Azoles
The azoles are the largest class of antifungal drugs and the mainstay of oral and prophylactic therapy. They contain a five membered ring with either two nitrogen atoms (imidazoles) or three (triazoles). The imidazoles (clotrimazole, miconazole, ketoconazole, econazole) are mostly topical, and the triazoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) are used systemically.
Oteseconazole is a tetrazole with high selectivity for the fungal enzyme. The azoles are fungistatic against yeasts and, for the mould active members, fungicidal against Aspergillus. Their main limitations are resistance, hepatotoxicity, and a large number of drug interactions.
The azole nitrogen binds the haem iron of the fungal cytochrome P450 enzyme lanosterol 14 alpha demethylase (encoded by ERG11 in yeasts, and cyp51A and cyp51B in Aspergillus). This blocks conversion of lanosterol to ergosterol, so the membrane is depleted of ergosterol and accumulates 14 alpha methylated sterols, including toxic sterols (14 alpha methyl 3,6 diol, produced through ERG3).
Membrane permeability and the function of membrane bound enzymes are altered, and growth stops. The less selective azoles (ketoconazole, itraconazole) also inhibit human cytochrome P450 enzymes and steroid synthesis.
| Drug | Generation | Spectrum | Notes |
|---|---|---|---|
| Fluconazole | First triazole | Candida albicans, Candida tropicalis, Candida parapsilosis, Cryptococcus, Coccidioides, dermatophytes, and Histoplasma (limited) | Inactive against moulds; Candida krusei intrinsically resistant, and Candida glabrata dose dependent; resistant Candida auris is frequent |
| Itraconazole | First triazole | Dermatophytes, Candida (including some fluconazole resistant), Aspergillus, Histoplasma, Blastomyces, Sporothrix, Talaromyces, Paracoccidioides, Coccidioides, dematiaceous fungi, Malassezia | Not active against Mucorales; poor Fusarium and Scedosporium activity |
| Voriconazole | Second generation | Candida (including Candida krusei), Aspergillus (the first line drug), Fusarium (variable), Scedosporium apiospermum, Cryptococcus, and dimorphic fungi | Inactive against Mucorales; Aspergillus species with cyp51A mutations are resistant |
| Posaconazole | Second generation | Most Candida, Aspergillus, Mucorales (with activity of clinical importance), Cryptococcus, dimorphic fungi, Fusarium (variable), dematiaceous fungi | The broadest spectrum oral azole; used for prophylaxis and salvage |
| Isavuconazole | Second generation | Aspergillus, Mucorales, Candida, Cryptococcus, dimorphic fungi | Water soluble prodrug; fewer adverse effects and interactions; activity against Fusarium is limited |
| Ketoconazole | First imidazole | Dermatophytes, Candida, Malassezia, dimorphic fungi | Oral use restricted for hepatotoxicity and adrenal suppression; topical use common; used in Cushing disease |
| Oteseconazole | Tetrazole | Candida albicans and non albicans species | Approved for recurrent vulvovaginal candidiasis; selective for fungal cytochrome |
| Topical imidazoles and triazoles | Various | Dermatophytes, Candida, Malassezia | Clotrimazole, miconazole, econazole, ketoconazole, sertaconazole, luliconazole, terconazole, butoconazole, efinaconazole |
| Drug | Bioavailability and absorption | Distribution | Metabolism and half life | Notes |
|---|---|---|---|---|
| Fluconazole | Over 90 percent, with or without food | Total body water; cerebrospinal fluid 50 to 90 percent of serum, urine, eye, and peritoneum | Renal clearance (80 percent unchanged); half life about 30 hours | Dose adjusted for renal impairment; loading dose doubles the first dose |
| Itraconazole | Capsules 55 percent with a full meal and acid; solution 30 percent higher on an empty stomach; SUBA capsules are less dependent on acid | Highly bound to protein (99.8 percent); high tissue levels in skin, nails, and lung, low in cerebrospinal fluid and urine | Hepatic (cytochrome 3A4) to active hydroxy itraconazole; half life 24 to 42 hours at steady state | Levels are measured by high performance liquid chromatography; nonlinear kinetics |
