What Antibiotic Exposures Are Required to Suppress the Emergence of Resistance for Gram-Negative Bacteria? A Systematic Review

Abstract

Background: The rates of antibiotic resistance in Gram-negative bacteria are increasing. One method to minimize resistance emergence may be optimization of antibiotic dosing regimens to achieve drug exposure that suppress the emergence of resistance. Objective: The aim of this systematic review was to describe the antibiotic exposures associated with suppression of the emergence of resistance for Gram-negative bacteria. Methods: We conducted a search of four electronic databases. Articles were included if the antibiotic exposure required to suppress the emergence of resistance in a Gram-negative bacterial isolate was described. Among studies, 57 preclinical studies (in vitro and in vivo) and 2 clinical studies 59 included investigated the monotherapy of antibiotics against susceptible and/or intermediate Gram-negative bacteria. Results: The pharmacokinetic/pharmacodynamic (PK/PD) indices reported to suppress the emergence of antibiotic resistance for various classes were β-lactam antibiotic minimum concentration to minimum inhibitory concentration (Cmin/MIC) ≥ 4; aminoglycoside maximum concentration to MIC (Cmax/MIC) ratio ≥ 20; fluoroquinolones, area under the concentration-time curve from 0 to 24 h to mutant prevention concentration (AUC24/MPC) ≥ 35; tetracyclines, AUC24 to MIC (AUC24/MIC) ratio ≥ 50; polymyxin B, AUC24/MIC ≥ 808; and fosfomycin, AUC24/MIC ≥ 3136. However, the exposures required to suppress the emergence of resistance varied depending on the specific antibiotic tested, the duration of the experiment, the bacterial species and the specific bacterial isolate tested. Importantly, antibiotic exposures required to suppress the emergence of resistance generally exceeded that associated with clinical efficacy. Conclusion: The benefits of implementing such high PK/PD targets must be balanced with the potential risks of antibiotic-associated toxicity.