Thursday, May 9, 2024
5/9/2024
Project Summary Extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) bloodstream infections (BSI) are associated with mortality upwards of 30%. It is unknown whether optimal antibiotic treatment differs based on the type of ESBL enzyme produced. Most microbiology laboratories do not test bacteria for ESBL production, opting instead to use non-susceptibility to third-generation cephalosporin antibiotics “3GCephNS” (e.g., ceftriaxone MIC =2 µg/mL) as a proxy for ESBL production. While this approach is pragmatic, it has hampered progress in understanding the molecular epidemiology and targeted treatment strategies for ESBL families. Our preliminary data suggest that 3 ESBL families account for ~99% of ESBLs: CTX-M (~60%), SHV-variants (~25%), and TEM-variants (~15%). However, our understanding of optimal treatment of ESBL-E is limited to CTX-M-producing infections. A resistance mechanism-based approach has been used to optimize antibiotic treatment against carbapenemase genes (e.g., blaKPC, blaNDM), contributing to a ~200% reduction in mortality. We believe a similar “precision medicine” approach should be investigated for treating ESBL-E BSI. The need to characterize the type of ESBL produced is demonstrated by a clinical trial comparing outcomes of patients with 3GCephNS BSIs receiving either piperacillin-tazobactam (PTZ) or meropenem. Mortality was significantly lower for patients receiving meropenem. Meropenem was henceforth adopted as first-line therapy for 3GCephNS BSIs (and by extension ESBL-E BSI). However, 87% of patients (no US patients included) were infected with CTX-M-producing isolates. While CTX-M are the most common ESBL enzymes, they are not the only ESBLs. It is unknown if meropenem is the preferred therapy for SHV and TEM ESBL variants. There are differences in preferred substrates, inhibitors, and hydrolyzing abilities across ESBL enzymes. PTZ may be effective treatment for BSI caused by specific ESBL families, as supported by our preliminary data. If indeed, PTZ is a reasonable treatment option for certain ESBL-E families, then prescribing meropenem for all ESBL-E infections without discrimination based on the type of ESBL family will only serve to fuel the crisis of carbapenem-resistant Enterobacterales, without leading to improvements in patient outcomes. Using a cohort of 2,000 consecutive 3GCephNS Enterobacterales BSI (diverse species) from 5 US hospitals, we will characterize the epidemiology of ß-lactamases. We hypothesize that blaCTX-M genes comprise ~60% of ß-lactamase genes. For ~40% of isolates, non-CTX-M ESBL genes (± ampC or narrow-spectrum ß-lactamase genes will be identified). Then, we will conduct an observational study to determine if patients infected with BSI isolates producing non-CTX-M ESBL enzymes (i.e., SHV or TEM) have improved outcomes if receiving meropenem vs. PTZ using a sophisticated inverse probability of treatment weighting approach incorporating propensity scores. We hypothesize that PTZ will be effective treatment for ESBL-E caused by SHV and TEM families given their reduced ß-lactam hydrolyzing potential.
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