possible ribavirin teratogenic and embryotoxic effects in humans, like those observed in small laboratory animals, pregnant members of the nursing staff are advised to avoid protracted exposure to ribavirin aerosol.

Nucleoside Reverse Transcriptase Inhibitors

Nucleoside reverse transcriptase inhibitors (NRTIs) are antiretroviral inhibitors comprising seven agents that are analogues of purines and pyrimidines used in the transcription of the HIV genome. The drugs require intracellular activation to a triphosphate nucleotide form, which is the active antiviral molecule. That is, they are in effect prodrugs. All NRTIs share a dual mechanism of action, namely as competitive inhibitors of reverse transcriptase (RT) and as chain terminators of HIV-DNA elongation, when they are incorporated into the elongating chain in place of the natural nucleotide. Mutation in the RT gene leads to viruses that are variably cross-resistant to other NRTIs. Genotypic resistance testing is needed to determine which NRTI will inhibit resistant mutants.

Collectively, NRTIs have a relatively short plasma t½ of one to several hours but their intracellular half-life is longer, at least 3 hours, thereby permitting their administration one to three times per day. As a class, they have low affinity for hepatic cytochrome P450 drug-metabolizing enzymes, so they do not cause important adverse drug interactions by this mechanism. In contrast, NRTIs as a class cause depletion of mitochondrial DNA by inhibiting human DNA polymerase γ and, hence, replication of mitochondrial DNA.167 As a result, mitochondrial DNA is depleted and drug toxicity occurs. Adverse reactions due at least in part to mitochondrial toxicity include hepatic steatosis, skeletal muscle and cardiac myopathies, peripheral neuropathy, and pancreatitis. Asymptomatic elevated serum lactate levels and fatal lactic acidosis also have been described as probable additional manifestations of NRTI mitochondrial toxicity. Mitochondrial toxicity is reversible on discontinuation of NRTI therapy.

All NRTI drugs are approved for use in combination therapy even though there are robust data supporting the use of azidothymidine (AZT) alone for peripartum prophylaxis to prevent transmission of HIV to the neonate.

These drugs competitively inhibit the use of different purines or pyrimidines by HIV RT. They also differ in the nature of the adverse reactions they cause.

The NRTIs and their analogous natural nucleosides are:

The following discussion aims to highlight noteworthy, clinically important aspects of these drugs because they might cause morbidity necessitating ICU admission or cause significant iatrogenic disease when administered to ICU patients.

Zidovudine

Clinical Pharmacology168

From 63% to 95% (mean, 90%) of an oral dose of AZT is absorbed. However, because of first-pass metabolism, the average oral bioavailability is 65% (range, 52% to 75%).169 Absorption is rapid, with peak Cp appearing within 30 to 90 minutes after ingestion. The effect of gastrointestinal disease, including HIV enteropathy, on AZT absorption has not been described. The drug distributes widely throughout the body. Concentrations in CSF average 15% to 64% of concurrent Cp. Hepatic glucuronidation yields an inactive, nontoxic metabolite. The plasma elimination t½ of AZT is approximately 1 hour. AZT and its glucuronide metabolite are eliminated primarily through the kidneys, contributing 14% and 74%, respectively, to urinary recovery. Renal elimination is by glomerular filtration and renal tubular secretion. Probenecid interferes with glucuronidation of AZT and inhibits renal excretion of the nontoxic glucuronide. In anuric patients, the plasma t½ of AZT increased to only 1.4 hours compared with 1 hour for controls with normal renal function. However, the plasma t½ of the principal metabolite (glucuronyl AZT) increased from 1 to 8 hours, with as yet incompletely understood clinical consequences. Hemodialysis has a negligible effect on AZT removal but accelerates clearance of the metabolite. Thus, AZT dose need not be adjusted for patients with renal disease, including those undergoing dialysis.

The effect of hepatic disease on AZT disposition has not been described. AZT accumulation to levels higher than that seen in subjects with normal liver function would be expected. Until more data permit development of validated dose schedules for patients with hepatic disease, one might try the following strategies for minimizing dose-related toxicity: use of smaller doses (e.g., 300 mg/d) and frequent assessment of reticulocytes, hemoglobin, and neutrophil concentrations, because these appear to be the most sensitive to toxic effects caused by AZT. Measuring Cp of AZT has no established place in this setting and is impractical.

Adverse Drug Reactions

In adults with HIV disease, AZT ADRs were more common in those with more advanced HIV disease and in those receiving larger doses.170 In all placebo-controlled studies, anemia and granulocytopenia were the most common ADRs observed: Anemia (hemoglobin <75 g/L) was observed in 9% and 5% of volunteers with asymptomatic and advanced HIV disease, respectively, treated with placebo and 1% (500 mg/d) or 6% (1500 mg/d) up to 29% (1500 mg/d) in AZT recipients in the two respective groups. Similarly, granulocytopenia (<750 cells/mm3, or <0.75 × 109/L) was observed in 2% and 10% of subjects in the two groups treated with placebo and 2% (500 mg/d) or 6% (1500 mg/d) up to 47% (1500 mg/d) in the two groups, respectively, treated with AZT. These hematologic toxic effects generally appeared after 4 to 6 weeks of therapy and reversed with reduction of AZT doses or temporary discontinuation.

Other reactions intensivists may see include severe headache (42% of AZT recipients and 37% of placebo-treated subjects), nausea (46% to 61% and 18% to 41%, respectively, in severe and asymptomatic HIV infection), vomiting (25% and 13%, respectively), insomnia (5% of AZT recipients and 1% of placebo-treated subjects), and myalgia (8% and 2%, respectively).

Considering the number of drugs administered concomitantly to HIV-infected patients receiving AZT, a paucity of clinically important interactions has been described. Ganciclovir and AZT produce additive suppression of myeloid precursors with granulocytopenia, acetaminophen may inhibit AZT metabolism and increase its Cp, and dapsone plus AZT increases the risk of anemia. Ribavirin antagonizes the anti-HIV effect of AZT by inhibiting its phosphorylation to AZT phosphate.

Lamivudine

Lamivudine (3TC), a dideoxy analogue of cytidine, is a potent, selective inhibitor of HIV-1 and HIV-2 replications in vitro.

Clinical Pharmacology171

Absolute oral bioavailability is 85%. The Cp rises linearly over the dose range of 0.25 to 20 mg/kg (usual oral dose is 150 mg twice daily or ∼2 mg/kg per dose). Mean elimination t½ is 2 to 4 hours. Mean ratio of CSF to serum in HIV-infected patients without clinical CNS disease is 0.06, similar to, or better than, that for ddC and ddI (0.0 to 0.2) but less than that for AZT (0.25 to 0.75). Metabolism of 3TC is a minor route of elimination. The majority of 3TC is eliminated unchanged in urine. 3TC clearance is markedly affected by renal functional impairment, with mean t½ values of 11.5, 14.1, and 20.7 hours in subjects with normal renal function, moderate renal impairment (creatinine clearance 10 to 40 mL/min), and severe dysfunction (creatinine clearance <10 mL/min), respectively. TMP decreases 3TC renal elimination, causing a 40% increase in 3TC Cp, probably by interfering with renal tubular secretion. This is not clinically important because 3TC has no dose-related toxic effects. 3TC dose reduction is recommended in patients with renal insufficiency; the dose should be halved for those with creatinine clearance of 30 to 49 mL/min; for patients with creatinine clearance of 15 to 29 mL/min, an initial dose of 150 mg followed by 100 mg/d is recommended; for patients with creatinine clearance of 5 to 14 mL/min, a 150-mg initial dose followed by 50 mg/d is recommended; for patients with creatinine clearance lower than 5 mL/min, a 50-mg initial dose is recommended followed by 25 mg/d. Dose adjustments for patients on dialysis are not available.

