Antifungal Drugs
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Direct answer
Antifungal drugs fall into three main groups: polyenes such as amphotericin B that bind ergosterol and disrupt the membrane, azoles that inhibit ergosterol synthesis through lanosterol 14-alpha-demethylase, and echinocandins that block beta-1,3-glucan synthesis in the cell wall. Fluconazole is the usual choice for many Candida infections, while amphotericin B remains the reference agent for severe invasive mycoses when other options are unsuitable.
What you must remember
- Amphotericin B: Binds ergosterol and causes infusion reactions with fever and rigors, nephrotoxicity, hypokalaemia and hypomagnesaemia; the liposomal form is less nephrotoxic.
- Fluconazole: Active against most Candida albicans and Cryptococcus; Candida krusei is intrinsically resistant and Candida glabrata often shows reduced susceptibility.
- Voriconazole: First-line for invasive aspergillosis, with visual disturbance, hepatotoxicity and photosensitivity, and it needs therapeutic drug monitoring because metabolism varies widely.
- Echinocandins: Caspofungin, micafungin and anidulafungin inhibit beta-1,3-glucan synthase, are first-line for candidaemia in many guidelines, and are poorly active against Cryptococcus and Mucorales.
- Azole interactions: Azoles inhibit CYP enzymes (mainly CYP3A4, with fluconazole and voriconazole also affecting CYP2C9), raising levels of tacrolimus, statins, warfarin and QT-prolonging drugs, whereas rifampicin lowers azole levels.
- Flucytosine: Converted to fluorouracil inside fungal cells, used with amphotericin for cryptococcal meningitis, and causes bone marrow suppression needing renal dose adjustment.
A worked example: candidaemia in a transplant recipient
Consider a 55-year-old in intensive care with Candida albicans in blood cultures who is also taking tacrolimus after a liver transplant. An echinocandin is chosen first, because it avoids the CYP3A4 interaction that would raise tacrolimus levels. Central venous catheters are removed where possible, and an ophthalmology review is arranged to exclude retinal involvement. If the isolate proves fluconazole-susceptible and the patient improves, the team steps down to fluconazole, while still watching tacrolimus levels because the interaction persists. Treatment continues for a defined period after blood cultures clear, as per current guidance. Had the patient been taking rifampicin for tuberculosis, the team would expect azole levels to fall, which would change the choice of agent entirely. Discharge planning includes a clear antifungal plan, a review of prophylaxis, and a statement that tacrolimus levels will be rechecked within a week of any azole being restarted. This sequence avoids the two commonest errors: switching agents without a susceptibility result, and forgetting the interaction when a new drug is added. Follow-up cultures confirm clearance, and hepatic and visual symptoms are asked about at each review while an azole continues.
Where the exam tries to catch you
The exam often tests spectrum by species rather than by drug name. Candida krusei is intrinsically less susceptible to fluconazole, and Candida glabrata shows reduced susceptibility, so a stem describing a resistant yeast in a patient on long-term fluconazole should prompt a switch to an echinocandin. Fluconazole has no useful activity against moulds, so it has no place in invasive aspergillosis, where voriconazole or isavuconazole is preferred. Cryptococcal meningitis is another favourite: induction uses amphotericin with flucytosine rather than an azole alone. Nystatin and clotrimazole are used for mucocutaneous candidiasis and not for systemic infection. Interactions are also a frequent question, since rifampicin lowers azole levels while azoles raise warfarin, statin and tacrolimus levels.
Frequently asked questions
Which antifungal is first-line for invasive aspergillosis?
Voriconazole is the usual first-line agent for invasive aspergillosis, given intravenously or orally. Isavuconazole and liposomal amphotericin B are recognised alternatives in many guidelines, chosen according to severity and drug interactions.
Why is fluconazole ineffective against Candida krusei?
Candida krusei is intrinsically less susceptible to fluconazole, so an azole is not reliable for that species even in candidaemia. Echinocandins or amphotericin B are preferred once the isolate is identified as Candida krusei, and susceptibility testing guides the final choice.
Why does voriconazole need therapeutic drug monitoring?
Voriconazole is metabolised mainly by CYP2C19 with wide inter-patient variation, so plasma levels can be unpredictably high or low. Monitoring helps avoid toxicity such as hepatotoxicity and visual disturbance, and the target concentration follows local laboratory practice.
Which antifungal interacts with rifampicin and why does it matter?
Rifampicin induces hepatic CYP enzymes, lowering the levels of itraconazole and voriconazole and sometimes making the azole ineffective. Alternative agents or dose changes are needed, which is why azole prescriptions for patients on antitubercular therapy need specialist review.