Abstract
The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance.
Highlights
The use of antimicrobial drugs has led to the emergence and spread of resistant strains of nearly every bacterial pathogen
Stable coexistence is possible in each model, but is not typical in the baseline case of model of single and dual colonization (model A); in appendix A, we show a bifurcation diagram for this model, indicating that there is a thin band in parameter space in which stable coexistence is possible
The simplest dynamic models that consider strict competition between strain types predict either the complete takeover or the disappearance of resistance; the strain that eventually dominates is determined by the balance of fitness costs imposed by resistance and the selective pressure of antibiotics
Summary
The use of antimicrobial drugs has led to the emergence and spread of resistant strains of nearly every bacterial pathogen. For some antimicrobial agents and bacterial species, resistant strains comprise nearly 100 per cent of the bacterial population. A notorious example is Staphylococcus aureus, which became almost universally resistant to penicillin within a few years of the introduction of this drug. Development of extended spectrum drugs such as oxacillin and methicillin addressed the emergence of these penicillin-resistant strains of S. aureus, but resistance to these antibiotics is common, and their effectiveness is declining (McDonald 2006). Resistant strains have become clinically important, but seem to remain at intermediate frequencies, neither dwindling to zero nor reaching 100 per cent. Examples include vancomycin resistance in Enterococcus (McDonald 2006), sulphonamide resistance in Escherichia coli (Enne et al 2001) and, seemingly, penicillin (and other drug) resistance in Streptococcus pneumoniae
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