Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes
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Date
2022
Journal Title
Journal ISSN
Volume Title
Publisher
Antibiotics
Abstract
Mycobacterium tuberculosis 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 Cmax 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.
Description
Keywords
tuberculosis, sepsis, treatment, pharmacokinetics, Cmax
Citation
Odongo, C. O., Nakiyingi, L., Nkeramihigo, C. G., Seifu, D., & Bisaso, K. R. (2022). Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes. Antibiotics, 11(7), 895.