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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.
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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.
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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.
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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
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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).
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Mechanisms of Resistance
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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.
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The penicillins can be divided into five classes based on their clinically most important antibacterial activity, notwithstanding substantial degrees of overlap demonstrable in vitro.
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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.
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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.
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Penicillinase-Resistant Penicillins
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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].
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Antipseudomonal Penicillins
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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.
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Extended-Spectrum Penicillins
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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.
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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).
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Clinical Pharmacology
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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.
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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
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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.
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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.
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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.
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Adverse Drug Reactions
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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.
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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.
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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.
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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.
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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.
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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.
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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).
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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.
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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.
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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.
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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.
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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.
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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.
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Mechanism of Resistance
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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.
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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).
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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.
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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.
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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.
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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.
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Clinical Pharmacology
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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:
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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.
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.
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.
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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.
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Adverse Drug Reactions
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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.
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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.
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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.
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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.
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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.
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Carbapenems and monobactams are two new classes of β-lactam antibiotics of importance to intensivists (Table 45-8).
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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.
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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.
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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
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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
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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).
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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.
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Clinical Pharmacology
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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.
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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.
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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.
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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
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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.
++
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
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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.
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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.
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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.
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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.
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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.
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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.
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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
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Until definitive data become available to guide the practice of once-daily administration of aminoglycosides, the following guidelines are recommended:
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Restrict the practice to the prescription of netilmicin, gentamicin, tobramycin, and amikacin.
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.
Doses: netilmicin 6 mg/kg; gentamicin and tobramycin 4 mg/kg; and amikacin 15 mg/kg.
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
Measure aminoglycoside Cp:
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%).
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.
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.
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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.
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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.
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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
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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
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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.
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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)
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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.
++
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.
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Clinical Pharmacology
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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.
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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.
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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
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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.
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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.
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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).
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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.
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Adverse Drug Reactions
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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
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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.
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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.
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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
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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
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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
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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.
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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.
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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.
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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.
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Mechanism of Resistance
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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.
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Overall, these data suggest that teicoplanin may be an alternative to vancomycin for some vancomycin-resistant infections.
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Clinical Pharmacology
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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.
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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.
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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.
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Adverse Drug Reactions
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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.
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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.
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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.
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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.
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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.
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Sulfonamides may be classified as follows:
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Sulfonamides rapidly absorbed and eliminated after oral administration.
Sulfisoxazole is the prototypical agent; sulfamethoxazole and sulfadiazine are other widely used members of this class.
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.
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.
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.
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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.
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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).
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Mechanisms of Resistance
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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
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Clinical Pharmacology
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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.
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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.
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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).
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Adverse Drug Reactions
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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.
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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
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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.
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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).
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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.
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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.
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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.
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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).
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Trimethoprim Combined with Sulfamethoxazole
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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.
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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.
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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.
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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
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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.
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Mechanisms of Resistance
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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.
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Clinical Pharmacology
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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.
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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.
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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.
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Adverse Drug Reactions
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Mechanisms of Resistance
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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
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Clinical Pharmacology
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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.
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Dose reductions are generally unnecessary for healthy elderly patients or patients with mild to moderately severe hepatic disease (Child-Pugh class B).
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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.
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Hypersensitivity reactions are uncommon; urticarial rash with eosinophilia has been reported in 0.5% to 1.0% of patients.
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Rare side effects observed with nalidixic acid that may occur with second-generation quinolones include intracranial hypertension, lactic acidosis, and hemolytic anemia.
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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.
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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.
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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
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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.
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Hypoglycemia has been reported in diabetic patients receiving insulin or glyburide plus fluoroquinolone, so their coadministration must be undertaken with care.
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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.
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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.
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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.
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Metronidazole is rapidly bactericidal by an immediate inhibition of DNA synthesis, but the mechanism of this action has not been fully elucidated.
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Mechanism of Resistance
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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.
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Clinical Pharmacology
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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.
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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.
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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.
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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.
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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.
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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).
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Macrolides, Lincosamides, and Ketolides
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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).
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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.
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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.
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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.
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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.
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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.
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Mechanism of Resistance
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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.
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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.
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Clinical Pharmacology
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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.
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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.
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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.
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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.
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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.
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In some individuals, erythromycin can inhibit elimination of astemizole, terfenadine, methylprednisolone, theophylline, carbamazepine, warfarin, and cyclosporine, with significant clinical consequences.
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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.
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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.
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Bacteria resistant to erythromycin are cross-resistant to clarithromycin and azithromycin.
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Clinical Pharmacology
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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.
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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.
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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.
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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.
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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.
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The following agents interact adversely with erythromycin and warrant prudence during coadministration with clarithromycin and azithromycin: cyclosporin, valproic acid, and phenytoin.
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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
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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.
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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.
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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.
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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.
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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.
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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.
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The mechanism of action of clindamycin is identical to that of erythromycin, and both are bacteriostatic.
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Mechanism of Resistance
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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.
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Clinical Pharmacology
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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.
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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
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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).
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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.
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Hypersensitivity reactions caused by clindamycin occur occasionally. In one study, rash occurred in 10% of patients. Drug fever and eosinophilia have also been reported.
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It is worth reiterating that no cross-allergenicity exists between clindamycin and penicillin.
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Unlike erythromycin, clindamycin does not cause clinically important interactions with other drugs.
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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
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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.
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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.
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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.
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Mechanism of Resistance
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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.
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Clinical Pharmacology
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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.
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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.
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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.
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Less common (0.4%) but more severe side effects included hepatitis, pseudomembranous colitis, and erythema multiforme.
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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.
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Telithromycin may prolong the QT interval when large doses are administered (see below).
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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.
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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
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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.
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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.
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Mechanism of Resistance
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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.
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Clinical Pharmacology
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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.
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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.
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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.
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Severe renal dysfunction (creatinine clearance 6 to 28 mL/min) did not significantly alter quinupristin and dalfopristin kinetics.
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Pharmacokinetic studies in elderly (69 to 74 years) adults or obese patients did not yield clinically important differences from values in healthy male volunteers.
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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).
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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.
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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.
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Conjugated hyperbilirubinemia has been reported in 9% of treated patients, possibly related to competition for hepatocyte biliary secretion.
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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.
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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.
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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).
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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.
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Mechanism of Resistance
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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
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Clinical Pharmacology
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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.
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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.
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Linezolid pharmacokinetic characteristics in subjects with mild to moderate hepatic dysfunction did not differ from those in controls.
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Adverse Drug Reactions
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Linezolid can cause two unusual, clinically important adverse effects, myelosuppression and drug–drug interactions with adrenergic and serotonergic drugs.
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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.
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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.
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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.
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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.