Chapter 2. Antimicrobial Therapy for Head & Neck Infection

A summary of empiric antimicrobial therapy for common conditions encountered in otolaryngology can be found in Table 2–1. In general, when culture and susceptibility data are finalized, it is important to use the narrowest agent possible. This may not only be cost effective in many cases but will also decrease selection pressure for the development of antimicrobial resistance.

Penicllins

Penicillins are a large group of β-lactam antibiotics. All share a common nucleus (6-aminopenicillanic acid) that contains a β-lactam ring, which is the biologically active moiety. The drugs work by binding to penicillin-binding proteins on the bacterial cell wall, which inhibits peptidoglycan synthesis. They also activate autolytic enzymes in the cell wall, resulting in cell lysis and death.

Natural Penicillins

This class includes parenteral penicillin G (eg, aqueous crystalline, procaine, and benzathine penicillin G) and oral formulations (eg, penicillin V).

Adverse Effects

The most common side effect of agents in the penicillin family is hypersensitivity, with anaphylaxis presenting in 0.05% of cases.

Clinical Uses

These drugs are most active against gram-positive organisms, but resistance is increasing. Natural penicillins are still widely used for streptococci, such as in streptococcal pharyngitis; however, 30–35% of pneumococci have intermediate- or high-level resistance to penicillin. They are also used for meningococci, Treponema pallidum and other spirochetes, and actinomyces.

Aminopenicillins

This extended-spectrum group includes ampicillin, which is administered intravenously, and amoxicillin (only oral formulation in the United States). These agents are susceptible to destruction by β-lactamases produced by staphylococci and other bacteria.

Adverse Effects

A maculopapular rash may occur in 65–100% of patients with infectious mononucleosis who are prescribed amoxicillin. This symptom is not a true penicillin allergy.

Clinical Uses

In addition to having the same spectrum of activity against gram-positive organisms as the natural penicillins, aminopenicillins also have some activity against gram-negative rods. Because of its pharmacokinetics, amoxicillin is active against strains of pneumococcus with intermediate resistance to penicillin, but not against strains with high-level resistance; it is therefore a first-line drug for the treatment of sinusitis and otitis.

Penicillinase-Resistant Penicillins

This class includes methicillin, dicloxacillin, and nafcillin. They are relatively resistant to β-lactamases produced by staphylococci.

Adverse Effects

Nafcillin in high doses can be associated with a modest leukopenia, particularly if given for several weeks.

Clinical Uses

These agents are used as antistaphylococcal drugs because they are less active than the natural penicillins against other gram-positives. They are still adequate in streptococcal infections.

Antipseudomonal Penicillins

This class includes the carboxypenicillins, such as ticarcillin (Ticar), and the ureidopenicillins, such as piperacillin (Pipracil).

Clinical Uses

These agents are used primarily for their activity against many strains of Pseudomonas. They also have better enterococcal coverage compared with penicillin, with piperacillin having better activity than ticarcillin.

Penicillins Combined with β-Lactamase Inhibitors

The addition of β-lactamase inhibitors to aminopenicillins and antipseudomonal penicillins can prevent inactivation by bacterial β-lactamases. These agents inactivate β-lactamases produced by S aureus, H influenzae, Moraxella catarrhalis, and Bacteroides fragilis, extending the activity of the parent drug to include these organisms. Augmentin (amoxicillin and clavulanic acid) is given orally. Unasyn (ampicillin and sulbactam), Zosyn (piperacillin and tazobactam), and Timentin (ticarcillin and clavulanic acid) are administered intravenously.

Adverse Effects

Augmentin is associated with some gastrointestinal intolerance, particularly diarrhea, which is decreased if administered twice a day.

Clinical Uses

Augmentin is used clinically for the treatment of refractory cases of sinusitis and otitis media that have not responded to less costly agents and may be due to anaerobes or S aureus. Unasyn, Zosyn, and Timentin are used as general broad-spectrum agents, with Zosyn having the most broad-spectrum activity. They are not active against methicillin-resistant S aureus and atypical organisms such as chlamydia and mycoplasma. Unasyn has no activity against Pseudomonas.

