Caspofungin (Cancidas, Merck) was the first of a new class of antifungal drug, the echinocandins, to be licensed. It is a semi-synthetic modification of a fermentation product from the fungus Glarea lozoyensis. Initially reported in 1989, clinical studies commenced in 1997, and it was licensed in 2002. It inhibits the function of beta-(1,3)-D-glucan synthase.
Dose & Delivery
Caspofungin is intravenous only. The standard dose is a 70mg loading dose with each subsequent dose being 50mg, each given once a day. In patients weighing more than 80kg it is recommended (in Europe) that 70mg a day is given rather than 50mg a day. Recent clinical study has shown no additional toxicities at doses of 150mg daily. Patients with moderate liver insufficiency should receive a dose of 35mg a day and it is possible that the drug is not appropriate for patients with severe liver disease although this has not been decided. The appropriate dose in children is 50mg/m2 daily.
Fungi which are sensitive
Caspofungin is active against all species of Candida, with few exceptions. It is extremely active and usually rapidly fungicidal against all species except Candida parapsilosis, Candida guilliermondii and Candida famata against which it is moderately active. It has activity against Candida biofilms, which azoles in general do not. Some resistant C. albicans, C. glabrata, C. tropicalis and C. krusei isolates have been described, almost all with mutations in 2 hot spots in the target gene.
Caspofungin is also against all Aspergillus species. It is not fungicidal against Aspergilli. It is not antagonistic when given in combination with amphotericin B or azoles against Aspergilli. It has limited activity against Coccidioides spp., Blastomyces dermatitidis, Scedosporium spp., Paecilomyces varioti and Histoplasma spp. which is not sufficient for clinical use. Recent model data suggests possible synergistic activity with amphotericin B against Rhizopus oryzae.
For all indications, 70mg, loading dose then 50mg a day, increased for people weighing over 80mg. It is possible that higher doses may be useful for some sanctuary site infections (brain, eye etc) and for isolates to which caspofungin has marginal activity, such as C. parapsilosis.
Metabolism and excretion
The drug is chemically degraded slowly in the body. This happens probably in multiple organs including the liver. As a result there are very few alterations to be made in patients with organ dysfunction or taking other drugs with the one exception of severe liver dysfunction.
Caspofungin is not an inhibitor and is a poor substrate for cytochrome people P450 enzymes, so drug interactions are few. It is not a substrate for P-glycoprotein. Concomitant use of ciclosporin with caspofungin increases the exposure to caspofungin by about a third. Caspofungin reduces the trough concentration of tacrolimus by about a quarter so in both instances monitoring of these drugs is appropriate. Concomitant use of caspofungin with rifampicin increases caspofungin exposure but this changes over the first two weeks of therapy. It is likely that strong enzyme inducers such as efavirenz and nevirapine, dexamethasome, phenytoin or carbamazepine may require a slight increase in caspofungin doses, typically 70mg a day. View drug interactions database.
Phlebitis was the commonest side effect in patients receiving caspofungin through a peripheral intravenous catheter. Fever, chills, abdominal pain, nausea, diarrhoea and vomiting were all common together with headache. All were mild and/or reversible when the drug was stopped. Raised liver enzymes occur in about 1 in 20 patients. Other side effects appeared to be rare.
Long term side effects have not been established with the echinocandins because they are relatively new compounds. The duration of therapy is uncertain but typically should be at least two weeks beyond the last evidence of active disease unless a switch to another antifungal is made.
Glarea lozoyensis, from which caspofungin is made.
Structure of caspofungin