Bacterial Replication Rate Modulation in Combination with Antimicrobial Therapy: Turning the Microbe against Itself [PublishAheadOfPrint]

A major clinical challenge for treating infectious diseases is the duration of antimicrobial therapy required to eradicate the pathogen. We hypothesized that modulating the bacterial replication rate in the context of an antimicrobial exposure is coupled with the rate and extent of bactericidal effects. Herein we describe results from in vitro infection model (one-compartment, 24 hour; hollow-fiber, 10 day) studies designed to probe the relationship between bacterial replication rate, and the rate and extent of bactericidal effects in the context of an effective antibiotic exposure. Bacterial replication rate was modulated by varying the sodium chloride concentration (0 to 8%) in the growth media (Mueller Hinton II broth). The study drug selected was levofloxacin and the challenge isolate was Staphylococcus aureus ATCC 29213 (levofloxacin MIC, 0.125 mg/L). Within each in vitro infection model, human levofloxacin concentration-time profiles (7 hour half-life) were simulated and the challenge isolate was subjected to an effective exposure (free-drug area under the concentration-time curve to MIC (AUC:MIC ratio), 65; administered as a single dose or daily for 10 days). Over the course of each study, samples were taken from each model for bacterial density determination and drug concentration assay using LC-MS/MS. In the 24 hour one-compartment in vitro infection model studies, as the bacterial replication rate increased so too did the rate (slope, 0-4 hours) and extent (24 hour CFU/mL) of bacterial killing. In the 10 day hollow-fiber infection model studies, the time until a reduction of bacterial density to 1 X 10² CFU/mL was 10 days in the media in which the challenge isolate grew slowly and approximately 2 days in the media in which the challenge isolate grew rapidly. Together, these data provide a proof-of-concept for new adjunctive therapeutic options to antimicrobial agents alone that reduce treatment durations. Such adjunctive therapies hold the promise for marked reductions in the tonnage of antimicrobial agents administered to patient populations and selection pressure toward antimicrobial resistances.

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