Suppression of Emergence of Resistance in Pathogenic Bacteria: Keeping Our Powder Dry, Part 1

Abstract

cWe 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 to preserve them as well and need to be put into national and international antibiotic resistance strategies. As importantly, from a regulatory perspective, new chemical entities should have a corresponding 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.

Prediction of antibiotic resistance: time for a new preclinical paradigm?

“…growth conditions affect the measured resistance levels. For some resistance mechanisms, bacterial growth is unaffected by the use of increasing concentrations of antibiotic, whereas for other mechanisms, growth decreases progressively until the minimal inhibitory concentration (MIC) is reached [14][15][16][17][18] . A potential complication of such measurements is the presence of cases of resistance that is only induced in response to the antibiotic (also known as inducible resistance) 19 .…”

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

“…A common belief is that high enough drug doses can prevent resistance [15][16][17][18][19][20] because higher drug concentrations are more likely to kill resistant mutants [15,21,22]. In the limit, this is clearly true, but if concentrations sufficient to kill all resistant mutants cannot be achieved, populations of surviving mutants rapidly expand to fill the niche vacated when pathogens are killed by chemotherapy [3,4,[23][24][25].…”

Pharmacokinetic and Pharmacodynamic Principles of Anti-infective Dosing

“…3,4 Despite antibiotic resistance having long been declared a major threat to global public health, 3,5,6 the landscape of antimicrobial development has remained arid, with no agents with novel mechanisms of action against resistant Gram-negative organisms currently in late-stage clinical trials. 7-9 It is abundantly clear that optimization of antibiotic prescribing is necessary to preserve our current armamentarium. While stewardship practices focusing on the restriction of use and shortening of treatment duration are well-cited, 10,11 further research on antibiotic pharmacokinetic (PK) and pharmacodynamic (PD) properties that maximize the probability of successful outcome is needed.…”