1. Precision medicine for drug-resistant tuberculosis in high-burden countries: is individualised treatment desirable and feasible?

Lancet Infect Dis. 2018 Mar 13. pii: S1473-3099(18)30104-X. doi:10.1016/S1473-3099(18)30104-X. [Epub ahead of print]

Cox H(1), Hughes J(2), Black J(3), Nicol MP(4).

ABSTRACT: Treatment for drug-resistant tuberculosis is largely delivered through standardised, empirical combination regimens in low-resource, high-burden settings. However, individualised treatment, guided by detailed drug susceptibility testing, probably results in improved individual outcomes and is the standard of care in well-resourced settings. Driven by the urgent need to scale up treatment provision, new tuberculosis drugs, incorporated into standardised regimens, are being tested. Although standardised regimens are expected to improve access to treatment in high-burden settings, they are also likely to contribute to the emergence of resistance, even with good clinical management. We argue that a balance is required between the need to improve treatment access and the imperative to minimise resistance amplification and provide the highest standard of care, through a precision medicine approach. In tuberculosis, as in other diseases, we should aim to reduce the entrenched inequalities that manifest as different standards of care in different settings.

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2. Bedaquiline and Delamanid for the Treatment of Multidrug-resistant Tuberculosis: A Multi-center Cohort Study in Korea.

Eur Respir J. 2018 Mar 15. pii: 1702467. doi: 10.1183/13993003.02467-2017. [Epub ahead of print]

Tae Kim C(1), Kim TO(2), Shin HJ(2), Chun Ko Y(3), Hun Choe Y(4), Kim HR(5), Kwon YS(2).

ABSTRACT: Relatively little is known about the efficacy and safety of the programmatic use of bedaquiline and delamanid in multidrug-resistant tuberculosis (MDR-TB) treatment. This study evaluated 61 patients with MDR-TB treated with bedaquiline (n=39), delamanid (n=11), or both, either sequentially (n=10) or in co-administration (n=1), for more than 1 month, combined with a World Health Organization-recommended regimen. Of these, 49 (80.3%) were men and 12 (19.7%) were women. The median age was 53 years (interquartile range [IQR]=38.5-61.0 years). Forty-two (68.9%) patients had fluoroquinolone-resistant MDR-TB and 16 (26.2%) had extensively drug-resistant TB. The median duration of treatment with bedaquiline and/or delamanid was 168 days (IQR 166.5-196.5 days), with 33 (54.1%) receiving linezolid for median 673 days (IQR 171-736 days). Of the 55 patients with positive sputum cultures at the start of bedaquiline and/or delamanid treatment, 39 (70.9%) achieved sputum culture conversion within a median of 119 days. Treatment was halted in four patients (6.6%) because of prolonged corrected QT interval. In conclusion, bedaquiline and delamanid were effective and safe for treating MDR-TB, with initial evidence of sequential administration of these two drugs as a viable treatment strategy for patients when an adequate treatment regimen cannot be constructed.

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3. Clinical Management of Multidrug-resistant Tuberculosis in 16 European Countries.

Am J Respir Crit Care Med. 2018 Mar 6. doi: 10.1164/rccm.201710-2141OC. [Epub ahead of print]

Günther G(1), van Leth F(2), Alexandru S(3), Altet N(4), Avsar K(5), Bang D(6), Barbuta R(7), Bothamley G(8), Ciobanu A(3), Crudu V(3), Danilovits M(9), Dedicoat M(10), Duarte R(11), Gualano G(12), Kunst H(13), de Lange W(14), Leimane V(15), McLaughlin AM(16), Magis-Escurra C(17), Muylle I(18), Polcová V(19), Popa C(20),  Rumetshofer R(21), Skrahina A(22), Solodovnikova V(23), Spinu V(24), Tiberi S(25), Viiklepp P(26), Lange C(27); for TBNET.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in Europe. Reported treatment success rates are around 50% or less and cure rates are even lower.

METHODS: We performed a prospective cohort study, analyzing management and treatment outcomes stratified by incidence of patients with MDR-TB in Europe. Treatment outcomes were compared by WHO and alternative simplified definitions.

RESULTS: 380 patients with MDR-TB were recruited and followed-up between 2010 and 2014 in 16 European countries. Patients in high-incidence countries compared with low-incidence countries were treated more frequently with standardized regimen (83.2% vs. 9.9%), had delayed treatment initiation (median 111 vs. 28 days), developed more additional drug resistance (23% vs. 5.8%), and had increased mortality (9.4% vs. 1.9%). Only 20.1% of patients using pyrazinamide had proven susceptibility to the drug. Applying WHO outcome definitions, frequency of cure (38.7% vs. 9.7%) was higher in high-incidence countries. Simplified outcome definitions that include one year of follow-up after the end of treatment showed similar frequency of relapse-free cure in low- (58.3%), intermediate- (55.8%) and high- incidence (57.1%) countries, but highest frequency of failure in high-incidence countries (24.1% vs. 14.6).

CONCLUSIONS: Conventional standard MDR-TB treatment regimens resulted in a higher frequency of failure compared to individualized treatments. Overall, cure from MDR-TB is substantially more frequent than previously anticipated, and poorly reflected by WHO outcome definitions.

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4. Global programmatic use of bedaquiline and delamanid for the treatment of multidrug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2018 Apr 1;22(4):407-412. doi: 10.5588/ijtld.17.0706.

Cox V(1), Brigden G(2), Crespo RH(3), Lessem E(4), Lynch S(5), Rich ML(6), Waning B(3), Furin J(7).

SETTING: The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.

DESIGN: A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up

Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use.

RESULTS: A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them.

CONCLUSION: While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

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1. Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in South Korea.

J Antimicrob Chemother. 2018 Feb 1;73(2):503-508. doi: 10.1093/jac/dkx373.

Mok J(1), Kang H(2), Hwang SH(2), Park JS(2), Kang B(3), Lee T(4), Koh WJ(5), Yim JJ(6), Jeon D(7).

OBJECTIVES: Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB.

METHODS: We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea.

RESULTS: A total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5-81) using solid medium and 57 days (range = 8-96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms.

CONCLUSIONS: The use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB.

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2. Incremental Cost Effectiveness of Bedaquiline for the Treatment of Rifampicin-Resistant Tuberculosis in South Africa: Model-Based Analysis.

Appl Health Econ Health Policy. 2018 Feb;16(1):43-54. doi: 10.1007/s40258-017-0352-8.

Schnippel K(1), Firnhaber C(2)(3), Conradie F(2), Ndjeka N(4), Sinanovic E(5).

BACKGROUND: Nearly 20,000 people were diagnosed with multi-drug and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa in 2015, yet only one-half of the patients who start treatment are expected to have a successful outcome. There is increasing evidence of the effectiveness and safety of new drug regimens containing bedaquiline for MDR/RR-TB; however, whether they are affordable for high-burden, limited-resource settings is uncertain.

OBJECTIVE: Our objective was to determine the incremental cost effectiveness of a bedaquiline-based regimen for MDR/RR-TB treatment in South Africa compared with the standard kanamycin-based regimen.

METHODS: We established a Markov model for ambulatory treatment of MDR/RR-TB in a high-HIV prevalence setting, parameterized using clinical outcomes from the South African National TB Programme (SA NTP) before (2012-2014) and after (2015-2016) bedaquiline roll-out. The effectiveness of treatment was evaluated in disability-adjusted life-years (DALYs). Ingredient costs from the provider’s perspective were collected in 2016 South African Rand and converted to $US, including bedaquiline at $US675.23 per 6-month treatment course. Culture conversion rates were derived from the phase IIb trial of bedaquiline, and disability adjustments were adapted from published literature. Costs and effectiveness were discounted at 3%.

