A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients

Background:  An increased mortality rate among patients with severe fungal infections has highlighted the importance of selecting proper antifungal agents.  Caspofungin is an antifungal agent with activity against Candida and Aspergillus that has been shown effective in adults.  The favorable efficacy and safety profile documented in adults also makes caspofungin an attractive choice for pediatric patients.

Objective:  to evaluate the safety, tolerability, and efficacy of caspofungin in pediatric patients with invasive aspergillosis, invasive candidiasis, or esophageal candidiasis.

Methods:  Open-label, noncomparative study conducted from May 2004- July 2007.  Patients were enrolled from 12 centers in the US, EU, Israel, and Taiwan.  Children and adolescents 3 months to 17 years of age were eligible if they met criteria for documented invasive Aspergillus, invasive candidiasis, or esophageal candidiasis.  Diagnosis of infection was based on clinical history, signs and symptoms of illness, radiographic evidence, and positive histopathology and/or culture for fungal organisms.  Patients with proven or probable invasive aspergillosis were enrolled only if they had failed to respond to or were intolerant of standard antifungal therapy.  Exclusion criteria for all of the patients included acute or chronic hepatic disease; concomitant rifampin, cyclosporin A, or systemic antifungal therapy; bilirubin >3 times the upper limit of normal (ULN) for age; (AST) or (ALT) >5 times the ULN for age; platelet count <5000/µL.  Assessment of signs and symptoms of the underlying fungal infection were performed at screening, daily during caspofungin therapy, and at the 14-day and 28-day follow-up visits. In patients with candidemia, blood cultures were drawn daily until they were negative for 48 hours. Investigators monitored the resolution or progression of each patient's fungal infection by assessment of signs and symptoms, cultures, and/or radiographic studies, as appropriate.  Duration of therapy was individualized for each patient based on current treatment guidelines.  The primary end point was the proportion of patients with a favorable response (either complete or partial) at the end of caspofungin therapy.  All of the patients received caspofungin monotherapy 50 mg/m2 per day after a 70-mg/m2 loading dose on day 1.  Caspofungin was given by intravenous infusion over 1 hour. Patients who failed to improve clinically after 4 days of caspofungin therapy were eligible to receive 70 mg/m2 until therapy was discontinued; if drug-related toxicity developed, the caspofungin dose could revert back to the 50 mg/m2 .  A total of 49 patients were enrolled in the study, 10 with invasive aspergillosis, 38 with invasive candidiasis, and 1 with esophageal candidiasis.  Only 1 patient was not included in the efficacy analysis in the Candida group due to infection with trichosporon rather than Candida.  Power was not reported.

Results:  Five patients (50%) in the aspergillosis group had a favorable outcome at the end of therapy.  30 out of 37 patients (81.1%) had a favorable outcome in the Candida group, and the one patient with esophageal candidiais was completely resolved of their infection.  Among all 49 of the patients, 13 (27%) had 1 clinical adverse event considered at least possibly related to caspofungin therapy. None of the drug-related clinical adverse events were considered serious or resulted in discontinuation of caspofungin therapy. The most common drug-related clinical adverse events were fever (3 patients [6%]) and rash (2 patients [4%]). Five patients (10%) died during the study; all 5 were being treated for invasive aspergillosis. None of the deaths were related to caspofungin therapy (4 were attributed to underlying disease or its complications and 1 to fungal infection).  Seventeen of the 49 patients had 1 laboratory adverse event that was determined by the investigator to be at least possibly related to caspofungin therapy. None of these events were serious or led to therapy interruption or discontinuation. The most common drug-related laboratory adverse event was elevated liver enzymes, which occurred in 10 patients. 

Strengths:  Doses of caspofungin were adequate for the pediatric population, and were supported by kinetic studies.    Patients were assessed often, including at baseline, daily during caspofungin therapy, and during follow-up visits. Patients enrolled were critically ill and were under constant observation. 

Weaknesses:  There were potential conflicts of interest with several of the authors who work and receive financial support from Merck.  The open-label noncomparitive design limits the conclusions that can be made.  Patients who saw any improvement in their signs/symptoms were considered to have had a positive response to caspofungin.  There were significant differences between patients at baseline.  Many had underlying diseases, such as malignancies, congenital disorders, neutropenia, transplant history, and cystic fibrosis.  Many other factors may have pre-disposed these patients to fungal disorders such as the use of TPN, broad spectrum antibiotics, immune-suppressing medications, and intravascular catheters.  The study had a small sample size of only 49 patients.

Conclusions: This study shows that pediatric patients with invasive systemic Candida or aspergillosis fungal infections may benefit from caspofungin therapy.   It is not known if caspofungin is more effective than other currently used therapies.  Caspofungin could be used in patients refractory to other treatment options.   Caspofungin was considered safe and relatively well-tolerated in the sample population. 

Zaoutis TE, Jafri HS, Huang LM, Locatelli F, et al.  A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients.  March 2009. Pediatrics. 123 (3).

Sean Lamont, Pharm D. Candidate 2009