Six Drugs Ideal for Treating Multidrug-Resistant TB

Tara Haelle

January 06, 2016

For patients with multidrug-resistant tuberculosis (TB), taking at least six potentially effective drugs, particularly including pyrazinamide, significantly increased the likelihood of achieving a sputum culture conversion, according to a prospective cohort study published online December 29 in PLOS Medicine.

Current guidelines from the World Health Organization on treating multidrug-resistant TB suggest patients receive at least four second-line drugs plus pyrazinamide.

"In our analysis, for most patients, the increased likelihood of sputum culture conversion associated with the presence of an additional effective drug in the regimen was greater than the acceleration associated with the presence of an additional ineffective drug," write Courtney M. Yuen, PhD, from the Centers for Disease Control and Prevention in Atlanta, Georgia, and colleagues. "This result suggests that tailoring regimens based on [drug susceptibility testing (DST)] results could improve treatment response."

The researchers analyzed data from 1137 adults enrolled in the prospective, observational Preserving Effective Tuberculosis Treatment Study (PETTS). All the adults were treated between 2005 and 2010 for multidrug-resistant TB and showed a resistance to isoniazid and rifampin. The Centers for Disease Control and Prevention conducted the participants' baseline DST for ciprofloxacin and ofloxacin, as well as the following drugs: isoniazid, rifampin, ethambutol, amikacin, capreomycin, kanamycin, streptomycin, rifabutin, ethionamide, and para-aminosalicylic acid.

The study involved collecting monthly sputum samples from all participants during a median 20 months of follow-up after treatment began. The researchers adjusted their analysis to account for each participant's country, baseline resistance pattern, past treatment history, sputum smear result, disease progression on chest X-ray, and number of drugs to which patients' baseline isolates were resistant. Participants came from one of nine countries: Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, Thailand, and Taiwan.

Participants who received at least six potentially effective drugs (ones for which DST indicated no resistance) daily were 36% more likely to show an initial sputum culture conversion than those who received an average of at least five (but fewer than six) potentially effective drugs daily (adjusted hazard ratio [aHR], 1.36; 95% confidence interval [CI], 1.09 - 1.69).

Participants who took pyrazinamide as one of their drugs were twice as likely to have sputum culture conversion (aHR, 2.00; 95% CI, 1.65 - 2.41), and they were 65% more likely to meet the primary outcome for each additional drug they took that was shown to be susceptible during DST (aHR, 1.65; 95% CI, 1.48 - 1.84).

For each drug they took for which DST indicated resistance, participants were 33% more likely to show culture conversion (aHR, 1.33; 95% CI, 1.18 - 1.51), which the authors noted was unexpected. "Possible explanations for this observation include infection with multiple strains with differing drug susceptibilities, strains with low-level resistance in vitro that were still susceptible in vivo to therapeutic drug concentrations, or synergistic effects between drugs," the authors write.

Participants who took a drug not considered in DST were only 39% more likely to show sputum culture conversion when they also took at least three other effective drugs (aHR, 1.39; 95% CI, 1.09 - 1.76, per drug after the three effective ones).

The authors urge caution in interpreting the finding of strong benefit from including pyrazinamide in the treatment regimen because "[i]t is possible that clinicians accurately assessed the likelihood that pyrazinamide would be effective before deciding to use it, that the prevalence of pyrazinamide resistance in the analyzed cohort was relatively low, or that the efficacy of pyrazinamide in those patients with pyrazinamide susceptibility was so great that an association was observed even though the drug was ineffective in a proportion of the patients who received it," they write. "In situations where undetected resistance renders pyrazinamide ineffective, a five-drug regimen that includes pyrazinamide would actually contain only four effective drugs, which could put patients at risk for poorer outcomes," they add.

The results may not be generalizable to areas with different multidrug-resistant TB, the authors note, and another study limitation was the inability to assess individual drug effects or control for their varying efficacies, the lack of long-term data to assess relapse or sputum culture reversion, limited data collection regarding drug use duration, and the study's observational design.

The research was funded by the US Agency for International Development, the Centers for Disease Control and Prevention, the National Institutes of Health, and the Korean Ministry of Health and Welfare. The authors have disclosed no relevant financial relationships.

PLOS Med. Published online December 29, 2015. Full text

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