RESULTS: For non-bedaquiline regimens, the total expected cost over the 10-year time horizon for a patient with MDR/RR-TB was $US4439 with disability-adjusted survival of 5.1 years. Replacing capreomycin with bedaquiline in patients who failed MDR/RR-TB treatment and required treatment for extensively drug-resistant (XDR-TB) resulted in cost savings ($US4356; 1.8% less) and similar effectiveness (0.02 DALYs averted). As a result, the standard regimen (no bedaquiline) was dominated. Replacing kanamycin with bedaquiline to provide all patients with MDR/RR-TB access to bedaquiline cost $US4647 (4.3% more) and averted 0.17 DALYs compared with the no bedaquiline regimen. The incremental cost-effectiveness ratio was $US1242/DALY averted.

CONCLUSION: Markov modelling indicates providing bedaquiline for all patients with MDR/RR-TB could increase the 24-month treatment success rate in South Africa from 56.3% using the current regimen to 60.6%, at a cost $US2.6 million over a 10-year horizon, less than 1% of the estimated $US425 million SA NTP annual budget.

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3. The Expanding Diversity of Mycobacterium tuberculosis Drug Targets.

ACS Infect Dis. 2018 Feb 15. doi: 10.1021/acsinfecdis.7b00255. [Epub ahead of print]

Wellington S(1)(2)(3), Hung DT(1)(2)(3).

ABSTRACT: After decades of relative inactivity, a large increase in efforts to discover

antitubercular therapeutics has brought insights into the biology of Mycobacterium tuberculosis (Mtb) and promising new drugs such as bedaquiline, which inhibits ATP synthase, and the nitroimidazoles delamanid and pretomanid, which inhibit both mycolic acid synthesis and energy production. Despite these advances, the drug discovery pipeline remains underpopulated. The field desperately needs compounds with novel mechanisms of action capable of inhibiting multi- and extensively drug -resistant Mtb (M/XDR-TB) and, potentially, non-replicating Mtb with the hope of shortening the duration of required therapy. New knowledge about Mtb, along with new methods and technologies, has driven exploration into novel target areas, such as energy production and central metabolism, that diverge from the classical targets in macromolecular synthesis. Here, we review new small molecule drug candidates that act on these novel targets to highlight the methods and perspectives advancing the field. These new targets bring with them the aspiration of shortening treatment duration as well as a pipeline of effective regimens against XDR-TB, positioning Mtb drug discovery to become a model for anti-infective discovery.

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4. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study.

Lancet Infect Dis. 2018 Feb 13. pii: S1473-3099(18)30100-2. doi: 10.1016/S1473-3099(18)30100-2. [Epub ahead of print]

Ferlazzo G(1), Mohr E(2), Laxmeshwar C(3), Hewison C(4), Hughes J(2), Jonckheere S(3), Khachatryan N(5), De Avezedo V(6), Egazaryan L(7), Shroufi A(2), Kalon S(3), Cox H(8), Furin J(9), Isaakidis P(10).

BACKGROUND: Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.

METHODS: We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.

FINDINGS: Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.

INTERPRETATION: Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.

FUNDING: Médecins Sans Frontières (MSF).

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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.

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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.

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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.

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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.

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1. Treatment outcomes of rifabutin-containing regimens for rifabutin-sensitive multidrug-resistant pulmonary tuberculosis.

Int J Infect Dis. 2017 Dec;65:135-141. doi: 10.1016/j.ijid.2017.10.013.

Lee H(1), Ahn S(2), Hwang NY(2), Jeon K(1), Kwon OJ(1), Huh HJ(3), Lee NY(3), Koh WJ(4).

OBJECTIVES: The aim of this study was to evaluate whether rifabutin can improve treatment outcomes in patients with rifabutin-sensitive MDR-TB.

METHODS: A retrospective cohort study was performed on 76 patients with rifabutin-sensitive MDR-TB who were treated with or without rifabutin between 2006 and 2011.

RESULTS: Overall, 75% (57/76) of patients achieved favorable outcomes, including cure (53/76, 70%) and treatment completion (4/76, 5%). In contrast, 25% (19/76) had unfavorable treatment outcomes, which included treatment failure (6/76, 8%), death (2/76, 3%), loss to follow-up (4/76. 5%), and no evaluation due to transfer to other institutions (7/76, 9%). Rifabutin was given to 52 (68%) of the 76 patients with rifabutin-sensitive MDR-TB. Although favorable treatment outcomes were more frequent in patients who received rifabutin [81% (42/52)] than in those who did not receive rifabutin [63% (15/24)], this difference was not statistically significant (P=0.154). However, in multivariable regression logistic analysis, use of rifabutin was significantly associated with favorable treatment outcomes in patients with rifabutin-sensitive MDR-TB (adjusted odds ratio=9.80, 95% confidence interval=1.65-58.37, P=0.012).

CONCLUSIONS: These results suggest that the use of rifabutin can improve treatment outcomes in patients with rifabutin-sensitive MDR-TB.

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2. Rapid Microarray-based Detection of Rifampicin-, Isoniazid- and Fluoroquinolone Resistance in Mycobacterium tuberculosis using a Single Cartridge.

J Clin Microbiol. 2017 Dec 6. pii: JCM.01249-17. doi: 10.1128/JCM.01249-17.

Havlicek J(1), Dachsel B(1), Slickers P(1), Andres S(2), Beckert P(3)(4), Feuerriegel S(3)(4), Niemann S(3)(4), Merker M(5)(4), Labugger I(1).

ABSTRACT: Rapid and robust identification of mutations in Mycobacterium tuberculosis complex (MTBC) strains mediating multidrug and extensively drug-resistant (M/XDR) phenotypes is crucial to combat the MDR tuberculosis (TB) epidemic. Currently available molecular TB drug susceptibility tests are either restricted to single targets/drugs (i.e. Xpert MTB/RIF) or aid the risk of cross-contaminations due to the design limitations of the open platform (i.e. line probe assays).With a good understanding of the technical and commercial boundaries we designed a test cartridge with an introduction of dried reagents, based on an oligonucleotide array, which has the ability to identify MTBC strains resistant to isoniazid, rifampicin and the fluoroquinolones. The melting curve assay interrogates in a closed cartridge system within 90 minutes 43 different mutations in the rifampicin resistance determining region (RRDR) of rpoB, rpoB codon 572, katG codon 315, the inhA promoter region, and the quinolone resistance determining region (QRDR) of gyrA The assay performance was evaluated with 265 clinical MTBC isolates from Swaziland including MDR/XDR, non-MDR, and fully susceptible isolates from a drug resistance survey performed in 2009/2010. In 99.5% of the cases, the results were consistent with the previously acquired data utilizing Sanger sequencing. By means of the closed cartridge system in combination with the battery-powered Alere™ q analyzer and with the potential to extent the current gene target panel the assay could serve as a rapid and robust point-of-care test in settings lacking comprehensive molecular laboratory infrastructure to differentiate MDR and non-MDR TB-patients and to assist clinicians in early treatment decisions.

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3. Limited Effect of Later-generation Fluoroquinolones in the Treatment of Ofloxacin-resistant and Moxifloxacin-susceptible Multidrug-resistant Tuberculosis.

Antimicrob Agents Chemother. 2017 Dec 4. pii: AAC.01784-17. doi: 10.1128/AAC.01784-17. [Epub ahead of print]

Lee H(1), Ahn S(2), Hwang NY(2), Jeon K(1), Kwon OJ(1), Huh HJ(3), Lee NY(3), Kim CK(4), Koh WJ(5).

