Antifungal Principles
Fungi are eukaryotes, so the drug targets that differ from human cells are few: ergosterol in the cell membrane, the cell wall (glucan and chitin), and a small number of enzymes in nucleic acid and cell wall precursor synthesis.
This limits the number of drug classes, narrows the therapeutic index of many agents, and produces overlapping toxicity and many drug interactions.
Selection of therapy depends on the pathogen, the site, the host, the drug's pharmacology, and the purpose of treatment (prophylaxis, empirical, pre-emptive, targeted, or suppressive).
| Class | Drugs | Target and mechanism |
|---|---|---|
| Polyenes | Amphotericin B (deoxycholate, liposomal, lipid complex), nystatin, natamycin | Bind ergosterol in the cell membrane, forming pores and extracting sterols, with leakage of ions and cell death; oxidative damage and immune modulation |
| Azoles (triazoles) | Fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, oteseconazole (selective) | Inhibit the cytochrome P450 enzyme lanosterol 14 alpha demethylase (ERG11 in yeasts, cyp51A and cyp51B in moulds), which blocks ergosterol synthesis and accumulates toxic sterols |
| Imidazoles (topical and a few oral) | Clotrimazole, miconazole, ketoconazole, econazole, sertaconazole, and others | Inhibit lanosterol 14 alpha demethylase; broader inhibition of human cytochrome enzymes |
| Echinocandins | Caspofungin, micafungin, anidulafungin, rezafungin | Inhibit beta 1,3 D glucan synthase (encoded by FKS1 and FKS2), reducing cell wall glucan; fungicidal against Candida, and fungistatic against Aspergillus (damage at hyphal tips) |
| Triterpenoid glucan synthase inhibitor | Ibrexafungerp | Inhibits beta 1,3 D glucan synthase at a site separate from the echinocandins; oral, active against some echinocandin resistant Candida |
| Pyrimidine analogue | Flucytosine | Taken up by cytosine permease and converted by cytosine deaminase to 5 fluorouracil, which inhibits thymidylate synthase and is incorporated into RNA; given with another drug because resistance develops rapidly |
| Allylamines and thiocarbamates | Terbinafine, naftifine, butenafine, tolnaftate | Inhibit squalene epoxidase, blocking ergosterol synthesis, with squalene accumulation; fungicidal against dermatophytes |
| Morpholines | Amorolfine | Inhibit sterol delta 14 reductase and delta 7 delta 8 isomerase |
| Griseofulvin | Griseofulvin | Binds tubulin and disrupts mitosis (fungistatic, dermatophytes only) |
| Others (topical) | Ciclopirox (iron chelation), tavaborole (inhibits leucyl tRNA synthetase), efinaconazole, selenium sulphide, zinc pyrithione, and others | Various |
| New classes | Olorofim (orotomide; inhibits dihydroorotate dehydrogenase and pyrimidine synthesis; active against Aspergillus, Scedosporium, Lomentosporium, and dimorphic fungi, not against Mucorales or yeasts), fosmanogepix (inhibits Gwt1 and glycosylphosphatidylinositol anchor synthesis; broad activity including Candida auris, Fusarium, Scedosporium, and Mucorales), opelconazole (inhaled azole), encochleated amphotericin B (oral), and others | In clinical development |
| Pathogen | Polyenes | Fluconazole | Mould active azoles | Echinocandins | Flucytosine | Allylamines |
|---|---|---|---|---|---|---|
| Candida albicans | Active | Active | Active | Active | Active | Not used |
| Candida glabrata | Active | Reduced | Variable | Active | Active | Not used |
| Candida krusei | Active | Resistant | Active (voriconazole) | Active | Poor | Not used |
| Candida parapsilosis | Active | Active | Active | Higher MIC, still active | Active | Not used |
| Candida auris | Variable | Often resistant | Variable | Active | Variable | Not used |
| Cryptococcus | Active | Moderate | Active | Inactive | Active | Not used |
| Aspergillus fumigatus | Active | Inactive | Active | Active (static) | Inactive | Not used |
| Aspergillus terreus | Resistant | Inactive | Active | Active | Inactive | Not used |
| Mucorales | Active | Inactive | Posaconazole and isavuconazole active | Inactive | Inactive | Not used |
