P-1292. Clinical and Genomic Features of Colistin Resistance Among Carbapenem-resistant Acinetobacter baumannii Isolated From Global Clinical Samples

TL;DR

This study examines global clinical and genomic features of colistin resistance in carbapenem-resistant Acinetobacter baumannii, finding higher mortality in patients with resistant infections and linking resistance to genetic mutations in the pmrB gene.

Contribution

The study identifies a link between colistin resistance in CRAb and mutations in pmrB, suggesting it as a potential drug development target.

Findings

18% of CRAb isolates were colistin-resistant, with resistant strains associated with higher 30-day mortality in monomicrobial infections.

Genomic analysis revealed that colistin resistance is concentrated in specific genetic lineages, particularly within clonal complex 2 (CC2).

Nonsynonymous mutations in the histidine kinase domain of pmrB were associated with colistin resistance.

Abstract

Carbapenem-resistant Acinetobacter baumannii (CRAb) is a multi-drug resistant, opportunistic pathogen. Colistin is one of a few remaining treatment options, but resistance exists globally.

Between 2017 and 2019, 551 CRAb isolates were collected through the international Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP). Demographics, clinical characteristics, mortality, and a desirability of outcome ranking (DOOR) measure combining lack of clinical response, unsuccessful discharge, renal failure, and C. difficile infection, were recorded for each patient. A central laboratory measured colistin minimum inhibitory concentrations (MICs), and each isolate was classified as colistin-intermediate (MIC ≤2µg/mL) or resistant (MIC ≥4µg/mL). All isolates were sequenced on the Illumina platform, and the genomes were used to construct a phylogenetic tree and assess for variants within known colistin resistance-related genes.

18% of the 551 isolates were colistin-resistant. Compared to patients with colistin-intermediate isolates, patients with resistant strains were more likely to have been admitted from a healthcare facility, but otherwise had similar demographics and Charlson comorbidity indices. Focusing on patients with bloodstream or respiratory infections (n=217) uncovered increased 30-day mortality in patients with monomicrobial, colistin-resistant infections (11/19, p=0.008) when compared to monomicrobial-intermediate (41/102), polymicrobial-resistant (4/20) and polymicrobial-intermediate infections (18/76). Comparative genomics indicated that the majority of isolates belonged to clonal complex 2 (CC2), and that colistin resistance concentrated in certain genetic lineages. Variant analysis uncovered nonsynonymous mutations near and within the histidine kinase domain of pmrB, part of the PmrAB two-component system that regulates lipopolysaccharide modifications which can alter colistin susceptibility.

In this global cohort, patients with monomicrobial, colistin-resistant CRAb infections had increased mortality. New treatment options are needed for multidrug-resistant CRAb, and this study provides further evidence that pmrB may serve as a worthwhile drug development target.

Madison Stellfox, MD, PhD, Cumberland Pharmaceuticals: Grant/Research Support Robin Patel, MD, a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection: a patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication, a patent on PET imaging of bacterial infection|MicuRx Pharmaceuticals and bioMérieux: Grant/Research Support|PhAST, Day Zero Diagnostics, DEEPULL DIAGNOSTICS, S.L., Nostics, HealthTrackRx, bioMérieux and CARB-X: Advisor/Consultant|Up-to-Date and the Infectious Diseases Board Review Course: Honoraria David van Duin, MD, PhD, British Society for Antimicrobial Chemotherapy: Editor stipend|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant Yohei Doi, MD, PHD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria