May 2017 eNewsletter

1. Pharmacokinetics of Levofloxacin in Multidrug- and Extensively Drug Resistant Tuberculosis patients.
Antimicrob Agents Chemother. 2017 May 15. pii: AAC.00343-17. doi: 10.1128/AAC.00343-17. [Epub ahead of print]
Van’t Boveneind-Vrubleuskaya N(1,)(2), Seuruk T(3), van Hateren K(2), van der Laan T(4), Kosterink JGW(2), van der Werf TS(5), van Soolingen D(4,)(6), van den Hof S(2,)(7), Skrahina A(3), Alffenaar JC(8).

ABSTRACT: Pharmacodynamics are important in treatment of especially multidrug- and extensively resistant tuberculosis (M/XDR-TB). The free area under the concentration time curve in relation to minimal inhibitory concentration (fAUC/MIC) is the most relevant pharmacokinetic (PK)-pharmacodynamic (PD) parameter to predict the efficacy of levofloxacin (LFX). The objective of our study was to assess LFX PK variability in M/XDR-TB patients and its potential consequence for fAUC/MIC ratios. Patients with pulmonary M/XDR-TB received LFX as part of treatment regimen at a dose of 15 mg/kg once daily. Blood samples obtained at steady state before- and 1, 2, 3, 4, 7, and 12 hrs after drug administration were measured by validated a liquid chromatography-tandem mass spectrometry. MIC values of LFX were determined by the agar dilution method on Middlebrook 7H10 and the MGIT960 system. Twenty patients with a mean age of 31 (IQR; 27-35) years were enrolled in this study. The median AUC0-24h was 98.8 mg/h/L (IQR; 84.8-159.6). The MIC median value for LFX was 0,5 mg/L with a range of 0.25 to 2.0 mg/L and the median fAUC0-24/MIC ratio was 109.5 (IQR; 48.5-399.4). In four of the 20 patients the value was below the target value of ≥100. When a MIC of 0.25, 0.5, 1.0 and 2.0 mg/L were applicable, 19, 18, 3 and no patients, respectively, had a fAUC/MIC ratio that exceeded 100. We observed a large variability in AUC. A fAUC0-24/MIC of ≥ 100 was only observed in case MIC values for LFX were 0.25-0.5 mg/L. Dosages exceeding 15mg/kg should be considered for target attainment if exposures are assumed to be safe.

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2. 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 May 9. pii: S1473-3099(17)30247-5. doi:10.1016/S1473-3099(17)30247-5. [Epub ahead of print]
Sharma A(1), Hill A(2), Kurbatova E(2), van der Walt M(3), Kvasnovsky C(4), Tupasi TE(5), Caoili JC(5), Gler MT(5), Volchenkov GV(6), Kazennyy BY(7), Demikhova OV(8), Bayona J(9), Contreras C(9), Yagui M(10), Leimane V(11), Cho SN(12), Kim HJ(13), Kliiman K(14), Akksilp S(15), Jou R(16), Ershova J(2), Dalton T(2), Cegielski P(2); 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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3. A combination of baseline plasma immune markers can predict therapeutic response in multidrug resistant tuberculosis.
PLoS One. 2017 May 2;12(5):e0176660. doi: 10.1371/journal.pone.0176660. eCollection 2017.
Ferrian S(1), Manca C(2), Lubbe S(3), Conradie F(4), Ismail N(5), Kaplan G(6), Gray CM(1), Fallows D(2).

OBJECTIVE: To identify plasma markers predictive of therapeutic response in patients with multidrug resistant tuberculosis (MDR-TB).
METHODS: Fifty HIV-negative patients with active pulmonary MDR-TB were analysed for six soluble analytes in plasma at the time of initiating treatment (baseline) and over six months thereafter. Patients were identified as sputum culture positive or negative at baseline. Culture positive patients were further stratified by the median time to sputum culture conversion (SCC) as fast responders (< 76 days) or slow responders (≥ 76 days). Chest X-ray scores, body mass index, and sputum smear microscopy results were obtained at baseline.
RESULTS: Unsupervised hierarchical clustering revealed that baseline plasma levels of IP-10/CXCL10, VEGF-A, SAA and CRP could distinguish sputum culture and  cavitation status of patients. Among patients who were culture positive at baseline, there were significant positive correlations between plasma levels of CRP, SAA, VEGF-A, sIL-2Rα/CD40, and IP-10 and delayed SCC. Using linear discriminant analysis (LDA) and Receiver Operating Curves (ROC), we showed that a combination of MCP-1/CCL2, IP-10, sIL-2Rα, SAA, CRP and AFB smear could distinguish fast from slow responders and were predictive of delayed SCC with high sensitivity and specificity.
CONCLUSION: Plasma levels of specific chemokines and inflammatory markers measured before MDR-TB treatment are candidate predictive markers of delayed SCC. These findings require validation in a larger study.

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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 May 19. pii: S1473-3099(17)30299-2. doi: 10.1016/S1473-3099(17)30299-2. [Epub ahead of print]
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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April 2017 eNewsletter

1. Adverse drug reactions during drug-resistant TB treatment in high HIV prevalence  settings: a systematic review and meta-analysis.
J Antimicrob Chemother. 2017 Apr 16. doi: 10.1093/jac/dkx107. [Epub ahead of print]
Schnippel K(1,)(2), Firnhaber C(2,)(3), Berhanu R(4,)(5), Page-Shipp L(6), Sinanovic E(1).

OBJECTIVES: To estimate the prevalence of adverse drug reactions or events (ADR) during drug-resistant TB (DR-TB) treatment in the context of settings with high HIV prevalence (at least 20% of patients).
METHODS: We conducted a systematic review and meta-analysis of articles in PubMed and Scopus. Pooled proportions of patients experiencing adverse events and relative risk with 95% CI were calculated.
RESULTS: The search yielded 24 studies, all observational cohorts. Ten reported on the number of patients experiencing ADR and were included in the meta-analysis representing 2776 study participants of whom 1943 were known to be HIV infected (70.0%). An average of 83% (95% CI: 82%-84%) of patients experienced one or more ADR. Among the seven articles ( n  =   664 study participants) with information on occurrence of severe ADR, 24% (95% CI: 21%-27%) of patients experienced at least one severe ADR during drug-resistant TB treatment. Sixteen of the 24 studies analysed the relative risk of ADR by HIV infection, nine of which found no statistically significant association between HIV infection and occurrence of drug-related ADR. There was insufficient information to disaggregate risk by concomitant treatment with HIV antiretrovirals or by immunosuppression (CD4 count).
CONCLUSIONS: No randomized clinical trials were found for WHO-recommended treatment of drug-resistant TB treatment where at least 20% of the cohort was coinfected with HIV. Nearly all patients (83%) experience ADR during DR-TB treatment. While no significant association between ADR and HIV coinfection was found, further research is needed to determine whether concomitant antiretrovirals or immunosuppression increases the risks for HIV-infected patients.

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2. Increased Tuberculosis Patient Mortality Associated with Mycobacterium tuberculosis Mutations Conferring Resistance to Second-line Antituberculous Drugs.
J Clin Microbiol. 2017 Apr 12. pii: JCM.00152-17. doi: 10.1128/JCM.00152-17. [Epub ahead of print]
Georghiou SB(1), Seifert M(2), Catanzaro DG(3), Garfein RS(2), Rodwell TC(2).

