AI Article Synopsis

  • Multi-drug resistant (MDR) pathogens, particularly Gram-negative ones, are becoming increasingly problematic, with limited treatment options leading to higher illness and death rates.
  • Sulbactam, a commonly used β-lactamase inhibitor, has antibacterial properties but is less effective due to the presence of β-lactamases, specifically class D oxacillinases, necessitating larger doses or alternative therapies.
  • Durlobactam is a novel non-β-lactam β-lactamase inhibitor that works well against MDR pathogens, particularly those resistant to carbapenems, and this study aims to establish effective dosing for sulbactam and durlobactam in clinical settings by analyzing their combined effects in

Article Abstract

Multi-drug resistant (MDR) is emerging as a pathogen of increasing prevalence and concern. Infections associated with this Gram-negative pathogen are often associated with increased morbidity and mortality and few therapeutic options. The β-lactamase inhibitor sulbactam used commonly in combination with ampicillin demonstrates intrinsic antibacterial activity against acting as an inhibitor of PBP1 and PBP3, which participate in cell wall biosynthesis. The production of β-lactamases, particularly class D oxacillinases, however, has limited the utility of sulbactam resorting to increased doses and the need for alternate therapies. Durlobactam is a non-β-lactam β-lactamase inhibitor that demonstrates broad β-lactamase inhibition including class D enzymes produced by and has shown potent activity against MDR , particularly carbapenem-resistant isolates in susceptibility and pharmacodynamic model systems. The objective of this study is to evaluate the exposure-response relationship of sulbactam and durlobactam in combination using neutropenic thigh and lung models to establish PK/PD exposure magnitudes to project clinically effective doses. Utilizing established PK/PD determinants of %T>MIC and AUC/MIC for sulbactam and durlobactam, respectively, non-linear regressional analysis of drug exposure was evaluated relative to the 24-hour change in bacterial burden (log CFU/g). Co-modeling of the data across multiple strains exhibiting a broad range of MIC susceptibility suggested net 1-log CFU/g0 reduction can be achieved when sulbactam T>MIC exceeds 50% of the dosing interval and durlobactam AUC/MIC is 10. These data were ultimately used to support sulbactam-durlobactam dose selection for Phase 3 clinical trials.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10777848PMC
http://dx.doi.org/10.1128/aac.00800-23DOI Listing

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