ABSTRACT: Recent data conflict on the clinical efficacy of later-generation fluoroquinolones, such as moxifloxacin or levofloxacin, for the treatment of multidrug-resistant tuberculosis (MDR-TB) that is resistant to ofloxacin but susceptible to moxifloxacin. The purpose of the present study was to evaluate whether later-generation fluoroquinolones can improve treatment outcomes in patients with ofloxacin-resistant/moxifloxacin-susceptible MDR-TB. A retrospective cohort study was performed on 208 patients with moxifloxacin-susceptible MDR-TB who were treated between 2006 and 2011. Later-generation fluoroquinolones were used in all patients. Overall, 171 patients (82%) had ofloxacin-susceptible/moxifloxacin-susceptible MDR-TB (ofloxacin-susceptible group) and 37 (18%) had ofloxacin-resistant/moxifloxacin-susceptible MDR-TB (ofloxacin-resistant group). Compared to the ofloxacin-susceptible group, the ofloxacin-resistant group was more likely to have a previous history of MDR-TB treatment (P < 0.001) and cavitary lesions on chest radiography (P < 0.001). In addition, the ofloxacin-resistant group was more likely than the ofloxacin-susceptible group to have drug resistance to pyrazinamide (P = 0.003), streptomycin (P = 0.015), prothionamide (P < 0.001), and para-aminosalicylic acid (P < 0.001). Favorable outcomes were more frequently achieved in the ofloxacin-susceptible group than in the ofloxacin-resistant group [91% (156/171) vs. 57% (21/37), respectively; P < 0.001]. In multivariable regression logistic analysis, the ofloxacin-susceptible group was about 5.36 (95% confidence interval = 1.55-18.53) times more likely than the ofloxacin-resistant group (P < 0.001) to have favorable outcomes. Despite in vitro moxifloxacin susceptibility, favorable treatment outcomes for ofloxacin-resistant MDR-TB were significantly lower than for ofloxacin-susceptible MDR-TB, even when later-generation fluoroquinolones were used, indicating that more aggressive therapies may be needed for ofloxacin-resistant MDR-TB.

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4. Population implications of the use of bedaquiline in people with extensively drug-resistant tuberculosis: are fears of resistance justified?

Lancet Infect Dis. 2017 Dec;17(12):e429-e433. doi: 10.1016/S1473-3099(17)30299-2. Epub 2017 May 19.

Kunkel A(1), Furin J(2), Cohen T(3).

ABSTRACT: Global rollout of the new antituberculosis drug bedaquiline has been slow, in part reflecting concerns about spread of bedaquiline resistance. Acquired resistance to bedaquiline is especially likely in patients with extensively

drug-resistant (XDR) tuberculosis. However, the very high mortality rates of patients with XDR not receiving bedaquiline, and promising cohort study results, suggest these patients also have greatest need for the drug. In this Personal View, we argue that resistance concerns should not forestall use of bedaquiline

in patients with XDR tuberculosis. Our position in favour of increased access to bedaquiline for these patients is based on three arguments. First, the use of drug combinations that include bedaquiline might prevent spread of XDR disease to others in the community. Second, until new combination regimens of novel drugs for XDR tuberculosis become available, patients with XDR disease and their infected contacts will face equivalent outcomes if bedaquiline is either not provided because of policy, or not effective because of resistance. Finally, because resistance to bedaquiline and other antituberculosis drugs is caused by mutations within a single bacterial chromosome, use of bedaquiline in patients with XDR tuberculosis will not substantially increase the risk of bedaquiline resistance in patients with drug-susceptible or multidrug-resistant (non‑XDR) tuberculosis strains.

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1. Pharmacokinetic interaction between bedaquiline and clofazimine in patients with drug-resistant tuberculosis.

Int J Tuberc Lung Dis. 2017 Nov 16. doi: 10.5588/ijtld.17.0615. [Epub ahead of print]

Maartens G(1), Brill MJE(2), Pandie M(1), Svensson EM(2).

BACKGROUND: Bedaquiline (BDQ) and clofazimine (CFZ) are both recommended for treating drug-resistant tuberculosis(DR-TB). As CFZ is an inhibitor of the cytochrome P450 isoenzyme 3A4 (CYP3A4) in vitro, and BDQ a substrate of CYP3A4, there is a potential for pharmacokinetic (PK) drug-drug interaction that may result in increased BDQ exposure when co-administered with CFZ, which could increase the toxicity of BDQ.

METHODS: We assessed the effect of co-administered CFZ on BDQ bioavailability, or on clearance of BDQ and its N-monodesmethyl metabolite (M2), in patients with DR-TB using a population PK model developed from data of patients with DR-TB. This was a secondary analysis of a study designed to explore drug-drug interactions between BDQ and antiretrovirals.

RESULTS: Of 46 participants, 30 were on concomitant CFZ when intensive PK sampling of BDQ was done. CFZ did not have a statistically significant effect on BDQ bioavailability (&minus;9.1&percnt;, 90&percnt;CI &minus;22.8 to &plus;7.1; P&equals; 0.19) or on BDQ and M2 clearance (&plus;12.2&percnt;, 90&percnt;CI &minus;13.7 to &plus;38; P &equals; 0.32).

CONCLUSION: We did not find a statistically significant PK drug-drug interaction between BDQ and CFZ, but cannot exclude a potentially clinically relevant interaction due to the wide confidence intervals of the estimated interaction effects.

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2. Levofloxacin population pharmacokinetics in South African children treated for multidrug-resistant tuberculosis.

Antimicrob Agents Chemother. 2017 Nov 13. pii: AAC.01521-17. doi: 10.1128/AAC.01521-17. [Epub ahead of print]

Denti P(1), Garcia-Prats AJ(2), Draper HR(2), Wiesner L(3), Winckler J(2), Thee S(4), Dooley KE(5), Savic RM(6), McIlleron HM(3), Schaaf HS(2), Hesseling AC(2).

BACKGROUND: Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited paediatric pharmacokinetic data to inform dose selection for children.

METHODS: Children routinely receiving levofloxacin (250 mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following a 15 or 20 mg/kg dose, given as whole tablet(s) or crushed, orally, or by nasogastric tube. Pharmacokinetic parameters were estimated using non-linear mixed effects modelling. Model-based simulations were performed to estimate doses across weight bands that would achieve adult exposures with 750mg once-daily dosing.

RESULTS: 109 children were included, median age 2.1 years (range 0.3-8.7); median weight 12 kg (range 6-22). Levofloxacin followed 2-compartment kinetics with 1st-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterised age-driven maturation of clearance (CL) with an effect reaching 50% around 2 months after birth and 100% by 2 years of age.. CL in a typical child (12 kg, 2-year-old) was 4.7 L/h. HIV infection reduced CL by 16%. Using the adult 250 mg formulation, Levofloxacin exposures were substantially lower than those reported in adults receiving a similar mg/kg dose. To achieve adult-equivalent exposures at a 750 mg daily dose, higher levofloxacin paediatric doses may be required -from 18 mg/kg/day for younger children with weights 3-4 kg (due to immature clearance) to 40 mg/kg/day for older children.

CONCLUSIONS: Currently recommended doses of levofloxacin for MDR-TB in children result in exposures considerably lower than in adults. The effect of different formulations and formulation manipulation require further investigation.We recommend age- and weight-banded doses of 250 mg tablets adult-formulation most likely to achieve target concentrations for prospective evaluation.

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3. What is resistance? Impact of phenotypic versus molecular drug resistance testing on multi- and extensively drug-resistant tuberculosis therapy.