ABSTRACT: Rapid molecular diagnostics have great potential to limit the spread of multi- and extensively drug-resistant tuberculosis (M/XDR-TB). These technologies detect mutations in the Mycobacterium tuberculosis (Mtb) genome that confer phenotypic drug resistance. However, there is little data published regarding the relationships between the detected Mtb resistance mutations and M/XDR-TB treatment outcomes, limiting our current ability to exploit the full potential of molecular diagnostics. We analyzed clinical, microbiological and sequencing data  for 451 patients and their clinical isolates collected in a multinational, observational cohort study to determine if there was an association between Mtb resistance mutations and patient mortality. Presence of an rrs 1401G mutation was associated with significantly higher odds of patient mortality [adj OR=5.72 (95% CI 1.65 to 19.84)] after adjusting for relevant patient clinical characteristics and all other resistance mutations. Further analysis of mutations, categorized by associated resistance level, indicated that the detection of mutations associated with high-level fluoroquinolone [OR 3.99 (95% CI 1.10-14.40)] and kanamycin [OR 5.47 (95% CI 1.64-18.24)] resistance were also significantly associated with higher odds of patient mortality, even after accounting for clinical site, patient age, reported smoking, BMI, diabetes, HIV, and all other resistance mutations. Specific gyrA and rrs resistance mutations, associated with high-level resistance, were associated with patient mortality when identified in clinical Mtb in a diverse M/XDR-TB patient population from three high burden clinical sites. These results have important implications for the interpretation of molecular diagnostics, including identifying patients at increased risk for mortality during treatment.

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3. Delamanid Kills Dormant Mycobacteria in Vitro and in the Guinea Pig Model of Tuberculosis.
Antimicrob Agents Chemother. 2017 Apr 3. pii: AAC.02402-16. doi: 10.1128/AAC.02402-16. [Epub ahead of print]
Chen X(1), Hashizume H(1), Tomishige T(1), Nakamura I(1), Matsuba M(1), Fujiwara M(1), Kitamoto R(1), Hanaki E(1), Ooba Y(1), Matsumoto M(2).

ABSTRACT: TB treatment is long and requires multiple drugs, likely due to various phenotypes of TB bacilli with variable drug-susceptibility. Drugs with broad activity are urgently needed. The study aimed to evaluate delamanid’s activity against growing or dormant bacilli in vitro as well as in vivo Culture of Mycobacterium bovis BCG Tokyo under aerobic and anaerobic condition was used to study delamanid’s activity against growing and dormant bacilli, respectively. Delamanid exhibited significant bactericidal activity against replicating and dormant bacilli at or above the concentrations of 0.016 and 0.4 mg/L, respectively. To evaluate delamanid’s anti-tuberculosis activity in vivo, we used a chronic tuberculosis infection guinea pig model with lung lesions similar to those in human TB disease. In the guinea pig TB model, daily dose of 100 mg/kg delamanid for 4 or 8 weeks demonstrated strong bactericidal activity against Mycobacterium tuberculosis Importantly, histological examination revealed that delamanid killed TB bacilli within hypoxic lesions of the lung. The combination regimens containing delamanid with rifampicin and pyrazinamide, or with levofloxacin, ethionamide, pyrazinamide, and amikacin were more effective than the standard regimen (rifampicin, isoniazid, and pyrazinamide). Our data show that delamanid is effective in killing both growing and dormant bacilli in vitro and in the guinea pig TB model. Adding delamanid to current TB regimens may improve treatment outcomes, as demonstrated in recent clinical trials in pulmonary MDR-TB patients. Delamanid may be an important drug for consideration when constructing new regimens to shorten TB treatment duration.

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4. Additional Drug Resistance Patterns among Multidrug-Resistant Tuberculosis Patients in Korea: Implications for Regimen Design.
J Korean Med Sci. 2017 Apr;32(4):636-641. doi: 10.3346/jkms.2017.32.4.636.
Mok JH(1), Kang BH(2), Lee T(3), Lee HK(4), Jang HJ(5), Cho YJ(6), Jeon D(7,)(8).

ABSTRACT: Detailed information on additional drug resistance patterns of multidrug-resistant tuberculosis (MDR-TB) is essential to build an effective treatment regimen; however, such data are scarce in Korea. We retrospectively analyzed the results of phenotypic drug susceptibility testing (DST) of culture confirmed-TB patients from January 2010 to December 2014 in 7 university hospitals in Korea. MDR-TB was identified among 6.8% (n = 378) of 5,599 isolates. A total of 57.1% (n = 216) of the MDR-TB patients had never been treated for TB. Strains from MDR-TB patients showed additional resistance to pyrazinamide (PZA) (35.7%), any second-line injectable drug (19.3%), and any fluoroquinolone (26.2%). Extensively drug resistant TB comprised 12.4% (n = 47) of the MDR-TB patients. Of 378 MDR-TB patients, 50.3% (n = 190) were eligible for the shorter MDR-TB regimen, and 50.0% (n = 189) were fully susceptible to the 5 drugs comprising the standard conventional regimen (PZA, kanamycin, ofloxoacin, prothionamide, and cycloserine). In conclusion, the proportion of new patients and the levels of additional drug resistance were high in MDR-TB patients. Considering the high levels of drug resistance, the shorter MDR-TB treatment regimen may not be feasible; instead, an individually tailored regimen based on the results of molecular and phenotypic DST may be more appropriate in MDR-TB patients in Korea.

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March 2017 eNewsletter

1. MDR-TB treatment as prevention: The projected population-level impact of expanded treatment for multidrug-resistant tuberculosis.
PLoS One. 2017 Mar 8;12(3):e0172748. doi: 10.1371/journal.pone.0172748. eCollection 2017.
Kendall EA(1), Azman AS(2), Cobelens FG(3), Dowdy DW(2).

BACKGROUND: In 2013, approximately 480,000 people developed active multidrug-resistant tuberculosis (MDR-TB), while only 97,000 started MDR-TB treatment. We sought to estimate the impact of improving access to MDR-TB diagnosis and treatment, under multiple diagnostic algorithm and treatment regimen scenarios, on ten-year projections of MDR-TB incidence and mortality.
METHODS: We constructed a dynamic transmission model of an MDR-TB epidemic in an illustrative East/Southeast Asian setting. Using approximate Bayesian computation, we investigated a wide array of potential epidemic trajectories consistent with current notification data and known TB epidemiology. RESULTS: Despite an overall projected decline in TB incidence, data-consistent simulations suggested that MDR-TB incidence is likely to rise between 2015 and 2025 under continued 2013 treatment practices, although with considerable uncertainty (median 17% increase, 95% Uncertainty Range [UR] -38% to +137%). But if, by 2017, all identified active TB patients with previously-treated TB could be tested for drug susceptibility, and 85% of those with MDR-TB could initiate MDR-appropriate treatment, then MDR-TB incidence in 2025 could be reduced by 26% (95% UR 4-52%) relative to projections under continued current practice. Also expanding this drug-susceptibility testing and appropriate MDR-TB treatment to treatment-naïve as well as previously-treated TB cases, by 2020, could reduce MDR-TB incidence in 2025 by 29% (95% UR 6-55%) compared to continued current practice. If this diagnosis and treatment of all MDR-TB in known active TB cases by 2020 could be implemented via a novel second-line regimen with similar effectiveness and tolerability as current first-line therapy, a 54% (95% UR 20-74%) reduction in MDR-TB incidence compared to current-practice projections could be achieved by 2025.
CONCLUSIONS: Expansion of diagnosis and treatment of MDR-TB, even using current sub-optimal second-line regimens, is expected to significantly decrease MDR-TB incidence at the population level. Focusing MDR diagnostic efforts on previously-treated cases is an efficient first-step approach.