| Fusarium | Variable | Inactive | Voriconazole variable | Inactive | Inactive | Not used |
| Scedosporium | Poor | Inactive | Voriconazole active | Poor | Inactive | Not used |
| Lomentosporium prolificans | Resistant | Resistant | Resistant | Resistant | Resistant | Terbinafine in combination |
| Endemic dimorphic fungi | Active | Moderate | Active | Poor | Poor | Not used |
| Pneumocystis jirovecii | Inactive | Inactive | Inactive | Active (cysts) | Inactive | Not used |
| Dermatophytes | Not used | Moderate | Active (itraconazole) | Inactive | Inactive | Active |
| Malassezia | Active | Variable | Active | Inactive | Inactive | Not used |
| Drug | Activity |
|---|---|
| Amphotericin B | Fungicidal against most yeasts and moulds |
| Echinocandins | Fungicidal against Candida (not Candida parapsilosis as strongly), fungistatic against Aspergillus, inactive against Cryptococcus |
| Azoles | Fungistatic against Candida and Cryptococcus, fungicidal against Aspergillus (voriconazole and posaconazole in vitro) |
| Flucytosine | Fungistatic alone, with synergy with amphotericin B |
| Terbinafine | Fungicidal against dermatophytes, and fungistatic against Candida |
Fungicidal drugs are preferred where host defences cannot help, such as in neutropenia, endocarditis, and meningitis, though clinical proof of superiority is limited.
| Drug | Absorption | Distribution | Elimination | Notes |
|---|---|---|---|---|
| Amphotericin B (all) | Not absorbed orally; intravenous only | Wide tissue distribution; low cerebrospinal fluid and urine levels (liposomal preparations reach brain tissue) | Slow (terminal half life up to 15 days for the conventional form); non renal | Liposomal forms reach high plasma levels (peak 83 micrograms per mL at 5 mg per kg) |
| Fluconazole | Over 90 percent bioavailable, independent of food and gastric acid | Excellent distribution to cerebrospinal fluid, eye, urine, and tissues; low protein binding | Renal (80 percent unchanged); half life 30 hours | Dose adjusted for renal function |
| Itraconazole | Capsules need food and gastric acid; solution on an empty stomach; SUBA formulation less variable | Highly protein bound, lipophilic; poor cerebrospinal fluid levels | Hepatic (cytochrome 3A4), active metabolite hydroxy itraconazole; half life 24 to 42 hours | Negative inotrope; avoid in heart failure |
| Voriconazole | 90 percent oral bioavailability; taken on an empty stomach | Wide, including the brain | Hepatic (cytochrome 2C19, 2C9, and 3A4); non linear kinetics; genetic variation (poor, extensive, and ultrarapid metabolisers) | Therapeutic drug monitoring needed |
| Posaconazole | Delayed release tablets taken with food; suspension needs a fatty meal; intravenous form for central veins | Highly protein bound; widely distributed | Glucuronidation; strong inhibitor of cytochrome 3A4; half life 25 to 30 hours | Trough monitoring |
| Isavuconazole | Prodrug isavuconazonium sulphate, good oral bioavailability | Wide, including the brain | Hepatic; half life about 130 hours | Shortens the QT interval; less hepatotoxic |
| Echinocandins | Not absorbed orally; intravenous only | Highly protein bound; poor cerebrospinal fluid, urine, and eye levels | Hepatic (hydrolysis, not cytochrome); half life 10 to 15 hours (rezafungin about 130 hours, once weekly) | No renal adjustment |
| Flucytosine | Well absorbed orally; intravenous form in some countries | Excellent, including cerebrospinal fluid | Renal (over 90 percent unchanged); half life 3 to 6 hours | Dose by renal function, with level monitoring |
| Terbinafine | Oral, with food | Lipophilic; concentrates in skin, nails, and fat | Hepatic (cytochrome 2D6); a long terminal half life (200 to 400 hours) | Persists in nails for months |
| Griseofulvin | Absorbed better with fatty food | Concentrates in keratin | Hepatic | Induces cytochrome enzymes |
| Class | Main adverse effects | Monitoring |
|---|---|---|
| Amphotericin B | Infusion reactions, nephrotoxicity, hypokalaemia, hypomagnesaemia, anaemia, and thrombophlebitis (deoxycholate) | Creatinine, potassium, magnesium, and full blood count, 2 to 3 times weekly |
