1. Genome-wide analysis of multi- and extensively drug-resistant Mycobacterium tuberculosis.
Nat Genet. 2018 Jan 22. doi: 10.1038/s41588-017-0029-0. [Epub ahead of print]
Coll F(1), Phelan J(1), Hill-Cawthorne GA(2)(3), Nair MB(2), Mallard K(1), Ali S(2), Abdallah AM(2), Alghamdi S(4), Alsomali M(2), Ahmed AO(5), Portelli S(1)(6), Oppong Y(1), Alves A(7), Bessa TB(8), Campino S(1), Caws M(9)(10), Chatterjee A(11), Crampin AC(12)(13), Dheda K(14), Furnham N(1), Glynn JR(12)(13), Grandjean L(15), Minh Ha D(10), Hasan R(16), Hasan Z(16), Hibberd ML(1), Joloba M(17), Jones-López EC(18), Matsumoto T(19), Miranda A(7), Moore DJ(1)(15), Mocillo N(20), Panaiotov S(21), Parkhill J(22), Penha C(23), Perdigão J(24), Portugal I(24), Rchiad Z(2), Robledo J(25), Sheen P(14), Shesha NT(26), Sirgel FA(27), Sola C(28), Oliveira Sousa E(8)(29), Streicher EM(27), Helden PV(27), Viveiros M(30), Warren RM(27), McNerney R(31)(32), Pain A(33)(34), Clark TG(35)(36).
ABSTRACT: To characterize the genetic determinants of resistance to antituberculosis drugs, we performed a genome-wide association study (GWAS) of 6,465 Mycobacterium tuberculosis clinical isolates from more than 30 countries. A GWAS approach within a mixed-regression framework was followed by a phylogenetics-based test for independent mutations. In addition to mutations in established and recently described resistance-associated genes, novel mutations were discovered for resistance to cycloserine, ethionamide and para-aminosalicylic acid. The capacity to detect mutations associated with resistance to ethionamide, pyrazinamide, capreomycin, cycloserine and para-aminosalicylic acid was enhanced by inclusion of insertions and deletions. Odds ratios for mutations within candidate genes were found to reflect levels of resistance. New epistatic relationships between candidate drug-resistance-associated genes were identified. Findings also suggest the involvement of efflux pumps (drrA and Rv2688c) in the emergence of resistance. This study will inform the design of new diagnostic tests and expedite the investigation of resistance and compensatory epistatic mechanisms.
2. Defining Bedaquiline Susceptibility, Resistance, Cross-Resistance and Associated Genetic Determinants: A Retrospective Cohort Study.
EBioMedicine. 2018 Jan 9. pii: S2352-3964(18)30005-7. doi: 10.1016/j.ebiom.2018.01.005. [Epub ahead of print]
Ismail NA(1), Omar SV(2), Joseph L(2), Govender N(2), Blows L(2), Ismail F(3), Koornhof H(2), Dreyer AW(2), Kaniga K(4), Ndjeka N(5).
BACKGROUND: Bedaquiline (BDQ) is a novel agent approved for use in combination treatment of multi-drug resistant tuberculosis (MDR-TB). We sought to determine BDQ epidemiological cut-off values (ECVs), define and assess interpretive criteria against putative resistance associated variants (RAVs), microbiological outcomes and cross resistance with clofazimine (CFZ).
METHODS: A retrospective cohort study was conducted. Minimal inhibitory concentrations (MIC) to BDQ were determined using 7H9 broth microdilution (BMD) and MGIT960. RAVs were genetically characterised using whole genome sequencing. BDQ ECVs were determined using ECOFFinder and compared with 6-month culture conversion status and CFZ MICs.
FINDINGS: A total of 391 isolates were analysed. Susceptible and intermediate categories were determined to have MICs of ≤0.125μg/ml and 0.25μg/ml using BMD and ≤1μg/ml and 2μg/ml using MGIT960 respectively. Microbiological failures occurred among BDQ exposed patients with a non-susceptible BDQ MIC, an Rv0678 mutation and ≤2 active drug classes. The Rv0678 RAVs were not the dominant mechanism of CFZ resistance and cross resistance was limited to isolates with an Rv0678 mutation.
INTERPRETATION: Criteria for BDQ susceptibility are defined and will facilitate improved early detection of resistance. Cross- resistance between BDQ and CFZ is an emerging concern but in this study was primarily among those with an Rv0678 mutation.