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2. Outcomes from the first multidrug-resistant tuberculosis programme in Kenya.
Int J Tuberc Lung Dis. 2017 Mar 1;21(3):314-319. doi: 10.5588/ijtld.16.0661.
Huerga H(1), Bastard M(1), Kamene M(2), Wanjala S(3), Arnold A(4), Oucho N(5), Chikwanha I(6), Varaine F(6).

SETTING: In March 2006, the first multidrug-resistant tuberculosis (MDR-TB) treatment programme was implemented in Kenya.
OBJECTIVE: To describe patients’ treatment outcomes and adverse events.
DESIGN: A retrospective case note review of patients started on MDR-TB treatment at two Médecins Sans Frontières-supported sites and the national referral hospital of Kenya was undertaken. Sites operated an ambulatory model of care. Patients were treated for a minimum of 24 months with at least 4-5 drugs for the intensive phase of treatment, including an injectable agent.
RESULTS: Of 169 patients, 25.6% were human immunodeficiency virus (HIV) positive and 89.3% were culture-positive at baseline. Adverse events occurred in 67.4% of patients: 45.9% had nausea/vomiting, 43.9% electrolyte disturbance, 41.8% dyspepsia and 31.6% hypothyroidism. The median time to culture conversion was 2 months. Treatment outcomes were as follows: 76.6% success, 14.5% deaths, 8.3% lost to follow-up and 0.7% treatment failure. HIV-positive individuals (adjusted odds ratio [aOR] 3.51, 95% confidence interval [CI] 1.12-11.03) and women (aOR 2.73, 95%CI 1.01-7.39) had a higher risk of unfavourable outcomes, while the risk was lower in those with culture conversion at 6 months (aOR 0.11, 95%CI 0.04-0.32).
CONCLUSION: In Kenya, where an ambulatory model of care is used for MDR-TBtreatment, treatment success was high, despite high rates of HIV. Almost half of the patients experienced electrolyte disturbance and one third had hypothyroidism; this supports the view that systematic regular biochemical monitoring is needed in Kenya.

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3. Latent tuberculous infection in household contacts of multidrug-resistant and newly diagnosed tuberculosis.
Int J Tuberc Lung Dis. 2017 Mar 1;21(3):297-302. doi: 10.5588/ijtld.16.0576.
Fox GJ(1), Anh NT(1), Nhung NV(2), Loi NT(1), Hoa NB(3), Ngoc Anh LT(4), Cuong NK(5), Buu TN(6), Marks GB(7), Menzies D(8).

BACKGROUND: Differences in the prevalence of latent tuberculous infection (LTBI) and tuberculosis (TB) disease among contacts of patients with multidrug-resistant TB(MDR-TB) and drug-susceptible TB are not well understood.
OBJECTIVE: To compare the prevalence of tuberculin skin test (TST) positivity in household contacts of patients with MDR-TB and in contacts of patients never previously treated for TB (‘new TB‘).
DESIGN: Consecutive patients with MDR-TB and their household contacts at nine urban district clinics in Viet Nam were screened for TB and LTBI, and followed up for 6 months. LTBI was defined as a TST result of at least 10 mm.
RESULTS: A total of 167 patients with TB and their 337 household contacts were recruited. A total of 167/180 (25.8%) contacts of new TB patients and 60/147 (40.8%) contacts of MDR-TB patients were TST-positive (odds ratio [OR] 2.0, 95%CI 1.3-3.2). Contacts of MDR-TB patients were more likely to have baseline chest radiograph findings consistent with TB (OR 2.6, 95%CI 1.4-5.0).
CONCLUSION: Contacts of MDR-TB patients have a high risk of developing TB. Measures to reduce Mycobacterium tuberculosis transmission and accelerate the detection of disease among high-risk contacts should be prioritised to curb the MDR-TB epidemic.

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4. The risk of global epidemic replacement with drug-resistant Mycobacterium tuberculosis strains.
Int J Infect Dis. 2017 Mar;56:14-20. doi: 10.1016/j.ijid.2017.01.031. Epub 2017 Feb 2.
McBryde ES(1), Meehan MT(2), Doan TN(3), Ragonnet R(4), Marais BJ(5), Guernier V(2), Trauer JM(6).

OBJECTIVES: Multidrug-resistant tuberculosis (MDR-TB) is a threat to tuberculosis (TB) control. To guide TB control, it is essential to understand the extent to which and the circumstances in which MDR-TB will replace drug-susceptible TB (DS-TB) as the dominant phenotype. The issue was examined by assessing evidence from genomics, pharmacokinetics, and epidemiology studies. This evidence was then synthesized into a mathematical model.
METHODS: This model considers two TB strains, one with and one without an MDR phenotype. It was considered that intrinsic transmissibility may be different between the two strains, as may the control response including the detection, treatment failure, and default rates. The outcomes were explored in terms of the incidence of MDR-TB and time until MDR-TB surpasses DS-TB as the dominant strain.
RESULTS AND CONCLUSIONS: The ability of MDR-TB to dominate DS-TB was highly sensitive to the relative transmissibility of the resistant strain; however, MDR-TB could dominate even when its transmissibility was modestly reduced (to between 50% and 100% as transmissible as the DS-TB strain). This model suggests that it may take decades or more for strain replacement to occur. It was also found that while the amplification of resistance is the early cause of MDR-TB, this will rapidly give way to person-to-person transmission.

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February 2017 e-Newsletter

1. Delays and loss to follow-up before treatment of drug-resistant tuberculosis following implementation of Xpert MTB/RIF in South Africa: A retrospective cohort study.
PLoS Med. 2017 Feb 21;14(2):e1002238. doi: 10.1371/journal.pmed.1002238. eCollection 2017.
Cox H(1,)(2), Dickson-Hall L(1), Ndjeka N(3), Van’t Hoog A(4,)(5), Grant
A(6,)(7,)(8), Cobelens F(4,)(5), Stevens W(9), Nicol M(1,)(2,)(10).

