Hunting Eagles with glass mice: revisiting the inoculum effect for Streptococcus pyogenes with a hollow fibre infection model

BackgroundSevere, invasive Streptococcus pyogenes (Strep A) infections result in greater than 500,000 deaths annually. First line treatment for such infections is combination benzylpenicillin and clindamycin, but treatment failure can occur with this regimen. This failure has been partially attributed to the inoculum effect, which presents as reduced antibiotic susceptibility during high bacterial density and plateau-phase growth. Hollow fibre infection models (HFIM) have been proposed as an alternative to in vivo research to study these effects. ObjectivesTo re-evaluate the inoculum effect for benzylpenicillin, clindamycin, linezolid and trimethoprim-sulfamethoxazole using a Strep A HFIM. MethodsDifferential antibiotic susceptibility of Strep A was measured in a HFIM starting from low- and high-density inocula. Dynamic antibiotic concentrations were delivered over 48 hours to simulate human pharmacokinetics. Differences in antibiotic susceptibility were determined at 24 and 48 hours by plate count of remaining viable colony-forming units. ResultsInoculum effects were seen in benzylpenicillin and linezolid at 24 hours, and benzylpenicillin, linezolid and clindamycin at 48 hours. The effect size was greatest for continuously infused benzylpenicillin. No inoculum effect was seen in trimethoprim-sulfamethoxazole. ConclusionsInoculum effects were seen in the HFIM model using benzylpenicillin, linezolid and clindamycin, which may predict reduced clinical efficacy following treatment delay. The model has proven robust and largely in agreeance with published data, recommending it for further Strep A study.