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 M75(611024), M1T1(5448) and M18(MGAS8232) were determined. All strains were studied in a hollow fibre model (initial inoculum 4 log(10) cfu/mL). Constant penicillin G concentrations of 0.008, 0.016 and 0.05 mg/L were examined against all strains, plus 0.012 mg/L against M18(MGAS8232). Viable counts were determined over 144 h. Subsequently, all penicillin G-treated cartridges were emptied, reinoculated with 5 log(10) cfu/mL and counts determined over a further 144 h. Mathematical modelling was performed. RESULTS: MIC and MBC were 0.008 mg/L for all strains; small subpopulations of M75(611024) and M1T1(5448), but not M18(MGAS8232), grew at 1× MIC. Following the first inoculation, 0.008 mg/L achieved limited killing and/or stasis against M75(611024) and M1T1(5448), with subsequent growth to ∼6 log(10) cfu/mL. Following both inocula, concentrations ≥0.016 mg/L suppressed M75(611024) and M1T1(5448) to <1 log(10) cfu/mL from 6 h onwards with eradication. Concentrations ≥0.008 mg/L suppressed M18(MGAS8232) to <1 log(10) cfu/mL from 24 h 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.