Antibiotic Dose Impact on Resistance Selection in the Community: a Mathematical Model of β-Lactams and Streptococcus pneumoniae Dynamics

Streptococcus pneumoniae is a major pathogen in the community and presents high rates of resistance to the available antibiotics. To prevent antibiotic treatment failure caused by highly resistant bacteria, increasing the prescribed antibiotic dose has recently been suggested. The aim of the present study was to assess the influence of beta-lactam prescribed doses on the emergence of resistance and selection in the community. A mathematical model was constructed by combining S. pneumoniae pharmacodynamic and population-dynamic approaches. The received-dose heterogeneity in the population was specifically modeled. Simulations over a 50-year period were run to test the effects of dose distribution and antibiotic exposure frequency changes on community resistance patterns, as well as the accuracy of the defined daily dose as a predictor of resistance. When the frequency of antibiotic exposure per year was kept constant, dose levels had a strong impact on the levels of resistance after a 50-year simulation. The lowest doses resulted in a high prevalence of nonsusceptible strains (>= 70%) with MICs that were still low (1 mg/liter), whereas high doses resulted in a lower prevalence of nonsusceptible strains (<40%) and higher MICs (2 mg/liter). Furthermore, by keeping the volume of antibiotics constant in the population, different patterns of use (low antibiotic dose and high antibiotic exposure frequency versus high dose and low frequency) could lead to markedly different rates of resistance distribution and prevalence (from 10 to 100%). Our results suggest that pneumococcal resistance patterns in the community are strongly related to the individual beta-lactam doses received: limiting beta-lactam use while increasing the doses could help reduce the prevalence of resistance, although it should select for higher levels of resistance. Surveillance networks are therefore encouraged to collect both daily antibiotic exposure frequencies and individual prescribed doses.