Five rules for resistance management in the antibiotic apocalypse, a road map for integrated microbial management.

Resistance to new antimicrobials can become widespread within 2-3 years. Resistance problems are particularly acute for bacteria that can experience selection as both harmless commensals and pathogenic hospital-acquired infections. New drugs, although welcome, cannot tackle the antimicrobial resistance crisis alone: new drugs must be partnered with more sustainable patterns of use. However, the broader experience of resistance management in other disciplines, and the assumptions on which resistance rests, is not widely appreciated in clinical and microbiological disciplines. Improved awareness of the field of resistance management could improve clinical outcomes and help shape novel solutions. Here, the aim is to develop a pragmatic approach to developing a sustainable integrated means of using antimicrobials, based on an interdisciplinary synthesis of best practice, recent theory and recent clinical data. This synthesis emphasizes the importance of pre-emptive action and the value of reducing the supply of genetic novelty to bacteria under selection. The weight of resistance management experience also cautions against strategies that over-rely on the fitness costs of resistance or low doses. The potential (and pitfalls) of shorter courses, antibiotic combinations and antibiotic mixing or cycling are discussed in depth. Importantly, some of variability in the success of clinical trials of mixing approaches can be explained by the number and diversity of drugs in a trial, as well as whether trials encompass single wards or the wider transmission network that is a hospital. Consideration of the importance of data, and of the initially low frequency of resistance, leads to a number of additional recommendations. Overall, reduction in selection pressure, interference with the transmission of problematic genotypes and multidrug approaches (combinations, mixing or cycling) are all likely to be required for sustainability and the protection of forthcoming drugs.