How competition governs whether moderate or aggressive treatment minimizes antibiotic resistance

Abstract

Understanding how our use of antimicrobial drugs shapes future levels of drug resistance is crucial. Recently, there has been debate over whether an aggressive (i.e., high dose) or more moderate (i.e., lower dose) treatment of individuals will most limit the emergence and spread of resistant bacteria. In this study, we demonstrate how one can understand and resolve these apparently contradictory conclusions. We show that a key determinant of which treatment strategy will perform best at the individual level is the extent of effective competition between resistant and sensitive pathogens within a host. We extend our analysis to the community level, exploring the spectrum between strict inter-strain competition and strain independence. From this perspective as well, we find that the magnitude of effective competition between resistant and sensitive strains determines whether an aggressive approach or moderate approach minimizes the burden of resistance in the population.DOI: http://dx.doi.org/10.7554/eLife.10559.001

Repeated sublethal freshwater exposures reduce the amoebic gill disease parasite, Neoparamoeba perurans, on Atlantic salmon

“…Using a moderate approach of repeated shorter freshwater bath treatments aimed at detaching rather than killing amoebae on gills may lead to reduced selection pressure for freshwater tolerant strains (some evidence from drug resistance evolution studies) (Kouyos et al., ). However, because freshwater tolerant N. perurans strains potentially outcompete susceptible ones under moderate sublethal exposures, which is how drug‐resistant bacteria can evolve from sublethal drug doses (Colijn & Cohen, ), current rates of freshwater tolerance evolution may remain unchanged or accelerate. In addition, Hughes and Andersson () acknowledged that mutation rates, performance of resistance mechanisms, fitness of resistant relative to susceptible strains, epistatic interactions, compensatory evolution and population bottlenecks can influence drug resistance evolution.…”

“…The interplay between the removal of N. perurans as they form floating pseudocysts in freshwater (Lima et al., ), along with the shedding of mucus and cellular debris (Adams & Nowak, ; Clark et al., ; Parsons et al., ), reveals the possibility of using sublethal freshwater exposures in AGD management. However, shorter, and in effect less aggressive, freshwater treatments may change the rates of freshwater tolerance evolution in N. perurans populations (Colijn & Cohen, ; Hughes & Andersson, ; Kouyos et al., ).…”

Population dynamics of epidemic and endemic states of drug-resistance emergence in infectious diseases

“…The time for start of the treatment can have a substantial influence on the underlying processes by which these factors are characterized. At the population level, the interplay between these factors manifests itself in the rise and fall of resistance (Lipsitch, 2001), making the identification of optimal treatment regimens extremely difficult to achieve in order to simultaneously minimize the incidence of disease and limit resistance emergence and spread (Colijn & Cohen, 2015; Day & Read, 2016). As has been demonstrated in recent studies, it is therefore important to develop multi-scale models that integrate both within-host infection dynamics and between-host disease transmission (Legros & Bonhoeffer, 2016).…”

Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations

“…In fact, recent work suggests that aggressive treatment strategies can hasten the emergence and spread of resistance [30][31][32][33][34][35][36][37][38][39][40][41]. In addition, numerous studies, both experimental and theoretical, provide evidence that less aggressive treatment strategies may be called for under some conditions [42][43][44][45][46][47][48][49][50], while several clinical trials have also demonstrated advantages of lower dose therapies [50][51][52][53][54][55][56][57][58]. The most frequently cited advantages of less aggressive therapies are reduced off-target selection for resistance and fewer adverse effects for the patient.…”