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Variation in bacterial drug susceptibility tied to TB relapse risk

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Small changes have value for predicting TB relapse

Although standard four-drug therapy has been shown to cure 90% of patients in several clinical trials, patients do relapse for reasons such as poor treatment adherence and “variations in the characteristics of the infected patients or the infecting pathogens,” wrote Eric J. Rubin, MD, in an accompanying editorial (N Engl J Med. 2018;379:882-3).

Current antibiotic susceptibility thresholds are often set by committees using models, said Dr. Rubin. “Given the uncertainties in modeling, as has been seen in clinical studies, these breakpoints can be imperfect predictors of treatment response.”

Dr. Rubin proposed that minimum inhibitory concentration (MIC) concentrations could be an alternative to in vitro testing as a predictor of treatment response.

“The clinical laboratory provides us not only with a breakpoint interpretation but also with raw data, a quantitative assessment of MIC values,” he noted. “These values can be thought of more as probabilities of successful therapy than as absolute thresholds, a change in attitude that may dispel a false sense of security about the choice of regimen in the treatment of patients with tuberculosis.”

Dr. Rubin is affiliated with the department of immunology and infectious diseases at the Harvard School of Public Health, Boston. He had no relevant financial conflicts to disclose.



Higher pretreatment drug concentrations close to a resistance breakpoint for susceptibility were associated with greater relapse risk in TB, based on data from 54 patients who relapsed and 63 who were treated and cured.

a strain of tuberculosis is shown iLexx/Thinkstock

“We postulated that drug-susceptible Mycobacterium tuberculosis might have a graded spectrum of susceptibilities that could be used to determine the risk of relapse,” wrote Roberto Colangeli, PhD, of Rutgers University, Newark, N.J., and his colleagues.

In a study published in the New England Journal of Medicine, the researchers examined pretreatment bacterial isolates from adults with TB who had experienced relapse and those who were cured. Using these isolates, they identified the minimum inhibitory concentration (MIC) – the lowest concentration of the drug that prevents visible bacterial growth in culture – for isoniazid and rifampin.

Overall, after controlling for other potential relapse risk factors, higher pretreatment MIC values for both isoniazid and rifampin were associated with an increased relapse risk. For isoniazid, the average MIC below the breakpoint was 0.0334 mcg/mL for relapsed patients and 0.0286 mcg/mL for cured patients. For rifampin, the average MIC below the breakpoint was 0.0695 mcg/mL for relapsed patients and 0.0453 mcg/mL for cured patients. The higher values for the relapsed versus cured patients were represented by factors of 1.17 and 1.53 for isoniazid and rifampin, respectively.

The average age of the patients was 41 years; 83% were men, and 35% were non-Hispanic white.

The study findings were limited by several factors, including the small sample size, retrospective design, and inability to test MIC values from primary cultures versus subcultures, the researchers wrote. However, the results suggest an impact of MIC values on treatment outcomes, and “additional studies that are performed in larger, well-defined prospective cohorts and that include MIC testing of pretreatment culture isolates will be useful to better validate these findings,”

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Colangeli reported no financial conflicts. Dr. Alland disclosed funding from Cepheid and several current and pending patents in the United States and Europe, with some royalties paid to Cepheid.

SOURCE: Colangeli R et al. N Engl J Med. 2018;379:823-33.

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