Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Nov 17;64(12):e00297-20.
doi: 10.1128/AAC.00297-20. Print 2020 Nov 17.

Activity of Aztreonam in Combination with Avibactam, Clavulanate, Relebactam, and Vaborbactam against Multidrug-Resistant Stenotrophomonas maltophilia

M Biagi  1 , D Lamm  1 , K Meyer  1 , A Vialichka  1 , M Jurkovic  1 , S Patel  1 , R E Mendes  2 , Z P Bulman  1 , E Wenzler  3
Affiliations

Activity of Aztreonam in Combination with Avibactam, Clavulanate, Relebactam, and Vaborbactam against Multidrug-Resistant Stenotrophomonas maltophilia

M Biagi et al. Antimicrob Agents Chemother. .

Abstract

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.

Keywords: L1; L2; MDR; Stenotrophomonas maltophilia; avibactam; aztreonam; clavulanate; metallo-β-lactamase; metalloenzymes; multidrug resistance; relebactam; smeABC; vaborbactam.

PubMed Disclaimer

Figures

FIG 1
FIG 1
Mean log10 CFU/ml versus time profile for aztreonam(ATM) alone and in combination with avibactam (AVI), clavulanate (CLAV), relebactam (REL), or vaborbactam (VAB) against six S. maltophilia strains (A to F). Curves represent average concentrations for triplicate experiments.
FIG 2
FIG 2
Expression of genes encoding L1, L2, and SmeA by isolates SM-1 (aztreonam-avibactam MIC of 0.5 mg/liter), SM-5 (aztreonam-avibactam MIC of 2 mg/liter), and SM-6 (aztreonam-avibactam MIC of 16 mg/liter) determined by qRT-PCR. Expression levels were normalized to 16S rRNA expression via the ΔΔCT method and are displayed relative to SM-1 as the reference. Bars represent mean ± SD values from three independent experiments in triplicate.
See this image and copyright information in PMC

References

    1. Calvopina K, Hinchliffe P, Brem J, Heesom KJ, Johnson S, Cain R, Lohans CT, Fishwick CWG, Schofield CJ, Spencer J, Avison MB. 2017. Structural/mechanistic insights into the efficacy of nonclassical beta-lactamase inhibitors against extensively drug resistant Stenotrophomonas maltophilia clinical isolates. Mol Microbiol 106:492–504. doi:10.1111/mmi.13831. - DOI - PubMed
    1. Walsh TR, MacGowan AP, Bennett PM. 1997. Sequence analysis and enzyme kinetics of the L2 serine beta-lactamase from Stenotrophomonas maltophilia. Antimicrob Agents Chemother 41:1460–1464. doi:10.1128/AAC.41.7.1460. - DOI - PMC - PubMed
    1. Cartwright SJ, Waley SG. 1984. Purification of beta-lactamases by affinity chromatography on phenylboronic acid-agarose. Biochem J 221:505–512. doi:10.1042/bj2210505. - DOI - PMC - PubMed
    1. Toleman MA, Bennett PM, Bennett DM, Jones RN, Walsh TR. 2007. Global emergence of trimethoprim/sulfamethoxazole resistance in Stenotrophomonas maltophilia mediated by acquisition of sul genes. Emerg Infect Dis 13:559–565. doi:10.3201/eid1304.061378. - DOI - PMC - PubMed
    1. Gales AC, Jones RN, Forward KR, Linares J, Sader HS, Verhoef J. 2001. Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY Antimicrobial Surveillance Program (1997–1999). Clin Infect Dis 32(Suppl 2):S104–S113. doi:10.1086/320183. - DOI - PubMed

Publication types