This survey provides the first representative data for Pakistan on its MDR-TB burden. The Xpert assay had nearly 100% specificity, even in a low MDR-TB prevalence setting. The use of this assay greatly simplifies survey logistics, making it a feasible option for survey implementation, especially in resource-constrained settings.
We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.
We discuss the possible reasons for the decrease in resistance rates in TB, putative drivers of resistance other than volume of FQ consumption, and the possible impact of the National Tuberculosis Programme and drug regulatory activities.
Bedaquiline is a novel anti-tuberculosis drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) recommended by the World Health Organization (WHO) [1] and recently upgraded to the group A classification of TB drugs as one of the three key drugs, along with linezolid and fluoroquinolones, to be included in all MDR-TB treatment regimens. Based on this grouping of second-line drugs, extensively drug-resistant tuberculosis (XDR-TB) is redefined as MDR- or rifampicin-resistant-TB that is resistant to a fluoroquinolone and to either bedaquiline or linezolid or both. Moreover, bedaquiline, in combination with pretomanid and linezolid, is a part of BPaL regimen recommended for treating adult pulmonary TB patients having pre-XDR-TB or MDR-TB which is either non-responsive or intolerant to recommended standard treatment [2]. However, globally emerging resistance to bedaquiline threatens the effectiveness of novel treatment regimens for drug-resistant TB.
20We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential 21 culture isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimen were 22 tested for minimum inhibitory concentration (MIC) and whole genome sequencing. An increase in MICs 23 associated with cross-resistance to clofazimine and appearance of specific mutations was documented in 24 six cases. The study underlines that appropriate monitoring is mandatory for the introduction of new drugs. 25 26 27 93 strains collected from two patients reported as "failure" at the end of treatment (patient-4 MIC 0.25 94 mg·L −1 , eight fold higher than baseline and patient-5 MIC 0.125 mg·L −1 , four fold higher than baseline) 95 would have been categorised as susceptible. This finding indicates that monitoring MICs during treatment 96 could be a better predictor for failure than single testing at critical concentration. The genetic basis of 97 4 resistance to bedaquiline is still the subject of much uncertainty. WGS analysis in different studies showed 98 that bedaquiline-clofazimine cross resistance arises through mutations in Rv0678 (6,7,8) and pepQ (9). In 99 this study, we show that the increase of MIC to bedaquiline and clofazimine could be explained by 100 mutations emerging during therapy in Rv0678. As reported in table 1 we observed four different mutations 101 and three of these were previously reported as associated 102 to bedaquiline resistance in MTB clinical strains (8). We show that the same mutations are associated to 103 Clofazimine resistance. As a result, regimens that contain both drugs might have to be reconsidered when 104 these mutations are identified, to reduce the risk of failure for the patients and transmission of such strains 105 in the community. Altogether, these data show that resistance to bedaquiline emerges during treatment 106 and emphasize the importance of using MIC and whenever possible molecular based surveillance in 107 national programmes implementing bedaquiline for the treatment of MDR/XDR-TB to monitor the 108 emergence of resistance. Moreover, a classification of mutations associated to bedaquiline and clofazimine 109 resistance is crucial to lead future development of tools for fast detection of resistance. Introducing drugs 110 without proper diagnostics to monitor drug resistance may lead to amplification of hardly treatable cases. 111 112 Ethics approval 113 Ethical clearance was approved by the Institutional review board for HIV, TB and Malaria programme, 114 Pakistan.
Background Pakistan is among top five high burden countries for tuberculosis and drug resistant TB. Among rifampicin sensitive new pulmonary TB (PTB), prevalence of isoniazid resistance is 8.3% (95%CI: 7.0-10.7) and resistance to fluoroquinolone is higher (11�1%, 95%CI: 7�8-14�3) than isoniazid resistance. Method Five year retrospective data (2015-2019) of drug susceptibility testing (DST) for Mycobacterium tuberculosis isolates, performed using recommended phenotypic (pDST) and/or genotypic (gDST) methods was analyzed stratified by rifampicin results for isoniazid resistance profiles and associated levofloxacin and pyrazinamide resistance.
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