In Vitro Activity of Amphotericin B in Combination with Colistin against Fungi Responsible for Invasive Infections

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.

Synergistic In Vitro Interaction of Isavuconazole and Isoquercitrin against Candida glabrata

“…When the interpretation of the results was carried out by response surface analysis, synergy was still obtained for 60% of the C. glabrata strains tested. The discrepancy between the FICI and the response surface analysis results can be explained by the stringent threshold (56.0) used in this study compared with previous works, where lower thresholds have been used [ 24 , 25 ]. Nevertheless, despite the indifference of 40% of the C. glabrata results by response surface analysis, the mean of the SUM-SYN-ANT metric of all strains was 64.15, and therefore higher than the threshold.…”

“…The strains not belonging to international collections were all identified to the species level by the sequencing of the complete Internal Transcribed Spacer (ITS)1–5.8S-ITS2 region, as described elsewhere [ 34 ]. All sequences were deposited at GenBank under the accession numbers OL351325 to OL351353, OL351355, and OL351356 [ 24 ], under OM859334 to OM859338 [ 23 ], and under ON391951 to ON391970. Each batch of microplates was tested by the quality control strains C. krusei ATCC 6258 and C. parapsilosis ATCC 22019, as recommended by EUCAST.…”

“…However, using the common antifungals, no promising combination for the treatment of invasive candidiasis has been found [ 22 ]. As shown for Candida [ 23 , 24 , 25 ], Aspergillus [ 26 , 27 ], and Mucorales [ 28 ], combinations of non-antifungals with antifungals can also exhibit synergy. Isavuconazole is a broad-spectrum azole drug with potent in vitro activity against Candida blood-stream isolates, particularly against C. albicans and C. glabrata [ 29 ].…”

Small molecules for combating multidrug-resistant superbug Candida auris infections

“…In contrast, the combination of colistin with micafungin showed indifferent interactions (FICI range: 0.51–1.01). Colistin also had in vitro synergistic interactions with amphotericin B (FICI range: 0.1563–0.375) 114 and isavuconazole (FICI range: 0.3125–0.5) 115 against C. auris strains.…”

Strategies to Prevent Transmission of Candida auris in Healthcare Settings

“…Emerging antifungal compounds being investigated include natural compounds, antimicrobial peptides, immunotherapy, metals and nano particles, photodynamic and combinational therapy, and repurposed drugs [ 118 , 125 , 126 •, 127 ]. Colistin showed synergistic activity with amphotericin B against C. auris [ 128 ], while farnesol boosted the antifungal effect of fluconazole [ 129 ]. Fluconazole-resistant C. auris isolates have higher levels of chitin in their cell wall and increased susceptibility to a glucosamine-6-phosphate synthase inhibitor [ 130 ].…”