| Fluconazole | Nausea, headache, rash, hepatotoxicity, QT prolongation, alopecia (long courses), and teratogenicity at high doses | Liver tests; electrocardiogram when risk factors exist |
| Itraconazole | Hepatotoxicity, heart failure, hypokalaemia, hypertension, oedema, gastrointestinal upset, peripheral neuropathy, and adrenal effects | Liver tests, blood pressure, potassium, and drug levels |
| Voriconazole | Visual disturbance (transient), hallucinations, hepatotoxicity, photosensitivity, skin cancer and periostitis with long term use (fluoride), QT prolongation, and neurotoxicity at high levels | Liver tests, drug levels, skin review, and electrocardiogram |
| Posaconazole | Gastrointestinal upset, hepatotoxicity, QT prolongation, hypertension, hypokalaemia (with mineralocorticoid excess at high doses) | Liver tests, drug levels, and electrocardiogram |
| Isavuconazole | Nausea, hepatotoxicity (milder), rash, QT shortening | Liver tests |
| Echinocandins | Phlebitis, fever, rash, histamine like reactions, raised liver tests | Liver tests |
| Flucytosine | Bone marrow suppression (leucopenia, thrombocytopenia), hepatotoxicity, diarrhoea, and enterocolitis, with toxicity from accumulation in renal failure | Full blood count twice weekly, liver and renal tests, and drug levels |
| Terbinafine | Taste disturbance, rash, hepatotoxicity (rare, severe), neutropenia, and drug interactions via cytochrome 2D6 | Liver tests at baseline and, in prolonged courses, during therapy |
| Griseofulvin | Headache, rash, photosensitivity, hepatotoxicity | Liver tests |
| Principle | Details |
|---|---|
| Azoles inhibit cytochrome P450 enzymes | Itraconazole and posaconazole (strong inhibitors of 3A4), voriconazole (2C19, 2C9, 3A4), fluconazole (2C9, 2C19, 3A4, moderate), isavuconazole (moderate inhibitor of 3A4); they raise levels of calcineurin inhibitors, sirolimus, vinca alkaloids, statins (simvastatin and lovastatin contraindicated), benzodiazepines, opioids, antiarrhythmics, direct oral anticoagulants, and many cancer drugs |
| Inducers lower azole levels | Rifampicin, rifabutin, carbamazepine, phenytoin, phenobarbital, efavirenz, and St John's wort |
| QT prolongation | Azoles (except isavuconazole), with other QT prolonging drugs (macrolides, fluoroquinolones, ondansetron, antipsychotics) |
| Gastric acid | Lowers absorption of itraconazole capsules, and of posaconazole suspension |
| Nephrotoxicity | Amphotericin B with ciclosporin, tacrolimus, aminoglycosides, vancomycin, and contrast |
| Hypokalaemia | Amphotericin B with corticosteroids, diuretics, and digoxin (digoxin toxicity) |
| Flucytosine | Accumulates with renal impairment and amphotericin B |
| Echinocandins | Few interactions; ciclosporin raises caspofungin levels; rifampicin lowers caspofungin (a dose increase is made), and rifampicin lowers micafungin slightly |
| Terbinafine | Inhibits cytochrome 2D6 (tricyclic antidepressants, beta blockers, and some antipsychotics) |
| Group | Principles |
|---|---|
| Renal impairment | Fluconazole and flucytosine are adjusted; amphotericin B is not adjusted but nephrotoxicity limits use (lipid forms are preferred); echinocandins, voriconazole tablets, and posaconazole are not adjusted (the intravenous voriconazole and posaconazole vehicles accumulate in severe renal failure, so oral therapy is preferred if the creatinine clearance is below 50 mL per minute) |
| Hepatic impairment | Dose reduction of voriconazole (half the maintenance dose in Child Pugh A and B), caspofungin (35 mg daily in moderate impairment after a 70 mg loading dose), and avoidance of azoles when severe |
| Pregnancy | Amphotericin B (liposomal) is the preferred drug in invasive disease; echinocandins have limited data; fluconazole at 400 mg per day or more in the first trimester is associated with craniofacial and skeletal abnormalities (a single 150 mg dose carries a low risk, though some association with spontaneous abortion has been reported); other azoles and flucytosine are avoided; topical clotrimazole and miconazole are used for vulvovaginal candidiasis |
