628. Characterizing a Sulbactam-Durlobactam Challenge Set of Acinetobacter baumannii Surveillance Isolates with Rapid Genotypic Testing (Carba-R) and Whole Genome Sequencing

TL;DR

This study examines resistance to a drug combination in Acinetobacter baumannii using genetic testing and whole genome sequencing.

Contribution

The study identifies genetic factors contributing to resistance to sulbactam-durlobactam in Acinetobacter baumannii isolates.

Findings

Most isolates were susceptible to sulbactam-durlobactam, with only 3.1% non-susceptible.

Non-susceptible isolates showed resistance mechanisms including NDM metallo-β-lactamase and efflux pump mutations.

Genetic analysis revealed the dominance of ST2 and the presence of emerging clones ST10 and ST499.

Abstract

Acinetobacter baumannii is emerging as an increasingly important opportunistic human pathogen. A 2023-2024 nationwide surveillance study focused on A. baumannii-calcoaceticus complex isolates among hospitalized patients (n=523) revealed that the majority of isolates were susceptible to sulbactam-durlobactam (SUD) (MIC50/90, 2/4 mg/L; 96.9% susceptible) with 3.1% of isolates (n=16) identified as non-susceptible. Comparative whole genome sequencing (WGS) and rapid genotypic analysis were performed to evaluate resistance mechanisms in this subset of non-susceptible isolates.Table 1.Isolate phenotypic and genotypic profiles

Isolate phenotypic and genotypic profiles

Of the 16 non-susceptible isolates, 12 were available for genotypic testing from contributing hospitals. WGS was performed, and data were analyzed using open-source tools while Xpert CarbaR was performed according to manufacturer instructions to detect blaKPC, blaVIM, blaOXA48, blaNDM and blaIMP carbapenemase genes. Isolates were epidemiologically typed through multi-locus sequence typing using the Institute Pasteur scheme.

SUD non-susceptible isolates were all carbapenem-resistant with meropenem MICs of ≥8 mg/L (Table 1). The globally dominant clone ST2 was the most prevalent sequence type identified. Emerging clones ST10 and ST499 were also observed. All sequenced strains harbored genes for Acinetobacter-derived cephalosporinase (ADC) Ambler class C β-lactamase such as ADC-73, as well as various Ambler class D OXA β-lactamases (OXA-23, OXA-58, OXA-66 carbapenemases). A metallo-β-lactamase (NDM) was identified in 4 isolates. Target site alterations in penicillin-binding protein 3 (PBP3) and mutations in the AdeIJK efflux system and its transcriptional regulator AdeN were noted (Table 1). Carba-R concordance with WGS was noted, with identification of 4 blaNDM-positive isolates.

All isolates exhibited mutations in efflux genes adeNIJK (which durlobactam is a substrate for) in addition to a mutation in PBP3 (n=8) or presence of an NDM gene (n=4). This study contributes to our understanding of clonality as well as the interplay of NDM production and mutations in efflux pumps and PBP present in SUD non-susceptible A. baumannii isolates. Further experiments are needed to identify the contribution of specific efflux gene variants to SUD non-susceptibility.

All Authors: No reported disclosures

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