Aubry Romain, Buyck Julien M, Chauzy Alexia, Prouvensier Laure, Decousser Jean-Winoc, Nordmann Patrice, Wicha Sebastian G, Marchand Sandrine, Grégoire Nicolas
INSERM U1070 PHAR2, Université de Poitiers, Poitiers, Nouvelle-Aquitaine, France.
Laboratoire de Toxicologie et de Pharmacocinétique, CHU de Poitiers, Poitiers, Nouvelle-Aquitaine, France.
Antimicrob Agents Chemother. 2025 May 7;69(5):e0179724. doi: 10.1128/aac.01797-24. Epub 2025 Apr 14.
The inoculum effect (IE) characterizes a decrease in the antimicrobial effect of antibiotics with increasing inoculum. To face antimicrobial resistance, antibiotic combinations are progressively used. In this context, the effect of combination may be affected by IE, especially drugs for which an IE has been described. The objective was to characterize the IE of a carbapenemase (KPC-3) isolate on the combination of ceftazidime/avibactam (CZA) and colistin (CST). time-kill curves with single and combined drugs were performed at four different inocula. The IE of each drug was described using pharmacokinetic/pharmacodynamic modeling, and interactions on IE were investigated with the general pharmacodynamic interaction model when drugs were combined. The IE was assessed by evaluating the significance of the parameters associated with the IE model compared to the no IE model and by comparing the CFU counts over time predicted with the IE model vs the no IE model. Rapid bacterial killing was observed at 10 CFU/mL. For both 5·10 and 10 CFU/mL inocula, initial decays followed by re-growth were observed with drugs alone, while the combination prevented the emergence of resistance. Eradication was never achieved at 10 CFU/mL. The IE was best modeled as a reduction of CZA maximum bactericidal effect and as an increase in CST EC with increasing inoculum. However, no interaction between IEs was significant, meaning that CST did not modify the IE of CZA and inversely. IE may be important at least as demonstrated by antibiotic combination studies.
接种物效应（IE）的特点是随着接种物增加，抗生素的抗菌效果降低。为应对抗菌药物耐药性，抗生素联合用药正逐渐被采用。在此背景下，联合用药的效果可能会受到接种物效应的影响，尤其是那些已被描述存在接种物效应的药物。目的是表征产碳青霉烯酶（KPC - 3）菌株对头孢他啶/阿维巴坦（CZA）和黏菌素（CST）联合用药的接种物效应。在四种不同接种量下进行了单药及联合用药的时间 - 杀菌曲线实验。每种药物的接种物效应通过药代动力学/药效学建模进行描述，联合用药时通过通用药效学相互作用模型研究对接种物效应的相互作用。通过评估与无接种物效应模型相比，与接种物效应模型相关参数的显著性，以及比较接种物效应模型与无接种物效应模型预测的随时间变化的菌落形成单位（CFU）计数，来评估接种物效应。在10 CFU/mL时观察到细菌快速被杀灭。对于5×10⁵和10⁶ CFU/mL的接种量，单独使用药物时观察到初始细菌数量下降随后又重新生长，而联合用药可防止耐药性的出现。在10⁷ CFU/mL时从未实现根除。接种物效应最好被模拟为随着接种量增加，CZA最大杀菌效应降低以及CST最低抑菌浓度（EC）增加。然而，接种物效应之间没有显著的相互作用，这意味着CST不会改变CZA的接种物效应，反之亦然。至少从抗生素联合用药研究来看，接种物效应可能很重要。
