Abstract
The in vitro interaction of amphotericin B in combination with colistin was evaluated against a total of 86 strains comprising of 47 Candida species (10 Candida albicans, 15 Candida auris, five Candida glabrata, three Candida kefyr, five Candida krusei, four Candida parapsilosis and five Candida tropicalis), 29 Aspergillus species (five Aspergillus flavus, 10 Aspergillus fumigatus, four Aspergillus nidulans, five Aspergillus niger, and five Aspergillus terreus), and 10 Rhizopus species (seven Rhizopus arrhizus, one Rhizopus delemar and two Rhizopus microsporus) strains. For the determination of the interaction, a microdilution checkerboard technique based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method for antifungal susceptibility testing was used. Results of the checkerboard technique were evaluated by the fractional inhibitory concentration index (FICI) based on the Loewe additivity model for all isolates. Different inhibition endpoints were used to capture both the interaction at MIC and sub-MIC levels. Additionally, checkerboard technique results for Candida species were evaluated by response surface analysis based on the Bliss independence model. Against common Candida species, the combination was synergistic for 75% of the strains by FICI and for 66% of the strains by response surface analysis. For C. tropicalis, the interaction was antagonistic for three isolates by FICI, but antagonism was not confirmed by response surface analysis. Interestingly, synergistic and antagonistic FICIs were simultaneously present on checkboard microplates of all three strains. Against C. auris the combination was synergistic for 73% of the strains by response surface analysis and for 33% of the strains by FICI. This discrepancy could be related to the insensitivity of the FICI to detect weak interactions. Interaction for all other strains was indifferent. For Aspergillus and Rhizopus species combination exhibited only indifferent interactions against all tested strains.
Highlights
Fungal infections are a leading cause of mortality, especially in immunocompromised patients
The calculated fractional inhibitory concentration index (FICI) using 50% or 90% of inhibition are presented in Tables 3 and 4 for Candida spp. and C. auris, respectively
Amphotericin B MICs were in the same ranges as previously reported for Rhizopus species [43], C. auris [44], and the different Candida species [45,46]
Summary
Fungal infections are a leading cause of mortality, especially in immunocompromised patients. Both yeast and filamentous invasive fungal infections are associated with poor outcomes and high mortality rates. In Europe, aspergillosis and mucormycosis are the two most frequent filamentous fungal infections with mortality rates in immunocompromised patients of about 60 and 53%, respectively [1,2,3]. Aspergillosis is a problem in severely ill COVID-19 patients, and mucormycosis, and candidiasis [7]. Severe COVID-19 infection is a risk factor for invasive candidiasis [9], and outbreaks of multidrug-resistant Candida auris have been reported [10]. COVID-unassociated mortality rates of invasive candidiasis due to common Candida species or C. auris of more than 35% are already high [11,12], COVID-associated mortality rates of about 45% for common Candida species [13], and 60% for C. auris are even higher [14]
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