| Voriconazole | About 90 percent; fasting dose (1 hour before or after meals) | Wide, including cerebrospinal fluid (50 percent) and brain | Hepatic (cytochrome 2C19, 2C9, 3A4); nonlinear kinetics; half life 6 hours dose dependent; poor metabolisers (CYP2C19) have 3 to 4 fold higher exposure and ultrarapid metabolisers have low levels | Levels needed |
| Posaconazole | Delayed release tablets 54 percent with food; suspension poor and variable; intravenous | Large volume of distribution; protein binding 98 percent; low cerebrospinal fluid levels | Glucuronidation, with an active parent compound; half life 26 to 31 hours | Tablets give reliable levels |
| Isavuconazole | Prodrug (isavuconazonium sulphate) with 98 percent bioavailability | Large volume of distribution; brain tissue penetration | Hepatic; very long half life (about 130 hours) | No food effect |
| Ketoconazole | Needs acid | Poor in cerebrospinal fluid | Hepatic | Inhibits steroid synthesis |
| Feature | Details |
|---|---|
| Indications | Oropharyngeal, oesophageal, and vulvovaginal candidiasis; candidaemia (step down, and first line when the species is susceptible and the patient is stable); candiduria; cryptococcal meningitis (consolidation and maintenance); coccidioidal meningitis; prophylaxis in neutropenia, transplant, and premature infants; tinea (alternative); and onychomycosis (alternative) |
| Adult doses | Oropharyngeal candidiasis: 100 to 200 mg once daily for 7 to 14 days; oesophageal: 200 to 400 mg once daily for 14 to 21 days; vulvovaginal: 150 mg once (recurrent: 150 mg weekly for 6 months after an induction of 150 mg every 72 hours for 3 doses); candidaemia: 800 mg loading (12 mg per kg) then 400 mg (6 mg per kg) once daily; cryptococcal consolidation: 800 mg once daily for 8 weeks, then 200 mg once daily maintenance for 12 months or more; coccidioidal meningitis: 800 to 1200 mg once daily; prophylaxis: 200 to 400 mg once daily |
| Children | Candidaemia: 12 mg per kg loading then 6 to 12 mg per kg once daily; neonates (prophylaxis) 3 to 6 mg per kg twice weekly |
| Renal impairment | Normal loading dose, then 50 percent of the dose when creatinine clearance is under 50 mL per minute; dialysis: a dose after each session |
| Adverse effects | Nausea, headache, rash, raised aminotransferases, QT prolongation, alopecia and dry skin (long term high doses), adrenal suppression (high dose), hypokalaemia, teratogenicity (high dose in the first trimester), and rarely Stevens Johnson syndrome and hepatic failure |
| Interactions | Inhibits cytochrome 2C9, 2C19, and 3A4 (warfarin, phenytoin, sulfonylureas, ciclosporin, tacrolimus, sirolimus, statins, and benzodiazepines) |
| Resistance | ERG11 mutations, up regulation of efflux pumps, and intrinsic resistance (Candida krusei); common in Candida glabrata (dose dependent), Candida auris, and Candida parapsilosis in some regions |
| Feature | Details |
|---|---|
| Indications | Endemic mycoses (histoplasmosis, blastomycosis, sporotrichosis, paracoccidioidomycosis, talaromycosis), chronic pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, chromoblastomycosis, eumycetoma, dermatophytosis, tinea capitis, onychomycosis, pityriasis versicolor, oral and oesophageal candidiasis (fluconazole refractory), and prophylaxis |
| Adult doses | Loading 200 mg three times daily for 3 days, then 200 mg once or twice daily; sporotrichosis 200 mg once daily for 3 to 6 months; onychomycosis 200 mg daily for 12 weeks (or pulse 200 mg twice daily for 1 week per month for 2 months for fingernails and 3 months for toenails); tinea corporis 100 mg daily for 2 weeks; pityriasis versicolor 200 mg daily for 5 to 7 days; oral solution 200 mg daily for oropharyngeal candidiasis; SUBA itraconazole 130 mg twice daily (a lower dose equivalent) |
