Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes

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 C_max 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.

Keywords: AUC; Cmax; pharmacokinetics; sepsis; treatment; tuberculosis.

Figure 1

Structures of anti-tuberculous drugs reviewed in this manuscript: (A) Isoniazid, (B) Ethambutol, (C) Pyrazinamide, (D) Pyrazinoic acid, (E) Rifampin.