JAC Advance Access originally published online on May 24, 2007
Journal of Antimicrobial Chemotherapy 2007 60(1):188-190; doi:10.1093/jac/dkm177
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Correspondence |
In vitro interaction of micafungin and fluconazole against Candida
1 Unitat de Microbiologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, España; 2 Departamento de Inmunología, Microbiología y Parasitología, Facultad de Medicina y Odontología, Universidad del País Vasco, Bilbao, España 3 Departamento de Microbiología, Asesoría Científica y de Investigación Aplicada, Barcelona, España
* Corresponding author. Tel: +34-977-759359; Fax: +34-977-759322; E-mail: franciscojavier.pastor{at}urv.cat
Keywords: antifungal drugs , echinocandins , azoles
Candida albicans and other emerging Candida spp. are a common cause of severe disseminated infections. Fluconazole has been traditionally used in the treatment of candidaemia. However, its activity against some species of Candida, such as Candida krusei and Candida glabrata, is very limited or even nil. In addition, emerging fluconazole resistance has been reported in species typically susceptible to this agent, such as C. albicans.1 The echinocandins have a different target from that of azoles, with potential both for additive effects with azoles and for activity against azole-resistant fungi.2 Micafungin is a new echinocandin with excellent in vitro and in vivo activities against Candida spp.1
In this study, we hypothesized that the combination of fluconazole with micafungin could be advantageous over each monotherapy against Candida spp. and as the mechanisms of action of both drugs are different, antagonism might not be expected. Moreover, the use of antifungal combinations permits smaller doses, shorter duration of therapy and a wider spectrum of activity.2 Synergistic interactions between fluconazole and micafungin have already been observed in previous in vitro studies on Cryptococcus spp. and other basidiomycetous yeasts.3,4
A total of 105 clinical isolates were tested (15 C. albicans, 20 Candida dubliniensis, 15 C. glabrata, 20 C. krusei, 10 Candida lusitaniae, 10 Candida parapsilosis and 15 Candida tropicalis). The isolates were subcultured on Sabouraud dextrose agar plates and incubated at 35°C for 24 h. Yeasts suspensions were adjusted to 1–5 x 106 cfu/mL by counting with a haemocytometer. Micafungin (Astellas Pharma Inc., Tokyo, Japan) and fluconazole (Pfizer Inc., Madrid, Spain) were obtained as pure powders and diluted in sterile distilled water. Drug interactions were assessed by the chequerboard microdilution method [according to the CLSI (formerly NCCLS) M27-A2 document] and included the MIC determinations of each drug alone.5 The MIC was defined as the lowest concentration that produced 50% growth inhibition (MIC-2). The temperature of incubation was 35°C, and MIC readings were recorded after 48 h. The fractional inhibitory concentration index (FICI) was used to classify drug interaction (
0.5, synergistic; >0.5 and 4, indifferent and >4, antagonistic).6 FICI is the sum of the FIC of each of the drugs, which in turn is defined as the MIC of each drug when it is used in combination divided by the MIC of the drug when it is used alone.
Mean geometric MICs of drugs alone and in combinations are shown in Table 1. MICs of both drugs alone agree with those obtained by other authors.7,8 Although MICs of both drugs in combination were generally lower here than those observed when the drugs were tested alone, indifference was observed in most cases. The MICs of fluconazole when combined were significantly lower than when alone for C. krusei and C. glabrata (P < 0.0105 and P < 0.0001, respectively), but not for the rest of the species. The MICs of micafungin when combined were significantly lower than when alone for C. albicans, C. krusei, C. glabrata and C. lusitaniae (P < 0.0032, P < 0.0267, P < 0.0001 and P < 0.0232, respectively). Synergistic interactions occurred against 33%, 26% and 7% of isolates of C. albicans, C. tropicalis and C. glabrata, respectively, in all cases, the FICI being <0.5. In the cases of synergism, fluconazole MICs changed from susceptible to more susceptible, with a few exceptions which changed from susceptible dose-dependent to susceptible, and micafungin MICs changed from susceptible to more susceptible. Micafungin shows a lower activity against C. parapsilosis, as has been previously observed by other authors.7 In our study, micafungin showed high MICs which tended to drop when this drug was combined with fluconazole. This combination could be of interest in those cases where the isolates of this species show high MICs of fluconazole. In spite of the predominance of indifferent interactions, which agrees with the results provided by other authors,2,9 the lack of antagonism and the percentages of synergism obtained against C. albicans and C. tropicalis are interesting issues. Although scarce in vivo data on the activity of this combination are available, it has been demonstrated that it was able to prolong survival and to reduce tissue burden in murine models of C. glabrata infection and in trichosporonosis.10,11 Therefore, combination of these agents may warrant future clinical evaluation in Candida infections.
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Transparency declarations
None to declare.
Acknowledgements
This work was supported by a grant from Fondo de Investigaciones Sanitarias from the Ministerio de Sanidad y Consumo of Spain (PI 050031).
References
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5 National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts-Second Edition: Approved Standard M27-A2 (2002) Wayne, PA, USA: NCCLS.
6
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Laverdiere M, Hoban D, Restieri C, et al. In vitro activity of three new triazoles and one echinocandin against Candida bloodstream isolates from cancer patients. J Antimicrob Chemother (2002) 50:119–23.
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10
Marine M, Serena C, Pastor FJ, et al. Combined antifungal therapy in a murine infection by Candida glabrata. J Antimicrob Chemother (2006) 58:1295–8.
11
Serena C, Pastor FJ, Gilgado F, et al. Efficacy of micafungin in combination with other drugs in a murine model of disseminated trichosporonosis. Antimicrob Agents Chemother (2005) 49:497–502.
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