• Part 1. Antibacterial Agents

• Part 2. Antiviral Agents

• Part 3. Antifungal Agents

• Part 4. Antiparasitic Agents

Antimicrobial agents consist of antibacterial, antiviral, antifungal, and antiparasitic medications. These drugs take advantage of the different structures or metabolism of the microbes versus human cells. The student should group classes of drugs together rather than memorize each individual agent. A systematic approach includes learning the agent, the mechanism of action, and the spectrum of activity.

Part 1. Antibacterial Agents

Antibacterial agents, which target specific components of microorganisms unique or more essential to their function than they are to humans, are classified according to their mechanisms of action. The component targets include enzymes necessary for bacterial cell wall synthesis, the bacterial ribosome, and enzymes necessary for nucleotide synthesis and DNA replication.

Resistance of pathogens to antibacterial and other chemotherapeutic agents may be the result of a natural resistance or may be acquired. In either case, it occurs through mutation, adaptation, or gene transfer. The mechanisms of resistance for any antibacterial agent vary, but are consequences of either changes in uptake of drug into, or its removal from, the bacterial cell, or to changes in the bacterial cell target site of the drug from a gene mutation. Multiple drug resistance is also a major impediment to antibacterial therapy and may be chromosomal or plasmid-mediated where genetic elements from resistant bacteria that code for enzymes that inactivate antibacterial agents are transferred to nonresistant bacteria. The emergence of drug resistance is to a large degree the result of the widespread and often unnecessary or inappropriate use of antibiotics in humans.

The penicillins include natural penicillins, penicillins that are resistant to staphylococcal b-lactamase, and extended-spectrum penicillins (Table II-1). The cephalosporins are classified as first to fourth generation according to their antibacterial spectrum (Table II-2). Aztreonam, which is relatively β-lactamase resistant, is the only available monobactam. It is nonallergenic and is active only against aerobic gram-negative bacilli (eg, Pseudomonas, Serratia). Refer to Table II-3 for a listing of selected antibacterial agents. The carbapenems (imipenem, meropenem, and ertapenem), which are resistant to most β-lactamases, have a wide spectrum of activity against gram-positive and gram-negative rods and anaerobes. To prevent its metabolism to a nephrotoxic metabolite, imipenem is administered with an inhibitor of renal tubule dehydropeptidase, cilastatin. Vancomycin, which is unaffected by β-lactamases, inhibits bacterial cell wall synthesis by covalent binding to the terminal 2 D-alanine residues of nascent peptidoglycan pentapeptide to prevent their elongation and cross-linking, thus increasing the susceptibility of the cell to lysis. It is active against gram-positive bacteria.

Part 2. Antiviral Agents

The 3 major classes of antiviral agents are DNA polymerase inhibitors, reverse transcriptase inhibitors, and protease inhibitors. It should be noted that HIV treatment usually includes the use of at least 2 reverse transcriptase inhibitors and 1 protease inhibitor. DNA polymerase inhibitors are subdivided into nucleoside and nonnucleoside. Drugs may target viral nucleic acid replication such as DNA polymerase either via nucleoside (purine or pyrimidine analogs) such as acyclovir or ribavirin, or by attacking a unique viral process needed in nucleic acid synthesis such as viral pyrophosphate (nonnucleoside type). Antiviral drugs used to treat herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV) infection can be classified as either nucleosides or non-nucleosides, or according to their site of action in the viral replicative cycle, or according to their clinical use.

COMMON ANTIVIRAL AGENTS

Influenza

Amantadine and rimantadine are primarily used against infections caused by the influenza A virus. Their mechanism of action is interfering with viral uncoating. Both agents are fairly well absorbed orally and cause some minor central nervous system (CNS) effects (rimantadine less so) and minor gastrointestinal (GI) effects (Table II-4).

