LAUSR

We thank Anthony and colleagues (1) for their interest in our work (2) and for emphasizing the potentially grave implications of pyrazinamide (PZA) resistance for the programmatic treatment of drug-resistant tuberculosis (TB). Indeed, as Anthony and colleagues note in their letter, the proportion of patients with multidrug-resistant (MDR) TB who also harbor resistance to PZA is alarmingly high in some settings, ranging from 36% to 81% in a recent population-based survey (3). Given such high prevalence, we agree that, in settings of high MDR TB burden, all patients should undergo rapid testing for susceptibility to rifampin before initiating a PZA-containing (or any other) regimen. Indeed, the use of empirical therapy in settings of high baseline drug resistance is likely to not only promote the spread of resistance at the population level but also result in poorer clinical outcomes for individual patients. Importantly, this is not true just of PZA but of antimicrobial agents for TB more broadly. Anthony and colleagues also suggest the possibility of withholding PZA until clinical response to other first-line drugs is observed. To the extent that PZA would not be replaced by another agent, the probability of success for such a regimen in areas of high rates of drug resistance (e.g., Belarus) would be unacceptably low. We instead propose a simpler solution, namely, never to recommend a TB regimen for which susceptibility to at least two, and ideally three, high-potency agents is either confirmed or can be reasonably presumed (e.g., where the baseline prevalence of resistance is below 5 to 10%). Individual exceptions must of course be made, for example, for patients who cannot produce sputum, but on a policy level, we advocate for more drug susceptibility testing rather than treatment with fewer agents. Nevertheless, we agree wholeheartedly with Anthony and colleagues that we must urgently develop an evidence base for action in these settings, where current treatment practices may be rapidly fueling the emergence of resistance to PZA, a critical agent in the anti-TB armamentarium. Ultimately, these data underscore the need to expand access to susceptibility testing for both firstand second-line drugs if we are to provide all TB patients with the effective treatment that they deserve. Although we do not wish to diminish the logistical and financial challenges of scaling up drug susceptibility testing, it is also important to note that such testing may save costs in settings of high underlying resistance (4). Additional epidemiological investigation, implementation research, economic evaluation, and modeling studies are greatly needed to assess the suitability of alternative diagnostic and treatment algorithms in specific epidemiological settings where the risk of fueling widespread resistance to PZA is high. Citation Fofana MO, Dowdy DW. 2017. Reply to Anthony et al., “Protecting pyrazinamide, a priority for improving outcomes in multidrugresistant tuberculosis treatment.” Antimicrob Agents Chemother 61:e00427-17. https://doi .org/10.1128/AAC.00427-17. Copyright © 2017 American Society for Microbiology. All Rights Reserved. Address correspondence to D. W. Dowdy, [email protected]. This is a response to a letter by Anthony et al. (https://doi.org/10.1128/AAC.00258-17). LETTER TO THE EDITOR