4.3 Antifungals, Antivirals & Antituberculars

Antifungals

Azole antifungals inhibit fungal 14-alpha-demethylase, blocking conversion of lanosterol to ergosterol and destabilizing the fungal membrane. The class differs in spectrum and toxicity:

• Fluconazole — Candida (though C. krusei is intrinsically resistant and C. glabrata often dose-dependently resistant) and cryptococcal meningitis. Excellent oral bioavailability and CSF penetration. It inhibits CYP2C9 and CYP3A4 (raising warfarin, phenytoin, and sulfonylurea levels), prolongs the QT interval, and can cause hepatotoxicity. Single-dose use for vaginal candidiasis is common, but prolonged high-dose exposure is avoided in pregnancy.
• Itraconazole — broader, including dimorphic fungi and onychomycosis. It is a negative inotrope and is contraindicated in heart failure; capsule absorption requires gastric acid (avoid proton pump inhibitors, take with food or cola), whereas the solution is taken on an empty stomach.
• Voriconazole — first-line for invasive aspergillosis. Signature adverse effects are transient visual disturbances (blurred vision, photophobia, altered color perception in up to a third of patients), phototoxicity with long-term skin cancer risk, hallucinations, and hepatitis. It is metabolized by CYP2C19, whose genetic polymorphism makes levels unpredictable — therapeutic drug monitoring is recommended. Like all azoles it is a strong CYP inhibitor with many interactions.

Amphotericin B binds ergosterol directly, forming membrane pores; it has the broadest antifungal spectrum and is reserved for severe systemic mycoses. Its conventional formulation is notorious for dose-limiting nephrotoxicity, infusion reactions (fever, rigors — "shake and bake" — managed with premedication and slow infusion), and electrolyte wasting (hypokalemia and hypomagnesemia). Liposomal amphotericin B substantially reduces nephrotoxicity and infusion reactions and is preferred when renal function or cost allows. Pre-hydration with normal saline further protects the kidney.

Echinocandins — caspofungin, micafungin, anidulafungin — inhibit 1,3-beta-D-glucan synthase, a target absent from human cells, making them exceptionally well tolerated. They are fungicidal against Candida and first-line for candidemia, but are intravenous-only and unreliable against Cryptococcus.

Terbinafine inhibits squalene epoxidase and is first-line oral therapy for onychomycosis (6 weeks fingernails, 12 weeks toenails). Counsel on hepatotoxicity — baseline and interval liver function tests — and taste disturbance (dysgeusia), which can persist for months. Topical agents round out the class: clotrimazole and miconazole creams for dermatophyte and candidal skin infections, oral terbinafine cream for tinea, and nystatin, which is not absorbed and is used topically or as an oral suspension for thrush.

Antivirals

Acyclovir and its oral prodrug valacyclovir are guanosine analogues activated by viral thymidine kinase (conferring selective toxicity), then incorporated into viral DNA as chain terminators. They treat HSV and VZV infections; higher doses are needed for herpes zoster and encephalitis. The key toxicity is renal crystalluria with obstructive nephropathy — preventable with adequate hydration and renal dose adjustment — and neurotoxicity (confusion, tremor) in renal impairment. Oseltamivir, a neuraminidase inhibitor, shortens influenza illness and is most effective when started within 48 hours of symptom onset; it is also used for post-exposure prophylaxis. Nausea and vomiting are the main adverse effects, and dosing is renally adjusted.

For HIV, combination antiretroviral therapy uses drugs from several classes: NRTIs (tenofovir, emtricitabine, lamivudine — and abacavir, which mandates HLA-B*57:01 screening because carriers risk a severe, potentially fatal hypersensitivity reaction), NNRTIs (efavirenz, notable for CNS effects and CYP interactions), integrase strand transfer inhibitors (dolutegravir, bictegravir — now preferred first-line anchors because of high barrier to resistance and tolerability), and boosted protease inhibitors. For hepatitis C, direct-acting antivirals such as sofosbuvir (NS5B polymerase inhibitor) combined with velpatasvir (NS5A inhibitor) are pangenotypic, oral, and cure over 95% of patients in 8–12 weeks; key checks before starting are drug-drug interactions (many are P-glycoprotein substrates affected by inducers like rifampicin) and hepatitis B screening because of reactivation risk.

Tuberculosis: RIPE Therapy

Active tuberculosis is treated with a standard short-course regimen: 2 months of HRZE (rifampicin, isoniazid, pyrazinamide, ethambutol) followed by 4 months of HR (rifampicin plus isoniazid) — written 2HRZE/4HR. Using four drugs initially prevents emergence of resistance while susceptibility results are awaited, and adherence is supported through directly observed therapy (DOTS)-style programs because defaulting breeds multidrug-resistant TB. Each first-line agent has a mechanism and a trademark toxicity:

Monitoring fundamentals for the regimen: baseline liver function, renal function, and visual testing; monthly clinical review for hepatitis symptoms (anorexia, dark urine, jaundice) — asymptomatic transaminase rises under three times the upper limit of normal are usually tolerated, but symptomatic hepatitis mandates stopping the hepatotoxic drugs. Women of childbearing age on rifampicin must be offered non-hormonal or higher-dose contraception because enzyme induction causes pill failure. Pyridoxine 10 mg daily accompanies isoniazid in neuropathy-prone patients. Finally, rifampicin's induction persists for about two weeks after stopping, so interaction management outlives the last dose — a detail that distinguishes strong candidates on CBT exams.