HERPES VIRUS

Acyclovir is used against HSV types 1 and 2. Acyclovir, a nucleoside DNApolymerase inhibitor, is a deoxyguanosine triphosphate analog, which is incorporated into the viral DNA and causes DNA chain termination. Its specificity is a result of the presence of herpes-specific thymidine kinase in infected cells, which phosphorylates acyclovir 100 times more efficiently than by uninfected cells. Acyclovir can be topically used, orally for recurrent genital herpes, and intravenously for immunocompromised patients or herpes encephalitis. Its adverse effects include headache, nausea, and rarely nephrotoxicity with intravenous use. Valacyclovir is an analog of acyclovir and is converted to acyclovir in the body. Its advantage is better bioavailability. See Table II-5 for listing of agents against herpes viruses.

Penciclovir is converted to the triphosphate form and inhibits viral DNA polymerase. Famciclovir is converted to the active agent penciclovir in the body. Penciclovir is used topically to treat herpes labialis “cold sores”; famciclovir is used for genital herpes or herpes zoster. Headache and GI effects are common. Ganciclovir is structurally similar to acyclovir and must be converted to the triphosphate form to be active; it competes with deoxyguanosine triphosphate for incorporation into viral DNA, thereby inhibiting DNA polymerase. Its primary role is against CMV and is far more effective than acyclovir. Ganciclovir can induce serious myelosuppression.

Foscarnet is a synthetic nonnucleoside analog of pyrophosphate and inhibits DNA polymerase or HIV reverse transcriptase by directly binding to the pyrophosphate-binding site. Its use is usually for acyclovir resistant herpes or CMV retinitis. Significant nephrotoxicity may occur with its use.

Sorivudine is a pyrimidine nucleoside analog and, on being converted to the triphosphate form, is active against herpes DNA synthesis. It is effective against VZV and is usually well tolerated. Idoxuridine is an iodinated thymidine analog, which inhibits herpes DNA synthesis in its triphosphate form. It is used primarily topically for herpes keratitis. Adverse effects include pain and inflammation. Vidarabine is an adenosine analog, which also needs to be in its triphosphate form and blocks herpes-specific DNA polymerase. It has been used for herpes encephalitis or zoster in immunocompromised individuals; however, because of its nephrotoxicity, it has largely been supplanted by acyclovir. Trifluridine is a fluorinated pyrimidine nucleoside analog. Its monophosphate form inhibits thymidylate synthetase and triphosphate form inhibits DNA polymerase. It is active against HSV types 1 and 2 and CMV, and it is used primarily against keratoconjunctivitis and recurrent keratitis.

ANTI-HIV AGENTS

Retrovir (azidothymidine or zidovudine) inhibits viral reverse transcriptase when its triphosphate form is incorporated into the nucleic acid and blocks further DNA chain elongation, leading to termination of the DNA. In addition, the monophosphate form of Retrovir may block deoxythymidine kinase and inhibit the production of normal dTTp. Its principal role is treating HIV infection, and adverse effects include headache, bone marrow suppression, fever, and abdominal pain.

Didanosine is also a nucleoside reverse transcriptase inhibitor, primarily used as an adjunct to Retrovir, or for those patients with HIV infection intolerant or unresponsive to zidovudine. Peripheral neuropathy and pancreatic damage are its adverse effects. Stavudine is a thymidine nucleoside analog that inhibits HIV-1 replication and that is used in patients with HIV infection unresponsive to other therapies.

PROTEASE INHIBITORS

Invirase or saquinavir blocks HIV protease activity, rendering the virus unable to generate essential proteins and enzymes including reverse transcriptase. It is used in combination with a conventional reverse transcriptase inhibitor.

Part 3. Antifungal Agents

In addition to the pyrimidine analog, flucytosine, and the penicillium-derived antifungal agent, griseofulvin, the 3 major classes of antifungal agents are the polyene macrolides, azoles, and allylamines (Table II-6).

Of all the available antifungal agents, amphotericin B has the broadest spectrum of activity, including activity against yeast, mycoses, and molds. It is the drug of choice for disseminated or invasive fungal infections in immunocompromised patients. The major adverse effect resulting from amphotericin B administration is the almost invariable renal toxicity that results from decreased renal blood flow and from tubular and basement membrane destruction that may be irreversible and may require dialysis. Other adverse effects of amphotericin B relate to its intravenous infusion and include fever, chills, vomiting, hypotension, and headache that can be ameliorated somewhat by careful monitoring and slow infusion.

