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Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents When Tested against a Large Collection of Contemporary Stenotrophomonas maltophilia Isolates from Medical Centers Worldwide.

ABSTRACT: Aztreonam-avibactam was tested against 1,839 Stenotrophomonas maltophilia isolates collected worldwide and demonstrated potent activity against isolates from all geographic regions and infection types (overall MIC_50/90, 4/4 mg/liter; 97.8% inhibited at ≤8 mg/liter). Trimethoprim-sulfamethoxazole (TMP-SMX) (MIC_50/90, ≤0.5/1 mg/liter; 95.4% susceptible) and minocycline (MIC_50/90, 0.5/2 mg/liter; 99.5% susceptible) were also very active. Aztreonam-avibactam inhibited 84.7% of non-TMP-SMX-susceptible isolates at ≤8 mg/liter. Aztreonam-avibactam may represent a valuable option for the treatment of S. maltophilia infections, addressing a major unmet medical need.

SUBMITTER: Sader HS

PROVIDER: S-EPMC7577171 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The intrinsic L1 metallo- and L2 serine-β-lactamases in Stenotrophomonas maltophilia make it naturally multidrug resistant and difficult to treat. There is a need to identify novel treatment strategies for this pathogen, especially against isolates resistant to first-line agents. Aztreonam in combination with avibactam has demonstrated potential, although data on other aztreonam-β-lactamase inhibitor (BLI) combinations are lacking. Additionally, molecular mechanisms for reduced susceptibility to these combinations have not been explored. The objectives of this study were to evaluate and compare the in vitro activities and to understand the mechanisms of resistance to aztreonam in combination with avibactam, clavulanate, relebactam, and vaborbactam against S. maltophilia A panel of 47 clinical S. maltophilia strains nonsusceptible to levofloxacin and/or trimethoprim-sulfamethoxazole were tested against each aztreonam-BLI combination via broth microdilution, and 6 isolates were then evaluated in time-kill analyses. Three isolates with various aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase PCR. Avibactam restored aztreonam susceptibility in 98% of aztreonam-resistant isolates, compared to 61, 71, and 15% with clavulanate, relebactam, and vaborbactam, respectively. The addition of avibactam to aztreonam resulted in a ≥2-log10-CFU/ml decrease at 24 h versus aztreonam alone against 5/6 isolates compared to 1/6 with clavulanate, 4/6 with relebactam, and 2/6 with vaborbactam. Molecular analyses revealed that decreased susceptibility to aztreonam-avibactam was associated with increased expression of genes encoding L1 and L2, as well as the efflux pump (smeABC). Aztreonam-avibactam is the most promising BLI-combination against multidrug-resistant S. maltophilia Decreased susceptibility may be due to the combination of overexpressed β-lactamases and efflux pumps. Further studies evaluating this combination against S. maltophilia are warranted.

Project description:We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n?=?1,904 isolates; 6 species), Cryptococcus neoformans (n?=?73), Aspergillus fumigatus (n?=?183), and Aspergillus flavus (n?=?45) isolates were tested for their susceptibility (S) to rezafungin as well as the comparators caspofungin, anidulafungin, micafungin, and azoles. Interpretive criteria were applied following CLSI published clinical breakpoints (CBPs) and epidemiological cutoff values (ECVs). Isolates displaying non-wild-type (non-WT) echinocandin MIC values were sequenced for hot spot (HS) mutations. Rezafungin inhibited 99.8% of Candida albicans isolates (MIC50/90, 0.03/0.06??g/ml), 95.7% of Candida glabrata isolates (MIC50/90, 0.06/0.12??g/ml), 97.4% of Candida tropicalis isolates (MIC50/90, 0.03/0.06??g/ml), 100.0% of Candida krusei isolates (MIC50/90, 0.03/0.06??g/ml), and 100.0% of Candida dubliniensis isolates (MIC50/90, 0.06/0.12??g/ml) at ?0.12??g/ml. All (329/329 [100.0%]) Candida parapsilosis isolates (MIC50/90,1/2??g/ml) were inhibited by rezafungin at ?4??g/ml. Fluconazole resistance was detected among 8.6% of C. glabrata isolates, 12.5% of C. parapsilosis isolates, 3.2% of C. dubliniensis isolates, and 2.6% of C. tropicalis isolates. The activity of rezafungin against these 6 Candida spp. was similar to the activity of the other echinocandins. Detection of the HS mutation was performed by sequencing echinocandin-resistant or non-WT Candida isolates. Good activity against C. neoformans was observed for fluconazole and the other azoles, whereas the echinocandins, including rezafungin, displayed limited activity. Rezafungin displayed activity similar to that of the other echinocandins against A. fumigatus and A. flavus These in vitro data contribute to accumulating research demonstrating the potential of rezafungin for preventing and treating invasive fungal infections.

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Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents When Tested against a Large Collection of Contemporary Stenotrophomonas maltophilia Isolates from Medical Centers Worldwide.

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