Материал: 2016_Kaplan_USMLE_Step_1_Lecture_Notes_Pharmacology

Section V λ Antimicrobial Agents

Chapter Summary (cont’d )

λThe fluoroquinones (e.g., ciprofloxacin) are nalidixic acid analogs that inhibit topoisomerase II (DNA gyrase) and topoisomerase IV. Their clinical use,

the relevant drugs in this class, their biodisposition, and side effects are reported.

λThe exact mode of metronidazole action is unknown. Its use as an antiprotozoal and antibacterial drug is discussed, as are its side effects.

Antitubercular Drugs

λInfections caused by Mycobacterium tuberculosis are treated with combination therapy. The primary drugs used are isoniazid, rifampin, ethambutol, and pyrazinamide. Highly resistant organisms may require the use of additional agents. Backup drugs include streptomycin, fluoroquinolones, capreomycin, and cycloserine.

λTable V-1-4 summarizes the actions, resistance, and side effects of the antitubercular drugs.

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Learning Objectives

Demonstrate understanding of the use and side effects of polyenes (amphotericin B, nystatin), azoles (ketoconazole, fluconazole, itraconazole, voriconazole), and other antifungals

Caspo “fungin”

inhibits Beta-glucan Cell wall synthesis

epoxidase

Figure V-2-1. Mechanism of Action of Antifungal Drugs

POLYENES (AMPHOTERICIN B [AMP B], NYSTATIN)

λMechanisms:

–Amphoteric compounds with both polar and nonpolar structural components—interact with ergosterol in fungal membranes to form artificial “pores,” which disrupt membrane permeability

–Resistant fungal strains appear to have low ergosterol content in their cell membranes

λActivity and clinical uses:

− Amphotericin B has wide fungicidal spectrum; remains the DOC (or co-DOC) for severe infections caused by Cryptococcus and Mucor

− Amphotericin B—synergistic with flucytosine in cryptococcoses − Nystatin (too toxic for systemic use)—used topically for localized

infections (e.g., candidiasis)

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Section V λ Antimicrobial Agents

λPharmacokinetics:

−Amphotericin B given by slow IV infusion—poor penetration into the CNS (intrathecal possible)

−Slow clearance (half-life >2 weeks) via both metabolism and renal elimination

λSide effects:

−Infusion-related

ºFever, chills, muscle rigor, hypotension (histamine release) occur during IV infusion (a test dose is advisable)

ºCan be alleviated partly by pretreatment with NSAIDs, antihistamines, meperidine, and adrenal steroids

−Dose-dependent

ºNephrotoxicity includes ↓ GFR, tubular acidosis, ↓ K+ and Mg2+, and anemia through ↓ erythropoietin

ºProtect by Na+ loading, use of liposomal amphotericin B, or by drug combinations (e.g., + flucytosine), permitting ↓ in amphotericin B dose

AZOLES (KETOCONAZOLE, FLUCONAZOLE,

ITRACONAZOLE, VORICONAZOLE)

λMechanism:

−“Azoles” are fungicidal and interfere with the synthesis of ergosterol by inhibiting 14-α-demethylase, a fungal P450 enzyme, which converts lanosterol to ergosterol

−Resistance occurs via decreased intracellular accumulation of azoles

λActivity and clinical uses:

−Ketoconazole

ºCo-DOC for Paracoccidioides and backup for Blastomyces and Histoplasma

ºOral use in mucocutaneous candidiasis or dermatophytoses

−Fluconazole

ºDOC for esophageal and invasive candidiasis and coccidioidomycoses

ºProphylaxis and suppression in cryptococcal meningitis

−Itraconazole and Voriconazole

ºDOC in blastomycoses, sporotrichoses, aspergillosis

ºBackup for several other mycoses and candidiasis

−Clotrimazole and miconazole

ºUsed topically for candidal and dermatophytic infections

λPharmacokinetics:

−Effective orally

−Absorption of ketoconazole ↓ by antacids

−Absorption of itraconazole ↑ by food

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Chapter 2 λ Antifungal Agents

−Only fluconazole penetrates into the CSF and can be used in meningeal infection. Fluconazole is eliminated in the urine, largely in unchanged form.

−Ketoconazole and itraconazole are metabolized by liver enzymes.

−Inhibition of hepatic P450s

λSide effects:

−↓ synthesis of steroids, including cortisol and testosterone → ↓ libido, gynecomastia, menstrual irregularities

−↑ liver function tests and rare hepatotoxicity

OTHER ANTIFUNGALS

λFlucytosine

−Activated by fungal cytosine deaminase to 5-fluorouracil (5-FU), which after triphosphorylation is incorporated into fungal RNA

−5-FU also forms 5-fluorodeoxyuridine monophosphate (5-Fd-UMP), which inhibits thymidylate synthase → ↓ thymine.

−Resistance emerges rapidly if flucytosine is used alone.

−Use in combination with amphotericin B in severe candidal and cryptococcal infections—enters CSF

–Toxic to bone marrow (see Anticancer Drugs, Section IX).

λGriseofulvin

− Active only against dermatophytes (orally, not topically) by depositing in newly formed keratin and disrupting microtubule structure

− Side effects:

º Disulfiram-like reaction

λTerbinafine

− Active only against dermatophytes by inhibiting squalene epoxidase → ↓ ergosterol

− Possibly superior to griseofulvin in onychomycoses

–Side effects: GI distress, rash, headache, ↑ liver function tests → possible hepatotoxicity

λEchinocandins (caspofungin and other “fungins”)

− Inhibit the synthesis of beta-1,2 glucan, a critical component of fungal cell walls

− Back-up drugs given IV for disseminated and mucocutaneous Candida infections or invasive aspergillosis

− Monitor liver function

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Section V λ Antimicrobial Agents

Chapter Summary

λIn eukaryotes, fungal metabolism is somewhat similar to that in humans. Thus, most bacterial antibiotics are ineffective, and many otherwise potentially effective drugs are also toxic to their human hosts. A difference between fungi and humans susceptible to exploitation by antibiotics is the high concentration of ergosterol in their membranes.

λThe polyenes amphotericin (amp B) are amphoteric compounds that bind to ergosterol, forming pores, which results in the leakage of intracellular contents. The activity, clinical uses, biodisposition, and side effects of these polyenes are discussed.

λThe azoles (ketoconazole, fluconazole, clotrimazole, miconazole, and itraconazole) kill fungi by interfering with ergosterol synthesis. The mechanisms of action, clinical uses, biodisposition, and side effects are considered.

λFlucytosine is activated by fungal cytosine deaminase to form 5-fluorouracil

(5-FU). It is sometimes used in combination with amp-B. Insomuch as 5-FU is a classic anticancer agent, it is not surprising that flucytosine is also toxic to bone marrow.

λGriseofulvin and terbinafine are active against dermatophytes. Griseofulvin interferes with microtubule function; terbinafine blocks ergosterol synthesis.

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