Activity of Aztreonam in Combination with Avibactam, Clavulanate, Relebactam, and Vaborbactam against Multidrug-Resistant Stenotrophomonas maltophilia
| Autor: | M Jurkovic, Kevin A. Meyer, Eric Wenzler, Zackery P Bulman, A Vialichka, D Lamm, R E Mendes, Mark Biagi, Shree Patel |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Avibactam
Stenotrophomonas maltophilia Aztreonam Microbial Sensitivity Tests Microbiology 03 medical and health sciences chemistry.chemical_compound Levofloxacin medicine polycyclic compounds Animals Humans Pharmacology (medical) Experimental Therapeutics Clavulanic Acid 030304 developmental biology Pharmacology 0303 health sciences Vaborbactam Sheep biology 030306 microbiology Broth microdilution biochemical phenomena metabolism and nutrition biology.organism_classification bacterial infections and mycoses Boronic Acids Anti-Bacterial Agents Multiple drug resistance Infectious Diseases chemistry bacteria Efflux Gram-Negative Bacterial Infections Azabicyclo Compounds medicine.drug |
| Zdroj: | Antimicrob Agents Chemother |
| Popis: | 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 activity and 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 non-susceptible 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 varying aztreonam-BLI MICs were subjected to whole-genome sequencing and quantitative reverse transcriptase polymerase chain reaction. 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 hours vs. 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 for L1, L2, and 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. |
| Databáze: | OpenAIRE |
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