Antimicrob Agents Chemother. 2017 Nov 13. pii: AAC.01550-17. doi: 10.1128/AAC.01550-17. [Epub ahead of print] 

Heyckendorf J(1)(2)(3), Andres S(4), Köser CU(5), Olaru ID(1)(2), Schön T(6)(7), Sturegård E(8), Beckert P(2)(9), Schleusener V(9), Kohl TA(2)(9), Hillemann D(4), Moradigaravand D(10), Parkhill J(10), Peacock SJ(5)(10)(11), Niemann S(12)(9), Lange C(13)(2)(3)(14)(15), Merker M(2)(9).

ABSTRACT: Rapid and accurate drug-susceptibility testing (DST) is essential for the treatment of multi- and extensively drug-resistant tuberculosis(M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using BACTEC 960 MGIT or Löwenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TBdrugs.Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs: Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0)] and whole genome sequencing (WGS) were translated into individual algorithm-derived treatment regimens for each patient. We further analysed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results.Compared with pDST, the average agreement in the number of drugs prescribed in ‘genotypic’ regimens ranged from just 49% (95% CI 39-59%) for Xpert and 63% (95% CI 56-70%) for LPAs to 93% (95% CI 88-98%) for WGS. Only the WGS regimens did not comprise any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampicin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high.WGS can be used to rule-in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be re-examined to avoid systematic false-susceptible results in low-level resistant isolates.

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4. Polyclonal Pulmonary Tuberculosis Infections and Risk for Multidrug Resistance, Lima, Peru.

Emerg Infect Dis. 2017 Nov;23(11):1887-1890. doi: 10.3201/eid2311.170077.

Nathavitharana RR, Shi CX, Chindelevitch L, Calderon R, Zhang Z, Galea JT, Contreras C, Yataco R, Lecca L, Becerra MC, Murray MB, Cohen T.

ABSTRACT: Because within-host Mycobacterium tuberculosis diversity complicates diagnosis and treatment of tuberculosis (TB), we measured diversity prevalence and associated factors among 3,098 pulmonary TB patients in Lima, Peru. The 161 patients with polyclonal infection were more likely than the 115 with clonal or the 2,822 with simple infections to have multidrug-resistant TB.

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October 2017 Newsletter

1. The Physicochemical Basis of Clofazimine-Induced Skin Pigmentation.
J Invest Dermatol. 2017 Oct 14. pii: S0022-202X(17)33040-3. doi: 10.1016/j.jid.2017.09.031. [Epub ahead of print]
Murashov MD(1), LaLone V(1), Rzeczycki PM(1), Keswani RK(1), Yoon GS(1), Sud S(1), Rajeswaran W(2), Larsen S(2), Stringer KA(3), Rosania GR(4).

ABSTRACT: Clofazimine is a weakly basic, FDA-approved antibiotic recommended by the World Health Organization to treat leprosy and multi-drug-resistant tuberculosis. Upon prolonged treatment, clofazimine extensively bioaccumulates and precipitates throughout the organism, forming crystal-like drug inclusions (CLDIs). Because of the drug’s red color, it is widely believed that clofazimine bioaccumulation results in skin pigmentation, its most common side effect. To test whether clofazimine-induced skin pigmentation is due to CLDI formation, we synthesized a closely related clofazimine analog that does not precipitate under physiological pH and chloride conditions that are required for CLDI formation. Despite the absence of detectable CLDIs in mice, administration of this analog still led to significant skin pigmentation. In clofazimine treated mice, skin cryosections revealed no evidence of CLDIs when analyzed with a microscopic imaging system specifically designed for detecting clofazimine aggregates. Rather, the reflectance spectra of the skin revealed a signal corresponding to the soluble, free base form of the drug. Consistent with the low concentrations of clofazimine in the skin, these results suggest that clofazimine-induced skin pigmentation is not due to clofazimine precipitation and CLDI formation, but rather to the partitioning of the circulating, free base form of the drug into subcutaneous fat.

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2. Bilateral cavitary multidrug- or extensively drug-resistant tuberculosis: role of surgery.
Eur J Cardiothorac Surg. 2017 Oct 10. doi:10.1093/ejcts/ezx350.
Marfina GY(1), Vladimirov KB(2), Avetisian AO(1), Starshinova AA(1), Kudriashov GG(1), Sokolovich EG(1), Yablonskii PK(1)(3).

OBJECTIVES: Cavitary disease and bilateral lesions are among the risk factors for poor outcome of pulmonary tuberculosis (TB). Our aim was to explore the value and limits of surgery in patients with advanced TB.
METHODS: A retrospective study of 57 consecutive patients who underwent thoracic surgery for culture-positive bilateral cavitary pulmonary TB was performed. Forty-four (77.2%) patients were men and 13 (22.8%) patients were women; their ages were in the range of 18-61 years. Twenty-two (38.6%) patients had multidrug-resistant (MDR) TB and 35 (61.4%) patients had extensively drug-resistant (XDR) TB confirmed with cultures. On admission, 49 (86.0%) patients had sputum smear microscopy positive for acid-fast bacilli. The main indication for surgery was treatment failure manifested as contagious persisting cavities despite best available therapy. The surgical procedures included combinations of pulmonary resections of different levels, selective thoracoplasties and/or endobronchial valve treatment. The operations were performed consecutively, starting with the most affected side. TB therapy preceded the operation for a minimum of 6 months and was continued after the operation on the basis of the patient’s susceptibility to drugs for Mycobacterium tuberculosis.
RESULTS: We performed 121 operations: 42 in 22 patients with MDR TB (1.9 operations per patient) and 79 procedures in 35 patients with XDR TB (2.3 operations per patient). No deaths occurred in the 1st year. Two late deaths followed, 1 unrelated to and 1 due to TB progression. Ten major complications (1 complication per patient) developed: main bronchus stump fistula (n = 4), prolonged air leak (n = 3), respiratory failure (n = 2) and wound seroma (n = 1). At the 1-month follow-up visit, sputum smear conversion was observed in 11(68.8%) patients with MDR and in 15 (45.5%) patients with XDR TB. At the late (20-36 months) follow-up visit, culture negativity was achieved in 21 (95.5%) patients with MDR TB and in 23 (65.7%) patients with XDR TB (P = 0.015).
CONCLUSIONS: Thoracic surgery may significantly improve patients’ outcomes and even result in a cure in a good portion of patients with bilateral cavitary MDR and XDR TB and should be considered as the essential element of multimodality treatment for MDR and XDR TB, even in patients with bilateral cavitary disease and borderline respiratory reserves.

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3. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance.
BMC Genomics. 2017 Oct 11;18(1):769. doi: 10.1186/s12864-017-4146-z.
Sheen P(1), Requena D(1), Gushiken E(1), Gilman RH(2), Antiparra R(1), Lucero B(1), Lizárraga P(1), Cieza B(1), Roncal E(1), Grandjean L(3), Pain A(4), McNerney R(5), Clark TG(5)(6), Moore D(5), Zimic M(7).

BACKGROUND: Tuberculosis (TB) is a major global health problem and drug resistance compromises the efforts to control this disease. Pyrazinamide (PZA) is an important drug used in both first and second line treatment regimes. However, its complete mechanism of action and resistance remains unclear.
RESULTS: We genotyped and sequenced the complete genomes of 68 M. tuberculosis strains isolated from unrelated TB patients in Peru. No clustering pattern of the strains was verified based on spoligotyping. We analyzed the association between PZA resistance with non-synonymous mutations and specific genes. We found mutations in pncA and novel genes significantly associated with PZA resistance in strains without pncA mutations. These included genes related to transportation of metal ions, pH regulation and immune system evasion.
CONCLUSIONS: These results suggest potential alternate mechanisms of PZA resistance that have not been found in other populations, supporting that the antibacterial activity of PZA may hit multiple targets.