Adverse Drug Reactions

3TC causes no dose-related adverse effects. Unlike the other marketed nucleoside RT inhibitors (AZT, d4T, ddC, and ddI), 3TC is noteworthy for causing few ADRs. The exception is a risk of pancreatitis in pediatric patients treated with 3TC combined with AZT. In one trial in which adult subjects ingested AZT 600 mg/d, 3TC 600 mg/d, or 3TC 300 or 600 mg/d plus AZT 600 mg/d, the 3TC groups reported no more adverse effects than the AZT-only group.

Didanosine

Clinical Pharmacology171,172

Didanosine (ddI) was initially licensed in 1991 in the United States. It is rapidly degraded at acid pH, so oral formulations contain buffers to decrease gastric pH and facilitate absorption as chewable or water-dispersible tablets administered twice daily.

Oral bioavailability has ranged from 20% to 40%, likely due to variations in gastric degradation by acid, motility, and transit time. As of 2002, a convenient new enteric-coated tablet has been licensed that provides oral bioavailability equivalent to the buffered tablets without the need to chew them or disperse them in water before ingestion. More recently, it has been demonstrated that tenofovir administered concurrently increases ddI oral bioavailability in 44% to 60% of subjects.

Didanosine undergoes extensive intracellular metabolism in the purine pool, resulting in formation of hypoxanthine and uric acid. From 35% to 60% of a dose is recovered unchanged in urine.

In patients weighing more than 60 kg with renal impairment, doses should be reduced: for creatinine clearance of 30 to 59 mL/min, the daily dose should be 200 mg; for creatinine clearance lower than 29 mL/min, the daily dose should be 125 mg. For patients on dialysis, the daily dose should be administered after dialysis. There is no need to give supplementary doses after dialysis because ddI is not dialyzable.

In patients with hepatic impairment, the risk of ddI toxicity may be increased but no specific recommendations for reducing doses are available.

Adverse Drug Reactions

Important serious adverse drug reactions include diarrhea, pancreatitis, peripheral neuropathy, lactic acid with hepatic steatosis, fulminant hepatic necrosis, and retinal depigmentation and vision loss. The risk of pancreatitis is 1% to 10%.

Allopurinol given concurrently appears to increase ddI AUC fourfold and thereby increases the risk of pancreatitis. Coadministration of ddI and allopurinol is not recommended.

Didanosine does not interact with other HIV-inhibitor drugs.

Stavudine

Clinical Pharmacology173

Only an oral capsule formulation of stavudine (d4T) is currently available. Oral bioavailability is 82% to 99%, but absorption in critically ill patients in the ICU is not known. AVD is 47.3 to 70 L in adults. Peak CSF concentrations are 16% to 72% of the concurrent plasma concentration. Plasma elimination t½ is 1.6 hours in HIV-infected patients, but the intracellular t½ is 3.5 hours, thus permitting twice-daily dosing.

About 40% of a dose is eliminated unchanged into urine. Renal clearance of d4T is about twice the creatinine clearance, indicating that net tubular secretion and glomerular filtration contribute to its renal elimination. Nonrenal clearance is hypothesized to involve intracellular metabolism and entry of metabolites into the pyrimidine pool. Less than 1% enters the bile.

Twice-daily doses are recommended to be reduced in adults with renal impairment: with creatinine clearance faster than 50 mL/min, doses are 40 mg twice daily for patients weighing at least 60 kg and 30 mg twice daily for those weighing less than 60 kg; with creatinine clearance of 26 to 50 mL/ min, doses are 20 and 15 mg twice daily, respectively, for the two weight groups; with creatinine clearance of 10 to 25 mL/ min, doses are 20 and 15 mg once daily, respectively, for the two weight groups.

No adjustment for patients with stable hepatic impairment is recommended.

Adverse Drug Reactions

Peripheral neuropathy is the most important ADR. It has occurred in 15% to 24% of patients in controlled trials, is dose related, requires drug discontinuation or reduction, and is generally reversible.

Elevated levels of lactic acid of long duration due to mitochondrial toxicity associated with NRTI have been observed particularly during therapy with d4T. Symptoms include fatigue, shortness of breath, weight loss, and lipid abnormalities.174 This syndrome is distinct from rare, potentially fatal lactic acidosis seen during NRTI therapy.

Zalcitabine

Clinical Pharmacology175

Oral bioavailability of zalcitabine (ddC) in adults is approximately 85%. AVD is 0.6 L/kg. Plasma t½ is 1.5 hours (range, 1.1 to 1.8 hours), and elimination is a first-order process. Urinary excretion of unchanged drug is the principal route of elimination, accounting for 62% to 75% of a dose. Approximately 10% of a dose is excreted unchanged in feces.

Renal clearance is decreased in the presence of renal dysfunction, suggesting a need for dose reduction in such patients. Doses of ddC should be reduced from 0.75 mg three times daily to 0.75 mg twice daily in adult patients with creatinine clearance of 10 to 40 mL/min and 0.75 mg once daily in those with creatinine clearance lower than 10 mL/min.

Apart from 25% reduced bioavailability when given with aluminum and magnesium hydroxide, no important drug interaction has been described.

Adverse Drug Reactions

Peripheral neuropathy occurs with a frequency up to 12%, pancreatitis in 1%, and ulcerative stomatitis in 0.2%. Anemia and neutropenia occurred in 6% to 8% of ddC recipients versus 6% to 9% of ddI recipients in one study.

The peripheral neuropathy is dose related and generally reversible with discontinuation of treatment.

Tenofovir

Tenofovir disoproxil fumarate is an acyclic nucleotide analogue of adenosine monophosphate that acts as an HIV RT inhibitor.176,177

Mechanism of Action

Unlike NRTIs such as AZT, tenofovir only undergoes two catalytic steps to convert it to its active antiviral molecule, tenofovir. Tenofovir inhibits RT and causes DNA chain termination on being incorporated into the elongating chain.

Clinical Pharmacology

Only an oral formulation is available. A high-fat meal increases oral bioavailability from 25% to 39%; tenofovir t½ in HIV patients averages 12 hours. Elimination is a first-order process. Drug is eliminated largely (75% of a dose) unchanged into urine. Renal clearance exceeds creatinine clearance, suggesting that glomerular filtration and tubular secretion contribute to tenofovir renal elimination.

As expected, renal impairment decreases tenofovir clearance. In the United States, tenofovir is relatively contraindicated in patients with moderate renal impairment (creatinine clearance <60 mL/min). In Europe, it is considered relatively contraindicated for patients with severe renal dysfunction (creatinine clearance not specified).

Tenofovir is efficiently removed by dialysis; median extraction is 54%. It can be inferred that one-half the dose should be administered after dialysis, but the validity of this inference has not been examined. Tenofovir is relatively contraindicated in patients with creatinine clearance lower than 60 mL/min.

Like the NRTIs, tenofovir is not metabolized by cytochrome P450 isozymes, so no interactions with drugs biotransformed by the isozyme are expected.