| Levels | Trough of itraconazole plus hydroxy itraconazole above 1 microgram per mL (above 0.5 for prophylaxis), and below 10 by bioassay |
| Administration | Capsules with a full meal and an acidic drink (avoid proton pump inhibitors and antacids); solution on an empty stomach |
| Adverse effects | Hepatotoxicity, negative inotropy and heart failure (contraindicated in heart failure), hypokalaemia, hypertension, oedema (a mineralocorticoid excess state), peripheral neuropathy, gastrointestinal upset, rash, and impotence; QT prolongation |
| Interactions | Strong cytochrome 3A4 inhibitor and P glycoprotein inhibitor: contraindicated with simvastatin, lovastatin, midazolam, triazolam, quinidine, dofetilide, and ergot alkaloids; raises levels of digoxin, calcineurin inhibitors, vincristine, and others; rifampicin and phenytoin lower its levels |
| Feature | Details |
|---|---|
| Indications | Invasive aspergillosis (first line), candidaemia and invasive candidiasis (alternative), oesophageal candidiasis, fusariosis, scedosporiosis, and prophylaxis in selected groups |
| Dose | Intravenous 6 mg per kg every 12 hours for 2 doses, then 4 mg per kg every 12 hours; oral 400 mg every 12 hours for 2 doses (weight above 40 kg), then 200 mg every 12 hours (up to 300 mg every 12 hours), and for under 40 kg 200 mg then 100 mg every 12 hours; children 2 to under 12 years: 9 mg per kg every 12 hours for 2 doses, then 8 mg per kg every 12 hours (intravenous), and oral 9 mg per kg every 12 hours (maximum 350 mg) |
| Levels | Trough 1 to 5.5 micrograms per mL (above 2 for severe or central nervous system disease); take levels 5 to 7 days after starting |
| Renal impairment | Oral therapy for creatinine clearance below 50 mL per minute, because the cyclodextrin vehicle (sulphobutyl ether beta cyclodextrin) of the intravenous form accumulates |
| Hepatic impairment | Half the maintenance dose in mild to moderate cirrhosis (Child Pugh A and B) |
| Adverse effects | Transient visual disturbances (30 percent; blurring, photopsia, colour changes), visual and auditory hallucinations, raised liver tests, rash and photosensitivity, periostitis and fluorosis (long term), skin squamous cell carcinoma (long term), neurotoxicity at high levels (encephalopathy), QT prolongation, and peripheral neuropathy |
| Interactions | Inhibits cytochrome 2C19, 2C9, and 3A4: contraindicated with sirolimus, rifampicin, rifabutin, carbamazepine, long acting barbiturates, efavirenz (high dose), ritonavir (high dose), St John's wort, and ergot alkaloids; tacrolimus dose cut to one third and ciclosporin to one half; omeprazole dose halved |
| Genetics | CYP2C19 poor metabolisers need dose reduction, and ultrarapid metabolisers need alternatives or higher doses |
| Feature | Details |
|---|---|
| Indications | Prophylaxis in acute myeloid leukaemia, myelodysplastic syndrome, and graft versus host disease; treatment of invasive aspergillosis (first line, equal to voriconazole in a trial) and mucormycosis (step down and salvage); refractory oropharyngeal and oesophageal candidiasis; salvage of other moulds |
| Doses | Delayed release tablets 300 mg twice daily on day 1, then 300 mg once daily; intravenous 300 mg twice daily on day 1, then 300 mg daily (through a central line); suspension 200 mg three times daily (prophylaxis) or 400 mg twice daily (treatment) with a fatty meal |
| Levels | Trough above 0.7 micrograms per mL (prophylaxis) and above 1 (treatment), with above 1.25 sometimes used for salvage |
| Adverse effects | Nausea, diarrhoea, headache, raised aminotransferases, QT prolongation, hypokalaemia, hypertension, oedema, and mineralocorticoid excess (at high exposure) |
| Interactions | Strong cytochrome 3A4 inhibitor and P glycoprotein inhibitor: contraindicated with simvastatin, lovastatin, ergot alkaloids, and sirolimus (reduce sirolimus by 90 percent if essential), and requires tacrolimus reduction to one third and ciclosporin to three quarters; vinca alkaloid neurotoxicity |