BACKGROUND: South Africa has a large burden of rifampicin-resistant tuberculosis (RR-TB), with 18,734 patients diagnosed in 2014. The number of diagnosed patients has increased substantially with the introduction of the Xpert MTB/RIF test, used for tuberculosis (TB) diagnosis for all patients with presumptive TB. Routine aggregate data suggest a large treatment gap (pre-treatment loss to follow-up) between the numbers of patients with laboratory-confirmed RR-TB and those reported to have started second-line treatment. We aimed to assess the impact of Xpert MTB/RIF implementation on the delay to treatment initiation and loss to follow-up before second-line treatment for RR-TB across South Africa.
METHODS AND FINDINGS: A nationwide retrospective cohort study was conducted to assess second-line treatment initiation and treatment delay among laboratory-diagnosed RR-TB patients. Cohorts, including approximately 300 sequentially diagnosed RR-TB patients per South African province, were drawn from the years 2011 and 2013, i.e., before and after Xpert implementation. Patients with prior laboratory RR-TB diagnoses within 6 mo and currently treated patients were excluded. Treatment initiation was determined through data linkage with national and local treatment registers, medical record review, interviews with health care staff, and direct contact with patients or household members. Additional laboratory data were used to track cases. National estimates of the percentage of patients who initiated treatment and time to treatment were weighted to account for the sampling design. There were 2,508 and 2,528 eligible patients in the 2011 and 2013 cohorts, respectively; 92% were newly diagnosed with RR-TB (no prior RR-TB diagnoses). Nationally, among the 2,340 and 2,311 new RR-TB patients in the 2011 and 2013 cohorts, 55% (95% CI 53%-57%) and 63% (95% CI 61%-65%), respectively, started treatment within 6 mo of laboratory receipt of their diagnostic specimen (p < 0.001). However, in 2013, there was no difference in the percentage of patients who initiated treatment at 6 mo between the 1,368 new RR-TB patients diagnosed by Xpert (62%, 95% CI 59%-65%) and the 943 diagnosed by other methods (64%, 95% CI 61%-67%) (p = 0.39). The median time to treatment decreased from 44 d (interquartile range [IQR] 20-69) in 2011 to 22 d (IQR 2-43) in 2013 (p < 0.001). In 2013, across the nine provinces, there were substantial variations in both treatment initiation (range 51%-73% by 6 mo) and median time to treatment (range 15-36 d, n = 1,450), and only 53% of the 1,448 new RR-TB patients who received treatment were recorded in the national RR-TB register. This retrospective study is limited by the lack of information to assess reasons for non-initiation of treatment, particularly pre-treatment mortality data. Other limitations include the use of names and dates of birth to locate patient-level data, potentially resulting in missed treatment initiation among some patients.
CONCLUSIONS: In 2013, there was a large treatment gap for RR-TB in South Africa that varied significantly across provinces. Xpert implementation, while reducing treatment delay, had not contributed substantially to reducing the treatment gap in 2013. However, given improved case detection with Xpert, a larger proportion of RR-TB patients overall have received treatment, with reduced delays. Nonetheless, strategies to further improve linkage to treatment for all diagnosed RR-TB patients are urgently required.

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2. Multidrug-resistant TB in Eastern region of the EU: is the shorter regimen an exception or a rule?
Thorax. 2017 Feb 16. pii: thoraxjnl-2016-209841. doi:10.1136/thoraxjnl-2016-209841. [Epub ahead of print]
Balabanova Y(1,)(2,)(3), Fiebig L(3), Ignatyeva O(4), Riekstina V(5), Danilovits
M(6), Jaama K(6), Davidaviciene E(7), Radiulyte B(7), Popa CM(8), Nikolayevskyy
V(1,)(2,)(9), Drobniewski F(1,)(2).

ABSTRACT: WHO recently recommended the use of a shorter multidrug-resistant TB (MDR-TB) regimen under programmatic conditions. We assessed eligibility for this regimen in a cohort of 737 adult patients with MDR-TB from Latvia, Lithuania, Estonia and Bucharest city recruited in 2007 and 2009. Only 4.2% of the patients were eligible for this regimen. Ethambutol (64%), pyrazinamide resistance (58%) and previous exposure to second-line TB drugs were major reasons for non-eligibility. High-level resistance to isoniazid is expected due to widespread prevalence of katG mutations. In Eastern Europe, the use of the shorter regimen might be an exception rather than a rule.

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3. Has universal screening with Xpert® MTB/RIF increased the proportion of multidrug-resistant tuberculosis cases diagnosed in a routine operational setting?
PLoS One. 2017 Feb 15;12(2):e0172143. doi: 10.1371/journal.pone.0172143. eCollection 2017.
Naidoo P(1), Dunbar R(1), Caldwell J(2), Lombard C(3), Beyers N(1).

SETTING: Primary health services in Cape Town, South Africa where the introduction of Xpert® MTB/RIF (Xpert) enabled simultaneous screening for tuberculosis (TB) and drug susceptibility in all presumptive cases.
STUDY AIM: To compare the proportion of TB cases with drug susceptibility tests undertaken and multidrug-resistant tuberculosis (MDR-TB) diagnosed pre-treatment and during the course of 1st line treatment in the previous smear/culture and the newly introduced Xpert-based algorithms.
METHODS: TB cases identified in a previous stepped-wedge study of TB yield in five sub-districts over seven one-month time-points prior to, during and after the introduction of the Xpert-based algorithm were analysed. We used a combination of patient identifiers to identify all drug susceptibility tests undertaken from electronic laboratory records. Differences in the proportions of DST undertaken and MDR-TB cases diagnosed between algorithms were estimated using a binomial regression model.
RESULTS: Pre-treatment, the probability of having a DST undertaken (RR = 1.82)(p<0.001) and being diagnosed with MDR-TB (RR = 1.42)(p<0.001) was higher in the Xpert-based algorithm than in the smear/culture-based algorithm. For cases evaluated during the course of 1st-line TB treatment, there was no significant difference in the proportion with DST undertaken (RR = 1.02)(p = 0.848) or MDR-TB diagnosed (RR = 1.12)(p = 0.678) between algorithms.
CONCLUSION: Universal screening for drug susceptibility in all presumptive TB cases in the Xpert-based algorithm resulted in a higher overall proportion of MDR-TB cases being diagnosed and is an important strategy in reducing transmission. The previous strategy of only screening new TB cases when 1st line treatment failed did not compensate for cases missed pre-treatment.

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4. Landmark legal ruling sees Indian girl prescribed bedaquiline for XDR-TB.
Lancet Respir Med. 2017 Feb 3. pii: S2213-2600(17)30042-5. doi: 10.1016/S2213-2600(17)30042-5. [Epub ahead of print]
Kirby T.

Read free Lancet article here 

January 2017 e-Newsletter

1. Drug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time.
Nat Commun. 2017 Jan 24;8:14183. doi: 10.1038/ncomms14183.
Lee BY(1), Clemens DL(1), Silva A(2), Dillon BJ(1), Masleša-Galić S(1), Nava S(1), Ding X(3), Ho CM(2,)(4), Horwitz MA(1).

ABSTRACT: The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.

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2. Reasons for Non-Enrollment in Treatment among Multi-Drug Resistant Tuberculosis Patients in Hunan Province, China.
PLoS One. 2017 Jan 23;12(1):e0170718. doi: 10.1371/journal.pone.0170718. eCollection 2017.
Xu Z(1), Xiao T(1), Li Y(1), Yang K(2), Tang Y(1), Bai L(3).

ABSTRACT: In 2015, only 49% of notified multi-drug resistant tuberculosis (MDR-TB) patients in China were estimated to have initiated treatment, compared with 90% of those worldwide. A case-control study was conducted to identify the reasons for non-enrollment in treatment among MDR-TB patients in Hunan province, China. All detected MDR-TB patients registered in designated MDR-TB hospitals in Hunan province from 2011 to 2014 were included and followed until June 2015 to determine their treatment status. Approximately 33.8% (482/1425) of patients were not enrolled in standardized treatment. Factors associated with lower enrollment rate were: age greater than 60 years, living in rural area, unemployed or occupation unreported. Of those who were not enrolled in MDR-TB treatment, the primary reasons for non-enrollment included economic hardship (23.0%), out-migration for work (18.0%), concerns about work and studies (13.7%), and the belief that they were cured after undergoing drug-sensitive TB treatment (12.4%).
Therefore, comprehensive strategies targeting priority populations, especially those enhancing treatment affordability and availability, need to be implemented to improve MDR-TB control.