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4. Fluoroquinolone Resistance Mutation Detection Is Equivalent to Culture-Based Drug Sensitivity Testing for Predicting Multidrug-Resistant Tuberculosis Treatment Outcome: A Retrospective Cohort Study.
Clin Infect Dis. 2017 Oct 15;65(8):1364-1370. doi: 10.1093/cid/cix556.
Farhat MR(1)(2), Jacobson KR(3), Franke MF(4), Kaur D(5), Murray M(4)(6), Mitnick CD(4)(7).

BACKGROUND: Molecular diagnostics that rapidly and accurately predict fluoroquinolone (FQ) resistance promise to improve treatment outcomes for individuals with multidrug-resistant (MDR) tuberculosis (TB). Mutations in the gyr genes, though, can cause variable levels of in vitro FQ resistance, and some in vitro resistance remains unexplained by gyr mutations alone, but the implications of these discrepancies for treatment outcome are unknown.
METHODS: We performed a retrospective cohort study of 172 subjects with MDR/extensively drug-resistant TB subjects and sequenced the full gyrA and gyrB open reading frames in their respective sputum TB isolates. The gyr mutations were classified into 2 categories: a set of mutations that encode high-level FQ resistance and a second set that encodes intermediate resistance levels. We constructed a Cox proportional model to assess the effect of the gyr mutation type on the time to death or treatment failure and compared this with in vitro FQ resistance, controlling for host and treatment factors.
RESULTS: Controlling for other host and treatment factors and compared with patients with isolates without gyr resistance mutations, “high-level” gyr mutations significantly predict poor treatment outcomes with a hazard ratio of 2.6 (1.2-5.6). We observed a hazard of death and treatment failure with “intermediate-level” gyr mutations of 1.3 (0.6-3.1), which did not reach statistical significance. The gyr mutations were not different than culture-based FQ drug susceptibility testing in predicting the hazard of death or treatment failure and may be superior.
CONCLUSIONS: FQ molecular-based diagnostic tests may better predict treatment response than traditional drug susceptibility testing and open avenues for personalizing TB therapy.

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5. The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?
Int J Tuberc Lung Dis. 2017 Nov 1;21(11):1114-1126. doi: 10.5588/ijtld.17.0468.
Reuter A(1), Tisile P(2), von Delft D(2), Cox H(3), Cox V(4), Ditiu L(5), Garcia-Prats A(6), Koenig S(7), Lessem E(8), Nathavitharana R(9), Seddon JA(10), Stillo J(11), von Delft A(12), Furin J(7).

ABSTRACT: For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

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September 2017 Newsletter

1. The TB Portals: An open-access, web-based platform for global drug-resistant tuberculosis data sharing and analysis.
J Clin Microbiol. 2017 Sep 13. pii: JCM.01013-17. doi: 10.1128/JCM.01013-17. [Epub ahead of print]
Rosenthal A(1), Gabrielian A(2), Engle E(2), Hurt DE(2), Alexandru S(3), Crudu V(3), Sergueev E(4), Kirichenko V(4), Lapitskii V(4), Snezhko E(4), Kovalev V(4), Astrovko A(5), Skrahina A(5), Taaffe J(2), Harris M(2), Long A(2), Wollenberg K(2), Akhundova I(6), Ismayilova S(6), Skrahin A(7), Mammadbayov E(6), Gadirova H(6), Abuzarov R(6), Seyfaddinova M(6), Avaliani Z(6), Strambu I(8), Zaharia D(8), Muntean A(8), Ghita E(8), Bogdan M(8), Mindru R(8), Spinu V(8), Sora A(8), Ene C(8), Vashakidze S(9), Shubladze N(9), Nanava U(9), Tuzikov A(4), Tartakovsky M(2).

ABSTRACT: The TB Portals Program is an international consortium of physicians, radiologists, and microbiologists from countries with a heavy burden of drug-resistant tuberculosis working with data scientists and IT professionals. Together, we have built the TB Portals, a repository of socioeconomic/geographic, clinical, laboratory, radiological, and genomic data from patient cases of drug-resistant tuberculosis and backed by shareable, physical samples. Currently, there are 1,299 total cases from five country sites (Azerbaijan, Belarus, Moldova, Georgia, and Romania), of which 976 (75.1%) are multi- or extensively drug resistant, and 38.2%, 51.9%, and 36.3% of cases contain X-ray, CT scan, and  genomic data, respectively. The top Mycobacterium tuberculosis lineages represented among collected samples are Beijing, T1, and H3, and SNPs that confer resistance to isoniazid, rifampicin, ofloxacin, and moxifloxacin occur the most frequently. These data and samples have promoted drug discovery efforts and research into genomics and quantitative image analysis to improve diagnostics, while also serving as a valuable resource for researchers and clinical providers. The TB Portals database and associated projects are continually growing, and we invite new partners and collaborations in our initiative. The TB Portals data and their associated analytical and statistical tools are freely available at:

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2. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis.
N Engl J Med. 2017 Sep 14;377(11):1043-1054. doi: 10.1056/NEJMoa1614915.
Xie YL(1), Chakravorty S(1), Armstrong DT(1), Hall SL(1), Via LE(1), Song T(1), Yuan X(1), Mo X(1), Zhu H(1), Xu P(1), Gao Q(1), Lee M(1), Lee J(1), Smith LE(1), Chen RY(1), Joh JS(1), Cho Y(1), Liu X(1), Ruan X(1), Liang L(1), Dharan N(1), Cho SN(1), Barry CE 3rd(1), Ellner JJ(1), Dorman SE(1), Alland D(1).

BACKGROUND: Fluoroquinolones and second-line injectable drugs are the backbone of treatment regimens for multidrug-resistant tuberculosis, and resistance to these drugs defines extensively drug-resistant tuberculosis. We assessed the accuracy of an automated, cartridge-based molecular assay for the detection, directly from sputum specimens, of Mycobacterium tuberculosis with resistance to fluoroquinolones, aminoglycosides, and isoniazid.
METHODS: We conducted a prospective diagnostic accuracy study to compare the investigational assay against phenotypic drug-susceptibility testing and DNA sequencing among adults in China and South Korea who had symptoms of tuberculosis. The Xpert MTB/RIF assay and sputum culture were performed. M.tuberculosis isolates underwent phenotypic drug-susceptibility testing and DNA sequencing of the genes katG, gyrA, gyrB, and rrs and of the eis and inhA promoter regions.
RESULTS: Among the 308 participants who were culture-positive for M.tuberculosis, when phenotypic drug-susceptibility testing was used as the reference standard, the sensitivities of the investigational assay for detecting resistance were 83.3% for isoniazid (95% confidence interval [CI], 77.1 to 88.5), 88.4% for ofloxacin (95% CI, 80.2 to 94.1), 87.6% for moxifloxacin at a critical concentration of 0.5 μg per milliliter (95% CI, 79.0 to 93.7), 96.2% for moxifloxacin at a critical concentration of 2.0 μg per milliliter (95% CI, 87.0 to 99.5), 71.4% for kanamycin (95% CI, 56.7 to 83.4), and 70.7% for amikacin (95% CI, 54.5 to 83.9). The specificity of the assay for the detection of phenotypic resistance was 94.3% or greater for all drugs except moxifloxacin at a critical concentration of 2.0 μg per milliliter (specificity, 84.0% [95% CI, 78.9 to 88.3]). When DNA sequencing was used as the reference standard, the sensitivities of the investigational assay for detecting mutations associated with resistance were 98.1% for isoniazid (95% CI, 94.4 to 99.6), 95.8% for fluoroquinolones (95% CI, 89.6 to 98.8), 92.7% for kanamycin (95% CI, 80.1 to 98.5), and 96.8% for amikacin (95% CI, 83.3 to 99.9), and the specificity for all drugs was 99.6% (95% CI, 97.9 to 100) or greater.
CONCLUSIONS: This investigational assay accurately detected M. tuberculosis mutations associated with resistance to isoniazid, fluoroquinolones, and aminoglycosides and holds promise as a rapid point-of-care test to guide therapeutic decisions for patients with tuberculosis. (Funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the Ministry of Science and Technology of China; number, NCT02251327).