The most important drug interaction is a 28% to 44% increase in ddI AUC during concurrent administration. Tenofovir AUC is not affected. The effect is believed to be due to enhanced ddI bioavailability, although the molecular mechanism is unclear.

Adverse Drug Reactions

Tenofovir is generally well tolerated. Adverse symptoms are primarily gastrointestinal, but placebo-controlled trials showed few differences between treatments in the incidence of adverse symptoms: nausea 11% and 10%, diarrhea 9% and 8%, and vomiting 5% and 2% in tenofovir recipients and placebo recipients, respectively, and abdominal pain 3% in both groups. Severe biochemical abnormalities were similarly not different between the tenofovir and placebo groups.

Postmarketing studies have described pancreatitis, lactic acidosis, and several other ADRs during tenofovir therapy.

Overall, tenofovir appears to be a potent, useful addition to the NRTI group of antiretroviral drugs due to its potency and tolerability.

Abacavir

Clinical Pharmacology178

Absolute oral bioavailability at 83% is excellent. Abacavir kinetics are nonlinear at doses smaller than 600 mg/d; however, because the recommended doses exceed this level, nonindependence of kinetics at smaller doses may not be clinically important.

Abacavir undergoes extensive hepatic metabolism, with less than 2% of a dose appearing in urine as parent drug. Metabolism in the liver yields two principal metabolites that are biologically inactive. They are eliminated (83%) into the urine. Plasma t½ is shorter than 2 hours, whereas intracellular t½ of the antiviral metabolite is 3.3 hours, thereby supporting administration two or three times daily.

Abacavir does not undergo substantial metabolism by cytochrome P450 enzymes and no important interactions with other retroviral inhibitors or other drugs have been described.

Adverse Drug Reactions

Hypersensitivity reactions occur in 4% (range, 0% to 7%) of patients given this agent. Manifestations include respiratory symptoms (pharyngitis, dyspnea, or cough), gastrointestinal complaints (nausea, vomiting, diarrhea, or abdominal pain), and skin rash. The reactions usually occur in the first 6 weeks after initiation of therapy (median, 11 days) and can appear within hours of reintroduction of abacavir in patients who interrupted therapy after an uneventful initial course of treatment. The cause is not known, but the scenario fits with the generalized propensity of HIV patients to develop hypersensitivity reactions to sulfonamides and fluoroquinolones. This reaction may be fatal, so abacavir is absolutely contraindicated in a patient diagnosed with a hypersensitivity reaction to it.

Overall, abacavir is a useful NRTI for combination therapy. Intensivists restarting abacavir in patients in the ICU must be aware of the small but definite risk of the hypersensitivity reaction.

Non-Nucleoside Reverse Transcriptase Inhibitors

Three non-nucleoside RT inhibitor (NNRTI) drugs are currently marketed: delavirdine, nevirapine, and efavirenz. All NNRTI, unlike NRTI, agents act directly to inhibit RT. They do not require intracellular phosphorylation, as do NRTIs, to generate antiviral molecules. The NNRTIs bind at a hydrophobic site close to the RT catalytic site and cause conformational change in the enzyme, whereas NRTIs bind to the catalytic site. The NNRTIs are noncompetitive inhibitors of RT, whereas NRTIs are competitive inhibitors. NNRTIs also inhibit HIV replication by inactivating RT, whereas NRTIs cause chain termination as their second antiviral mechanism of action.

NNRTIs differ structurally, so cross-allergenicity does not occur. Nonetheless, rash is a common adverse effect of all currently licensed members of the class and represents the major adverse effect of the NNRTI drugs. Most cases are mild and not life-threatening. Although the mechanism of rash is not known, “… most experts do not recommend use of any NNRTI in a patient who has had a severe hypersensitivity reaction to one of the drugs.''179,180

All NNRTIs are approved for treatment of HIV infection in combination with other HIV-inhibitor drugs. Although nevirapine monotherapy was reported to be more effective than AZT to prevent HIV transmission from infected pregnant women to their neonates, it is not approved for that indication. A mutation in the RT gene at amino acid 103 can cause 20-fold decreased susceptibility to all NNRTIs.

From the point of view of their clinical pharmacology, they demonstrate different capacities to interact with a host of other compounds catabolized by hepatic cytochrome P450 isozymes and cause clinically important interactions. As a class, all NNRTIs are cleared primarily by the hepatic cytochrome P450 isozyme CYP 3A4, although other isozymes may contribute (efavirenz is also cleared by CYP 2B6 and delavirdine, possibly by CYP 2D6). Concomitant administration of other drugs has resulted in a range of interactions extending from asymptomatic reduction in clearance (demonstrated as increased AUC) to fatal adverse effects. Accordingly, caution always must be exercised in co-prescribing other drugs cleared by the liver and in some cases should be avoided. The following drugs are contraindicated in patients receiving delavirdine or efavirenz:

The clearance of many other drugs that are also metabolized by hepatic CYP 3A4 and other isozymes may be altered during concomitant therapy with NNRTI agents. Effects of the interactions are less predictably serious than those for the agents listed above, so they are considered to be only relatively contraindicated.180

The following review focuses on clinical pharmacologic characteristics and adverse reactions that are deemed important for intensivists to be aware of as they consider prescribing these drugs to ICU patients.

Delavirdine

Clinical Pharmacology180,181

Only an oral formulation is available. Oral bioavailability is 85%. Antacids and gastric hypoacidity due to inhibition of gastric acid secretion or disease decrease oral bioavailability by approximately 50%. The AVD is about 65 L. Delavirdine is highly protein bound (∼98%), mainly to albumin, so drug–drug interactions due to displacement of other highly bound drugs such as warfarin or phenytoin can occur. It is almost completely metabolized by hepatic cytochrome P450 isozymes CYP 3A (major) and CYP 2D6 (minor). Less than 5% of a dose is eliminated into urine. Half the metabolites appear in urine and half in feces, presumably with bile.

Delavirdine elimination is dose dependent and not first order as demonstrated by an increase in plasma t½ from 2.4 to 4.1 hours as dose is increased from 200 to 400 mg three times daily.

Due to its extensive biotransformation by cytochrome P450 isozymes, delavirdine interacts with a wide range of drugs given concurrently because similar biotransformation is a common route of elimination for many agents.

Adverse Drug Reactions

Delavirdine is generally well tolerated in combination therapy for HIV. The most common adverse effects are skin rash (38% vs. 5% for AZT or ddI), headache (24% vs. 15%), nausea (15% vs. 5%), and pruritus (10% vs. 7%).

Skin rash is usually a pruritic erythematous maculopapular eruption that appears 7 to 15 days after initiation of therapy. Rash does not resolve more rapidly with discontinuation of delavirdine. Severe or life-threatening rash (e.g., Stevens-Johnson syndrome) has rarely been reported (1 case per 1000).

Clinical and biomedical hepatotoxicities have not been observed more frequently in delavirdine-treated patients than in recipients of control HIV treatment.

Nevirapine

Clinical Pharmacology

Nevirapine is currently available as an oral formulation, and its bioavailability exceeds 90%.182,183 It is lipophilic and thus distributes widely. AVD is 1.4 to 1.5 L/kg body weight in adults. The ratio of CSF to plasma is 29%.