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3. Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.
Nat Genet. 2017 Jan 16. doi: 10.1038/ng.3767. [Epub ahead of print]
Manson AL(1), Cohen KA(1,)(2,)(3), Abeel T(1,)(4), Desjardins CA(1), Armstrong DT(5), Barry CE 3rd(6), Brand J(7); TBResist Global Genome Consortium, Chapman SB(1), Cho SN(8), Gabrielian A(9), Gomez J(1), Jodals AM(10), Joloba M(11), Jureen P(12), Lee JS(8), Malinga L(7), Maiga M(13), Nordenberg D(14), Noroc E(15), Romancenco E(15), Salazar A(1,)(4), Ssengooba W(11), Velayati AA(16), Winglee K(5), Zalutskaya A(17), Via LE(6), Cassell GH(18), Dorman SE(5), Ellner J(19), Farnia P(16), Galagan JE(1,)(20), Rosenthal A(9), Crudu V(15), Homorodean D(10), Hsueh PR(21), Narayanan S(22), Pym AS(2), Skrahina A(17), Swaminathan S(22), Van der Walt M(7), Alland D(23), Bishai WR(2,)(5), Cohen T(24,)(25), Hoffner S(12), Birren BW(1), Earl AM(1).
COLLABORATORS: Brand J, Jureen P, Malinga L, Nordenberg D, Velayati AA, Cassell GH, Farnia P, Homorodean D, Van der Walt M, Hoffner S.

ABSTRACT: Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.

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4. Estimated generic prices for novel treatments for drug-resistant tuberculosis.
J Antimicrob Chemother. 2017 Jan 10. pii: dkw522. doi: 10.1093/jac/dkw522. [Epub ahead of print]
Gotham D(1), Fortunak J(2), Pozniak A(3), Khoo S(4), Cooke G(5), Nytko FE 3rd(2), Hill A(3).

BACKGROUND: The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course.
OBJECTIVES: To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture.
METHODS: Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per-step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines.
RESULTS: Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen.
CONCLUSIONS: Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets.

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5. Reduced chance of hearing loss associated with Therapeutic Drug Monitoring of Aminoglycosides in the treatment of Multidrug Resistant Tuberculosis.
Antimicrob Agents Chemother. 2017 Jan 9. pii: AAC.01400-16. doi: 10.1128/AAC.01400-16. [Epub ahead of print]
van Altena R(1,)(2), Dijkstra JA(3), van der Meer ME(3), Borjas Howard JF(4), Kosterink JG(3,)(5), van Soolingen D(6,)(7), van der Werf TS(2,)(4), Alffenaar JW(8).

ABSTRACT: Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to maintain efficacy while preventing (oto-) toxicity. To evaluate this strategy, we retrospectively evaluated medical charts of TB patients treated with amikacin or kanamycin in the period 2000 – 2012. Patients with culture-confirmed multi- or extensively drug resistant tuberculosis (MDR/XDR-TB) receiving amikacin or kanamycin as part of their TB treatment for at least 3 days were eligible for inclusion in this retrospective study. Clinical data, including Cmax, Cmin and audiometry data were extracted from the patients’ medical charts. 80 patients met the inclusion criteria. The mean weighted Cmax/MIC ratio obtained from 57 patients was 31.2 for amikacin and 12.3 for kanamycin. The extent of hearing loss was limited and correlated with the cumulative drug dose per kg body weight during daily administration. At follow-up, 35 (67.3%) of all patients had successful outcome; there were no relapses. At a median dose of 6.5 mg/kg a correlation was found between the dose per kg bodyweight during daily dosing and the extent of hearing loss in dB at 8000 Hz. This study suggests that the efficacy at this lower dosage is maintained with limited toxicity. A randomized controlled trial should provide final proof of the safety and efficacy of TDM-guided use of aminoglycosides in MDR-TB treatment.

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December eNewsletter

1. Improving access to tuberculosis preventive therapy and treatment for children.
Int J Infect Dis. 2016 Dec 16. pii: S1201-9712(16)31658-7. doi:10.1016/j.ijid.2016.12.015. [Epub ahead of print]
Marais BJ(1).

ABSTRACT: Children suffer a huge burden of disease in tuberculosis (TB) endemic countries. This disease burden was largely invisible when TB control programs focussed exclusively on adults with sputum smear-positive disease. High level advocacy and better data have improved visibility, but the establishment of functional paediatric TB programs remains challenging. The key issues that limit children’s access to TB preventive therapy and treatment in endemic areas are briefly discussed. Barriers to preventive therapy include: 1) the perceived inability to rule out active disease, 2) fear of creating drug resistance, 3) non-implementation of existing guidelines in the absence of adequate monitoring and 4) poor adherence with long preventive therapy courses. Barriers to TB treatment include: 1) perceived diagnostic difficulties, 2) non-availability of chest radiography, 3) young children presenting to unprepared maternal and child health (MCH) services and 4) the absence of child friendly formulations. With drug resistant disease there is currently no guidance on the use of preventive therapy and treatment is usually restricted to cases with bacteriologically confirmed disease, which excludes most young children from care, even if their likely source case has documented drug resistant TB.

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2. Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis.
Lancet Respir Med. 2016 Dec 15. pii: S2213-2600(16)30423-4. doi:10.1016/S2213-2600(16)30423-4. [Epub ahead of print]
Kendall EA(1), Fojo AT(2), Dowdy DW(3).

BACKGROUND: In May, 2016, WHO endorsed a 9 month regimen for multidrug-resistant  tuberculosis that is cheaper and potentially more effective than the conventional, longer (20-24 month) therapy. We aimed to investigate the population-level implications of scaling up this new regimen.
METHODS: In this population modelling analysis, we developed a dynamic transmission model to simulate the introduction of this short-course regimen as an instantaneous switch in 2016. We projected the corresponding percentage reduction in the incidence of multidrug-resistant tuberculosis by 2024 compared with continued use of longer therapy. In the primary analysis in a representative southeast Asian setting, we assumed that the short-course regimen would double treatment access (through savings in resources or capacity) and achieve long-term efficacy at levels seen in preliminary cohort studies. We then did extensive sensitivity analyses to explore a range of alternative scenarios.
FINDINGS: Under the optimistic assumptions in the primary analysis, the incidence of multidrug-resistant tuberculosis in 2024 would be 3·3 (95% uncertainty range 2·2-5·6) per 100 000 population with the short-course regimen and 4·3 (2·9-7·6) per 100 000 population with continued use of longer therapy – i.e., the short-course regimen could reduce incidence by 23% (10-38). Incidence would be reduced by 14%  (4-28) if the new regimen affected only treatment effectiveness and by 11% (3-24) if it affected only treatment availability. Under more pessimistic assumptions, the short-course regimen would have minimal effect and even potential for harm-eg, when 30% of patients are ineligible for the new regimen because of second-line drug resistance, we projected a change in incidence of -2% (-20 to +28). The new regimen’s effect was greater in settings with more ongoing transmission of multidrug-resistant tuberculosis, but results were otherwise similar across settings with different levels of tuberculosis incidence and prevalence of multidrug resistance.
INTERPRETATION: The short-course regimen has potential to substantially lessen the multidrug-resistant tuberculosis epidemic, but this effect depends on its long-term efficacy, its ability to expand treatment access, and the role of second-line drug resistance.
FUNDING: US National Institutes of Health and Bill & Melinda Gates Foundation.

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3. Beyond pills and tests: addressing the social determinants of tuberculosis.
Clin Med (Lond). 2016 Dec;16(Suppl 6):s79-s91.
Wingfield T, Tovar MA, Huff D, Boccia D, Saunders MJ, Datta S, Montoya R, Ramos E, Lewis JJ, Gilman RH, Evans C.