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3. Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.
PLoS One. 2017 Sep 7;12(9):e0184270. doi: 10.1371/journal.pone.0184270. eCollection 2017.
Khaparde S(1), Raizada N(2), Nair SA(3), Denkinger C(4), Sachdeva KS(1), Paramasivan CN(2), Salhotra VS(5), Vassall A(6)(7), Hoog AV(6).

BACKGROUND: India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India.
METHODS: Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients.
RESULTS: The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US $1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099).
CONCLUSIONS: The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.

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4.Treatment outcomes for isoniazid-resistant tuberculosis under program conditions in British Columbia, Canada.
BMC Infect Dis. 2017 Sep 4;17(1):604. doi: 10.1186/s12879-017-2706-0.
Romanowski K(1), Chiang LY(1), Roth DZ(1), Krajden M(2), Tang P(2)(3), Cook VJ(1)(4), Johnston JC(5)(6).

BACKGROUND: Every year, over 1 million people develop isoniazid (INH) resistant tuberculosis (TB). Yet, the optimal treatment regimen remains unclear. Given increasing prevalence, the clinical efficacy of regimens used by physicians is of interest. This study aims to examine treatment outcomes of INH resistant TB patients, treated under programmatic conditions in British Columbia, Canada.
METHODS: Medical charts were retrospectively reviewed for cases of culture-confirmed INH mono-resistant TB reported to the BC Centre for Disease Control (BCCDC) from 2002 to 2014. Treatment regimens, patient and strain characteristics, and clinical outcomes were analysed.
RESULTS: One hundred sixty five cases of INH mono-resistant TB were included in analysis and over 30 different treatment regimens were prescribed. Median treatment duration was 10.5 months (IQR 9-12 months) and treatment was extended beyond 12 months for 26 patients (15.8%). Fifty six patients (22.6%) experienced an adverse event that resulted in a drug regimen modification. Overall, 140 patients (84.8%) had a successful treatment outcome while 12 (7.2%) had an unsuccessful treatment outcome of failure (n = 2; 1.2%), relapse (n = 4; 2.4%) or all cause mortality (n = 6; 3.6%).
CONCLUSION: Our treatment outcomes, while consistent with findings reported from other studies in high resource settings, raise concerns about current recommendations for INH resistant TB treatment. Only a small proportion of patients completed the recommended treatment regimens. High quality studies to confirm the effectiveness of standardized regimens are urgently needed, with special consideration given to trials utilizing fluoroquinolones.

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August 2017 Newsletter

1. Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis.
Bull World Health Organ. 2017 Aug 1;95(8):584-593. doi: 10.2471/BLT.17.193375.
Ho J(1), Byrne AL(1), Linh NN(2), Jaramillo E(2), Fox GJ(3).

OBJECTIVE: To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches.
METHODS: We searched, the Cochrane library, Embase®, Google Scholar, LILACS, PubMed®, Web of Science and the World Health Organization’s portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses.
FINDINGS: Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes.  The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01-1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38-1.13), for death RR: 1.01 (95% CI: 0.67-1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48-2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models.
CONCLUSION: Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings.

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2. A systematic review of national policies for the management of persons exposed to tuberculosis.
Int J Tuberc Lung Dis. 2017 Aug 1;21(8):935-940. doi: 10.5588/ijtld.17.0061.
Rodriguez CA(1), Sasse S(1), Yuengling KA(2), Azzawi S(1), Becerra MC(3), Yuen CM(3).

OBJECTIVE: To describe mandates and policy gaps in tuberculosis (TB) contact investigation and management.
DESIGN: We conducted a systematic review of national TB policy documents obtained using a systematic internet search and by contacting national TB programs. We included policies published in English, Spanish, and French, and abstracted data using a standardized form.
RESULTS: We reviewed policy documents for 68 of 216 (31%) countries and territories. All countries recommended performing contact investigations, but 40% did not specify how contacts enter the health system for evaluation or who was responsible for this process. All countries recommended preventive therapy for contacts, but in 14 (21%) countries only young children were eligible. While four preventive therapy regimens exist, 48 (71%) countries recommended only isoniazid monotherapy. In addition, 28 (41%) countries lacked guidance on whether to give preventive therapy to contacts exposed to drug-resistant TB. Policies in 28 (41%) countries lacked recommendations for managing contacts with the human immunodeficiency virus (HIV) after new TB exposure.
CONCLUSION: Policies recommending contact investigation and preventive therapy for contacts are widespread, but policy gaps exist in the areas of ensuring accountability and the management of vulnerable populations such as people living with HIV and those exposed to drug-resistant TB.

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3. What happened to patients with RMP-resistant/MDR-TB in Zambia reported as lost to follow-up from 2011 to 2014?
Int J Tuberc Lung Dis. 2017 Aug 1;21(8):887-893. doi: 10.5588/ijtld.16.0933.
Kasapo CC(1), Chimzizi R(1), Simwanza SC(1), Mzyece J(1), Chizema E(2), Mariandyshev A(3), Lee HY(4), Harries AD(5), Kapata N(6).

SETTING: University Teaching Hospital, Lusaka, and Ndola Central Hospital, Ndola, Zambia, which implemented active tracing of multidrug-resistant tuberculosis (MDR-TB) patients reported as lost to follow-up (LTFU).
OBJECTIVE: To determine 1) the number of patients treated for MDR-TB between 2011 and 2014; 2) the number, proportion, month when LTFU and characteristics of patients registered as LTFU; and 3) final outcomes observed following active patient tracing.
DESIGN: Retrospective cohort study.
RESULTS: Of 184 patients treated for confirmed MDR-TB, 76 (41%) were reported as LTFU. From 2011 to 2014, the proportions reported each year as LTFU were respectively 21%, 47%, 51% and 39%. Of patients who were LTFU, 43 (57%) had stopped attending the clinic during the intensive phase. These patients were predominantly male, aged 15-44 years, had pulmonary disease and had failed previous treatment. Of 57 (75%) patients with known human immunodeficiency virus (HIV) status, 42 (74%) were HIV-positive, 57% of whom were on antiretroviral treatment. After active patient tracing, 29 (38%) patients could not be found and the observed outcome remained LTFU. Of the remaining 47 patients, 29 (62%) were alive and had completed or were still on treatment, 14 (30%) were alive but had stopped treatment and 4 (8%) had died.
CONCLUSION: Zambia has been underreporting its favourable outcomes for MDR-TB treatment and should continue with active tracing of LTFU patients.

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4. Addressing the tuberculosis-depression syndemic to end the tuberculosis epidemic.
Int J Tuberc Lung Dis. 2017 Aug 1;21(8):852-861. doi: 10.5588/ijtld.16.0584.
Sweetland AC(1), Kritski A(2), Oquendo MA(3), Sublette ME(1), Norcini Pala A(1), Silva LRB(4), Karpati A(5), Silva EC(6), Moraes MO(4), Silva JRLE(7), Wainberg ML(1).