The principal route of elimination is by hepatic biotransformation followed by renal excretion. Only 3% is excreted as the parent compound in urine. Nevirapine hydroxylation and glucuronidation of metabolites are catalyzed by cytochrome P450 isozymes, primarily CYP 3A4 and CYP 2B6. The elimination t½ decreases over 2 weeks due to autoinduction of metabolism: plasma t½ after initial doses averages 40 hours and then 20 to 30 hours 2 weeks later. This well-described phenomenon underlies the strategy of giving 200 mg daily for 2 weeks followed thereafter by 200 mg twice daily in adults.

When administered to pregnant women to prevent neonatal HIV infection, its pharmacokinetic characteristics in women in the third trimester are not different from those in nonpregnant women. However, if initiated in labor, its kinetic characteristics are significantly altered. Systemic clearance increases on average by 30%, AVD doubles on average, AUC decreases by 15%, and t½ increases by 70%. The drug readily crosses the placenta as demonstrated by high concentrations in cord blood. Breast milk concentrations average 61% of maternal blood concentrations, but the total amount of drug delivered to the baby is small if given to the woman during labor.

Nevirapine not only induces its own metabolism but also has the potential to interact with a wide range of other drugs also catabolized by CYP 3A4 and CYP 2B6 isozymes (see above).

Nevirapine pharmacokinetic features have not been described in patients with renal or hepatic impairment. However, because less than 5% of the drug is excreted into urine as the active parent compound, it is unlikely that nevirapine disposition is significantly affected by renal impairment or that dose reductions are required to minimize toxicity. Pre-existing hepatic impairment is likely to affect nevirapine clearance, so caution is recommended when nevirapine is administered to patients with moderate to severe hepatic dysfunction; no specific dose recommendations have been provided by the manufacturer.

Adverse Drug Reactions

The most common ADR is rash, observed in approximately 17% of adults, usually within 6 weeks of initiation of therapy. The rash is usually an erythematous maculopapular eruption of mild to moderate severity. It may be treated with antihistamines or topical glucocorticoids.

In 6% of patients, the rash is severe enough to necessitate discontinuation of therapy. In 0.5%, it progresses to Stevens-Johnson syndrome.

Uncommonly (<5% of patients), nausea and elevated hepatic enzymes are observed. Although uncommon, hepatitis and fatal hepatic necrosis have been associated with nevirapine use. The manufacturer therefore recommends intensive monitoring in the first 8 to 12 weeks of nevirapine therapy to detect the earliest manifestation of severe and life-threatening skin rash or hepatitis. “Intensive'' monitoring of liver function tests during this period is recommended without specification of an exact frequency. In the ICU setting, once-weekly testing seems reasonable.

Efavirenz

Clinical Pharmacology184

Efavirenz is administered orally once daily. Absorption increases with increasing doses from 100 to 1600 mg but not proportionately, suggesting a saturable mechanism or process. A fatty meal increases AUC by 50%. Most of a dose (16% to 61%) is eliminated in feces as unchanged drug, 14% to 34% in urine as metabolites, and less than 1% in urine as unchanged drug. The drug is 99.5% bound to human plasma protein, so interaction due to displacement of other highly bound drugs with a narrow therapeutic:toxic ratio may cause clinically significant effects (e.g., warfarin and phenytoin).

Efavirenz crosses the blood-brain barrier, but CSF concentrations are 0.26% to 1.19% of plasma levels, suggesting minimal diffusion. It is metabolized in the liver, predominantly by cytochrome P450 CYP 3A4 and 2B6 isozymes, as is the case for nevirapine. The t½ is 40 to 55 hours at steady state.

Efavirenz pharmacokinetic features have not been rigorously studied in patients with renal or hepatic impairment. However, because less than 5% of efavirenz is excreted unchanged into urine, it is unlikely that renal dysfunction would cause significant accumulation of the pharmacologically active parent molecule. Conversely, efavirenz probably should be decreased in patients with significant hepatic dysfunction. However, no validated dose recommendations are available and therapeutic drug monitoring is not practicable. Caution in this circumstance is recommended.

Adverse Drug Reactions

Neurologic symptoms are the most common side effect. Headache, dizziness, insomnia, and fatigue were reported by 48% and 54% of patients receiving efavirenz plus indinavir or AZ T plus 3TC, respectively. Rash was the second most common side effect, being reported by 10% and 15% of subjects receiving efavirenz plus AZT and 3TC or indinavir, respectively. Neurologic and dermatologic ADRs with efavirenz tend to be mild to moderate in severity. Rashes may respond to antihistamines and topical corticosteroids, and neurologic symptoms may be decreased by drug administration at bedtime.

Protease Inhibitors of HIV

Six protease inhibitors of HIV have recently been licensed for combination therapy of HIV-1 infection: saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, and lopinavir. These agents inhibit HIV replication by preventing cleavage of polyprotein precursors essential for synthesis of progeny virions. Protease inhibitors used in combination with other retrovirus inhibitors have produced the most marked and sustained reductions in HIV plasma concentrations observed to date. They are generally active against strains sensitive and resistant to NRTI and NNRTI, and cross-resistance is not uniform. The durability of this effect and the effectiveness of these drugs in patients measured by clinical and laboratory end points, and their efficacy in patients with advanced HIV-1 disease are substantial.

The protease inhibitor drugs, like the NNRTIs, are cleared primarily by transformation to inactive metabolites by the hepatic cytochrome P450 CYP 3AP isozyme. In addition, they may be substrates for one or more isozymes: lopinavir is also catabolized by CYP 2D6, whereas ritonavir also is a substrate for CYPs 2C9, 2C19, 2A6, 1A2, and 2E6. Not surprisingly, ritonavir interacts with a wide variety of other drugs administered concurrently. As noted for the NNRIs, the same list of drugs considered contraindicated in patients receiving one of those three agents should be considered contraindicated in patients receiving a protease inhibitor agent.

The protease inhibitor agents cause a variety of adverse effects, of which one collection of metabolic or endocrine effects appears to be a common class effect: hyperglycemia with a diabetogenic effect, adipogenic effects, hyperlipidemia and hypercholesterolemia, and spontaneous bleeding episodes.191

Saquinavir185

Mechanism of Resistance

Decreased sensitivity to saquinavir does not occur readily in vitro or in treated patients. In vitro, saquinavir resistance is associated with mutations at amino acid 90 (more common; leucine to methionine) or at amino acid 48 (less common; glycine to valine). In patients treated with saquinavir alone, 45% had saquinavir-resistant phenotypes at 1 year, which did not differ from the incidence in patients treated with saquinavir plus AZT or ddC. However, the three-drug combination of saquinavir with ddC and AZT seemed to restrict emergence of resistance to AZT and saquinavir (to 22%).

Saquinavir-resistant HIV strains do not appear to be cross-resistant to indinavir or ritonavir.

Clinical Pharmacology

Saquinavir is poorly bioavailable, with less than 1% of oral doses being absorbed under fasting conditions. Food enhances saquinavir absorption to about 30%, but only 4% reaches the systemic circulation owing to extensive first-pass metabolism. Saquinavir partitions extensively into tissues as demonstrated by an AVD of 10 L/kg body weight.

Saquinavir is extensively metabolized by the hepatic microsomal cytochrome P450 system into a number of inactive hydroxylated compounds. These are secreted into the bile and, hence, into the feces. Less than 5% is excreted into urine. Mean residence time is 7 hours. Doses need not be adjusted for patients with mild to moderate renal or hepatic insufficiency; in those with severe hepatic or renal disease, the drug should be prescribed with caution.

