Penicillin G concentrations required for prophylaxis against Group A Streptococcus infection evaluated using a hollow fibre model and mathematical modelling. (26th April 2022)

• Record Type: Journal Article
• Authors: Tait, Jessica R; Barnett, Timothy C; Rogers, Kate E; Lee, Wee Leng; Page-Sharp, Madhu; Manning, Laurens; Boyd, Ben J; Carapetis, Jonathan R; Nation, Roger L; Landersdorfer, Cornelia B
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 77:Number 7(2022)
• Page Start: 1923
• Page End: 1930
• Publication Date: 2022-04-26
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkac124
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: 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 log10 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 log10 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 log10 cfu/mL. Following both inocula, concentrations ≥0.016 mg/L suppressed M75 611024 and M1T1 5448 to <1 log10 cfu/mL from 6 h onwards with eradication. Concentrations ≥0.008 mg/L suppressed M18 MGAS8232 to <1 log10 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.