Other β-Lactam Drugs

Other β-lactam drugs include monobactams (aztreonam [Azactam]), and carbapenems (imipenem [Primaxin], meropenem [Merrem], doripenem [Doribax], and ertapenem [Invanz]). Monobactams have activity limited to gram-negative organisms, including Pseudomonas. Carbapenems have a wider spectrum. Imipenem is a broad-spectrum antibiotic and covers most gram-negative organisms, gram-positive organisms, and anaerobes, with the exception of Stenotrophomonas maltophilia, Enterococcus faecium, and most methicillin-resistant S aureus and Staphylococcus epidermidis. Meropenem and doripenem has a similar spectrum of activity. Ertapenem has a narrower spectrum of activity, with no coverage against Pseudomonas, Acinetobacter, or Enterococcus faecalis.

Adverse Effects

Despite the structural similarity of aztreonam to penicillin, cross-reactivity is limited and the drug can be given to those with a history of penicillin allergy, including IgE-mediated reactions. Patients allergic to penicillins may be allergic to imipenem and meropenem. Imipenem is associated with seizures, particularly if used in higher doses in elderly patients with decreased renal function, cerebrovascular disease, or seizure disorders. Meropenem is less likely to cause seizures and is associated with less nausea and vomiting than imipenem.

Clinical Uses

Aztreonam is useful for the treatment of confirmed pseudomonal infections in patients with allergies to penicillin and cephalosporins. Imipenem and meropenem should not be routinely used as a first-line therapy unless treating known multidrug-resistant organisms that are sensitive to these agents. However, in an appropriate patient who has been hospitalized for a prolonged period and who may experience infection with organisms resistant to multiple drugs, imipenem or meropenem may be used while awaiting culture results.

Cephalosporins

First-Generation Cephalosporins

These agents generally have good activity against aerobic gram-positive organisms (group A streptococcus, methicillin-sensitive S aureus, and viridans streptococci) and some community-acquired gram-negative organisms (Proteus mirabilis, E coli, and the Klebsiella species). Agents in this class include the orally administered cephalexin (eg, Keflex) and the parenteral cefazolin (eg, Ancef).

Adverse Effects

In general, cephalosporins are safe. However, patients with a history of IgE-mediated allergy to a penicillin (eg, anaphylaxis) should not be administered a cephalosporin. Patients with a history of developing a maculopapular rash in response to penicillins have a 5–10% risk of a similar rash with cephalosporins.

Clinical Uses

Oral first-generation cephalosporins are commonly used for the treatment of minor staphylococcal infections such as in cellulitis. Intravenous first-generation cephalosporins are the drugs of choice for surgical prophylaxis in head and neck surgery if oral or pharyngeal mucosa is involved, such as in laryngeal tumor resection.

Second-Generation Cephalosporins

This is a heterogeneous group that includes cefuroxime (Zinacef), cefoxitin (Mefoxin), and cefotetan. In general, they provide slightly more gram-negative coverage than the first-generation cephalosporins, including activity against indole-positive Proteus, Klebsiella, M catarrhalis, and the Neisseria species. They have slightly less gram-positive activity than the first-generation cephalosporins. Cefoxitin and cefotetan also have activity against many strains of Bacteroides.

Clinical Uses

In patients with a mild allergy to ampicillin or amoxicillin, cefuroxime is an alternative agent for the treatment of sinusitis and otitis because it has activity against β-lactamase-producing strains such as H influenzae and M catarrhalis. Because of additional anaerobic activity, cefoxitin and cefotetan may be options for mixed (aerobic and anaerobic) infections of the head and neck.

Third-Generation Cephalosporins

Examples of these agents include orally administered cefixime (Suprax), cefpodoxime (Vantin), and intravenously or intramuscularly administered ceftazidime (Fortaz), ceftriaxone (Rocephin), and cefotaxime. In general, these agents are less active against gram-positive organisms, including S aureus, but most streptococci are inhibited. Of these, ceftriaxone has the most reliable pneumococcal coverage. They all have expanded gram-negative coverage. Ceftazidime has good activity against Pseudomonas aeruginosa. Ceftriaxone is the first-line agent for gonorrhea. Cefixime and cefpodoxime are oral alternatives for gonorrhea.

Adverse Effects

Ceftriaxone is associated with a dose-dependent gallbladder sludging (which can be seen by ultrasound imaging) and pseudocholelithiasis; both of these disorders can be found particularly in patients who are not eating and who are receiving total parenteral nutrition.

Clinical Uses

Because of their penetration into cerebrospinal fluid, third-generation cephalosporins are widely used to treat meningitis. Ceftriaxone can be used to treat meningitis caused by susceptible pneumococci, meningococci, H influenzae, and enteric gram-negative rods. It is also used for meningitis caused by the Pseudomonas species. Ceftriaxone, cefpodoxime, and cefixime are used for the treatment of gonorrhea, including pharyngeal disease.

