Antifungals

The major systemic antifungal drug classes in clinical practice are the azoles, echinocandins, polyenes, and the pyrimidine analogue flucytosine. Each has a distinct mechanism of action, spectrum of activity, route of administration and toxicity profile.

Rational selection is guided by the fungal pathogen, the site and severity of infection, and individual patient factors. These include renal and hepatic function and drug interaction potential. For several agents, significant interpatient pharmacokinetic variability also makes therapeutic drug monitoring necessary.

The specific application of each class depends on the individual fungal infection being treated.

Classification by mechanism

• Azoles (triazoles and imidazoles) inhibit fungal cytochrome P450 dependent 14 alpha demethylase. This blocks ergosterol synthesis and disrupts fungal cell membrane integrity.
• The principal systemic azoles in current clinical use are fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole. Each has a differing spectrum, bioavailability and interaction profile.
• Echinocandins (caspofungin, micafungin, anidulafungin) inhibit synthesis of beta 1,3 glucan, an essential component of the fungal cell wall not present in mammalian cells. This confers a favourable safety profile.
• Echinocandins are fungicidal against Candida species specifically. Activity against Cryptococcus is limited, and there is no activity against Mucorales.
• Polyenes (amphotericin B) bind ergosterol within the fungal cell membrane, creating pores that disrupt membrane integrity. Formulations are conventional deoxycholate and, now predominantly used, lipid formulations including liposomal amphotericin B.
• Polyenes offer the broadest spectrum of antifungal activity of any available class. Toxicity is significant and dose limiting, particularly nephrotoxicity, and is substantially reduced with lipid formulations.
• Flucytosine, a pyrimidine analogue, is converted within fungal cells to 5 fluorouracil, disrupting fungal deoxyribonucleic acid and protein synthesis.
• Flucytosine is used almost exclusively in combination with amphotericin B, given rapid emergence of resistance with monotherapy. Its indications are cryptococcal meningitis and, in some contexts, severe candidiasis.

• The clinical presentation requiring antifungal treatment depends entirely on the underlying fungal infection (candidiasis, aspergillosis, cryptococcal meningitis, and others). It is not a feature of the antifungal agents themselves.
• Recognising drug specific adverse effects is an important skill for safe antifungal prescribing.
  • Amphotericin B is classically associated with infusion related reactions (fever, rigors, myalgia, often mitigated with premedication). It also causes dose dependent nephrotoxicity with electrolyte wasting (particularly potassium and magnesium).
  • Azoles are associated with hepatotoxicity, requiring baseline and periodic liver function monitoring. Voriconazole specifically causes visual disturbance and photosensitivity.
  • Echinocandins have a generally favourable tolerability profile. Infusion related histamine mediated reactions are the principal recognised concern.
• Drug interactions are a major, clinically significant consideration, particularly for the azole class. Potent cytochrome P450 inhibition (variable between agents) affects metabolism of numerous other medications.
• These include immunosuppressants (calcineurin inhibitors, sirolimus), certain chemotherapy agents, and specific antiretroviral drugs. Review co-administered medications whenever an azole antifungal is introduced, and frequently adjust their doses.

• Antifungal selection relies fundamentally on accurate identification of the causative fungal organism. Use susceptibility testing where available and clinically relevant.
• This matters because susceptibility varies significantly, and sometimes unpredictably, between fungal species and, increasingly, between strains within a single species.
• Therapeutic drug monitoring is an essential component of safe and effective use for several agents. The most notable is voriconazole, which shows substantial interpatient pharmacokinetic variability related to genetic polymorphism in its principal metabolic pathway. A target trough level of 1 to 5.5 mg per litre is generally recommended.
• Itraconazole and posaconazole levels are also monitored where available. Adequate drug exposure relates directly to treatment efficacy, and excessive levels to toxicity risk.
• Renal function monitoring is essential with amphotericin B, given its characteristic, dose related nephrotoxicity.
• Flucytosine level monitoring, where available, supports both efficacy assessment and avoidance of the myelosuppression associated with excessive levels. This is particularly relevant with any degree of renal impairment, given predominantly renal elimination.

• Fluconazole has excellent oral bioavailability and generally good tolerability. It is a mainstay for candidiasis (mucocutaneous and, following appropriate echinocandin induction, many cases of invasive disease caused by susceptible species) and for cryptococcal disease (consolidation and maintenance phases).
• Fluconazole lacks meaningful activity against Aspergillus and several non albicans Candida species, including Candida glabrata and Candida krusei, which show intrinsic or acquired reduced susceptibility.
• Voriconazole is first line treatment for invasive aspergillosis and requires therapeutic drug monitoring. Take careful account of its numerous significant drug interactions.
• Specific adverse effects of voriconazole are visual disturbance, typically transient, and photosensitivity requiring sun protection advice. There is also a recognised association with periostitis and, rarely, squamous cell carcinoma with very prolonged use.
• Isavuconazole and, in some contexts, posaconazole are effective alternatives to voriconazole for invasive aspergillosis. They also have activity against Mucorales, the causative organisms of mucormycosis.
• This is important where this aggressive, angioinvasive fungal infection is a relevant differential or confirmed diagnosis. Neither fluconazole, voriconazole nor the echinocandins have meaningful activity against this group.
• Echinocandins are the preferred first line empirical therapy for suspected or confirmed invasive candidiasis in most clinical guidelines. They have broad activity across Candida species, including several azole resistant strains, and a favourable safety profile. This is particularly relevant in critically ill patients with frequently compromised renal and hepatic function.
• Liposomal amphotericin B remains essential for mucormycosis as first line treatment, often combined with aggressive surgical debridement given the angioinvasive, tissue destructive nature of this infection.
• It is also essential for cryptococcal meningitis induction (combined with flucytosine as detailed under that condition). It is a broad spectrum option for severe or refractory invasive fungal infection where the causative organism or its susceptibility pattern is not yet established.
• Prophylactic antifungal therapy is used in specific high risk populations. Examples are certain haematological malignancy and stem cell transplant protocols, given the substantial risk of invasive fungal infection during profound, prolonged neutropenia. Agent selection is guided by the fungal risk profile of the individual protocol and local epidemiology.
• Antifungal selection, dosing, monitoring and interaction management are complex. Specialist infectious disease, microbiology or, where relevant, haematology input is valuable in complex or severe invasive fungal infection.
• This applies particularly in significantly immunocompromised patients, where the consequences of both undertreatment and drug related toxicity or interaction can be substantial.