3. Catastrophic total costs in tuberculosis-affected households and their determinants since Indonesia’s implementation of universal health coverage.
Infect Dis Poverty. 2018 Jan 12;7(1):3. doi: 10.1186/s40249-017-0382-3.
Fuady A(1)(2), Houweling TAJ(3), Mansyur M(4), Richardus JH(3).
BACKGROUND: As well as imposing an economic burden on affected households, the high costs related to tuberculosis (TB) can create access and adherence barriers. This highlights the particular urgency of achieving one of the End TB Strategy’s targets: that no TB-affected households have to face catastrophic costs by 2020. In Indonesia, as elsewhere, there is also an emerging need to provide social protection by implementing universal health coverage (UHC). We therefore assessed the incidence of catastrophic total costs due to TB, and their determinants since the implementation of UHC.
METHODS: We interviewed adult TB and multidrug-resistant TB (MDR-TB) patients in urban, suburban and rural areas of Indonesia who had been treated for at least one month or had finished treatment no more than one month earlier. Following the WHO recommendation, we assessed the incidence of catastrophic total costs due to TB. We also analyzed the sensitivity of incidence relative to several thresholds, and measured differences between poor and non-poor households in the incidence of catastrophic costs. Generalized linear mixed-model analysis was used to identify determinants of the catastrophic total costs.
RESULTS: We analyzed 282 TB and 64 MDR-TB patients. For TB-related services, the median (interquartile range) of total costs incurred by households was 133 USD (55-576); for MDR-TB-related services, it was 2804 USD (1008-4325). The incidence of catastrophic total costs in all TB-affected households was 36% (43% in poor households and 25% in non-poor households). For MDR-TB-affected households, the incidence was 83% (83% and 83%). In TB-affected households, the determinants of catastrophic total costs were poor households (adjusted odds ratio [aOR] = 3.7, 95% confidence interval [CI]: 1.7-7.8); being a breadwinner (aOR = 2.9, 95% CI: 1.3-6.6); job loss (aOR = 21.2; 95% CI: 8.3-53.9); and previous TB treatment (aOR = 2.9; 95% CI: 1.4-6.1). In MDR-TB-affected households, having an income-earning job before diagnosis was the only determinant of catastrophic total costs (aOR = 8.7; 95% CI: 1.8-41.7).
CONCLUSIONS: Despite the implementation of UHC, TB-affected households still risk catastrophic total costs and further impoverishment. As well as ensuring access to healthcare, a cost-mitigation policy and additional financial protection should be provided to protect the poor and relieve income losses.
4. Meropenem-clavulanate for drug-resistant tuberculosis: a follow-up of relapse-free cases.
Int J Tuberc Lung Dis. 2018 Jan 1;22(1):34-39. doi: 10.5588/ijtld.17.0352.
Payen MC(1), Muylle I(2), Vandenberg O(3), Mathys V(4), Delforge M(1), Van den Wijngaert S(3), Clumeck N(1), De Wit S(1)
BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB), defined as TB caused by a Mycobacterium strain resistant to at least rifampicin, isoniazid, any fluoroquinolone and one of the injectable anti-tuberculosis drugs, remains a worldwide public health threat. Among repurposed drugs empirically used for XDR-TB cases, carbapenems have been studied in vitro and in animal models, with encouraging results. However, only short-term follow-up data from clinical studies are currently available.
OBJECTIVES: To study the long-term follow-up of XDR-TB cases treated with a regimen containing meropenem-clavulanate (M/Clav).
DESIGN: Retrospective observational case series study at a single hospital.
METHODS: All hospitalised drug-resistant TB patients who received M/Clav as part of their treatment from 2009 to 2016 were included. Demographic and clinical data were extracted from medical records.
RESULTS: Eighteen XDR-TB patients were included in the analysis. The successful outcome and mortality rates were respectively 83.3% and 11.1%. No relapses were observed in cured patients after a median follow-up of 4 years. No specific adverse events were attributed to treatment with M/Clav.
CONCLUSION: The rate of sustained successful treatment outcome observed here is far higher than the 26% observed in the 2014 World Health Organization XDR-TB cohort, suggesting that carbapenems may be beneficial for the treatment of difficult-to-treat TB cases.