ABSTRACT: Poverty drives tuberculosis (TB) rates but the approach to TB control has been disproportionately biomedical. In 2015, the World Health Organization’s End TB Strategy explicitly identified the need to address the social determinants of TB through socio-economic interventions. However, evidence concerning poverty reduction and cost mitigation strategies is limited. The research described in this article, based on the 2016 Royal College of Physicians Linacre Lecture, aimed to address this knowledge gap. The research was divided into two phases: the first phase was an analysis of a cohort study identifying TB-related costs of TB-affected households and creating a clinically relevant threshold above which those costs became catastrophic; the second was the design, implementation and evaluation of a household randomised controlled evaluation of socio-economic support to improve access to preventive therapy, increase TB cure, and mitigate the effects of catastrophic costs. The first phase showed TB remains a disease of people living in poverty – ‘free’ TB care was unaffordable for impoverished TB-affected households and incurring catastrophic costs was associated with as many adverse TB treatment outcomes (including death, failure of treatment, lost to follow-up and TB recurrence) as multidrug resistant (MDR) TB. The second phase showed that, in TB-affected households receiving socio-economic support, household contacts were more likely to start and adhere to TB preventive therapy, TB patients were more likely to be cured and households were less likely to incur catastrophic costs. In impoverished Peruvian shantytowns, poverty remains inextricably linked with TB and incurring catastrophic costs predicted adverse TB treatment outcome. A novel socio-economic support intervention increased TB preventive therapy uptake, improved TB treatment success and reduced catastrophic costs. The impact of the intervention on TBcontrol is currently being evaluated by the Community Randomized Evaluation of a Socio-economic Intervention to Prevent TB (CRESIPT) study.

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4. Role of pyrazinamide in the emergence of extensively drug-resistant tuberculosis: a multi-strain mathematical model.
Antimicrob Agents Chemother. 2016 Dec 12. pii: AAC.00498-16. [Epub ahead of print]
Fofana MO(1), Shrestha S(1), Knight GM(2,)(2), Cohen T(3), White RG(2), Cobelens F(4,)(5), Dowdy DW(6,)(7).

ABSTRACT: Several infectious diseases of global importance – e.g. HIV, tuberculosis (TB) – require prolonged treatment with combination antimicrobial regimens, typically involving high-potency “core” agents coupled with additional “companion” drugs that protect against de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are re-used in sequential (first-line, second-line, etc…) regimens. We used a multi-strain model of M. tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an Approximate Bayesian Computational approach. We reported the proportion of data-consistent simulations in which the prevalence of pre-extensively drug resistant (pre-XDR) TB – defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones) – exceeded pre-defined acceptability thresholds (1-2 cases per 100,000 population by 2035). Using pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations exceeding the pre-XDR acceptability threshold seven-fold, compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those most strongly correlated with projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.

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5. Mobility patterns of persons at risk for drug-resistant tuberculosis in Mumbai, India.
Int J Tuberc Lung Dis. 2016 Dec;20(12):1633-1638.
Conners E(1), Garfein RS(2), Rodwell TC(2), Udwadia ZF(3), Catanzaro DG(4).

SETTING: Tuberculosis (TB) hospital in Mumbai, India.
OBJECTIVE: To describe the mobility patterns of persons with suspected drug-resistant tuberculosis (DR-TB) and to assess whether there were significant differences in demographic or risk characteristics based on mobility.
DESIGN: Observational cohort study of TB clinic patients at risk for DR-TB.
RESULTS: Among 602 participants, 37% had ever moved from their place of birth; 14% were local movers (within state), and 23% were distant movers, between states or countries. Univariate multinomial logistic regression models showed that distant movers were more likely than non-movers to have lower income, less education, a greater number of previous TB episodes, and to have ever smoked. Compared to non-movers, local movers were more likely to have lower income and were more likely to have seen a doctor in the past 2 years. Clinical outcomes, including DR-TB, diabetes, and human immunodeficiency virus (HIV), did not differ between the three mobility groups.
CONCLUSION: Mobility was common among patients at risk for DR-TB in Mumbai. TB programs should consider the implications of mobility on the protracted treatment for DR-TB in India.

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November eNewsletter

1. Treatment of isoniazid-resistant tuberculosis with first-line drugs: a systematic review and meta-analysis.
Lancet Infect Dis. 2016 Nov 16. pii: S1473-3099(16)30407-8. doi: 10.1016/S1473-3099(16)30407-8. [Epub ahead of print]
Gegia M(1), Winters N(2), Benedetti A(2), van Soolingen D(3), Menzies D(4).

BACKGROUND: The results of some reports have suggested that treatment of isoniazid-resistant tuberculosis with the recommended regimens of first-line drugs might be suboptimal. We updated a previous systematic review of treatment outcomes associated with use of first-line drugs in patients with tuberculosis resistant to isoniazid but not rifampicin.
METHODS: In this systematic review, we updated the results of a previous review to include randomised trials and cohort studies published in English, French, or  Spanish to March 31, 2015, containing results of standardised treatment of patients with bacteriologically confirmed isoniazid-resistant tuberculosis (but not multidrug-resistant tuberculosis-ie, not resistant to rifampicin) in whom failure and relapse were bacteriologically confirmed. Results in patients with drug-sensitive tuberculosis included in the same studies were also analysed. We pooled treatment outcomes with random-effects meta-analysis.
FINDINGS: We identified 19 cohort studies and 33 trials with 3744 patients with isoniazid-resistant tuberculosis and 19 012 patients with drug-sensitive disease. The pooled rates of failure or relapse, or both, and acquired drug resistance with all drug regimens were 15% (95% CI 12-18) and 3·6% (2-5), respectively, in patients with isoniazid-resistant tuberculosis and 4% (3-5) and 0·6% (0·3-0·9) in those with drug-sensitive tuberculosis. Of patients with initial isoniazid-resistant tuberculosis with acquired drug resistance, 96% (93-99) had acquired multidrug-resistant disease. Treatment of isoniazid-resistant tuberculosis with the WHO standard regimen for new patients resulted in treatment failure, relapse, and acquired multidrug resistance in 11% (6-17), 10% (5-15) and 8% (3-13), respectively; treatment with the standard WHO regimen for previously treated patients resulted in treatment failure in 6% (2-10), relapse in 5% (2-8), and acquisition of multidrug resistance in 3% (0-6). For patients with drug-sensitive disease treated with the standard retreatment regimen the rates were 1% (0-2), 5% (4-7), and 0·3% (0-0·6).
INTERPRETATION: Treatment of isoniazid-resistant tuberculosis with first-line drugs resulted in suboptimal outcomes, supporting the need for better regimens. Standardised empirical treatment of new cases could be contributing substantially to the multidrug-resistant epidemic, particularly in settings where the prevalence of isoniazid resistance is high.
FUNDING: Canadian Institutes of Health Research.

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2. Population Pharmacokinetics of Bedaquiline and Metabolite M2 in Patients With Drug-Resistant Tuberculosis: The Effect of Time-Varying Weight and Albumin.
CPT Pharmacometrics Syst Pharmacol. 2016 Nov 8. doi: 10.1002/psp4.12147. [Epub ahead of print]
Svensson EM(1), Dosne AG(1), Karlsson MO(1).

