Journal Article

The carbapenem inoculum effect provides insights into the molecular mechanisms underlying carbapenem resistance in the Enterobacterales

Taylor, Kyra L., Lopez, Leslie C., Su, Jennifer, Bhattacharyya, Roby P., Jaramillo Cartagena, Alexis, Earl, Ashlee M., Smith, Joshua T., Manson, Abigail L., Chen, Jonathan D., Pierce, Virginia M.

2025

Overview

Infections caused by carbapenem-resistant Enterobacterales (CRE) pose significant threats to patients and public health worldwide. Carbapenem resistance can occur through several molecular mechanisms, including enzymatic hydrolysis by carbapenemases and reduced influx via porin mutations. Identifying carbapenemase-producing isolates could enable tailored antibiotic selection to improve patient outcomes and infection control measures to prevent further carbapenemase transmission. In a large collection of CRE isolates, we found that only carbapenemase-producing CRE exhibited an inoculum effect, in which their measured resistance varies markedly with cell density, which risks misdiagnosis. Further, this inoculum effect occurred under conditions where bacteria released carbapenemases to the community upon exposure to antibiotics that resulted in cell death. Measuring this inoculum effect, or integrating other data from routine antimicrobial susceptibility testing, enhanced carbapenem resistance detection, paving the way for more effective strategies to combat this growing public health crisis.

• Publisher: American Society for Microbiology,American Society for Microbiology (ASM)
• Subject: Anti-Bacterial Agents - pharmacology / Antibiotic Penetration and Uptake / Antibiotic Resistance / Antibiotic Resistance Mechanisms / Antibiotic-Resistant Bacterial Infections / Antibiotics / Antimicrobial Chemotherapy / Antimicrobial Resistance / bacterial genomics / Bacterial Infections / Bacterial Proteins - genetics / Bacterial Proteins - metabolism / Bacteriology / Beta-lactam Resistance / beta-Lactamases - genetics / beta-Lactamases - metabolism / Carbapenem-Resistant Enterobacteriaceae - drug effects / Carbapenem-Resistant Enterobacteriaceae - genetics / Carbapenemase / carbapenemases / Carbapenems / Carbapenems - pharmacology / Cell culture / Cell death / Cell density / Classification / Clinical Detection of Resistance / clinical microbiology / Clinical Microbiology and Infectious Diseases / Drug resistance / Drug Resistant Pathogens / E coli / Emerging Resistant Pathogens / Enterobacterales / Enterobacteriaceae Infections - microbiology / Enzymatic Inactivation of Antibiotics / Ertapenem / Escherichia coli - drug effects / Escherichia coli - genetics / Evolution of Antibiotic Resistance / Genera / Humans / Hydrolysis / Inoculum / inoculum effect / Laboratories / Mechanisms of Resistance / Meropenem / Meropenem - pharmacology / Microbial Pathogenesis and Immunology / Microbial Physiology and Genetics / Microbial Sensitivity Tests / Molecular modelling / Pathogens / Porins / Porins - genetics / Porins - metabolism / Public health / Public Health Microbiology / Research Article / Resistance in Clinical Isolates / Special Series: Inaugural Articles by American Academy of Microbiology Fellows