# P-1296. Impact of Metallo-Beta Lactamases on Outcomes in Patients with Carbapenem-Resistant Gram-Negative Infections

## TL;DR

This study examines how metallo-beta-lactamase (MBL) enzymes affect outcomes in patients with carbapenem-resistant Gram-negative infections, finding that MBL presence is linked to worse outcomes in some infection types.

## Contribution

The study provides new insights into the clinical impact of MBL-producing bacteria in carbapenem-resistant infections, particularly in non-fermenter infections.

## Key findings

- MBL presence was not associated with increased 30- or 90-day mortality in the overall cohort.
- In non-fermenter infections (CRPA/CRAb), MBL presence was linked to less desirable outcomes.
- The association between MBL and worse outcomes was not observed in carbapenem-resistant Enterobacterales (CRE).

## Abstract

Treatment options for Carbapenem-resistant (CR) Gram-negative infections due to metallo-beta-lactamase (MBL) enzymes are limited. The clinical impact of MBLs vs. other mechanisms of carbapenem resistance in Enterobacterales and non-fermenting bacteria remains unclear.Table 1.Demographics, isolate characteristics, and outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusFigure 1.30-day desirability of outcome ranking (DOOR) outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL statusCRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. DOOR events assessed at 30 days include: unsuccessful discharge, lack of clinical response, and C. difficile infection and/or renal failure. Not all rows total to 100 due to rounding. P-value calculated using Wilcoxon test.

Demographics, isolate characteristics, and outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL status

30-day desirability of outcome ranking (DOOR) outcomes of patients with carbapenem-resistant Gram-negative infections, stratified by MBL status

CRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. DOOR events assessed at 30 days include: unsuccessful discharge, lack of clinical response, and C. difficile infection and/or renal failure. Not all rows total to 100 due to rounding. P-value calculated using Wilcoxon test.

We conducted a matched cohort study of patients enrolled in one of three MDRO Network studies, POP (CR Pseudomonas aeruginosa [CRPA]), SNAP (CR Acinetobacter baumannii [CRAb]), or CRACKLE-2 (CR-Enterobacterales [CRE]) with isolates that met infection criteria. Patients with MBL-producing isolates (blaVIM, blaIMP, or blaNDM present) were matched 1:2 to patients with non-MBL CR isolates (a different carbapenemase or CR without a carbapenemase) based on study, region, and anatomical source. We compared baseline characteristics, 30- and 90-day mortality, and 30-day desirability of outcome ranking (DOOR) scores.30-day Desirability of Outcome Ranking (DOOR) Probability by MBL StatusLegend: CI – confidence interval, CRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. The DOOR probability was calculated as the probability of a more desirable result in the presence of MBL as compared to non-MBL isolate. Confidence intervals were calculated using the method in Halperin et al (Biometric 1989; 45:500-521), and CI’s that do not include 50% are considered statistically significant. Estimates less than 50% signify a less favorable outcome for the MBL group, while estimates greater than 50% signify more favorable outcomes for the MBL group.

30-day Desirability of Outcome Ranking (DOOR) Probability by MBL Status

Legend: CI – confidence interval, CRPA – carbapenem-resistant Pseudomonas aeruginosa, CRAb – carbapenem-resistant Acinetobacter baumannii, CRE – carbapenem-resistant Enterobacterales, DOOR – desirability of outcome ranking. MBL – metallo-beta-lactamase. The DOOR probability was calculated as the probability of a more desirable result in the presence of MBL as compared to non-MBL isolate. Confidence intervals were calculated using the method in Halperin et al (Biometric 1989; 45:500-521), and CI’s that do not include 50% are considered statistically significant. Estimates less than 50% signify a less favorable outcome for the MBL group, while estimates greater than 50% signify more favorable outcomes for the MBL group.

In total, 170 MBL isolates were matched to 340 non-MBL isolates from 10 countries (Table 1). The cohort included 42% CRPA (216/510), 5% CRAb (24/510), and 53% CRE (270/510). Demographics were balanced between groups; median age at culture was 61 (Q1, 44, Q3 73) years. Common infection sources were respiratory (151/510, 30%), urine (141/510, 28%), and blood (105/510, 21%). Of the MBL isolates, 92/170 harbored blaNDM (54%), 62/170 harbored blaVIM (36%), and 20/170 harbored blaIMP (12%); four isolates co-harbored two distinct MBL enzymes. All-cause 30-day mortality was 19% (33/170) for MBL vs 18% (61/340) for non-MBL (p=0.69); MBL presence was not associated with 30- or 90-day mortality. DOOR outcomes at 30-days (Figure 1) did not differ by MBL status in the full cohort or the CRE subgroup, but did differ in the CRPA/CRAb subgroup (p=0.037). Among CRPA/CRAb infections, MBL presence was associated with less desirable outcomes (DOOR probability 42.1%; 95% Halperin confidence interval: 35.0%-49.5%, Figure 2).

MBL presence was not associated with increased 30- or 90-day mortality compared to matched non-MBL isolates. However, in non-fermenter infections (CRPA/CRAb), MBL presence was linked to less desirable outcomes, an association not seen in CRE. These findings may inform prioritization of anti-MBL agents in future drug development.

Angelique E. Boutzoukas, MD, MPH, Elion Therapeutics: Advisor/Consultant|Innoviva Speciality Therapeutics: DSMB Participant Souha S. Kanj, MD, Menarini: Honoraria|pfizer: Honoraria Vance G. Fowler, MD, MHS, Affinergy, Janssen, Contrafect: Advisor/Consultant|AstraZeneca; EDE; Basilea: Grant/Research Support|Debiopharm, GSK; Affinium, Basilea,: Advisor/Consultant|Destiny, Amphliphi, Armata, Akagera: Advisor/Consultant|Merck; Contrafect; Karius; Janssen: Grant/Research Support|UpToDate: Royalties|Valanbio: Stock options Yohei Doi, MD, PHD, GSK: Advisor/Consultant|Meiji Seika Pharma: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Michael Satlin, MD, MS, AbbVie: DSMB Participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|SNIPRBiome: Grant/Research Support Robert A. Bonomo, MD, Merck: Grant/Research Support|Shinogi: Grant/Research Support|VenatoRx: Grant/Research Support 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