Adverse Drug Reactions

Saquinavir is well tolerated. Diarrhea, abdominal discomfort, nausea, and dyspepsia occur in 2% to 4% of saquinavir recipients and in 2% to 3% of recipients of saquinavir plus ddC or AZT. Nervous system side effects such as headache, dizziness, and myalgias occur with low (1% to 3%) frequency at similar rates in saquinavir recipients and recipients of saquinavir plus ddC or AZT. Adverse symptoms are generally mild. Studies have indicated that saquinavir does not alter the rate or severity of adverse effects from AZT or ddC; this finding correlates with studies finding no pharmacokinetic interactions during combination therapy.

Ritonavir186,187

Mechanism of Resistance

Decreased HIV sensitivity to ritonavir appears to develop at a rate similar to that of saquinavir, although only limited data are available. Genotypically, ritonavir-resistant HIV-1 strains have changes at amino acids 54, 71, and 84. These alterations are distinct from those associated with saquinavir resistance. Clinically, waning of the antiviral effect of ritonavir monotherapy was observed beginning at 4 weeks and was inversely related to dose. In those receiving the largest dose, 600 mg twice daily, mean reductions in plasma HIV-1 RNA concentration were 15-fold at 4 weeks (maximal) and sixfold at 32 weeks. In recipients of 300 or 400 mg twice daily, mean concentrations at 32 weeks did not differ from pretreatment levels. Ritonavir potency when used alone appears to be similar to that of indinavir or AZT combined with 3TC and greater than that observed with saquinavir alone.

Ritonavir-resistant strains are not uniformly cross-resistant to indinavir and saquinavir.

Clinical Pharmacology

Ritonavir is well absorbed and produces high concentrations in serum that exceed the minimum inhibitory concentration despite 90% serum protein binding. The serum t½ is 3 to 4 hours. Elimination is primarily by hepatic metabolism.

Adverse Drug Reactions

Given alone, ritonavir caused adverse effects including nausea, vomiting, diarrhea, asthenia, and circumoral and peripheral paresthesias and altered taste in 5% to 26% of subjects compared with 1% to 6% in placebo recipients. Greater than twofold increases in serum concentrations of triglycerides, creatinine phosphokinase, and transaminases were observed in 6% to 15% of ritonavir recipients and in 1% to 7% in placebo recipients. These appear to be independent of dose, being observed in more than 85% of recipients receiving ritonavir 600 to 1200 mg/d. The mechanism of the elevated triglyceride level is not clear but does not appear to be caused by pancreatitis.

Many drugs interact with ritonavir because of metabolism by the same common pathway involving hepatic cytochrome P450 isozymes. At least 25 drugs are considered to be contraindicated in patients receiving ritonavir.188 Ritonavir should be administered with caution and appropriate monitoring due to pharmacokinetic interactions: ritonavir causes a large increase in the AUC of the coadministered drug (AUC increase greater than three- to fourfold; 33 drugs), a moderate increase (1.5-fold to threefold increase; 39 drugs), a moderate increase or decrease (17 drugs), or a possible decrease in AUC (19 drugs).188

Indinavir Sulfate189

Mechanism of Resistance

Resistance to indinavir was observed in 43% of individuals receiving the recommended dose of 2.4 g/d after 24 weeks of therapy compared with 65% receiving only AZT and 18% receiving indinavir plus AZT. These initial data suggest that resistance to indinavir appears at a slightly slower rate than resistance to ritonavir during monotherapy and that combined therapy with AZT decreases the rate of emergence of indinavir resistance. Indinavir resistance is directly associated with cumulative amino acid mutations in as many as 11 RT sites.

Indinavir-resistant HIV-1 strains are cross-resistant to ritonavir and variably resistant to saquinavir.

Clinical Pharmacology

Indinavir is readily absorbed, although large meals reduce absorption by 75% judging by reduction in AUC. Less than 10% of a dose is excreted unchanged in urine. The majority of the drug undergoes metabolism before elimination in feces and urine. The serum t½ is 1.8 hours in subjects with normal renal and hepatic functions. In patients with mild to moderate hepatic insufficiency, the t½ almost doubles. The effects of severe hepatic disease or renal insufficiency have not been studied. Penetration into CSF has not been described.

Adverse Drug Reactions

Indinavir is generally tolerated as well as, or better than, AZT or ritonavir. Nephrolithiasis with flank pain and hematuria occurs in 4% of patients, and asymptomatic indirect hyperbilirubinemia occurs in 10%. Other ADRs include abdominal pain (9% vs. 5% AZT alone), fatigue (4% vs. 8% AZT alone), diarrhea (5% vs. 2% AZT alone), and insomnia (3% vs. 0% AZT alone).

Phlebitis owing to the alkaline pH of the solution also has been reported.

Nelfinavir

Clinical Pharmacology190

Oral nelfinavir is 70% to 80% bioavailable when administered with food. Bioavailability is 50% to 73% less when administered in a fasting state. AVD is 2 to 7 L/kg. Plasma protein binding is high at 98%, primarily to α1-acid glycoprotein.

Nelfinavir is metabolized in the liver by cytochrome P450 isozymes CYP 3A4, 2C9, 2C19, and 2D6. Elimination is primarily by fecal (biliary) excretion of a hydroxylated metabolite (78%); 22% of drug excreted in feces is unchanged drug, and 1% to 2% of nelfinavir is excreted in urine as unchanged drug. Plasma t½ is 3.5 to 5 hours.

The pharmacokinetic characteristics of nelfinavir have not been described in patients with renal or hepatic impairment. Less than 2% of nelfinavir is excreted into urine as unchanged drug, so renal dysfunction is unlikely to significantly affect the pharmacodynamics of the active parent compound. Because the drug is primarily inactivated in the liver, caution is recommended when it is administered to patients with hepatic impairment, but the manufacturer provides no specific dose recommendations.

Adverse Drug Reactions

Nelfinavir is generally well tolerated, but ADRs were severe enough to necessitate treatment discontinuation in 1.5% to 4% of 690 subjects in controlled trials. A retrospective comparison suggested nelfinavir tolerability exceeds that of indinavir, saquinavir, or amprenavir.

Diarrhea is the commonest ADR but is generally mild to moderate in severity and usually can be controlled with drugs that decrease gastrointestinal motility (e.g., loperamide). Diarrhea of moderate to severe intensity was reported by 20% of recipients of nelfinavir with AZT and 3TC compared with 3% in recipients of AZT and 3TC alone. A comparison of ADRs concluded that nelfinavir has better gastrointestinal tolerability than indinavir, saquinavir soft gel capsules, or ritonavir in causing only diarrhea (26% incidence) and nausea (5% incidence) but no vomiting, dyspepsia, abdominal pain, or taste perversion.191

Amprenavir

Clinical Pharmacology192,193

From 35% to 90% of an oral dose of amprenavir is absorbed. AUC increases proportionally to dose over the range of 300 to 1600 mg (the therapeutic adult dose is 1200 mg twice daily). The drug is 90% bound to plasma proteins; α1-acid glycoprotein is the principal amprenavir binding protein. AVD is said to be 430 L in adults, suggesting sequestration in tissues outside the plasma compartment.

Elimination is by hepatic cytochrome P450 isozymes, primarily CYP 3A4. The plasma elimination t½ is 7 to 11 hours, which is the longest for any of the licensed protease inhibitors. Amprenavir is excreted predominantly as metabolites into feces (75%) and urine (14%). Hence, amprenavir pharmacokinetics would not be expected to be affected by renal impairment. Clearance is decreased as the severity of cirrhosis increases (Child-Pugh score). The manufacturer recommends caution in the use of amprenavir in such patients, without recommending specific dose reductions.

Adverse Drug Reactions

The most common adverse reactions observed in two controlled trials involving 358 patients who received highly active antiretroviral therapy (HAART) including amprenavir were nausea (15%), diarrhea (14%), rash (11%), and vomiting (5%). In a controlled trial in which all subjects received AZT plus 3TC with amprenavir or its placebo, the incidence of all the aforementioned complaints was 20% to 100% less in the placebo recipients. Grade 3 or 4 increases in alanine aminotransferase and/or aspartate aminotransferase and neutropenia also were more common in amprenavir than placebo recipients (5% vs. 3% and 5% vs. 0%, respectively).

Lopinavir

Clinical Pharmacology194,195

Lopinavir is marketed as a soft gel capsule containing 133.3 mg lopinavir and 33.3 mg ritonavir. The absolute bioavailability of lopinavir-ritonavir has not been established. Compared with ingestion in a fasting state, administration of lopinavir-ritonavir capsules with a moderately fat meal (23% to 25% fat) or high fat meal (56% fat) increased lopinavir AUC by 48% or 97%, respectively.

Lopinavir is 98% to 99% protein bound in human plasma, more to α1-acid glycoprotein than to albumin. AVD has not been described.

Lopinavir is catabolized by hepatic cytochrome P450 isozymes, primarily CYP 3A4. This process yields metabolites with relatively little antimicrobial activity. Ritonavir is a potent inhibitor of CYP 3A4, which inhibits lopinavir metabolism and thereby increases lopinavir AUC. A study using isotope-labeled lopinavir reported that 89% of the plasma radioactivity after a single oral dose of isotope-labeled lopinavir with unlabeled ritonavir (400/100 mg) was parent lopinavir compound. The AUC of lopinavir (100 to 800 mg) increases greater than 100-fold when coadministered with ritonavir 50 to 200 mg. Lopinavir plasma t½ was 5.8 hours at steady state during treatment with lopinavir-ritonavir 400 and 100 mg twice daily. After a single dose of the same mixture, 10% and 83% of isotope-labeled lopinavir was recovered in urine and feces, respectively, over 8 days. Unchanged lopinavir accounted for about 2% and 20% of drug in urine and feces, respectively.

Lopinavir pharmacokinetics have not been studied in patients with renal impairment, but no or perhaps trivial effect of renal insufficiency is anticipated.

Lopinavir-ritonavir disposition has not been studied in patients with hepatic impairment, but decreased clearance of both would be expected. In such patients the manufacturer recommends caution in the administration of lopinavir-ritonavir but has provided no specific dose guidelines.

Other drug interactions due to lopinavir and/or ritonavir inhibition on CYP 3A4 are to be expected during concurrent therapy. A list of drugs that could be affected has been published.188

Adverse Drug Reactions

In controlled trials involving 612 patients receiving HAART and including lopinavir-ritonavir or nelfinavir, the drug was generally well tolerated. ADRs necessitated discontinuation of lopinavir-ritonavir in 3% of patients in the groups treated with lopinavir-ritonavir and nelfinavir.

The most common ADR in lopinavir-ritonavir recipients was diarrhea (14%), which occurred with the same frequency in recipients receiving nelfinavir, d4T, and 3TC. In lopinavir-ritonavir recipients given therapy for another 48 weeks, diarrhea was reported by 24% of patients. Grade 3 or 4 increases in alanine aminotransferase and/or aspartate aminotransferase were observed in fewer than 1% of lopinavir-ritonavir recipients compared with 2% to 2.5% of subjects receiving nelfinavir, d4T, and 3TC. The rates of neutropenia at 24 weeks were 0.6% and 1.6% in the two groups, respectively.

Despite its inherent toxicity and the continuing development of new, potent, better tolerated imidazole antifungal drugs, amphotericin B administered alone or in combination with another antifungal agent remains the standard therapy for serious systemic mycoses. Although the arbitrary distinction between antifungal drugs used exclusively for topical therapy of superficial infection or for treatment of mycotic infections of viscera (deep mycoses) is becoming blurred with the development of the newer imidazoles, this discussion is limited to those agents that are licensed for therapy for deep mycoses:196 amphotericin B, 5-fluorocytosine, some of the imidazoles (ketoconazole), structurally related N-substituted triazoles (fluconazole, itraconazole, and voriconazole), and an echinocandin (caspofungin).

Amphotericin B

(See ref. 197.) Amphotericin B is an antifungal antibiotic produced by Streptomyces nodosus. It exhibits amphoteric behavior, forming relatively soluble salts in basic or acid aqueous media, but is extremely insoluble in aqueous solutions at physiologic pH. Accordingly, for clinical use, amphotericin B is formulated for intravenous administration as a colloidal suspension by using the bile salt deoxycholate and sodium phosphate buffer. Recently, interest was focused on the formulation of amphotericin B with lipids to decrease its toxic effects.198 Three lipid-associated amphotericin B preparations are currently on the market.199 AmBisome is a true liposomal suspension consisting of vesicles comprising a phospholipid bilayer stabilized with cholesterol resulting in an intravesicular hydrophilic and external hydrophobic environment. The amphipathic character of amphotericin B makes it ideal for entrapment in those liposomes. Abelcet consists of a suspension of 1600- to 11,000-nm ribbon-like bilayers in which the amphotericin B is trapped. Amphocil consists of a colloidal dispersion of amphotericin embedded in 120- to 140-nm disks of cholesteryl sulfate.

In vitro susceptibility testing of fungi and yeasts, as with viruses, remains an inexact science. Although improvements are being made in all facets of standardization of techniques and interpretation,200 published data from different laboratories are difficult to compare. Notwithstanding this fact, there is general agreement that an inverse relation exists between concentrations of antifungal agents required to inhibit growth in vitro and their therapeutic efficacy. The following yeasts and fungi have MIC values below 1 mg/L to amphotericin B and are considered highly sensitive to this drug: Cryptococcus neoformans, Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, Sporotrichum schenckii, Candida albicans, Paracoccidiodes brasiliensis, and the zygomycoses (Mucor, Rhizopus, Absidia, and Cunninghamella). Aspergillus species are usually sensitive. The causative agents of chromomycosis (Phialophora species and Cladosporidium carrionii) are usually resistant to amphotericin B alone but can be effectively inhibited by amphotericin B in combination with 5-fluorocytosine. Prototheca species, which cause chronic persistent granulomatous skin and visceral infections, are usually sensitive to amphotericin B.

Combining amphotericin B with certain antibacterial drugs such as rifampicin and tetracycline in vitro yields additive or synergistic antifungal effects, owing to enhanced penetration of the fungal cell by these two inhibitors of protein synthesis, because of enhanced permeability caused by amphotericin B. However, data from studies of animals with experimental fungal infections do not suggest a consistent, predictable, additive or synergistic effect of the combinations sufficient to warrant their use in patients.