Fourth-Generation Cephalosporins

Cefepime (Maxipime) is currently the only available fourth-generation cephalosporin. It has activity against Enterobacter, Citrobacter, and Pseudomonas species and similar activity to ceftriaxone against gram-positive organisms.

Clinical Uses

Cefepime is typically used for gram-negative organisms resistant to other cephalosporins, such as Enterobacter and Citrobacter. It is also used empirically in patients with febrile neutropenia.

Fifth-Generation Cephalosporins

Ceftaroline (Teflaro) is a new fifth-generation cephalosporin. It has activity against gram-positive organisms, including methicillin-resistant S aureus, and gram-negative organisms with the notable exception of P aeruginosa.

Clinical Uses

Based on clinical studies, ceftaroline can be used as an alternative agent for the treatment of skin and soft tissue infections, or community acquired pneumonia where methicillin-resistant S aureus is suspected.

Quinolones

This class has a broad spectrum of activity and generally low toxicity. Quinolones include the newer fluorinated agents such as ciprofloxacin (Cipro), levofloxacin (Levaquin), gemifloxacin (Factive), and moxifloxacin (Avelox). The drugs inhibit bacterial DNA synthesis by blocking the action of the enzyme DNA gyrase. In general, quinolones have moderate gram-positive activity, especially levofloxacin, gemifloxacin, and moxifloxacin, and good gram-negative activity, with ciprofloxacin and levofloxacin providing the best activity against P aeruginosa, although resistance has been increasing. Only moxifloxacin has moderate anaerobic activity (eg, B fragilis and oral anaerobes). In contrast to ciprofloxacin and levofloxacin, moxifloxacin has poor activity against P aeruginosa.

Adverse Effects

The most commonly reported side effects are nausea, vomiting, and diarrhea. The prolongation of the QT interval has been observed in fluoroquinolones as a class. Tendonitis and tendon rupture have been reported, particularly in patients taking glucocorticoids or who have concomitant liver or renal failure. There is also a possible adverse effect on joint cartilage, which has been noted only in animal studies. Gemifloxacin is associated with rash in women under 40 years old taking drug for more than 7 days.

Clinical Uses

Because of their broad spectrum, quinolones should not be typically used as first-line agents in relatively minor infections such as sinusitis, otitis, and pharyngitis when there are less expensive alternatives with narrower spectrums available. Because of the increasing prevalence of fluoroquinolone-resistant Neisseria gonorrhoeae in the United States and in some areas of the world, quinolones are no longer being recommended for the treatment of gonorrhea, including gonococcal pharyngitis in the United States. Ciprofloxacin has been used for the treatment of complicated soft tissue infections and osteomyelitis caused by gram-negative organisms. Ciprofloxacin, administered as 500–750 mg twice daily for at least 6 weeks, is used for the treatment of malignant external otitis. Ciprofloxacin has also been used to eradicate meningococci from the nasopharynx of carriers. Because of their superior activity against Pneumococcus, some of the newer quinolones such as levofloxacin can be used when drug-resistant Streptococcus pneumoniae is suspected in cases of sinusitis. However, quinolones are not reliable in the treatment of methicillin-resistant S aureus or enterococcal infections.

Sulfonamides & Antifolate Drugs

Sulfonamides are structural analogs of p-aminobenzoic acid (PABA) and compete with PABA to block its conversion to dihydrofolic acid. Almost all bacteria, with the exception of enterococci, that use PABA to synthesize folates and pyrimidines are inhibited by these agents. Mammalian cells use exogenous folate and are unaffected. Antifolate drugs such as trimethoprim block the conversion of dihydrofolic acid to tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. Typically, these agents are used in combination, such as trimethoprim–sulfamethoxazole (eg, Bactrim, Septra) to treat a variety of bacterial and parasitic infections.

Adverse Effects

At high doses, some of the antifolate drugs also inhibit mammalian dihydrofolate reductase (pyrimethamine and trimetrexate) so that these drugs are typically coadministered with folinic acid (leucovorin) to prevent bone marrow suppression. Adverse effects to sulfonamides, usually mild rashes or gastrointestinal disturbances, occur in 10–15% of patients without AIDS; in patients with AIDS, these adverse effects are experienced in up to 50% of patients and include rash, fever, neutropenia, and thrombocytopenia, all of which may be severe enough to discontinue therapy.

