Odongo Charles Okot, Nakiyingi Lydia, Nkeramihigo Clovis Gatete, Seifu Daniel, Bisaso Kuteesa Ronald
Division of Basic Medical Sciences, School of Medicine, University of Global Health Equity, Kigali P.O. Box 6955, Rwanda.
Department of Internal Medicine, School of Medicine, College of Health Sciences, Makerere University, Kampala P.O. Box 7072, Uganda.
Antibiotics (Basel). 2022 Jul 5;11(7):895. doi: 10.3390/antibiotics11070895.
is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the drug concentration at the disease site and time above MIC are critical to treatment outcomes. We elaborate on sepsis pathophysiology and show how it adversely affects antituberculous drug kinetics. Expanding distribution volumes secondary to an increased vascular permeability prevents the attainment of target C concentrations for nearly all drugs. Furthermore, sepsis-induced metabolic acidosis promotes protonation, which increases renal clearance of basic drugs such as isoniazid and ethambutol, and hence AUCs are substantially reduced. Compared with the treatment of non-sepsis TB disease, these distorted kinetics underlie the poor treatment outcomes observed with bloodstream infections. In addition to aggressive hemodynamic management, an increase in both the dose and frequency of drug administration are warranted, at least in the early phase of treatment.
是艾滋病毒感染成人中脓毒症的主要病因，但有效的治疗仍然是一项挑战。抗结核药物的疗效通过高曲线下面积与最低抑菌浓度（AUC/MIC）比值得以优化，这表明疾病部位的药物浓度和高于MIC的时间对治疗结果都至关重要。我们详细阐述了脓毒症的病理生理学，并展示了它如何对抗结核药物动力学产生不利影响。血管通透性增加导致分布容积扩大，几乎所有药物都无法达到目标C浓度。此外，脓毒症诱导的代谢性酸中毒促进质子化，增加了异烟肼和乙胺丁醇等碱性药物的肾清除率，因此AUC大幅降低。与非脓毒症结核病的治疗相比，这些扭曲的动力学是血流感染治疗效果不佳的原因。除了积极的血流动力学管理外，至少在治疗早期，有必要增加药物给药的剂量和频率。
