Severe, invasive Streptococcus pyogenes (Strep A) infections result in greater than 500,000 deaths annually. First line treatment for such infections is benzylpenicillin, often with the addition of 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 in vitro alternative to in vivo research to study these effects. To re-evaluate the inoculum effect for benzylpenicillin, clindamycin, linezolid, and trimethoprim-sulfamethoxazole using a Strep A HFIM. Differential antibiotic susceptibility of Strep A was measured in a HFIM starting from low- and high-density inocula with an average difference in bacterial concentration of 56-fold. Dynamic antibiotic concentrations were delivered over 48 h to simulate in vivo human pharmacokinetics in an in vitro model. Differences in antibiotic susceptibility were measured by plate count of colony-forming units over time. Inoculum effects were seen in benzylpenicillin and linezolid at 24 h, and benzylpenicillin, linezolid, and clindamycin at 48 h. The effect size was greatest for continuously infused benzylpenicillin at 48 h with a log₁₀-fold difference of 4.02 between groups. No inoculum effect was seen in trimethoprim-sulfamethoxazole, with a maximal log₁₀-fold difference of 0.40. Inoculum effects were seen 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.

严重的侵袭性化脓性链球菌(Strep A) 感染每年导致超过 500,000 人死亡。此类感染的一线治疗是苄青霉素，通常加入克林霉素，但这种方案可能会导致治疗失败。这种失败部分归因于接种效应，其表现为在高细菌密度和平台期生长期间抗生素敏感性降低。中空纤维感染模型 (HFIM) 已被提议作为体内研究的体外替代方法来研究这些影响。使用链球菌 A HFIM 重新评估苄青霉素、克林霉素、利奈唑胺和甲氧苄啶-磺胺甲恶唑的接种效果。Strep A 的差异抗生素敏感性在 HFIM 中测量，从低密度和高密度接种开始，细菌浓度的平均差异为 56 倍。在 48 小时内提供动态抗生素浓度，以在体外模型中模拟体内人体药代动力学。通过菌落形成单位随时间的平板计数测量抗生素敏感性的差异。在 24 小时时在苄青霉素和利奈唑胺中观察到接种效果，在 48 小时时在苄青霉素、利奈唑胺和克林霉素中观察到接种效果。连续输注苄青霉素 48 小时的效果最大，log组间 4.02 的₁₀倍差异。在甲氧苄啶-磺胺甲恶唑中未观察到接种效果，最大对数₁₀倍差异为 0.40。使用苄青霉素、利奈唑胺和克林霉素观察到接种效果，这可能预示治疗延迟后临床疗效降低。该模型已被证明是稳健的，并且在很大程度上与已发布的数据一致，推荐将其用于进一步的 Strep A 研究。