Clinical Uses

Sulfonamides are the drugs of choice for infections caused by Nocardia. Trimethoprim–sulfamethoxazole (Bactrim, Septra) is often used for the treatment of acute sinusitis and otitis, although resistant Pneumococcus is limiting its use.

Erythromycins (Macrolides)

This class includes erythromycin, azithromycin (Zithromax), and clarithromycin (Biaxin). They inhibit protein synthesis of bacteria by binding to the 50S ribosomal subunits. In vitro data demonstrating an effect on cytokine production suggest an anti-inflammatory effect as well.

Adverse Effects

Nausea, vomiting, and diarrhea may occur, particularly with erythromycin, which can cause uncoordinated peristalsis. Azithromycin and clarithromycin cause milder symptoms. Reversible ototoxicity can occur after high doses of these agents, especially with concomitant hepatic and renal insufficiency. Macrolides (especially erythromycin and clarithromycin) inhibit cytochrome P450 and can significantly increase levels of oral anticoagulants, digoxin, cyclosporin, and theophylline with concomitant use. Levels should be monitored and doses appropriately adjusted.

Clinical Uses

Macrolides are the drugs of choice for infections caused by Legionella, Mycoplasma, and Chlamydia. Azithromycin and clarithromycin are approved for the treatment of streptococcal pharyngitis, but some areas are reporting high rates (20%) of resistance, and less expensive alternatives are available. Azithromycin and clarithromycin are frequently used to treat sinusitis, although amoxicillin and doxycycline are equally efficacious and less expensive.

Ketolides

Ketolides such as telithromycin (Ketek) are derivatives of the macrolides, but they have activity against macrolide-resistant and penicillin-resistant S pneumoniae. They inhibit bacterial protein synthesis by binding to two sites on the 50S bacterial ribosome. They do not have significant gram-negative activity.

Adverse Effects

Upper gastrointestinal symptoms are the most common drug-associated effect. Other potential effects include blurred vision, resulting from reversible alteration in accommodation (seen in young women in particular). Fatal exacerbations of myasthenia gravis have been reported. There have been several reports of severe liver toxicity including death or the need for liver transplantation. Telithromycin is a potent inhibitor of cytochrome P450 and can significantly increase levels of several drugs such as warfarin and benzodiazepines. Statins should be temporarily stopped while patients are taking telithromycin.

Clinical Uses

Telithromycin is an alternative to quinolones for community-acquired pneumonia in which resistant S pneumoniae is suspected. However, patients should be carefully monitored for liver toxicity. Telithromycin is no longer recommended for the treatment of acute bacterial sinusitis or bronchitis, given the risk of severe hepatotoxicity.

Tetracyclines

Doxycycline and other drugs in this class inhibit protein synthesis. Their spectrum of activity is similar to that of macrolides.

Adverse Effects

Gastrointestinal side effects are common. Drugs in this class can be bound to calcium in growing bones and teeth, causing discoloration and growth inhibition.

Clinical Uses

Similar to the macrolides, tetracyclines can be used to treat infections caused by Legionella, Mycoplasma, and Chlamydia.

Glycylcyclines

Tigecycline (Tygacil), a derivative of minocycline, is the first of this new class of antibiotics. The spectrum of activity includes resistant gram-positive organisms (eg, methicillin-resistant S aureus, penicillin-resistant S pneumoniae, and vancomycin-resistant enterococci) as well as several gram-negative organisms and anaerobes, but not P aeruginosa.

Adverse Effects

Nausea and vomiting are the most commonly reported effects reported with glycylcyclines. Like tetracyclines, tigecycline may also cause photosensitivity and pseudotumor cerebri. Its use is contraindicated in children and pregnant women.

Clinical Uses

These agents constitute another intravenously administered option against complicated skin and soft tissue infections with resistant gram-positive organisms.

Aminoglycosides

This group includes gentamicin and tobramycin. They inhibit protein synthesis in bacteria by attaching to the 30S ribosomal subunit.

Adverse Effects

All aminoglycosides can cause ototoxicity and nephrotoxicity. Ototoxicity can be irreversible and is cumulative. It can be manifested both as cochlear injury (eg, hearing loss) and vestibular injury (eg, vertigo and ataxia). Nephrotoxicity is more common and is frequently reversible.

Clinical Uses

These agents are generally used in serious infections caused by gram-negative bacteria. Their use is limited by toxicity.

Clindamycin

Clindamycin (Cleocin) acts by inhibiting the initiation of peptide chain synthesis in bacteria. It resembles the macrolides in its spectrum and structure.

