Fast track — ArticlesMicafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial
Introduction
The increasing prevalence of serious infections caused by Candida spp, in particular those caused by non-albicans species,1 has been met with an increasing number of antifungal therapies. Problems associated with long-established treatment options are well known, the most important being the renal toxicity associated with amphotericin B2, 3, 4 and the limited spectrum of activity of fluconazole.5, 6, 7 These limitations seem to have been largely overcome with liposomal amphotericin B, voriconazole, and the echinocandins caspofungin and anidulafungin.8, 9, 10, 11 Liposomal amphotericin B combines broad-spectrum activity with a narrow toxicity profile.8 Voriconazole has a broader range of activity than fluconazole but shares reduced susceptibility in fluconazole-resistant strains, and its use is restricted by drug-drug interactions, variable pharmacokinetics, and drug-related toxicity.12, 13, 14 Micafungin, like other echinocandins, is active against both Candida spp and Aspergillus spp. There is little mechanism-based toxicity because the inhibition of fungal cell wall synthesis effected by echinocandins has no relevance for mammalian cells.15, 16
Micafungin has been shown to be effective in oesophageal candidosis, and high success rates have been seen in an open-label candidaemia study.17, 18 Our aim was to determine whether micafungin is non-inferior to liposomal amphotericin B in the treatment of adult patients with candidaemia or invasive candidosis.
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Patients
The study was done between January, 2003, and November, 2004, at 115 study sites in Europe, India, Brazil, North America, Thailand, South Africa, and Australia. Patients were eligible for enrolment if they were at least 16 years old, had clinical signs of systemic candida infection, and had one or more positive candida cultures from blood or another sterile site within the previous 4 days. Patients were excluded if they had positive cultures only from oropharyngeal, oesophageal, urine, sputum,
Results
537 patients were enrolled: 181 patients in Europe, 122 in India, 115 in Brazil, 40 in North America, 40 in Thailand, 21 in South Africa, and 18 in Australia. 531 patients received the study drugs (figure 1). The micafungin and liposomal amphotericin B groups were much the same in terms of demographic or baseline characteristics, including established risk factors (table 1). The concordance between the independent data review board and investigator assessment of the primary diagnosis was 94·7%
Discussion
Our results indicate that micafungin is non-inferior to liposomal amphotericin B in the first-line treatment of candidaemia and invasive candidosis. Our findings were robust across all three analysis populations—per protocol, intention to treat, and modified intention to treat—and were consistent irrespective of Candida spp and of prognostic factors (eg, neutropenic status, APACHE II score, or catheter status). Our data also show that micafungin has a better safety profile than does liposomal
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