The azole antifungal agents have a broad spectrum of activity, including activity against candidiasis, mycoses, and dermatophytes, among many others. As topical agents they are relatively safe. Administered orally, their most common adverse effect is GI dysfunction. Hepatic dysfunction may rarely occur. Oral azoles are contraindicated for use with midazolam and triazolam because of potentiation of their hypnotic and sedative effects, and with β-hydroxy-β-methylglutaryl-coenzyme A reductase inhibitors because of an increased risk of rhabdomyolysis. Itraconazole has been associated with heart failure when used to treat onychomycosis and, therefore, should not be used in patients with ventricular abnormalities. Monitoring patients who receive itraconazole for potential hepatic toxicity is also highly recommended. Voriconazole frequently causes an acute blurring of vision with changes in color perception that resolves quickly.

The allylamine antifungal agents, naftifine and terbinafine, are used topically to treat dermatophytes. Contact with mucous membranes may lead to local irritation and erythema and should be avoided. Terbinafine administered orally is effective against the onychomycosis. Monitoring for potential hepatic toxicity is highly recommended.

Flucytosine is active against only a relatively restricted range of fungal infections. Because of rapid development of resistance, it is used concomitantly for its synergistic effects with other antifungal agents. The most commonly reported adverse effect is bone marrow suppression, probably because of the toxicity of the metabolite fluorouracil, and should be continuously monitored. Other reported less common adverse effects include reversible hepatotoxicity, enterocolitis, and hair loss.

Griseofulvin, the use of which is declining relative to terbinafine and itraconazole, is an effective antifungal agent that is used only systemically to treat a very limited range of dermatophyte infections. The most common adverse effects include hypersensitivity (fever, skin rash, serum-sickness–like syndrome) and headache. It is teratogenic.

MECHANISM OF ACTION

Nystatin and amphotericin B bind to ergosterol, a major component of fungal cell membranes. This disrupts the stability of the cell by forming pores in the cell membrane that result in leakage of intracellular constituents. Bacteria are not susceptible to these agents because they lack ergosterol.

Azoles (imidazoles less so) have a greater affinity for fungal than human cytochrome P₄₅₀ enzymes and, therefore, more effectively reduce the synthesis of fungal cell ergosterol than human cell cholesterol.

The allylamine antifungal agents, naftifine and terbinafine, decrease ergosterol synthesis and increase fungal membrane disruption by inhibiting the enzyme squalene epoxidase.

Flucytosine must first be transported into fungal cells via a cytosine permease and converted to 5-fluorouracil and then sequentially converted to 5-fluorodeoxyuridylic acid, which disrupts DNA synthesis by inhibiting thymidylate synthetase. Human cells are unable to synthesize the active flucytosine metabolites.

The mechanism of antifungal action of griseofulvin is not definitely known. It acts only on growing skin cells and has been reported to inhibit cell wall synthesis, interfere with nucleic acid synthesis, and disrupt microtubule function, among other activities.

ADMINISTRATION

Amphotericin B is insoluble in water; therefore, it is generally administered as a colloidal suspension with sodium deoxycholate. Because of its poor absorption from the GI tract, amphotericin B must be given intravenously to treat systemic disease, although it is effective orally for fungal infections within the GI lumen. Likewise, nystatin is poorly absorbed but may also be used for fungal infection of the GI tract. It is too toxic for systemic use; therefore, it is mostly used topically to treat fungal infections of the skin and mucous membranes (eg, oropharyngeal thrush, vaginal candidiasis). Costly lipid formulations of amphotericin B are available for intravenous use, which reduce its nonspecific binding to cholesterol of human cell membranes and, thus, its potential to cause renal damage. Griseofulvin is administered in a microparticulate form to improve absorption.

Part 4. Antiparasitic Agents

Parasitic infections affect one-half of the world’s population and are particularly prevalent in developing countries. Immunocompromised individuals such as those with HIV infection are also prone to parasitic disease. These medications can be categorized as active against malaria, toxoplasmosis, Cyclospora, cryptosporidia, Pneumocystis, amebiasis, leishmaniasis, helminths, trematodes, and cestodes (Table II-7).

REFERENCES