Nicholas A. Kartsonis

A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis

BACKGROUNDnCandida esophagitis remains an important cause of morbidity in patients with advanced human immunodeficiency virus (HIV) infection. Fluconazole is widely regarded as the treatment of choice for this condition.nnnMETHODSnThe efficacy and safety of caspofungin were compared with fluconazole in adult patients with Candida esophagitis in a double-blind randomized trial. Eligible patients had symptoms compatible with esophagitis, endoscopic demonstration of mucosal plaques, and microscopic demonstration of Candida from the esophageal lesions. Patients were randomly assigned to receive caspofungin (50 mg) or fluconazole (200 mg) intravenously once daily for 7 to 21 days. The primary endpoint was the combined response of symptom resolution and significant endoscopic improvement 5 to 7 days after discontinuation of treatment. Data were analyzed with a modified intention-to-treat analysis, which excluded 2 ineligible patients.nnnRESULTSnMost patients (154/177; 87%) had HIV infection, with a median CD4 count of 30 cells/mm(3). Candida albicans was the predominant isolate. Favorable response rates were achieved in 66 (81%) of the 81 patients in the caspofungin arm and in 80 (85%) of the 94 patients in the fluconazole arm (difference = -4%; 95% confidence interval: -15% to +8%). Symptoms had resolved in >50% of patients in both groups by the fifth day of treatment. No patient in the caspofungin group developed a serious drug-related adverse event; therapy was only discontinued in 1 patient (receiving fluconazole) due to a drug-related adverse experience. Four weeks after stopping study drug, symptoms had recurred in 18 (28%) of 64 patients given caspofungin and in 12 (17%) of 72 patients given fluconazole (P = 0.19).nnnCONCLUSIONSnIn this study, caspofungin appeared to be as efficacious and generally as well tolerated as fluconazole in patients with advanced HIV infection and documented Candida esophagitis.

Caspofungin: the first in a new class of antifungal agents

Caspofungin is the first approved agent from a new class of antifungals, the echinocandins. By targeting the fungal cell wall (as opposed to the fungal cell membrane), the echinocandins exhibit a unique mechanism of action relative to the other currently approved antifungal agents. Preclinical (in vitro and in vivo) studies have demonstrated activity for caspofungin against the most commonly encountered fungi in the hospital setting, namely Candida and Aspergillus species. Caspofungin is administered as a once-a-day, intravenous formulation. Notably, caspofungin is neither an inhibitor, inducer, nor metabolite of the cytochrome p450 system. To date, few drug-drug interactions have been seen for this echinocandin. A number of Phase II and III clinical studies in documented invasive candidiasis, esophageal candidiasis, and invasive aspergillosis have been completed and have demonstrated efficacy for caspofungin against all three diseases. In all studies, caspofungin manifested an excellent safety profile with few serious, drug-related adverse events or discontinuations due to drug-related adverse events. Isolated symptoms compatible with histamine release have been infrequently reported. In clinical studies, drug-related nephrotoxicity with caspofungin has been rare, and the incidence of liver transaminase elevations has been similar to the incidence seen with comparator agents. Results from a Phase III study as empirical therapy in patients with febrile neutropenia are anticipated in late 2003. Overall, caspofungin represents an important addition to the current antifungal armamentarium.

Caspofungin in the treatment of symptomatic candiduria.

BACKGROUNDnBecause the urine concentrations achieved by echinocandin antifungal agents are low, drugs from this class are excluded from consideration when candiduria treatment is selected.nnnMETHODSnWe performed a retrospective view (sponsored by Merck Research Laboratories) of case records of patients participating in phase II-III clinical studies of caspofungin to identify patients with candiduria.nnnRESULTSnOf 12 case records collected by Merck Research Laboratories, 6 met the criteria for significant candiduria, allowing the evaluation of caspofungin therapy as judged by J.D.S. Three reported cases of candiduria secondary to hematogenous renal candidiasis were promptly eradicated. Of greater significance are 3 cases of complicated, ascending Candida glabrata infection (i.e., C. glabrata infection plus renal insufficiency), which were successfully treated with caspofungin.nnnCONCLUSIONSnCaspofungin may have a role in treating complicated Candida urinary tract infections, especially when the infection is caused by non-albicans species of Candida.

Evaluation of Serum Sandwich Enzyme-Linked Immunosorbent Assay for Circulating Galactomannan during Caspofungin Therapy: Results from the Caspofungin Invasive Aspergillosis Study

There has been minimal clinical experience with the use of the Aspergillus galactomannan enzyme-linked immunosorbent assay (ELISA) for patients receiving echinocandin therapy. We reviewed the experience with the galactomannan ELISA for 17 patients in a study of caspofungin treatment for invasive aspergillosis. The rate of successful outcomes for these patients was similar to that overall for participants in the study. Trends in antigenemia levels correlated with clinical and radiographic findings.

Population Pharmacokinetics and Pharmacodynamics of Caspofungin in Pediatric Patients

ABSTRACT We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC0–24), the concentration at the end of infusion (1 h after the start of infusion; C1), and the trough concentration (24 h after the start of infusion; C24) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C1, 45 to 78% for C24, ∼40% for AUC0–24) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiple-linear-regression model. Weight and disease state had statistically significant (P < 0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C24 in a limited number of patients (n = 4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C1/MIC, and C24/MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m2 daily dosing regimen (after a 70-mg/m2 loading dose) in children ages 3 months to 17 years.

Efficacy and safety of caspofungin in obese patients

Safety and efficacy outcomes were retrospectively compared for obese versus non-obese patients who received standard caspofungin doses for different clinical conditions in nine clinical trials within the Merck caspofungin database. Favorable outcomes were as defined in specific protocols. Safety was assessed based on drug-related adverse experiences (AEs). The proportion of obese patients in the esophageal candidiasis and invasive aspergillosis studies was lower than seen in the invasive candidiasis and empirical therapy studies. The proportions of patients with a favorable response were generally similar in non-obese and obese patients with invasive candidiasis (73% versus 77%) or patients receiving empirical therapy (33% versus 40%). The efficacy analysis in patients with invasive aspergillosis or esophageal candidiasis was limited due to the small number of obese patients. The proportion of favorable responses in these two infections was similar among normal/underweight patients as compared to obese/overweight patients, i.e., esophageal candidiasis 81% versus 88% and invasive aspergillosis 48% versus 44%, respectively. AEs related to caspofungin occurred in similar proportions with non-obese and obese patients across all and within the four clinical conditions. The proportion of obese patients with serious drug-related AEs (1%) or caspofungin discontinuations due to toxicity (5%) was low. In the post-hoc analysis, caspofungin appeared to be as efficacious and well-tolerated in obese patients as in non-obese patients.