Resistant Plus Susceptible Tuberculosis: The Undiscovered Country

Before the emergence of molecular epidemiology techniques, the conceptual approach to tuberculosis treatment seemed straightforward. The clinical laboratory sent the patient’s isolate (singular) for testing at a reference laboratory, which would perform a drug-susceptibility test (DST) whose findings were reported as a categorical result (ie, susceptible or resistant). This information then guided selection of appropriate antimicrobial therapy, and in clinical trials, this approach worked in the vast majority of cases. With the advent of molecular typing methods, a core premise of the classical paradigm was challenged. Genetic analyses of cultures, and even patient samples, provided evidence that a minority of patients with tuberculosis harbor >1 strain of bacteria at the same time [1–6] and that some of these mixed infections involve both drug-susceptible and drug-resistant organisms [7, 8]. What then are the consequences for patient management? [9]. In previous reports, mixed infection has been identified as the cause of discrepant DST results in pretreatment isolates [8] and of results that change during the course of therapy [7]. Thus, in patients whose initial phenotypic DST identifies only susceptible isolates, mixed infection can explain the subsequent growth of resistant organisms, offering an alternative explanation to reinfection or acquired resistance. In this situation, a patient would typically receive only first-line medications. Given that these antibiotics have little activity against the subpopulation of resistant organisms, one can readily envision how treatment failure could ensue. In the converse situation, the initial DST identifies drug-resistant organisms, but because of mixed infection there is subsequent growth of susceptible isolates. Is it possible that this situation would also result in an adverse treatment outcome if first-line drugs are withheld from patients with a subpopulation of drug-susceptible organisms? In this issue of the Journal, Zetola et al ask precisely this question. To define mixed infection, Zetola et al identified sputum cultures from patients with MDR tuberculosis that demonstrated the presence of isoniazidand rifampin-susceptible strains within the first 3 months of treatment; the authors referred to this situation as phenotypic DST heterogeneity. In this cohort in Botswana, phenotypic DST heterogeneity was observed in 7% of patients (33/475) and was not associated with baseline patient characteristics. In multivariable analyses, the rate of poor clinical outcomes (death, treatment failure, or treatment default) was 2-fold higher in patients with phenotypic DST heterogeneity, achieving statistical significance overall, and also among people living with human immunodeficiency virus (HIV). Together, these observations led the investigators to ponder whether the addition of the most potent tuberculosis drugs, isoniazid and rifampin, might have improved outcomes in these patients with mixed infections. The authors presented a strong argument in favor of a link between phenotypic DST heterogeneity and poor treatment outcomes by controlling for several potential confounders, such as correlates of tuberculosis severity (smear status) and the degree of immunosuppression. However, whether this link is causal requires further investigation. The DST results at the time of culture conversion or of treatment failure and/or death did not obviously explain how the presence of isoniazidand rifampin-susceptible isolates could have led to poor outcomes. Among patients with phenotypic DST heterogeneity, drugsusceptible isolates were detected in the last positive culture in 9 of 16 patients who experienced culture conversion, yet in only 5 of 19 patients who experienced poor outcomes. This suggests the possibility of alternative explanations for Received and accepted 23 January 2014; electronically published 12 February 2014. Correspondence: Marcel Behr, MD, MSc, Department of Medicine, McGill University, McGill International TB Centre, 1650 Cedar Ave, Rm A5.156, Montreal, QC H3G-1A4 Canada (marcel.behr@mcgill.ca). The Journal of Infectious Diseases 2014;209:1682–4 © The Author 2014. 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/infdis/jiu078