ABSTRACT: Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time. Bedaquiline and M2 disposition were well described by three and one-compartment models, respectively. Weight and albumin were correlated, typically increasing after the start of treatment, and significantly affected bedaquiline and M2 plasma disposition. Additionally, age and race were significant covariates, whereas concomitant human immunodeficiency virus (HIV) infection, sex, or having extensively drug-resistant TB was not. This is the first population model simultaneously characterizing bedaquiline and M2 PKs in its intended use population. The developed model will be used for efficacy and safety exposure-response analyses.

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3. New/Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis: Practice-Based Recommendations.
Am J Respir Crit Care Med. 2016 Nov 17. [Epub ahead of print]
Harausz EP(1), Garcia-Prats AJ(2), Seddon JA(3), Schaaf HS(4), Hesseling AC(5), Achar J(6), Bernheimer J(7), Cruz A(8), D’Ambrosio L(9,)(10), Detjen A(11), Graham SM(12), Hughes J(13), Jonckheere S(14), Marais BJ(15), Battista Migliori G(16), McKenna L(17), Skrahina A(18), Tadolini M(19), Wilson P(20), Furin J(21); Sentinel Project on Pediatric Drug-Resistant Tuberculosis.

ABSTRACT: It is estimated that 33,000 children develop multidrug-resistant tuberculosis (MDR-TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR-TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR-TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR-TB literature by providing practice-based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR-TB drugs and the new shorter MDR-TB regimen in children and adolescents.

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4. Carbapenems against Mycobacterium tuberculosis: a review of the evidence.
Int J Tuberc Lung Dis. 2016 Nov;20(11):1436-1447.
Jaganath D(1), Lamichhane G(2), Shah M(2).

ABSTRACT: Carbapenems, a more recent β-lactam class, represent a unique anti-tuberculosis option, as emerging evidence demonstrates that they target the Mycobacterium tuberculosis cell wall and β-lactamase. This provides a potentially new agent against M. tuberculosis, in particular for multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), where options are limited. In this review, we examine the current evidence on the activity of carbapenems against M. tuberculosis. The predominance of work is in vitro, and suggests that carbapenems kill M. tuberculosis at least in the active phase, with possible greater potency with the addition of a β-lactamase inhibitor. The few in vivo and clinical studies suggest that there are benefits and that they are generally tolerated, although the variability in duration, dosing, and background regimen and lack of pharmacokinetic analyses limit interpretation of efficacy. We outline further areas of research to better understand the role of carbapenems to add a needed new agent to the treatment of MDR- and XDR-TB.

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5. Outcome of culture-confirmed isoniazid-resistant rifampicin-susceptible tuberculosis in children.
Int J Tuberc Lung Dis. 2016 Nov;20(11):1469-1476.
Garcia-Prats AJ(1), du Plessis L(1), Draper HR(1), Burger A(2), Seddon JA(3), Zimri K(1), Hesseling AC(1), Schaaf HS(1).

SETTING: Isoniazid-resistant rifampicin-susceptible (H(R)R(S)) tuberculosis (TB)  is the most prevalent form of drug-resistant TB globally, and may be a risk factor for poor outcomes, but has been poorly described in children.
OBJECTIVE: To characterise the clinical presentation, treatment, and clinical and microbiological outcomes among children with culture-confirmed H(R)R(S) TB.
DESIGN: Retrospective hospital-based cohort study.
RESULTS: Of the 72 children included in the study, the median age was 50.1 months (IQR 21.5-102.5); 42% were male. Forty-four (51%) had a potential source case; only 13 were confirmed H(R)R(S) TB. Of 66 tested, 12 (17%) were human immunodeficiency virus (HIV) infected, and 36 (60%) of the 60 with pulmonary TB (PTB) had severe disease. Seventy children had treatment data; the median total duration of treatment was 11.3 months (IQR 9-12.3); 25 (36%) initiated treatment  with a three-drug intensive phase; 52 (74%) received a fluoroquinolone. Of 63 children with known outcomes, 55 (88%) had a favourable outcome, 1 died and 3 had treatment failure. Ten had positive follow-up cultures at ⩾2 months after starting treatment. Older age (P = 0.008), previous anti-tuberculosis treatment (P = 0.023) and severe PTB (P = 0.018) were associated with failure to culture-convert at ⩾2 months.
CONCLUSIONS: Although overall outcomes were good, prolonged culture positivity and cases of treatment failure emphasise the need for additional attention to the management of children with H(R)R(S) TB.

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October eNewsletter

1. Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study.
BMC Infect Dis. 2016 Oct 21;16(1):593.
Schnippel K(1,)(2,)(3), Berhanu RH(4,)(5,)(6), Black A(7), Firnhaber C(4,)(8), Maitisa N(7,)(9), Evans D(5), Sinanovic E(10).

BACKGROUND: According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of
multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg,
South Africa.
METHODS: We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 – December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment.
RESULTS: Across the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (≤50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43.8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts ≤100 cells/mm(3) and those newly initiating ART were more likely to experience a severe AE (sHR: 2.76, 95 % CI: 1.30-5.84 and sHR: 3.07, 95 % CI: 1.46-6.46, respectively).
CONCLUSION: Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment.

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2. Individualizing management of extensively drug-resistant tuberculosis:diagnostics, treatment, and biomarkers.
Expert Rev Anti Infect Ther. 2016 Oct 20. [Epub ahead of print]
Alffenaar JW(1), Akkerman OW(2,)(3), Anthony R(4), Tiberi S(5), Heysell S(6),Grobusch MP(7), Cobelens F(8,)(9,)(10), van Soolingen D(11,)(12).

INTRODUCTION: Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure. Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of XDR-TB. Improved diagnostic procedures and rapid molecular tests help to select appropriate drugs and dosages. Drugs dosages can be further tailored to the specific conditions of the patient based on quantitative susceptibility testing of the M. tuberculosis isolate and use of therapeutic drug monitoring. Pharmacovigilance is important for preserving activity of the novel drugs bedaquiline and delamanid. Furthermore, biomarkers of treatment response must be developed and validated to guide therapeutic decisions. Expert commentary: Given the currently poor treatment outcomes and the association of XDR-TB with HIV in endemic regions, a more patient oriented approach regarding diagnostics, drug selection and tailoring and treatment evaluation will improve treatment outcome. The different areas of expertise should be covered by a multidisciplinary team and may involve the transition of patients from hospitalized to home or community based treatment.

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3. Eligibility for the Shorter Multidrug-Resistant Tuberculosis Regimen: Ambiguities in the World Health Organization Recommendations.
Am J Respir Crit Care Med. 2016 Oct 15;194(8):1028-1029.
Varaine F(1), Guglielmetti L(1,)(2), Huerga H(3), Bonnet M(3,)(4), Kiria N(5), Sitienei JK(6), Rich M(7), Mitnick CD(8).

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4. Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis.
PLoS Med. 2016 Oct 11;13(10):e1002142. doi: 10.1371/journal.pmed.1002142. eCollection 2016.
Kunkel A(1,)(2), Cobelens FG(3,)(4), Cohen T(2).

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5. Limited Benefit of the New Shorter Multidrug-Resistant Tuberculosis Regimen in Europe.
Am J Respir Crit Care Med. 2016 Oct 15;194(8):1029-1031.
Lange C(1,)(2,)(3,)(4,)(5), Duarte R(6), Fréchet-Jachym M(7), Guenther G(1,)(2,)(3,)(5), Guglielmetti L(7,)(8), Olaru ID(1,)(2,)(3), Oliveira O(6), Rumetshofer R(9), Veziris N(8,)(10), van Leth F(11,)(12); European MDR-TB database collaboration.

