Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria
Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria
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DOI：
10.1093/jac/dkaa412
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发表时间：
2021-01-01
影响因子：
5.2
通讯作者：
Sofjan, Amelia K.
中科院分区：
文献类型：
--
作者：
Tam, Vincent H.;Abodakpi, Henrietta;Sofjan, Amelia K.
目的：β-内酰胺对密集细菌群体的体外活性降低是公认的。这通常归因于β-内酰胺酶的存在，目前尚不清楚β-内酰胺酶抑制剂是否会减弱接种物效应。我们评估了不同的β-内酰胺/β-内酰胺酶抑制剂组合在抑制高接种量的产ESBLs bacteries.Methods：检测了三株表达代表性ESBLs的临床分离株（CTX-M-15和SHV-12）。通过抑制性S形E-max模型表征β-内酰胺酶抑制剂（他唑巴坦或阿维巴坦）浓度递增对β-内酰胺（哌拉西林或头孢他啶）MIC降低的影响。使用%T->MICi预测β-内酰胺/β-内酰胺酶抑制剂组合的各种给药方案的效果，并在120 h内在中空纤维感染模型中对选定的暴露进行实验验证。结果：β-内酰胺的最低抑菌浓度呈浓度依赖性降低（r（2）>= 0.93）。使用%T->MICi >= 73.6%，在所有六个实验中可以抑制再生长，但是六个实验中只有一个低于阈值（P= 0.015）。使用临床剂量的阿维巴坦可能会达到抑制再生长的暴露量，但他唑巴坦需要比标准剂量高得多的剂量。结论：选择的β-内酰胺/β-内酰胺酶抑制剂组合的优化给药方案可以抑制密集的产ESBL菌群。酶抑制作用的可逆性在降低接种效应中起重要作用。在体内研究，以验证这些发现是必要的。
Objectives: Reduced in vitro beta-Lactam activity against a dense bacterial population is well recognized. It is com- monly attributed to the presence of beta-Lactamase(s) and it is unknown whether the inoculum effect could be diminished by a beta-Lactamase inhibitor. We evaluated different beta-Lactam/beta-Lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria.Methods: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating beta-Lactamase inhibitor (tazobactam or avibactam) concentrations on beta-Lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid E-max model. The effect of various dos- ing regimens of beta-Lactam/beta-Lactamase inhibitor combinations was predicted using %T->MICi , and selected expo- sures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to sup- press bacterial regrowth was identified using recursive partitioning.Results: A concentration-dependent reduction in B-Lactam MIC was observed (r(2) >= 0.93). Regrowth could be suppressed in all six experiments using %T->MICi >= 73.6%, but only one out of six experiments below the threshold (P= 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam.Conclusions: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regi- men of selected beta-Lactam/beta-Lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.