Echinocandins
The echinocandins are cyclic lipopeptides that inhibit beta 1,3 D glucan synthase, a target absent in human cells, so they are well tolerated. They are fungicidal against Candida and fungistatic against Aspergillus, are not active against Cryptococcus, Mucorales, Fusarium, or most other moulds, and are given intravenously because oral absorption is minimal. The class includes caspofungin, micafungin, anidulafungin, and rezafungin (a long acting member). They are the first line drugs for invasive candidiasis and candidaemia in most patients.
| Feature | Details |
|---|---|
| Target | Non competitive inhibition of the catalytic subunit (FKS1 and FKS2) of beta 1,3 D glucan synthase, which produces the glucan of the cell wall |
| Effect | Depletion of glucan, weakening of the wall, osmotic instability, and cell lysis (in yeasts, where glucan is abundant); in Aspergillus, damage to growing hyphal tips with abnormal branching |
| Pharmacodynamics | Concentration dependent killing, with the ratio of area under the curve to MIC predicting response; a prolonged post antifungal effect for Candida |
| Paradoxical effect | Growth at high concentrations in vitro for caspofungin, of uncertain clinical relevance |
| Group | Activity |
|---|---|
| Candida | Active against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, and Candida auris (most isolates); higher MICs in Candida parapsilosis (still active) and Candida guilliermondii; resistance in Candida glabrata and Candida auris is due to FKS mutations |
| Aspergillus | Fungistatic; used in salvage and in combination, not as primary monotherapy |
| Pneumocystis jirovecii | Active against cysts (not a standard treatment) |
| Others | Poor or no activity against Cryptococcus, Mucorales, Fusarium, Scedosporium, Trichosporon, Rhodotorula, Malassezia, and dimorphic fungi in the yeast phase |
| Feature | Caspofungin | Micafungin | Anidulafungin | Rezafungin |
|---|---|---|---|---|
| Adult dose | 70 mg on day 1, then 50 mg once daily (70 mg daily if over 80 kg) | 100 mg once daily (candidaemia); 150 mg for oesophageal candidiasis; 50 mg daily for prophylaxis | 200 mg on day 1, then 100 mg once daily (oesophageal: 100 mg then 50 mg) | 400 mg on week 1, then 200 mg once weekly |
| Children | 70 mg per square metre loading then 50 mg per square metre daily (maximum 70 mg) | 2 mg per kg daily (maximum 100 mg); neonates 10 mg per kg | 3 mg per kg loading then 1.5 mg per kg | Not established |
| Half life | 9 to 11 hours | 11 to 17 hours | 24 to 26 hours | About 130 hours |
| Metabolism | Hydrolysis and N acetylation (slow); cytochrome independent | Hepatic (arylsulphatase and catechol O methyltransferase) | Spontaneous chemical degradation; no hepatic metabolism | Minimal metabolism |
| Hepatic impairment | 35 mg daily after loading in moderate (Child Pugh B) | No adjustment in mild to moderate | No adjustment | No adjustment |
| Renal impairment | None | None | None | None |
| Interactions | Ciclosporin raises caspofungin; rifampicin, phenytoin, efavirenz, and carbamazepine lower it (70 mg daily); tacrolimus levels fall slightly | Sirolimus and nifedipine levels rise slightly | Few | Few |
| Central nervous system penetration | Poor | Better in animal models (limited) | Poor | Poor |
| Indication | Role |
|---|---|
| Candidaemia and invasive candidiasis | First line in most patients, particularly those who are critically ill, neutropenic, previously exposed to azoles, or infected with Candida glabrata or Candida auris; duration 14 days after the first negative blood culture; step down to fluconazole once stable with a susceptible isolate |
| Oesophageal candidiasis | Alternative to fluconazole (caspofungin 50 mg, micafungin 150 mg, or anidulafungin 100 mg daily) |
| Empirical therapy | Persistent fever in neutropenia (caspofungin or micafungin), or suspected invasive candidiasis in the critically ill |
| Prophylaxis | Micafungin 50 mg daily in stem cell transplant and neutropenia (an alternative to fluconazole), and in liver transplant (100 mg) |
| Invasive aspergillosis | Salvage monotherapy (caspofungin 70 mg then 50 mg), and combination therapy with voriconazole (voriconazole with anidulafungin improved survival at 6 weeks in a subgroup with a positive galactomannan in a randomised trial, with a trend only for the whole population) |
| Chronic pulmonary aspergillosis | Alternative, with limited evidence |
| Peritonitis and intra-abdominal candidiasis | Echinocandin with source control |
| Endocarditis, osteomyelitis, and central nervous system disease | High doses (for example caspofungin 150 mg daily, micafungin 150 mg daily) may be used with limited evidence |
| Pneumocystis pneumonia | Salvage with trimethoprim sulfamethoxazole (limited evidence) |
| Weekly rezafungin | Candidaemia and invasive candidiasis (non inferior to caspofungin in a randomised trial), potentially for outpatient therapy and prophylaxis |
| Limitation | Details |
|---|---|
| Penetration | Poor levels in urine, eye (vitreous), and cerebrospinal fluid; not for candiduria, endophthalmitis, or meningitis as sole therapy |
| Intravenous only | Oral step down uses fluconazole or another azole |
| Spectrum | No activity against Cryptococcus, Mucorales, and many moulds |
| Resistance | FKS1 and FKS2 hot spot mutations in Candida glabrata, Candida auris, Candida albicans, and others, after prolonged exposure |
| Intrinsic reduced susceptibility | Candida parapsilosis (higher MIC due to a natural polymorphism), though outcomes remain acceptable |
| Biofilm and abscess penetration | Variable |
| Cost | High compared with fluconazole |
| Adverse effect | Features |
|---|---|
| Infusion related | Fever, flushing, phlebitis, and histamine like reactions (rapid infusion), mostly with caspofungin |
| Hepatic | Raised aminotransferases (5 to 15 percent), rare hepatitis; caspofungin with ciclosporin raises transaminases |
| Gastrointestinal | Nausea, vomiting, and diarrhoea |
| Others | Hypokalaemia, rash, headache, anaemia, and thrombocytopenia (rare); anidulafungin infusion rate 1.1 mg per minute to avoid reactions |
| Pregnancy | Animal teratogenicity (skeletal) with caspofungin and micafungin at high doses, so avoided unless essential |
