Elsevier

The Lancet

Volume 369, Issue 9572, 5–11 May 2007, Pages 1519-1527
The Lancet

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Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial

https://doi.org/10.1016/S0140-6736(07)60605-9Get rights and content

Summary

Background

Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis.

Methods

We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288.

Findings

264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89·6%) patients treated with micafungin and 170 (89·5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0·7% (95% CI −5·3 to 6·7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events—including those that were serious or led to treatment discontinuation—with micafungin than there were with liposomal amphotericin B.

Interpretation

Micafungin was as effective as—and caused fewer adverse events than—liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

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.

Section snippets

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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