ABSTRACT: Tuberculosis (TB) and depression act synergistically via social, behavioral, and biological mechanisms to magnify the burden of disease. Clinical depression is a common, under-recognized, yet treatable condition that, if comorbid with TB, is associated with increased morbidity, mortality, community TB transmission, and drug resistance. Depression may increase risk of TB reactivation, contribute to disease progression, and/or inhibit the physiological response to anti-tuberculosis treatment because of poverty, undernutrition, immunosuppression, and/or negative coping behaviors, including substance abuse.
Tuberculous infection and/or disease reactivation may precipitate depression as a result of the inflammatory response and/or dysregulation of the hypothalamic-pituitary-adrenal axis. Clinical depression may also be triggered by TB-related stigma, exacerbating other underlying social vulnerabilities, and/or may be attributed to the side effects of anti-tuberculosis treatment. Depression may negatively impact health behaviors such as diet, health care seeking, medication adherence, and/or treatment completion, posing a significant challenge for global TB elimination. As several of the core symptoms of TB and depression overlap, depression often goes unrecognized in individuals with active TB, or is dismissed as a normative reaction to situational stress. We used evidence to reframe TB and depression comorbidity as the ‘TB-depression syndemic’, and identified critical research gaps to further elucidate the underlying mechanisms. The World Health Organization’s Global End TB Strategy calls for integrated patient-centered care and prevention linked to social protection and innovative research. It will require multidisciplinary approaches that consider conditions such as TB and depression together, rather than as separate problems and diseases, to end the global TB epidemic.

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5. Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval
by the US Food and Drug Administration
JAMA. 2017;318(7):626-636. doi:10.1001/jama.2017.9415
Huseyin Naci, PhD, MHS; Katelyn R. Smalley, BSc; Aaron S. Kesselheim, MD, JD, MPH

IMPORTANCE: Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements.
OBJECTIVE: To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval.
DESIGN AND SETTING: Publicly available FDA documents were reviewed to identify the pre-approval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA’s database of post-marketing requirements and commitments,, and matched peer-reviewed publications. Follow-up ended on April 7, 2017.
EXPOSURES: Granting of accelerated approval.
MAIN OUTCOMES AND MEASURES: Characteristics of pre-approval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized.
RESULTS: The FDA granted accelerated approval to 22 drugs for 24 indications (19for indications involving cancer treatment) between 2009 and 2013. A total of 30 pre-approval studies supported the 24 indications. The median number of participants enrolled in the pre-approval studies was 132 (interquartile range, 89-224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, −15% to 46%; P = .31). Post-approval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit
in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior.
CONCLUSIONS AND RELEVANCE: Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in post-approval trials a minimum of 3 years after approval, although confirmatory trials and pre-approval trials had similar design elements, including reliance on surrogate measures as outcomes.

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July 2017 Newsletter

1. Polymorphisms in the vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa.
PLoS One. 2017 Jul 10;12(7):e0180916. doi: 10.1371/journal.pone.0180916. eCollection 2017.
Magee MJ(1), Sun YV(2), Brust JCM(3), Shah NS(4), Ning Y(3), Allana S(2), Campbell A(2), Hui Q(2), Mlisana K(5), Moodley P(5), Gandhi NR(2)(6)(7).

BACKGROUND: Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa.
METHODS: We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion.
RESULTS: Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29-42). Smoking was reported by 21% of subjects and most subjects had HIV (80%),  were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17-114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14-0.67).
CONCLUSIONS: Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in
South Africa.

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2. Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia.
BMC Infect Dis. 2017 Jul 12;17(1):491. doi: 10.1186/s12879-017-2594-3.
Sengstake S(1)(2), Bergval IL(3)(4), Schuitema AR(3), de Beer JL(5), Phelan J(6), de Zwaan R(5), Clark TG(6)(7), van Soolingen D(5), Anthony RM(3)(5).

BACKGROUND: The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region.
METHODS: Phenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the pncA gene was sequenced and whole genome sequencing was performed on two isolates.
RESULTS: Out of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single pncA mutation. All of these 33 isolates were MDR-TB strains. pncA mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the pncA gene. From the two major MDR-TB clusters represented (94-32 and 100-32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in pncA and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region.
CONCLUSION: In this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.

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3. The sterilizing effect of ertapenem-clavulanate in a hollow fiber model of tuberculosis and implications on clinical dosing.
Antimicrob Agents Chemother. 2017 Jul 10. pii: AAC.02039-16. doi: 10.1128/AAC.02039-16. [Epub ahead of print]
van Rijn SP(1), Srivastava S(2), Wessels MA(1), van Soolingen D(3)(4), Alffenaar JC(5), Gumbo T(2).

ABSTRACT: Carbapenems are now being explored for treatment of multi-drug resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple parenteral doses per day, and lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once a day dose for clinical use. We utilized the hollow fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time-points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid Emax modeling was used to identify the relationship between total bacterial burden and the drug exposure, and identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose-fractionation hollow fiber study, efficacy was linked to percentage of the 24 hour dosing interval of ertapenem concentration persisting above MIC (%TMIC).  We performed a 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed %TMIC ≥40%. We identified an intravenous dose of 2 grams once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC 2 mg/L was identified for that dose. An ertapenem dose of 2g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.

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4. Management of child MDR-TB contacts across countries in the WHO European Region: a survey of current practice.
Int J Tuberc Lung Dis. 2017 Jul 1;21(7):774-777. doi: 10.5588/ijtld.16.0949.
Turkova A(1), Tebruegge M(2), Brinkmann F(3), Tsolia M(4), Mouchet F(5), Kampmann B(6), Seddon JA(7).

ABSTRACT: The World Health Organization European Region has one of the highest rates of multidrug-resistant tuberculosis (MDR-TB) in the world, resulting in many vulnerable children being exposed each year. Evidence for preventive therapy following MDR-TB exposure is limited and current guidance is conflicting. An internet-based survey was performed to determine clinical practice in this region. Seventy-two clinicians from 25 countries participated. Practices related  to screening and decision-making were highly variable. Just over half provided preventive therapy for children exposed to MDR-TB; the only characteristic associated with provision was practice within the European Union (adjusted OR 4.07, 95%CI 1.33-12.5).

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5. Estimating the future burden of multidrug-resistant and extensively drug-resistant tuberculosis in India, the Philippines, Russia, and South Africa: a mathematical modelling study.
Lancet Infect Dis. 2017 Jul;17(7):707-715. doi: 10.1016/S1473-3099(17)30247-5. Epub 2017 May 9.
Sharma A, Hill A, Kurbatova E, van der Walt M, Kvasnovsky C, Tupasi TE, Caoili JC, Gler MT, Volchenkov GV, Kazennyy BY, Demikhova OV, Bayona J, Contreras C, Yagui M, Leimane V, Cho SN, Kim HJ, Kliiman K, Akksilp S, Jou R, Ershova J, Dalton T, Cegielski P; Global Preserving Effective TB Treatment Study Investigators.

