Caspofungin acetate is the first antifungal medication of the echinocandins class to receive marketing approval from the Food and Drug Administration (FDA). Its introduction was in 2001, approved for use in adults and pediatric patients (3 months of age and older).
The FDA-approved indications include:
The non-FDA approved indications are:
Caspofungin, along with other echinocandins, works by noncompetitive inhibition of the enzyme beta-(1,3)-D-glucan synthase, which is a critical component to the synthesis of the fungal cell wall; this enzyme is not present in mammalian cells.
Caspofungin exhibits a fungicidal activity against Candida species, including triazole-resistant isolates and fungistatic activity against Aspergillus species. It displays triphasic nonlinear pharmacokinetics. After an initial intravenous administration of the drug, there is a rapid decrease in plasma levels due to tissue distribution, followed by a gradual re-release of the drug from the extravascular tissues as well as slow hepatic metabolism. It undergoes hepatic metabolism via hydrolysis and slow N-acetylation into two inactive metabolites; dose reduction is, therefore, advisable in severe hepatic insufficiency. Caspofungin also undergoes spontaneous disintegration to an open-ring compound.
Reduction of the dose in hepatic insufficiency is recommended based on Child-Pugh (C-P) score. In critically ill patients, however, the dose should not be reduced unless there is evidence of liver cirrhosis. No dose reduction is necessary for renal impairment; echinocandin passage through the membranes seems low because of high protein binding, 97% to albumin. Additionally, an increase in maintenance dose of caspofungin is recommended with coadministration of potent inducers of cytochrome P450 3A4 metabolism. Some of these agents may include rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin. Concomitant use of caspofungin with cyclosporine has also been linked to increased caspofungin-induced hepatotoxicity, although a number of case reports describe patients treated with both drugs without clinically important signs or symptoms of liver toxicity.
The pharmacokinetics of caspofungin also show an increased accumulation as the dose increases, and there is a dose-related dependency in the time to reach steady-state upon multiple-dose administration. A loading dose followed by a lower once-daily dose is therefore required to attain an initial therapeutic plasma level and avoid drug accumulation. This approach results in a trough concentration of at least 1 mcg/mL (proposed target concentration in invasive infections; derived from in vitro susceptibility testing of Candida spp.).
Caspofungin has a short alpha-phase half-life (t 1/2 ) of 1 to 2 hours (volume of distribution of 9.7L) and a beta-phase t 1/2 of 9 to 11 hours that exhibits log linearity. Unlike the other phases, the gamma-phase t 1/2 of 40 to 50 hours appears to be nonlinear and is responsible for the accumulation of caspofungin over time. Caspofungin gets slowly eliminated from plasma, with a clearance of 10 to 12 ml/minute. Approximately 75% of a radioactive dose gets recovered after 27 days, with 41% in urine and 35% in feces. Only about 2% of caspofungin is excreted unchanged in the urine.
Caspofungin acetate is administered solely by the intravenous (IV) route. Because the echinocandins have a large molecular weight, they are poorly bioavailable for oral use. The IV infusion should take place slowly over an hour. It should neither be given by IV bolus administration nor mixed or co-infused with other medications. Do not use diluents containing dextrose (alpha-D-glucose).
The dosage forms include 50 mg and 70 mg. The dosage varies by patient population.
For all indications except esophageal candidiasis - An initial dose of 70 mg (loading dose) followed by 50 mg once IV daily. The daily dose may be increased to 70mg if there is no response or if cytochrome P450 3A4 inducers such as rifampin, nevirapine, efavirenz, carbamazepine, dexamethasone, and phenytoin are coadministered. The maximum daily dose should not exceed 70 mg.
For esophageal candidiasis, the dose is 50 mg once daily with no loading dose.
The basis for dosing is on the patient’s body surface area.
For all indications - a single 70 mg/m2 loading dose on day 1, followed by 50 mg/m2 once daily
The dosage for adult patients with moderate hepatic impairment is reduced: 35 mg once daily, with a 70 mg loading dose on day 1 where appropriate.
Use of caspofungin with cytochrome P450 3A4 inducers (see above), the daily dose may be increased to 70 mg. The maximum daily dose should not exceed 70 mg.
For patients not showing any improvement, the daily dose may increase to 70 mg. The maximum daily dose should not exceed 70 mg.
Caspofungin has a relatively low incidence of adverse effects; the most commonly reported adverse events include chills, fever, phlebitis/thrombophlebitis, tachycardia, nausea, vomiting, rash, abdominal pain, headache, and diarrhea. Reports also exist of a modest elevation of aminotransferases has also been reported.
Caspofungin has been found to cause erosions similar to those seen in toxic epidermal necrolysis (TEN). In fact, a case report by Lee et al. describes the development of a skin rash - erythematous macules and plaques - that quickly progressed to blisters and skin erosions after the administration of caspofungin in an 86-year-old-man with disseminated Candida krusei infection.
The main contraindication is known hypersensitivity to caspofungin acetate or any other ingredients in the formulation.
There is currently inadequate data regarding the use of caspofungin in pregnancy; thus, clinicians should use it cautiously. When treatment of systemic fungal infections is necessary during pregnancy, Amphotericin B is the first-line therapy; other agents are alternatives.
Given the hepatic adverse effects associated with caspofungin, monitoring the liver function is essential.
Caspofungin is known to release histamine in peripheral blood cells, which predisposes patients to potentially developing histamine-mediated symptoms ranging from severe to fatal anaphylaxis. As a result, monitoring patients for anaphylaxis, skin rash, or histamine-related reactions (e.g., facial swelling, bronchospasm, a sensation of warmth) is of paramount importance, to decrease the risk of morbidity and mortality.
Although these rarely occur, clinically significant hepatitis, hepatomegaly, hyperbilirubinemia, and there are reports of hepatic failure with the echinocandins. Checking hepatic aminotransferases regularly during caspofungin therapy is thus recommended.
Caspofungin has significant assets, which include its safety profile and minimal drug interactions. These factors have led to its use for the treatment of several medical conditions. However, it is important to note the side effects, albeit low in incidence, of caspofungin (Level II). Monitoring patients’ liver function to minimize toxicity is also critical, especially given the fact this organ metabolizes the drug. Furthermore, caspofungin is associated with some drug-drug interactions, especially CYP450 3A4 inducers, which cause caspofungin levels to be subtherapeutic (Level I). Before prescribing caspofungin for patients who are taking several medications, the physician should consult with:
Nursing will also play a significant role with inpatient administration, and monitoring to treatment effectiveness as well as checking for adverse effects of the medication and reporting findings to the healthcare team.
Ultimately, adopting an interprofessional team approach with collaboration with infectious diseases physicians and other sub-specialties, primary care physicians, nurses, pharmacists, and other healthcare personnel is essential, to facilitate the administration of the drugs based on current guidelines and maximize patient outcomes while minimizing any adverse reactions. [Level V]
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