Adverse Effects

These drugs are the most frequently implicated in causing Clostridium difficile colitis.

Clinical Uses

Clindamycin is one of the first-line drugs for the treatment of parapharyngeal space infections (including Ludwig angina), as well as jugular vein septic phlebitis (eg, Lemierre disease). It is recommended as an alternative to amoxicillin as prophylaxis against endocarditis following oral procedures. Clindamycin has good anaerobic activity, but resistance has been reported in up to 25% of B fragilis isolates, thus limiting its use in serious anaerobic infections due to these organisms. Because of existing evidence suggesting that clindamycin reduces toxin production in several organisms, it is often used concomitantly with penicillin in the treatment of group A streptococcal toxic shock syndrome. Clindamycin can also be used in the treatment of brain abscesses, although it is not effective in treating meningitis.

Metronidazole

Metronidazole (Flagyl) is an antiprotozoal drug that has excellent anaerobic activity, particularly against anaerobic gram-negative organisms.

Adverse Effects

Alcohol must be avoided for the duration of the antibiotic and for 48 hours afterward to prevent a disulfiram-like reaction. Metronidazole can also decrease the metabolism of warfarin and increase the prothrombin time, necessitating careful monitoring during concomitant use.

Clinical Uses

This agent can be used in the treatment of brain abscesses, parapharyngeal space infections (including Ludwig angina), as well as septic phlebitis of the jugular vein (Lemierre disease), in combination with either penicillin or a third-generation cephalosporin. It is more predictable than clindamycin and second-generation cephalosporins in the treatment of B fragilis infections.

Glycopeptides

Vancomycin

Vancomycin activity is limited to gram-positive organisms, and it is used as a bactericidal agent for most of these organisms, including staphylococci and streptococci. Vancomycin-resistant enterococcal strains have become a major problem.

Adverse Effects

This agent is rarely ototoxic when given with aminoglycosides. There is also potential nephrotoxicity when coadministered with aminoglycosides. The rapid infusion of vancomycin can result in diffuse hyperemia (“red man syndrome”).

Clinical Uses

Vancomycin is the drug of choice for methicillin-resistant S aureus and S epidermidis. Serious staphylococcal, enterococcal, and other gram-positive infections in patients allergic to penicillin can also be treated with vancomycin.

Telavancin

Like vancomycin, the spectrum of activity is limited to gram-positive microbes. Telavancin inhibits cell wall synthesis and disrupts membrane permeability. Given a long half-life of up to 9 hours, once-daily dosing is possible.

Adverse Effects

The most common adverse effects in trials are gastrointestinal, including metallic taste, nausea, and vomiting. Central nervous system symptoms such as insomnia and headaches are also reported.

Clinical Uses

Telavancin has U.S. FDA approval for its use in complicated skin and soft tissue infections. It can be considered as an alternative to vancomycin for methicillin-resistant S aureus skin and soft tissue infections, but there is less clinical experience compared with other drugs. The precise role for this agent in other methicillin-resistant S aureus infections such as endocarditis, bacteremia, and pneumonia still needs to be defined.

Streptogramins

These agents are structurally similar to macrolides. They work by binding to bacterial ribosomes and include Synercid (a combination of quinupristin and dalfopristin). Synercid has a spectrum of activity primarily against gram-positive organisms, including E faecium (but not E faecalis) and methicillin-resistant S aureus.

Adverse Effects

Phlebitis occurs with peripheral administration, so a central line is recommended. The most common adverse effects are myalgias and arthralgias.

Clinical Uses

Streptogramins are rarely used and only in cases of serious infections secondary to vancomycin-resistant E faecium.

Oxazolidinones

Linezolid (Zyvox) is the first agent of this class of antibiotics. It is active against aerobic gram-positive infections, including E faecium, E faecalis, and methicillin-resistant S aureus and S epidermidis.

Adverse Effects

Nausea, vomiting, and diarrhea are the most common adverse effects. Reversible thrombocytopenia, neutropenia, and anemia can occur if treatment is prolonged. If more than 2 weeks of treatment are planned, blood counts should be monitored.

Clinical Uses

These agents are used in cases of serious infections secondary to vancomycin-resistant E faecium and E faecalis, and in patients with methicillin-resistant S aureus infections who are intolerant to vancomycin.

Daptomycin

This bactericidal lipopeptide works by inserting itself into the bacterial cell membrane, causing depolarization, efflux of potassium, and cell death. Its spectrum of activity is similar to that of linezolid, targeting resistant gram-positive organisms (eg, methicillin-resistant S aureus and vancomycin-resistant enterococci). It is available only as a parenteral agent.

