Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 2

Abstract

We are in a crisis of bacterial resistance. For economic reasons, most pharmaceutical companies are abandoning antimicrobial discovery efforts, while, in health care itself, infection control and antibiotic stewardship programs have generally failed to prevent the spread of drug-resistant bacteria. At this point, what can be done? The first step has been taken. Governments and international bodies have declared there is a worldwide crisis in antibiotic drug resistance. As discovery efforts begin anew, what more can be done to protect newly developing agents and improve the use of new drugs to suppress resistance emergence? A neglected path has been the use of recent knowledge regarding antibiotic dosing as single agents and in combination to minimize resistance emergence, while also providing sufficient early bacterial kill. In this review, we look at the data for resistance suppression. Approaches include increasing the intensity of therapy to suppress resistant subpopulations; developing concepts of clinical breakpoints to include issues surrounding suppression of resistance; and paying attention to the duration of therapy, which is another important issue for resistance suppression. New understanding of optimizing combination therapy is of interest for difficult-to-treat pathogens like Pseudomonas aeruginosa, Acinetobacter spp., and multidrug-resistant (MDR) Enterobacteriaceae. These lessons need to be applied to our old drugs as well to preserve them and to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a resistance suppression plan at the time of regulatory review. In this way, we can make the best of our current situation and improve future prospects.

FIG 1

(A and B) For cefepime (CFPM) and tobramycin (Tobra or TOB) as monotherapy against P. aeruginosa in the hollow-fiber infection model, regimen failure was seen even with supraphysiologic dosing. WT or wt, wild type. Q8h, every 8 h. (C) Combination chemotherapy drove regimen success.

FIG 2

Western blotting for the amount of expressed AmpC β-lactamase in control cultures as well as in cultures exposed to cefepime (Cef.), tobramycin (Tobra), and the combination (Combo.) of cefepime plus tobramycin over time.

FIG 3

(A) First trial of moxifloxacin (Moxi) plus rifampin (Rif) in the 7-day/7-day (7/7) versus 5-day/7-day (5/7) regimens. The AUC exposures in the symbol keys are the free AUC 24-h exposures that were infused into that particular hollow-fiber-system experimental arm on the days that the drugs were administered. (B) Second trial of moxifloxacin plus rifampin in the 7-day/7-day versus 5-day/7-day regimens. The AUC exposures in the figure legends are the free AUC 24-h exposures that were infused into that particular hollow-fiber-system experimental arm on the days that the drugs were administered. Resistance occurred only in the 5-day/7-day therapy arms at the lowest exposures.

FIG 4

System simulation (1,000-iterate Monte Carlo simulation), susceptible counts (Cts), and subpopulations less susceptible to the study drugs (linezolid [LZD] and rifampin [RIF]) from the Bayesian posterior parameter vectors. The median values and the standard deviations are displayed.