ABSTRACT
BACKGROUND: Due to the emergence of Mycobacterium tuberculosis (M.tb) clinical isolates resistant to most potent first-line drugs (FLD), second-line drugs (SLD) are being prescribed more frequently. We explore the genetic characteristics and molecular mechanisms of M.tb isolates phenotypically resistant to SLD, including pre-extensively drug-resistant (pre-XDR) and extensively drug-resistant (XDR) isolates. METHODS: Drug-resistant (DR) M.tb isolates collected from 2012 to 2017 were tested using sequencing and phenotypic drug susceptibility testing. Genotypes were determined to explore their links with SLD resistance patterns. RESULTS: Of the 272 DR M.tb isolates, 6 non-multidrug resistant (non-MDR) isolates were fluoroquinolones (FQ)-resistant, 3 were XDR and 16 were pre-XDR (14 resistant to FQ and 2 to second-line injectable drugs). The most frequent mutations in FQ-resistant and second-line injectable drugs resistant isolates were gyrA D94G (15/23) and rrs a1401g (3/5), respectively. Seventy-five percent of pre-XDR isolates and 100% of XDR isolates harbored mutations conferring resistance to pyrazinamide. All XDR isolates belonged to the Beijing genotype, of which one, named XDR+, was resistant to all drugs tested. One cluster including pre-XDR and XDR isolates was observed. CONCLUSION: This is the first description of SLD resistance in Cambodia. The data suggest that the proportion of XDR and pre-XDR isolates remains low but is on the rise compared to previous reports. The characterization of the XDR+ isolate in a patient who refused treatment underlines the risk of transmission in the population. In addition, genotypic results show, as expected, that the Beijing family is the main involved in pre-XDR and XDR isolates and that the spread of the Beijing pre-XDR strain is capable of evolving into XDR strain. This study strongly indicates the need for rapid interventions in terms of diagnostic and treatment to prevent the spread of the pre-XDR and XDR strains and the emergence of more resistant ones.
ABSTRACT
INTRODUCTION: Prolonged inpatient multidrug-resistant tuberculosis (MDR-TB) treatment for all patients is not sustainable for high-burden settings, but there is limited information on community-based treatment programme outcomes for MDR-TB. METHODS: The Cambodian Health Committee, a non-governmental organisation (NGO), launched the Cambodian MDR-TB programme in 2006 in cooperation with the National Tuberculosis Program (NTP) including a community-based treatment option as a key programme component. The programme was transferred to NTP oversight in 2011 with NGO clinical management continuing. Patients electing to receive home-based treatment were followed by a dedicated adherence supporter and a multidisciplinary outpatient team of nurses, physicians and community health workers. Patients hospitalised for >1 month of treatment (hospital based) received similar management after discharge. All patients received a standardised second-line MDR-TB regimen and were provided nutritional and adherence support. Outcomes were reviewed for patients completing 24 months of treatment and predictors of treatment success were evaluated using logistic regression. RESULTS: Of 582 patients with MDR-TB who initiated treatment between September 2006 and June 2016, 20% were HIV coinfected, 288 (49%) initiated community-based treatment and 294 (51%) received hospital-based treatment. Of 486 patients with outcomes available, 364 (75%) were cured, 10 (2%) completed, 28 (6%) were lost to follow-up, 3 (0.6%) failed and 77 (16%) died. There was no difference between treatment success in community versus hospital-based groups (adjusted OR (aOR) 1.0, p=0.99). HIV infection, older age and body mass index <16 were strongly associated with decreased treatment success (aOR 0.33, p<0.001; aOR 0.40, p<0.001; aOR 0.40; p<0.001). CONCLUSIONS: Cambodia's NGO-NTP partnership successfully developed and scaled up a model MDR-TB treatment programme. The first large-scale MDR-TB programme in Asia with a significant community-based component, the programme achieved equally high treatment success in patients with community-based compared with hospital-based initiation of MDR treatment.