Adverse Effects

The main potential drug-related effect is reversible, dose-dependent myopathy, which is seen more than 7 days after initiating therapy.

Clinical Uses

Daptomycin is used in complicated skin and soft tissue infections with known or suspected resistant gram-positive organisms.

Amphotericin B

Amphotericin B has a broad spectrum of activity against many fungi that can cause systemic disease, such as Aspergillus, Histoplasmosis, Coccidioides, and Candida. Notable exceptions are Pseudallescheria boydii and Fusarium. Lipid-based amphotericin B products, such as amphotericin B lipid complex, amphotericin B colloidal dispersion, and liposomal amphotericin B, have less nephrotoxicity than amphotericin.

Adverse Effects

Amphotericin B often produces fever, chills, vomiting, and headaches. Premedication with acetaminophen and diphenhydramine may help, and the addition of 25 mg of hydrocortisone to the infusion may decrease the incidence of rigors. Nephrotoxicity and electrolyte disturbances are common side effects, and close monitoring is essential.

Clinical Uses

In immunocompromised patients, this agent is used as an initial therapy for sinus disease or other invasive disease caused by Aspergillus, Zygomycetes, and other molds. Amphotericin is sometimes used in the treatment of resistant thrush.

Triazoles

These drugs inhibit ergosterol synthesis, resulting in inhibition of membrane-associated enzyme activity and cell wall growth and replication. Fluconazole (Diflucan) can be effective in treating infections due to Candida (albicans in particular), Cryptococcus, and Blastomyces. Itraconazole (Sporanox) has a similar spectrum to fluconazole, but may also be used to treat invasive disease caused by Aspergillus. There is no activity against Fusarium and Zygomycetes. Newer-generation azoles such as voriconazole (Vfend) have a broader spectrum of activity, including Aspergillus and Fusarium, but not Zygomycetes. Posaconazole has a similar spectrum of activity as voriconazole, but can also be used to treat Zygomycetes.

Adverse Effects

Triazoles are generally well tolerated. Itraconazole and voriconazole have several drug interactions. Itraconazole can increase levels of cyclosporin, digoxin, and warfarin with concomitant use, necessitating the dose adjustment of these medications. Voriconazole is a potent inhibitor of cytochrome P450 isoenzymes, also mandating the dose adjustment and monitoring of cyclosporin and warfarin, as well as tacrolimus. Sirolimus is contraindicated. The most common adverse effects associated with voriconazole were reversible visual disturbances and liver toxicity.

Clinical Uses

Itraconazole, voriconazole, and posaconazole can be used in the treatment of sinus disease caused by Aspergillus. Voriconazole can also be used in disease caused by Fusarium. Fluconazole is typically a first-line treatment of thrush. Itraconazole and voriconazole also have activity against Candida, including some of the non-albicans species. Posaconazole is an alternative amphotericin for the treatment of Zygomycetes.

Candins

These drugs act by inhibiting fungal wall synthesis. Caspofungin (Cancidas), micafungin (Mycamine), and anidulafungin (Eraxis) are FDA-cleared agents in this class. They are active against Candida, including non-albicans species, and Aspergillus. They are not active against the other molds.

Adverse Effects

Candins are remarkably well-tolerated drugs and are associated with few significant drug interactions.

Clinical Uses

These drugs are recommended for patients intolerant of or refractory to treatment of Aspergillus disease with amphotericin or itraconazole.

Acyclovir, Famciclovir & Valacyclovir

In cells infected with herpesvirus, these drugs are selectively active against viral DNA polymerase, inhibiting viral proliferation. They are useful for infections caused by herpes simplex and in herpes zoster–varicella infections. Famciclovir (Famvir) is selectively active against herpes DNA polymerase and inhibits viral proliferation. It is a prodrug of penciclovir. Herpes simplex and varicella zoster strains resistant to acyclovir are also resistant to famciclovir. Valacyclovir (Valtrex) is the prodrug of acyclovir and has increased oral bioavailability, allowing less frequent dosing.

Adverse Effects

These drugs are relatively nontoxic.

Clinical Uses

Antiviral agents are used for the treatment and prophylaxis of mucocutaneous oral lesions caused by herpes simplex. Oral acyclovir is significantly more effective than the currently available topical ointment, 5% acyclovir. Penciclovir 1% cream is effective but must be applied every 2 hours to work.