Editorial Commentary: Pharmacokinetic Variability and Tuberculosis Treatment Outcomes, Including Acquired Drug Resistance

In this issue of Clinical Infectious Diseases, Pasipanodya et al present a metaanalysis regarding the “pharmacokinetic variability hypothesis” for tuberculosis treatment outcomes, including acquired drug resistance [1]. We commend the authors for their in-depth analysis and for the substantial effort expended in collating the studies, performing the necessary statistical analyses, and interpreting the results. The power of metaanalysis lies in its ability to combine studies relating to a single topic. Its Achilles’ heel lies in the quality of the data available for the analysis. In this case, the authors provided a clear hypothesis and performed a systematic analysis. They focused on isoniazid, one of the most important tuberculosis drugs. Until now, it had been widely recognized that isoniazid acetylator status was associated with clinical and microbiological outcomes in older, once-weekly treatment regimens involving para-aminosalicylic acid and streptomycin. Beyond that, the “dogma” was that isoniazid acetylator status did not produce clinical significant differences in outcomes for fast versus slow acetylators. The work by Pasipanodya et al calls that dogma into question. For this analysis, a relatively limited number of acceptable studies were available. Furthermore, 9 of the 13 studies evaluated isoniazid within nonrifamycin regimens. Only 2 of the 4 remaining studies contained rifampin, the most commonly used rifamycin. Although the presence or absence of a rifamycin has no bearing on a patient’s acetylator status, nonrifamycin regimens last many more months, and they are associated with more microbiological failures. Thus, some caution should be exercised in generalizing these metaanalysis findings to rifamycin-based regimens. That said, some of the most compelling data come from those 4 rifamycin-based studies. Additionally, rifabutin-based studies also support the association between adequate drug concentrations and tuberculosis treatment outcomes [2, 3]. The authors briefly discuss the topic of pharmacokinetic mismatch and, in particular, the pairing of tuberculosis drugs with short versus long half-lives. Examples include the pairing of isoniazid (a drug with a short half-life) with either rifapentine or rifabutin (both with long half-lives), especially within intermittent regimens (once-, twice-, or thrice-weekly dosing). At least on the surface, this seems analogous to the situation with efavirenz and nucleoside reverse-transcriptase inhibitors; when discontinuing treatment with efavirenz (with its long half-life), it is widely accepted that one needs to continue taking nucleoside reverse-transcriptase inhibitors (with their short half-lives) for several days to prevent efavirenz resistance while efavirenz slowly leaves the body [4, 5]. For tuberculosis, with its slower rate of multiplication compared with human immunodeficiency virus (HIV), this area of research still is being explored. It is fair to say that there is growing concern about using intermittent tuberculosis regimens in general, and mismatched ones in particular, especially in HIV-positive patients and especially early in treatment. All of this can be summed up in one phrase: drug exposure. In the treatment of tuberculosis, our primary weapons are the drugs. Both mouse and human studies show that more drug exposure leads to more killing of tuberculosis and better treatment outcomes [6, 7]. It follows from this that it would be entirely reasonable to control and optimize tuberculosis drug exposures to facilitate these desired outcomes. We long have Received 15 March 2012; accepted 21 March 2012; electronically published 30 March 2012. Correspondence: Charles A. Peloquin, PharmD, FCCP, College of Pharmacy, and Emerging Pathogens Institute, University of Florida, 1600 SW Archer Rd, Room P4-33, PO Box 100486, Gainesville, FL 32610-0486 (peloquin@cop.ufl.edu). Clinical Infectious Diseases 2012;55(2):178–9 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cis366