Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.
Faculty of Health and Medical Sciences, The University of Sydney Medical Program, Sydney, The University of Sydney, Camperdown, New South Wales, Australia.
Eur J Clin Microbiol Infect Dis. 2021 Oct;40(10):2137-2144. doi: 10.1007/s10096-021-04262-x. Epub 2021 May 4.
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 log-fold difference of 4.02 between groups. No inoculum effect was seen in trimethoprim-sulfamethoxazole, with a maximal log-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.
严重的侵袭性化脓链球菌（酿脓链球菌）感染每年导致超过 50 万人死亡。此类感染的一线治疗药物是青霉素 G，通常会添加克林霉素，但这种治疗方案可能会失败。这种失败部分归因于接种效应，即在细菌密度高和平台期生长时，抗生素敏感性降低。中空纤维感染模型（HFIM）已被提议作为替代体内研究的体外方法，用于研究这些影响。使用酿脓链球菌 HFIM 重新评估青霉素 G、克林霉素、利奈唑胺和复方磺胺甲噁唑的接种效应。从低浓度和高浓度接种物开始，在 HFIM 中测量酿脓链球菌的抗生素药敏性，细菌浓度的平均差异为 56 倍。在 48 小时内以模拟体内人类药代动力学的方式输送动态抗生素浓度，在体外模型中进行模拟。随着时间的推移通过平板计数法测量细菌计数来测量抗生素敏感性的差异。在 24 小时时观察到青霉素 G 和利奈唑胺的接种效应，在 48 小时时观察到青霉素 G、利奈唑胺和克林霉素的接种效应。在 48 小时时连续输注青霉素 G 的效应最大，组间对数差为 4.02。在复方磺胺甲噁唑中未观察到接种效应，最大对数差为 0.40。观察到青霉素 G、利奈唑胺和克林霉素的接种效应，这可能预示着治疗延迟后临床疗效降低。该模型已被证明稳健且与已发表的数据基本一致，建议将其用于进一步的酿脓链球菌研究。