BACKGROUND: Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are emerging worldwide. The Green Light Committee initiative supported programmatic management of drug-resistant tuberculosis in 90 countries. We used estimates from the Preserving Effective TB Treatment Study to predict MDR and XDR tuberculosis trends in four countries with a high burden of MDR tuberculosis: India, the Philippines, Russia, and South Africa.
METHODS: We calibrated a compartmental model to data from drug resistance surveys and WHO tuberculosis reports to forecast estimates of incident MDR and XDR tuberculosis and the percentage of incident MDR and XDR tuberculosis caused by acquired drug resistance, assuming no fitness cost of resistance from 2000 to 2040 in India, the Philippines, Russia, and South Africa.
FINDINGS: The model forecasted the percentage of MDR tuberculosis among incident cases of tuberculosis to increase, reaching 12·4% (95% prediction interval 9·4-16·2) in India, 8·9% (4·5-11·7) in the Philippines, 32·5% (27·0-35·8) in Russia, and 5·7% (3·0-7·6) in South Africa in 2040. It also predicted the percentage of XDR tuberculosis among incident MDR tuberculosis to increase, reaching 8·9% (95% prediction interval 5·1-12·9) in India, 9·0% (4·0-14·7) in the Philippines, 9·0% (4·8-14·2) in Russia, and 8·5% (2·5-14·7) in South Africa in 2040. Acquired drug resistance would cause less than 30% of incident MDR tuberculosis during 2000-40. Acquired drug resistance caused 80% of incident XDR tuberculosis in 2000, but this estimate would decrease to less than 50% by 2040.
INTERPRETATION: MDR and XDR tuberculosis were forecast to increase in all four countries despite improvements in acquired drug resistance shown by the Green Light Committee-supported programmatic management of drug-resistant tuberculosis. Additional control efforts beyond improving acquired drug resistance rates are needed to stop the spread of MDR and XDR tuberculosis in countries with a high burden of MDR tuberculosis.
FUNDING: US Agency for International Development and US Centers for Disease Control and Prevention, Division of Tuberculosis Elimination.

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June 2017 Newsletter

1. Cryptic Micro-heteroresistance Explains M. tuberculosis Phenotypic Resistance.
Am J Respir Crit Care Med. 2017 Jun 14. doi: 10.1164/rccm.201703-0556OC. [Epub ahead of print]
Metcalfe JZ(1), Streicher E(2), Theron G(3), Colman RE(4), Allender C(5), Lemmer
D(6), Warren R(7), Engelthaler DM(8).

BACKGROUND: Minority resistant M. tuberculosis subpopulations can be associated with phenotypic resistance, but are poorly detected by Sanger sequencing or commercial molecular diagnostic assays. The role of targeted next generation sequencing (NGS) in resolving these minor variant subpopulations is unclear.
METHODS: We utilized Single Molecule-Overlapping Reads (SMOR), a targeted NGS approach that dramatically reduces sequencing error, to analyze primary cultured isolates phenotypically resistant to rifampin, fluoroquinolones, or aminoglycosides, but for which Sanger sequencing found no resistance-associated variants (RAVs) within respective resistance determining regions (RDRs) (Study Group). Isolates also underwent single-colony selection on antibiotic-containing agar, blinded to sequencing results. As a positive control, isolates with multiple co-localizing chromatogram peaks were also analyzed (Control Group).
RESULTS: Among 61 primary culture isolates (25 study group and 36 control group), SMOR described 82 (54%) and 61 (40%) of 151 total heteroresistant RAVs at frequencies <5% and <1% of the total mycobacterial population, respectively. In the study group, SMOR detected minor resistant variant subpopulations in 84% (n=21/25) of isolates with no Sanger-identified RAVs (median subpopulation size 4.1%, interquartile range 2.6-7.5%). Single-colony selection on drug-containing media corroborated SMOR results for 91% (n=19/21) of RAV-containing specimens, and the absence of RAVs in 75% (n=3/4) of isolates. Overall, Sanger sequencing was concordant with SMOR for 77% (n=53/69) of macro-heteroresistant (5-95% total population), but only 4% of micro-heteroresistant (<5%) subpopulations (n=3/82) across both groups.
CONCLUSION: Cryptic minor variant mycobacterial subpopulations exist below the resolving capability of current DST methodologies, and may explain an important proportion of false-negative resistance determinations.

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2. Treatment outcomes of MDR-TB and HIV co-infection in Europe.
Eur Respir J. 2017 Jun 8;49(6). pii: 1602363. doi: 10.1183/13993003.02363-2016. Print 2017 Jun.
Magis-Escurra C(1)(2), Günther G(3)(4)(2), Lange C(5)(4)(6)(7)(2), Alexandru
S(8), Altet N(9), Avsar K(10), Bang D(11), Barbuta R(12), Bothamley G(13),
Ciobanu A(8), Crudu V(8)(14), Davilovits M(15), Dedicoat M(16)(17), Duarte
R(18)(19), Gualano G(20), Kunst H(21)(22), de Lange W(23)(24), Leimane V(25),
McLaughlin AM(26), Muylle I(27), Polcová V(28), Popa C(29), Rumetshofer R(30),
Skrahina A(31), Solodovnikova V(31), Spinu V(29), Tiberi S(22)(32)(33), Viiklepp
P(34), van Leth F(35)(36)(2); for TBnet.

EXTRACT: The ongoing HIV epidemic and the increasing number of patients with drug-resistant tuberculosis (TB) are seriously hampering global TB-control activities, including those in the World Health Organization (WHO) Region Europe. Overall, the prevalence of HIV co-infection in TB patients increased from 3.4% in 2008 to 8% in 2014 in the region. The prevalence of multidrug-resistant (MDR)-TB (drug resistance against at least isoniazid and rifampicin) reported for Europe – 15% in newly diagnosed TB patients and 48% in previously treated TB patients – is the highest in the world.

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3. In vitro and in vivo activity of biapenem against drug-susceptible and
rifampicin-resistant Mycobacterium tuberculosis.
J Antimicrob Chemother. 2017 Jun 1. doi: 10.1093/jac/dkx152. [Epub ahead of
Kaushik A(1), Ammerman NC(1), Tasneen R(1), Story-Roller E(1), Dooley KE(1),
Dorman SE(1), Nuermberger EL(1), Lamichhane G(1).

BACKGROUND: Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis.
OBJECTIVES: Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis, in vitro and in the mouse model.
METHODS: Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis: strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo, we first conducted a dose-ranging experiment with biapenem against H37Rvin the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain.
RESULTS: In vitro, synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo , biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains.
CONCLUSIONS: Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a ‘new’ – and desperately needed – drug for the treatment of drug-resistant TB.

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4.Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study.
Eur Respir J. 2017 May 21;49(5). pii: 1700387. doi: 10.1183/13993003.00387-2017.
Print 2017 May.
Borisov SE(1)(2), Dheda K(3)(2), Enwerem M(4)(2), Romero Leyet R(5)(2),
D’Ambrosio L(6)(7)(2), Centis R(6)(2), Sotgiu G(8)(2), Tiberi S(9)(10)(2),
Alffenaar JW(11)(2), Maryandyshev A(12)(2), Belilovski E(1)(2), Ganatra S(13)(2),
Skrahina A(14)(2), Akkerman O(15)(16), Aleksa A(17), Amale R(13), Artsukevich
J(17), Bruchfeld J(18), Caminero JA(19)(20), Carpena Martinez I(21), Codecasa
L(22), Dalcolmo M(23), Denholm J(24), Douglas P(25), Duarte R(26), Esmail A(27),
Fadul M(27), Filippov A(1), Davies Forsman L(18), Gaga M(28), Garcia-Fuertes
JA(29), García-García JM(30), Gualano G(31), Jonsson J(32), Kunst H(10), Lau
JS(33), Lazaro Mastrapa B(34), Teran Troya JL(34), Manga S(35), Manika K(36),
González Montaner P(37), Mullerpattan J(13), Oelofse S(27), Ortelli M(38),
Palmero DJ(37), Palmieri F(31), Papalia A(39), Papavasileiou A(40), Payen MC(41),
Pontali E(42), Robalo Cordeiro C(43), Saderi L(8), Sadutshang TD(44), Sanukevich
T(17), Solodovnikova V(14), Spanevello A(45)(46), Topgyal S(44), Toscanini F(47),
Tramontana AR(48), Farokh Udwadia Z(13), Viggiani P(39), White V(49), Zumla
A(50), Migliori GB(51)(2).

ABSTRACT: Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents. 428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related. Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

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