Studies of amphotericin B combined with other selected antifungal agents in vitro, in animals with experimental fungal infections and some patients, have demonstrated effects that are at least additive. Amphotericin B with 5-fluorocytosine is at least additive in vitro and in animals with experimental candida and cryptococcal infections. This has permitted the use of smaller doses of amphotericin B with lesser attendant toxicity in patients with cryptococcal meningitis and perhaps candidal meningitis and arthritis. In a murine model of systemic aspergillosis, these two drugs produced better results than either agent administered alone, and some clinicians recommend their combined use in patients with serious aspergillus infection, especially with significant immunosuppression.

Results have been conflicting when amphotericin B is combined with imidazole antifungal drugs. Indifference, synergy, and antagonism have been observed in studies in vitro and in vivo in animals with experimental mycoses. In view of the unpredictable effects of combining imidazoles and amphotericin, intensivists should be careful about the use of combined therapy in ICU patients.

Specific recommendations for the treatment of deep mycoses are found in Chaps. 46, 49, and 50. Amphotericin B alone is the drug of choice for some C. albicans infections (esophagitis, peritonitis complicating peritoneal dialysis, fungemia, and endophthalmitis), coccidioidomycosis (progressive pulmonary infection and meningitis), histoplasmosis, zygomycoses, and sporotrichosis (systemic, articular, or pulmonary). Amphotericin B combined with 5-fluorocytosine is recommended for therapy of cryptococcal meningitis or disseminated infection especially in the immunocompromised host, systemic candidiasis except as noted above, Candida (formerly Torulopsis) glabrata endocarditis, invasive aspergillosis, and chromomycosis.

To date, no unambiguous proof of consistently enhanced efficacy of any lipid-associated amphotericin B formulations compared with the standard colloidal suspension in desoxycholate solution has been reported. Overall, at this time, it appears that lipid-associated amphotericin B formulations require larger doses to achieve comparable therapeutic benefits and cause fewer of the significant adverse effects of colloidal amphotericin B, namely hypokalemia, nephrotoxicity, and infusion-related reactions.

Mechanism of Action

The antifungal action of amphotericin B is complex and largely dependent on its interaction with sterols, primarily ergosterol, in the cytoplasmic membrane of sensitive fungi. The drug appears to form channels or pores that lead to leakage of essential metabolites and, eventually, lysis of the cell. In low concentrations, the effect is reversible and the result is inhibition of fungal cell growth. However, at higher concentrations, the effect is irreversible; hence, the drug is fungicidal.

Amphotericin B potentiates the antifungal effect of 5-fluorocytosine and other agents by enhancing their entry into fungal cells.

Mechanism of Resistance201

Natural and acquired resistances to amphotericin B during therapy with clinical failure have been considered to be uncommon and not a clinical problem. However, in one survey, 7% of 747 strains of C. albicans, Candida tropicalis, and C. glabrata were resistant to amphotericin B. Resistance was observed only in isolates obtained from oncology patients. These data suggest, contrary to general opinions, that resistance may not be uncommon and that selection pressure from extensive amphotericin B use in granulocytopenic oncology patients may contribute to resistance development. It is postulated that a major reason that C. albicans resistance to amphotericin B antibiotics is uncommon is because it lacks a haploid sexual stage in its life cycle. Thus, the frequency of mutational events that will alter the specific locus where amphotericin B acts will be low. This would also explain the higher frequency of resistance observed with C. glabrata, which is haploid.

Clinical Pharmacology

Absorption of amphotericin B after oral administration is negligible. Amphotericin B may be administered intravenously, intrathecally, intra-articularly, instilled into the infected urinary bladder, and in dilute solution into the peritoneal cavity of patients with fungal peritonitis.

After intravenous infusion, the drug dissociates from deoxycholate in the blood, binds extensively (90%) to plasma proteins (mostly β lipoprotein), and distributes widely throughout the body but not into CSF or the vitreous humor. Even in patients with cryptococcal meningitis, amphotericin B concentrations in CSF were less than 10% of serum values. The AVD is 4 L/kg but with wide variation. This is consistent with the observed, extensive binding of biologically active amphotericin B in tissues, particularly to sterols in hepatocytes and erythrocytes, in which the concentration is up to 30 times greater than in plasma. The Cp of amphotericin B declines in a biexponential manner after intravenous infusion. There is an initial phase of rapid decline, with t½ of 24 to 48 hours and a slow terminal phase of 15 days. Kinetically, this biphasic pattern is consistent with amphotericin B infusion into a central compartment and its equilibration rapidly into two peripheral compartments. The rapid decline in plasma amphotericin B represents equilibration into the former, and the phase of slow decline represents the slow release of amphotericin B back into the central compartment from which it was eliminated.

Approximately 2% to 5% of a dose is recovered as unchanged drug in the urine. From 16% to 94% (median, 33%) of injected doses can be recovered unchanged by extraction of tissues. The remainder is assumed to be metabolized, but data are not available on this aspect of its disposition. Blood levels are unaffected by hepatic or renal failure. Dose modifications are not required in patients with renal failure to compensate for any effect of oliguria on amphotericin B disposition, but doses may be decreased to mitigate further nephrotoxic effects of the drug. Hemodialysis does not enhance amphotericin B clearance, so such patients do not require alterations in the standard dose. At steady state, plasma amphotericin B concentrations after infusion of 0.5 mg/kg are 1.0 to 1.5 mg/L, with reduction to 0.5 to 1.0 mg/L 24 hours later. Hyperlipidemic and dyslipidemic states, such as occur in animals with uncontrolled experimental diabetes, alter the distribution of amphotericin B, with reduced liver and kidney concentrations, diminished nephrotoxicity, and reduced clearance, associated paradoxically with a fourfold increase in apparent volume of distribution. The clinical implications of such altered disposition of amphotericin B remain to be elucidated.

The disposition of amphotericin B administered other than intravenously has not been extensively studied. Limited data on the decline in amphotericin B concentrations in CSF after instillation of drug into the lumbar sac or cerebral ventricle have been published. Intrathecally administered amphotericin B (0.3 mg) produces peak concentrations of 0.6 to 0.8 mg/L, which decline to 0.2 to 0.3 mg/L after 24 hours. Amphotericin B injected into a cerebral ventricle (0.5 mg) yielded mean ventricular CSF concentrations of 1.7, 0.27, and 0.16 mg/L at 4, 24, and 48 hours, respectively, after injection. For treatment of yeast peritonitis in renal failure patients undergoing chronic dialysis, amphotericin B is diluted to yield a final dialysate concentration of 1 mg/L. Between dialysis sessions, 25 mg amphotericin B is instilled in 250 mL 5% dextrose in water solution, with 25 mg hydrocortisone every 48 hours. With this regimen, peritoneal fluid predose concentration increased from 1.6 to 2.2 mg/L, and concentrations 4 hours after instillation increased from 2.5 to 3.6 mg/L. Concurrent serum amphotericin B concentrations were 15% to 33% as high. These data suggest amphotericin B is sequestered in the peritoneal cavity because the diluent solution is absorbed and that little diffuses into serum.

The clinical pharmacokinetic features of liposome-encapsulated amphotericin B also have not been well studied. In mice and rabbits, liposomal amphotericin B distribution was primarily to organs rich in reticuloendothelial cells, including liver, spleen, and bone marrow. A pharmacokinetic study in mice reported a reduced area under the serum concentration-time curve for liposomal compound compared with colloidal amphotericin B. It was suggested that liposomal amphotericin B is sequestered in tissues until the vesicles are removed from the circulation by phagocytic cells in the liver and other organs.

