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Empiric antifungal drugs demonstrate safety, efficacy in neutropenic pediatric patients
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Empiric antifungal therapies liposomal amphotericin B and caspofungin were equivalent in tolerability, safety and efficacy for treatment of febrile, neutropenic children who are at risk for invasive fungal infections, recent study data suggest.
“Invasive fungal infections are an important cause of morbidity and mortality in patients with neutropenia who receive chemotherapy for cancer and following hematopoietic stem-cell transplantation (HSCT),” wrote researchers from 17 sites in the United States and Europe. “As early, definitive diagnosis is difficult, empiric administration of antifungal agents has become a standard of practice in neutropenic patients who remain persistently febrile despite broad spectrum antibacterial therapy.”
The researchers noted, however, that few clinical trials have analyzed the use of liposomal amphotericin B (L-AmB) and caspofungin in febrile, neutropenic pediatric patients. They conducted a prospective, randomized, double blind study from June 2004 to September 2006 to assess the safety and efficacy of caspofungin and L-AmB as treatment for suspected invasive fungal infections in children.
The researchers included children aged 2 to 17 years who had received chemotherapy for cancer or undergone HSCT. Patients also had to be persistently febrile and neutropenic, and they had to have received perenteral broad-spectrum antibacterial therapy for at least 96 hours to qualify for inclusion.
Patients were randomly assigned to receive either IV caspofungin plus placebo corresponding to L-AmB or L-AmB plus placebo corresponding to caspofungin in a 2:1 ratio. The researchers administered an initial dose of 70 mg/m2 and then subsequent daily doses of 50 mg/m2 of caspofungin to the first group and 3 mg/kg of L-AmB daily to the second.
Eighty-two patients received therapy, according to the researchers, with 81 supplying data on efficacy. More than 60% of patients in both groups had acute leukemia, and proportions of acute myeloid leukemia and acute lymphoblastic leukemia were similar between the study arms.
Results indicated that the overall rate of drug-related clinical adverse events was 48.2% for the caspofungin group (95% CI, 34.7-62.0) and 46.2% for the L-AmB group (95% CI, 26.6-66.6). Serious drug-related health problems surfaced in both treatment groups, according to the researchers, with one caspofungin patient developing hypotension, and three L-AmB patients exhibiting hyperbilirubinemia; circumoral edema; and angioneurotic edema with dsypnea, laryngospasm and tachycardia.
All discontinued therapy, and one patient who developed a caspofungin-related rash also discontinued treatment.
The researchers also reported that two patients in the caspofungin group and one in the L-AmB group died due to nondrug-related adverse events that occurred more than seven days after completing therapy.
Fever and other systemic infusion-related events were the most commonly reported drug-related clinical adverse events among both treatment arms.
Although drug-related adverse lab events occurred in both groups, none were serious or caused discontinuation of therapy. The overall rate of drug-related lab adverse events, however, was lower in the caspofungin group (10.7%; 95% CI, 4.0-21.9) when compared with the L-AmB group (19.2%; 95% CI, 6.6-39.4).
Data also showed that 46.4% of patients receiving caspofungin and 32% of those receiving L-AmB had favorable responses to treatment. Among high-risk patients, the researchers observed a 60% success rate for those in the caspofungin group.
No high-risk patients in the L-AmB arm, however, had positive responses. Both therapies demonstrated higher efficacy in patients with acute myeloid leukemia as opposed to those with acute lymphoblastic leukemia.
The researchers also noted that the groups were comparable in efficacy in the context of three outcomes: successful treatment of baseline fungal infection, absence of breakthrough fungal infection and survival for at least seven days after completion of therapy.
“This report demonstrates the feasibility of conducting such studies to advance our understanding of the treatment and prevention of invasive mycoses in children with cancer,” the researchers wrote. – by Melissa Foster
Maertens JA. Pediatr Infect Dis J. 2010;29:415-420.
This is a very well designed and implemented study that has considerable value for demonstrating the efficacy, tolerability and safety of the two antifungals, caspofungin and liposomal amphotericin B in the empirical treatment of children whose defenses were compromised because of neutropenia as a result of chemotherapy, and/or hematopoetic stem cell transplantation. Such a study had not previously been done in children, and thus was warranted. The randomization, and criteria for inclusion, and exclusion with the careful review by an Adjudication Committee gives the assurance of a consistent methodology for participation as having probable or proven infections. The one question relates to the relatively small sample size for a 2:1 ratio distribution, and the greater proportion receiving the caspofungin treatment. However, the conclusion affirms the comparability between the two treatment regimens in terms of tolerability, safety, and efficacy for such empirical therapy, and allows for the treating clinicians to consider these options when faced with such challenging circumstances associated with considerable morbidity and mortality.
– Fernando Guerra, MD
Infectious Diseases in Children Editorial Board
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