Short-Course Regimen for Multidrug-Resistant Tuberculosis: A Decade of Evidence

Abstract

About ten years ago, the first results of the so-called “Bangladesh regimen”, a short regimen lasting nine months instead of 20 months, revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment. Similar short regimens were studied in different settings, relying for their efficacy on a later generation fluoroquinolone, either gatifloxacin, moxifloxacin, or levofloxacin. We review the published material on short MDR-TB regimens, describe their different compositions, their results in national tuberculosis programs in middle- and low-income countries, the risk of acquiring resistance to fluoroquinolone, and the occurrence of adverse events. With over 80% success, the regimen performs much better than longer regimens (usually around 50%). Monitoring of adverse events allows adapting its composition to prevent severe adverse events such as deafness. We discuss the current applicability and usefulness of the short injectable-containing regimen given the 2019 recommendation of the World Health Organization (WHO) for a new long all-oral regimen. We conclude that the most effective fluoroquinolone is gatifloxacin, currently not listed as an essential medicine by WHO. It is a priority to restore its status as an essential medicine.

The continued hunt for the elusive standard short regimen for treatment of multidrug-resistant tuberculosis

“…At first, the results were plausible because the principle that "more drugs are better" had deep historical roots in TB chemotherapy. Subsequently, these results were replicated in observational studies in many countries [7,8], followed by the first-ever full-length, multinational randomised controlled treatment trial for MDR-TB (STREAM Stage 1, ClinicalTrials.gov NCT02409290), comparing the WHO-recommended standardised shorter regimen with standardised longer regimens based on WHO recommendations in effect at that time [9,10]. In every case, the results show approximately ⩾80% success rates against MDR-TB caused by Mycobacterium tuberculosis strains without known resistance to the drugs in the regimen (with the only exception of isoniazid), similar to outcomes with conventional longer regimens.…”

Injectables’ key role in rifampicin-resistant tuberculosis shorter treatment regimen outcomes

“…The gatifloxacin-based STR is the first treatment regimen that consistently achieved high RR-TB treatment success as well as very low recurrence rates without creating any additional resistance to this core drug in a wide range of countries, and does so for more than a decade [15]. In contrast with the WHO recommended approach of combining "at least 4 likely active drugs" [2], the effectiveness of the STR stems from combining drugs with complementary activity [16].…”

Initial resistance to companion drugs should not be considered an exclusion criterion for the shorter multidrug-resistant tuberculosis treatment regimen

“…The shorter treatment regimen has since been successfully implemented in many countries worldwide. Resistance to fluoroquinolones has been found to be the major predictor of adverse treatment outcome ( Rigouts et al, 2016 , Trébucq et al, 2019 , Van Deun et al, 2019 ). The importance of resistance to the other drugs in the regimen is insufficiently understood ( Trébucq et al, 2019 ).…”

“…Resistance to fluoroquinolones has been found to be the major predictor of adverse treatment outcome ( Rigouts et al, 2016 , Trébucq et al, 2019 , Van Deun et al, 2019 ). The importance of resistance to the other drugs in the regimen is insufficiently understood ( Trébucq et al, 2019 ). Originally designed as a standardized regimen in a low-resource setting, the shorter treatment regimen was administered without prior drug susceptibility testing (DST).…”

“…However, in this cohort, very few patients had an adverse bacteriological outcome (12/249; with eight failures and four relapses), limiting the estimation of predictors of poor outcome. Moreover, kanamycin resistance is quite rare in most settings where the regimen has been studied, restricting analyses of its association with adverse outcome ( Trébucq et al, 2019 ). A recent individual patient data meta-analysis found that, except in low-income settings, kanamycin worsened MDR-TB treatment outcomes, which led to the WHO recommendation to stop using kanamycin ( Ahmad et al, 2018 , WHO, 2019c ).…”