| Acid suppression | Reduces suspension absorption; tablets are not affected |
| Feature | Details |
|---|---|
| Indications | Invasive aspergillosis (non inferior to voriconazole with fewer adverse events), mucormycosis (first line when amphotericin B cannot be used, step down), and invasive candidiasis (investigational use in some regions) |
| Dose | Isavuconazonium sulphate 372 mg (isavuconazole 200 mg) every 8 hours for 6 doses, then 372 mg once daily, orally or intravenously |
| Adverse effects | Nausea, vomiting, diarrhoea, raised aminotransferases (less than with voriconazole), headache, infusion reactions, hypokalaemia; QT shortening (contraindicated in familial short QT syndrome) |
| Interactions | Moderate cytochrome 3A4 inhibitor: ciclosporin, tacrolimus, and sirolimus levels need monitoring; strong inducers (rifampicin, carbamazepine) and strong inhibitors (ketoconazole) are contraindicated or adjusted |
| Advantages | Water soluble formulation (no cyclodextrin, so no renal restriction), no food effect, fewer visual and neurological effects, and a long half life |
| Therapeutic drug monitoring | Not routinely needed |
| Drug | Use |
|---|---|
| Ketoconazole (oral) | 200 to 400 mg daily for histoplasmosis, blastomycosis, and paracoccidioidomycosis in settings where itraconazole is unavailable; severe hepatotoxicity (boxed warning), adrenal suppression, and QT prolongation, so it is no longer first line; used in Cushing disease and prostate cancer for steroid inhibition |
| Ketoconazole (topical) | Cream 2 percent once or twice daily for 2 to 4 weeks (tinea, cutaneous candidiasis, seborrhoeic dermatitis); shampoo 2 percent twice weekly for pityriasis versicolor and dandruff |
| Clotrimazole | Cream 1 percent twice daily for 2 to 4 weeks (tinea, candidiasis); vaginal pessary 500 mg once or 200 mg for 3 nights; oropharyngeal troche 10 mg five times daily for 7 to 14 days |
| Miconazole | Cream 2 percent twice daily; vaginal; buccal tablet 50 mg once daily for 7 to 14 days (oropharyngeal candidiasis); oral gel 2 percent (interacts with warfarin) |
| Econazole, sertaconazole, luliconazole | Creams used once or twice daily for 2 to 4 weeks (luliconazole 1 percent once daily for 1 to 2 weeks) |
| Terconazole, butoconazole | Vaginal creams for vulvovaginal candidiasis for 3 to 7 days |
| Efinaconazole | 10 percent topical solution once daily to the toenail for 48 weeks (onychomycosis) |
| Oteseconazole | Oral, for recurrent vulvovaginal candidiasis: 600 mg on day 1, 450 mg on day 2, then 150 mg once weekly for 11 weeks; contraindicated in females of reproductive potential (long half life of 138 days) and in pregnancy |
Resistance arises through mutations in ERG11 and cyp51A, overexpression of the target (promoter tandem repeats TR34 and TR46 in Aspergillus fumigatus), up regulation of efflux pumps (CDR1, CDR2, MDR1), changes in sterol biosynthesis (ERG3), aneuploidy, and biofilm formation. Environmental exposure to agricultural azole fungicides selects resistant Aspergillus fumigatus. Cross resistance within the class is usual, but varies (isavuconazole and voriconazole MICs rise together, and posaconazole is sometimes less affected).
| Group | Principles |
|---|---|
| Pregnancy | Systemic azoles are avoided, because high dose fluconazole (400 mg per day or more) in the first trimester is linked to craniofacial and skeletal malformations (a single 150 mg dose has a low risk), and voriconazole is teratogenic in animals and in case reports; topical clotrimazole and miconazole are used for vulvovaginal candidiasis |
| Breastfeeding | Fluconazole is compatible in single doses; others have little data |
| Children | Higher per kg doses, and drug level monitoring for voriconazole and posaconazole |
| Elderly | Interactions and hepatic function are the main concerns |
| Liver disease | Dose reductions and avoidance of ketoconazole |
| Kidney disease | Fluconazole adjusted; voriconazole intravenous avoided |