Adverse Drug Reactions

The inherent toxicity of amphotericin B is demonstrated by a high frequency of adverse effects whether the drug is administered intravenously or by any other route. This propensity to cause side effects is compounded by the need, in most patients, for prolonged therapy.

Some patients may tolerate full intravenous doses of amphotericin B without difficulty, but immediate and long-term side effects frequently necessitate dose reductions or interruptions in therapy. Acute intolerance manifested by fever, chills, malaise, muscle and joint pain, nausea, vomiting, and hypotension often begins within 1 to 2 hours after initiation of therapy and lasts 2 to 4 hours. The observation that liposomal encapsulation of amphotericin B decreases production of proinflammatory cytokines by phagocytic cells is consistent with the lesser propensity of lipid-associated amphotericin B to cause infusion-related toxicity. Antipyretic, antiemetic, and antihistaminic drugs may provide some symptomatic relief, but controlled trials have provided little support for these practices.

Therapy should be initiated with a test dose of 1 mg in 20 mL 5% dextrose in water infused over 20 to 30 min, followed by a dose of 0.3 mg/kg infused over 2 to 3 hours. Thereafter, to minimize infusion-associated adverse effects, the dose should be gradually increased, if the acuity and severity of the illness permits, to the usual dose of 0.5 mg/kg per day. The maximum recommended dose is 1.5 mg/d. However, there is no proof from controlled trials that this regimen decreases infusion-related adverse effects, at least one of which was observed in 71% of patients in one large survey.202 No more effective in preventing infusion-related toxicity was intravenous administration of amphotericin B in 4 hours versus 1 hour, although toxic reactions occurred sooner with the latter (at approximately 2 to 3 hours vs. 1 to 2 hours, respectively).203

Some prophylactic measures have been demonstrated to be efficacious in controlled trials:

1. Ibuprofen, 10 mg/kg, a potent inhibitor of prostaglandin synthesis, administered orally 30 minutes before initiation of amphotericin B infusion decreased the frequency of chilling from 87% to 49% in placebo recipients.204

2. Hydrocortisone, 25 mg, injected directly into the intravenous tubing at the start of amphotericin B therapy decreased the frequency of fever and chills from 78% to 56% in placebo recipients. However, the severity of chills and the level of fever was not less in the hydrocortisone-treated group. Hydrocortisone 50 mg was possibly more effective than 25 mg (reactions decreased from 36% to 22%). Hydrocortisone 50 mg was not different from pretreatment with 900 mg aspirin plus 50 mg diphenhydramine.205

3. Meperidine in an average intravenous dose of 45 mg (range, 25 to 60 mg) stopped shaking chills induced by amphotericin B in 11 minutes, whereas interruption of amphotericin B resulted in cessation of the reaction spontaneously in an average of 38 minutes (range, 8 to 95 minutes).206

4. In experiments in dogs and patients, pretreatment by infusion of 0.15 M NaCl aqueous solution decreased the nephrotoxic effect of amphotericin B. Administration of 1 L physiologic saline before administration of the daily dose of amphotericin B, where the patient's condition permits, was recommended.207

Nephrotoxicity is the most important adverse effect of amphotericin B therapy. Creatinine clearance decreases by about 40% soon after commencing therapy in all patients and usually stabilizes at 20% to 60% of normal thereafter during continued treatment. The appearance of red and white blood cells, albumin, and casts in the urine usually accompanies the decrease in glomerular filtration rate. Thus, no nonnephrotoxic therapeutic dose of amphotericin B exists. However, evidence indicates that the severity of the renal injury is increased by larger doses, so the manufacturer recommends an absolute limit of 1.5 mg/kg per day. The nephrotoxic effect of amphotericin B appears related to induction of renal vasoconstriction and cortical ischemia. In some patients, amphotericin B causes a syndrome similar to renal tubular acidosis with its attendant risk of nephrocalcinosis and renal failure. Early recognition and alkali therapy may help avert or minimize irreversible renal injury. In about 25% of patients being treated with amphotericin B, hypokalemia and mild to moderate hypomagnesemia from renal potassium and magnesium wasting, respectively, occur and require careful monitoring and replacement.

Amphotericin B administration can be made more convenient by giving 2 days' total dose on alternate days, provided the dose to be infused is less than 1.5 mg/kg. This strategy does not affect efficacy if the alternative dose is twice the daily dose and does not decrease the nephrotoxic ADR. Animal studies demonstrating that intravenous mannitol could attenuate amphotericin B nephrotoxicity were not borne out in a controlled study in patients. Other nephrotoxic drugs such as the aminoglycosides and cyclosporine can add to the adverse effect of amphotericin B on the kidney and should be avoided.

If the patient's serum creatinine level increases from the normal range to 170 mmol/L or higher, amphotericin B should be stopped until the creatinine concentration decreases below that level. However, the severity of the fungal infection may necessitate continuing therapy at a smaller dose despite evidence of mild to moderate renal dysfunction. This appears acceptable because the renal dysfunction usually resolves after completion of a full course treatment unless the total dose exceeds 4 to 5 g.

A reversible normochronic, normocytic anemia occurs in most patients during amphotericin B therapy; the hematocrit frequently declines to stable levels of 22% to 35%. Anemia appears to be due to a suppressive effect of amphotericin B on erythropoietin production. Leukopenia and thrombocytopenia are rarely observed.

Hepatic dysfunction is rare; anaphylaxis and hypersensitivity rashes are uncommon.

Extravasated drug may cause cellulitis. Whether this is caused by the polyene drug or the deoxycholate is unclear. A similar reaction probably accounts for the arachnoiditis commonly observed with intrathecal injection. This chemical meningitis can cause nerve palsies, manifest as difficulty in voiding, impaired vision, paraplegia, and convulsions.

An adverse interaction of amphotericin B with leukocyte transfusion, causing acute dyspnea, hypoxemia, and interstitial infiltrates has been described by one group but challenged by others. However, since amphotericin B can cause polymorphonuclear leukocytes to aggregate in vitro, such an adverse interaction is biologically plausible.

Liposomal amphotericin B has been demonstrated in animals with experimental fungal infections and small numbers of patients208 to have a better therapeutic index than the colloidal formulation available commercially. Both acute infusion-related and chronic renal toxicity side effects were less frequent and severe and liposomal amphotericin B appeared to be effective in patients unresponsive to colloidal amphotericin B. This has been hypothesized to be due to specific, selective delivery of amphotericin B to fungal cells, often in the reticuloendothelial system. However, absence of data from controlled trials comparing results of therapy with liposomal and standard amphotericin B precludes conclusions about the advantages of the liposomal formulation.

Caspofungin

Caspofungin is the first marketed member of a new class of antifungals, the glucan synthesis inhibitors or echinocandins.209

It is approved for the treatment of invasive candidiasis, most commonly fungemic infection, esophageal candidiasis, and invasive aspergillosis in individuals who are refractory to or intolerant of other therapies. Caspofungin is as good as, or superior to, amphotericin B and fluconazole in controlled clinical trials. The usual dose is 50 mg/d infused over 60 minutes. A 70-mg loading dose is administered initially. Treatment is continued to the point of clinical and/or mycologic cure.