| Breastfeeding | Fluconazole and amphotericin B pass little into milk; echinocandins have no data |
| Children | Dosing by weight or surface area with higher per kg doses (clearance is faster); voriconazole 9 mg per kg every 12 hours twice on day 1 then 8 mg per kg every 12 hours in children under 12 years (and under 50 kg); caspofungin 70 mg per square metre loading then 50 mg per square metre; micafungin 2 mg per kg (maximum 100 mg), and for neonates 10 mg per kg; fluconazole 12 mg per kg loading then 6 to 12 mg per kg; liposomal amphotericin B 3 to 5 mg per kg |
| Obesity | Loading doses by actual weight, with dose capped for some drugs; therapeutic drug monitoring |
| Critical illness and extracorporeal support | Altered pharmacokinetics (low levels of voriconazole, fluconazole, and posaconazole in some), with levels checked |
| Strategy | Purpose and approach |
|---|---|
| Prophylaxis | Prevent infection in high risk groups, with a drug chosen by the pathogen risk (fluconazole for yeasts, a mould active azole for moulds), interactions, and local epidemiology |
| Empirical therapy | Treatment of persistent fever in neutropenia or of suspected invasive candidiasis in the critically ill, before a diagnosis |
| Pre-emptive therapy | Treatment guided by biomarkers, imaging, and early tests, in high risk patients |
| Targeted therapy | Treatment after identification, with an active drug at the site |
| Step down | Change from intravenous to oral therapy when the patient is stable and the isolate is susceptible (fluconazole for Candida, voriconazole or posaconazole for moulds) |
| De-escalation | Narrowing the spectrum after culture and susceptibility results |
| Combination | Used in cryptococcal meningitis (amphotericin B with flucytosine), mould infections that are refractory (limited evidence), and Lomentosporium (voriconazole with terbinafine) |
| Source control | Removal of catheters, drainage, and surgery are central to success |
| Duration | Guided by the site and by resolution: 14 days after clearance of candidaemia, and months for moulds and endemic mycoses |
| Suppressive and secondary prophylaxis | Prevents relapse during continued immunosuppression |
| Stewardship | Avoids unnecessary treatment (for example, treating candiduria or colonisation), checks doses and levels, and shortens the course when possible |
| Mechanism | Examples |
|---|---|
| Target alteration | ERG11 mutations and cyp51A mutations (azoles); FKS1 and FKS2 hot spot mutations (echinocandins) |
| Target overexpression | ERG11 up regulation (azoles); cyp51A promoter tandem repeats (TR34, TR46) in Aspergillus fumigatus |
| Efflux pumps | CDR1, CDR2 (adenosine triphosphate binding cassette transporters), and MDR1 (major facilitator) up regulated through TAC1, MRR1, and UPC2 gain of function mutations; Candida auris efflux |
| Alterations in sterol biosynthesis | ERG3 mutations (azole resistance with cross resistance to amphotericin B in some species), and ERG2, ERG6, ERG11 mutations (amphotericin B resistance with low ergosterol) |
| Aneuploidy and genome plasticity | Isochromosome formation in Candida albicans (fluconazole heteroresistance) |
| Biofilm | Matrix glucan binding of drugs, efflux, and persister cells; common on devices |
| Tolerance and heteroresistance | Subpopulations that survive drug exposure |
| Intrinsic resistance | A species property (Candida krusei and fluconazole, Aspergillus terreus and amphotericin B, Cryptococcus and echinocandins) |
| Environmental selection | Agricultural azole fungicides select for azole resistant Aspergillus fumigatus (TR34/L98H, TR46/Y121F/T289A), which causes disease in azole naive patients |
| Stress responses | Heat shock protein 90, calcineurin, and cell wall repair pathways that allow adaptation |
| Clinical risk factors | Prior azole or echinocandin exposure, prolonged therapy and prophylaxis, intensive care, catheters, and transmission in hospitals (Candida auris) |
