Penicillin G concentrations required for prophylaxis against Group A Streptococcus infection evaluated using a hollow fibre model and mathematical modelling

Background: Acute rheumatic fever (ARF), an autoimmune reaction to Group A Streptococcus (Streptococcus pyogenes; Strep A) infection, can cause rheumatic heart disease (RHD). New formulations of long-acting penicillins are being developed for secondary prophylaxis of ARF and RHD. 

Objectives: To evaluate the penicillin G concentrations required to suppress growth of Strep A. Methods: Broth microdilution MIC and MBC for Strep A strains M75611024, M1T15448 and M18MGAS8232 were determined. All strains were studied in a hollow fibre model (initial inoculum 4log10 cfu/mL). Constant penicillin G concentrations of 0.008, 0.016 and 0.05mg/L were examined against all strains, plus 0.012mg/L against M18MGAS8232. Viable counts were determined over 144h. Subsequently, all penicillin G-treated cartridges were emptied, reinoculated with 5log10 cfu/mL and counts determined over a further 144h. Mathematical modelling was performed. 

Results: MIC and MBC were 0.008mg/L for all strains; small subpopulations of M75611024 and M1T15448, but not M18MGAS8232, grew at 1× MIC. Following the first inoculation, 0.008mg/L achieved limited killing and/or stasis against M75611024 and M1T15448, with subsequent growth to ∼6log10 cfu/mL. Following both inocula, concentrations ≥0.016mg/L suppressed M75611024 and M1T15448 to <1log10 cfu/mL from 6h onwards with eradication. Concentrations ≥0.008mg/L suppressed M18MGAS8232 to <1log10 cfu/mL from 24h onwards with eradication after both inoculations. Mathematical modelling well described all strains using a single set of parameter estimates, except for different maximum bacterial concentrations and proportions of bacteria growing at 1× MIC. 

Conclusions: In the absence of validated animal and human challenge models, the study provides guidance on penicillin G target concentrations for development of new penicillin formulations.