Abstract
The frequency of resistance to antibiotics in Streptococcus pneumoniae has been stable over recent decades. For example, penicillin non-susceptibility in Europe has fluctuated between 12% and 16% without any major time trend. In spite of long-term stability, resistance fluctuates over short time scales, presumably in part due to seasonal fluctuations in antibiotic prescriptions. Here, we develop a model that describes the evolution of antibiotic resistance under selection by multiple antibiotics prescribed at seasonally changing rates. This model was inspired by, and fitted to, published data on monthly antibiotics prescriptions and frequency of resistance in two communities in Israel over 5 years. Seasonal fluctuations in antibiotic usage translate into small fluctuations of the frequency of resistance around the average value. We describe these dynamics using a perturbation approach that encapsulates all ecological and evolutionary forces into a generic model, whose parameters quantify a force stabilizing the frequency of resistance around the equilibrium and the sensitivity of the population to antibiotic selection. Fitting the model to the data revealed a strong stabilizing force, typically two to five times stronger than direct selection due to antibiotics. The strong stabilizing force explains that resistance fluctuates in phase with usage, as antibiotic selection alone would result in resistance fluctuating behind usage with a lag of three months when antibiotic use is seasonal. While most antibiotics selected for increased resistance, intriguingly, cephalosporins selected for decreased resistance to penicillins and macrolides, an effect consistent in the two communities. One extra monthly prescription of cephalosporins per 1000 children decreased the frequency of penicillin-resistant strains by 1.7%. This model emerges under minimal assumptions, quantifies the forces acting on resistance and explains up to 43% of the temporal variation in resistance.
Highlights
The evolution of antimicrobial resistance in many pathogens is an important public health concern [1]
Resistance can evolve over time scales of a few months: fluctuations in the frequency of drug resistance have been observed in many important pathogens such as Plasmodium falciparum, a protozoan parasite causing malaria [2], and the bacterial species Neisseria gonorrhoeae [3], Campylobacter spp. [4], Pseudomonas aeruginosa [5], Escherichia coli [6], Staphylococcus aureus [6] and Streptococcus pneumoniae [7,8]
We introduce these methodological developments, and we illustrate them in the context of antibiotic resistance in S. pneumoniae
Summary
The evolution of antimicrobial resistance in many pathogens is an important public health concern [1]. The first aim of the paper is to develop a generic model of adaptation to a fluctuating environment, applicable to a variety of settings and pathogens, in order to analyse longitudinal data on the frequency of resistance and antimicrobial consumption, and give a clear evolutionary interpretation to these patterns. We introduce these methodological developments, and we illustrate them in the context of antibiotic resistance in S. pneumoniae. The second aim is to learn about the population genetics of drug resistance in S. pneumoniae by applying the newly developed method
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