Resistance profile of drugs composing the “shorter” regimen for multidrug-resistant tuberculosis in Brazil, 2000–2015

Abstract

The difficulties in managing multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant (XDR) TB are well known. The regimens are very expensive, often toxic, and require up to 24 months to achieve an acceptable probability of success [1-3]. Based on successful experiences in different settings, the World Health Organization (WHO) recently provided recommendations on the prescription of a new "shorter" regimen to treat MDR-TB, which is also known as the "Bangladesh regimen" [4-8]. The regimen is composed of kanamycin, moxifloxacin (gatifloxacin being the fluoroquinolone originally used in the "Bangladesh" regimen), prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol for an initial period (4-6 months), then moxifloxacin, clofazimine, pyrazinamide and ethambutol for the continuation phase (5 months) [8]. The regimen has interesting characteristics. It is considerably cheaper than the traditional "long" regimen (<USD1000 versus >USD20 000 or more), has a much shorter duration (9-12 months), and achieves relapse-free success rates exceeding 90% (the positive outcomes of the traditional "longer" regimen are on the order of 50-60%) [8]. The regimen is indicated for patients not previously treated with second-line drugs and unlikely to be resistant to them. WHO recommended the extensive use of rapid molecular testing for the detection of resistances to second-line drugs (Geno Type MTBDRsl) to allow prescription of this regimen to the patients who can benefit from it without risk of developing further drug resistance [8]. Recently, several contributions tried to estimate the proportion of eligible patients in different geographical settings. This ranged from ∼10% in Europe to 50% in Pakistan [9-12]. No countrywide information in this sense is available from Latin America. As part of an ongoing collaboration project between the European Respiratory Society (ERS), the Brazilian Society of Respiratory Medicine (SBPT) and the Brazilian National TB Programme, we analysed the information provided by the Brazilian national register (SITE TB), including all patients needing a treatment different from the standard 6 month regimen for (drug-susceptible) TB cases. The aim of this study is to describe the resistance profile of the drugs composing the "shorter" regimen among MDR-TB cases diagnosed between 2000 and 2015. In Brazil, the MDR-TB regimen is standardised in the majority of cases [13]. Originally, it contained clofazimine and ofloxacin, but in 2006 pyrazinamide replaced clofazimine and in 2010 levofloxacin replaced ofloxacin as the backbone fluoroquinolone (5 months with amikacin or streptomycin (five times a week for 1 month and three times a week for the following 4 months), ethambutol, levofloxacin, pyrazinamide and terizidone, and 12 months with ethambutol, levofloxacin and terizidone). On this basis we analysed, separately, individuals enrolled between 2000 and 2010 from those treated between 2011 and 2015. Absolute frequencies (percentages) and medians (interquartile ranges; IQR...

ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update

“…The WHO criteria preventing the use of the "shorter regimen" include [12,28,29,62,76,[83][84][85][86][87][88][89][90][91][92][93]: 1) confirmed resistance or presumed ineffectiveness to a medicine in the shorter MDR-TB regimen; 2) exposure to ⩾1 second-line medicines in the shorter MDR-TB regimen for >1 month; 3) intolerance to ⩾1 medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug−drug interactions); 4) pregnancy; 5) extrapulmonary disease; and 6) at least one medicine in the shorter MDR-TB regimen not available.…”

The shorter multidrug-resistant tuberculosis treatment regimen in Singapore: are patients from South-East Asia eligible?

“…Publications from Europe have reported eligibility rates ranging from 6.2% to 14% [7][8][9][10]. Data from Pakistan and Brazil showed more optimistic eligibility rates of 50% or higher [11,12]. A multicountry population-based survey showed that, although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug might still be effective in 19-63% of patients with rifampicin-resistant TB, and that the worrisome high level of ofloxacin resistance in Pakistan ( probably reflecting extensive, unregulated use of fluoroquinolones in some parts of Asia) was tempered by the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites [13].…”

Multidrug-resistant tuberculosis and beyond: an updated analysis of the current evidence on bedaquiline

“…The scientific debate is presently focused on the proportion of suitable patients in some geographical settings and on the impact on the MDR-TB epidemic [27][28][29][30][31][32].…”