Read free AJRCCM article here 

September eNewsletter

1. Treatment Outcomes in Multidrug-Resistant Tuberculosis.
N Engl J Med. 2016 Sep 15;375(11):1103-5. doi: 10.1056/NEJMc1603274.
Günther G(1), Lange C(1), Alexandru S(2), Altet N(3), Avsar K(4), Bang D(5), Barbuta R(6), Bothamley G(7), Ciobanu A(2), Crudu V(2), Danilovits M(8), Dedicoat M(9), Duarte R(10), Gualano G(11), Kunst H(12), de Lange W(13), Leimane V(14), Magis-Escurra C(15), McLaughlin AM(16), Muylle I(17), Polcová V(18), Popa C(19), Rumetshofer R(20), Skrahina A(21), Solodovnikova V(21), Spinu V(19), Tiberi S(22), Viiklepp P(23), van Leth F(24); for TBNET.

Read free article in the New England Journal of Medicine here.

2. The socioeconomic impact of multidrug resistant tuberculosis on patients: results from Ethiopia, Indonesia and Kazakhstan.
BMC Infect Dis. 2016 Sep 5;16:470. doi: 10.1186/s12879-016-1802-x.
van den Hof S(1,)(2), Collins D(3), Hafidz F(4), Beyene D(5), Tursynbayeva A(6), Tiemersma E(7,)(8).

BACKGROUND: One of the main goals of the post-2015 global tuberculosis (TB) strategy is that no families affected by TB face catastrophic costs. We revised an existing TB patient cost measurement tool to specifically also measure multi-drug resistant (MDR) TB patients’ costs and applied it in Ethiopia, Indonesia and Kazakhstan.
METHODS: Through structured interviews with TB and MDR-TB patients in different stages of treatment, we collected data on the direct (out of pocket) and indirect (loss of income) costs of patients and their families related to the diagnosis and treatment of TB and MDR-TB. Direct costs included costs for hospitalization, follow-up tests, transport costs for health care visits, and food supplements. Calculation of indirect costs was based on time needed for diagnosis and treatment. Costs were extrapolated over the patient’s total treatment phase.
RESULTS: In total 406 MDR-TB patients and 197 other TB patients were included in the survey: 169 MDR-TB patients and 25 other TB patients in Ethiopia; 143 MDR-TB patients and 118 TB patients in Indonesia; and 94 MDR-TB patients and 54 other TB patients in Kazakhstan. Total costs for diagnosis and current treatment episode for TB patients were estimated to be USD 260 in Ethiopia, USD 169 in Indonesia, and USD 929 in Kazakhstan, compared to USD 1838, USD 2342, and USD 3125 for MDR-TB patients, respectively. These costs represented 0.82-4.6 months of pre-treatment household income for TB patients and 9.3-24.9 months for MDR-TB patients. Importantly, 38-92 % reported income loss and 26-76 % of TB patients lost their jobs due to (MDR) TB illness, further aggravating the financial burden.
CONCLUSIONS: The financial burden of MDR-TB is alarming, although all TB patients experienced substantial socioeconomic impact of the disease. If the patient is the breadwinner of the family, the combination of lost income and extra costs is generally catastrophic. Therefore, it should be a priority of the government to relieve the financial burden based on the cost mitigation options identified.
Read free PMC article here.

3. Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method.
Eur Respir J. 2016 Sep 1. pii: ERJ-00462-2016. doi: 10.1183/13993003.00462-2016. [Epub ahead of print]
Mitnick CD(1), White RA(2), Lu C(3), Rodriguez CA(4), Bayona J(5), Becerra MC(6), Burgos M(7), Centis R(8), Cohen T(9), Cox H(10), D’Ambrosio L(11), Danilovitz M(12), Falzon D(13), Gelmanova IY(14), Gler MT(15), Grinsdale JA(16), Holtz TH(17), Keshavjee S(6), Leimane V(18), Menzies D(19), Migliori GB(8), Milstein MB(20), Mishustin SP(21), Pagano M(22), Quelapio MI(23), Shean K(24), Shin SS(25), Tolman AW(4), van der Walt ML(26), Van Deun A(27), Viiklepp P(28);  on behalf of the Collaborative Group for Analysis of Bacteriology Data in MDR-TB Treatment.

ABSTRACT: Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection.We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference. Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34-0.42) for all patients and 0.33 (0.25-0.42) for HIV-co-infected patients.Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.
Read free ERS article here.

4. Faster for less: the new “shorter” regimen for multidrug-resistant tuberculosis.
Eur Respir J. 2016 Sep 1. pii: ERJ-01249-2016. doi: 10.1183/13993003.01249-2016. [Epub ahead of print]
Sotgiu G(1), Tiberi S(2), D’Ambrosio L(3), Centis R(4), Alffenaar JW(5), Caminero JA(6), Abdo Arbex M(7), Alarcon Guizado V(8), Aleksa A(9), Dore S(10), Gaga M(11), Gualano G(12), Kunst H(13), Payen MC(14), Roby Arias AJ(15), Skrahina A(16), Solovic I(17), Sulis G(18), Tadolini M(19), Zumla A(20), Migliori GB(21); International Carbapenem Study Group.
Read free ERS extract here.

August eNewsletter

1. Discovery of novel oral protein synthesis inhibitors of Mycobacterium tuberculosis that target leucyl-tRNA synthetase.
Antimicrob Agents Chemother. 2016 Aug 8. pii: AAC.01339-16. [Epub ahead of print]
Palencia A, Li X, Bu W, Choi W, Ding CZ, Easom EE, Feng L, Hernandez V, Houston P, Liu L, Meewan M, Mohan M, Rock FL, Sexton H, Zhang S, Zhou Y, Wan B, Wang Y, Franzblau SG, Woolhiser L, Gruppo V, Lenaerts AJ, O’Malley T, Parish T, Cooper CB, Waters MG, Ma Z, Ioerger TR, Sacchettini JC, Rullas J, Angulo-Barturen I, Pérez-Herrán E, Mendoza A, Barros D, Cusack S, Plattner JJ, Alley MR.

ABSTRACT: The recent development and spread of extensively (XDR) and totally resistant (TDR) strains of Mycobacterium tuberculosis, highlights the need for new
antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although the parenteral aminoglycosides are a key component in multidrug-resistant (MDR) TB therapy, the oxazolidinone, linezolid, is the only orally available protein synthesis inhibitor that is effective against TB. Herein, we show that small molecule inhibitors of aminoacyl-tRNA synthetases (AARS), known to be excellent antibacterial protein synthesis targets, can be designed that are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide design of LeuRS inhibitors that have good biochemical potency and excellent whole cell activity against M. tuberculosis. Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with comparable potency to the frontline drug isoniazid.
Read abstract here

2. Multidrug-Resistant Tuberculosis Treatment in North Korea: Is Scale-Up Possible?
PLoS Med. 2016 Aug 2;13(8):e1002062. doi: 10.1371/journal.pmed.1002062. eCollection 2016.
Seung KJ, Franke M, Linton SW.

ABSTRACT: Kwonjune Seung and colleagues describe the Eugene Bell Foundation’s experience of treating MDR-TB in North Korea.
Read free article on PLoS Medicine here

3. Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons have we learnt and how can we do better?
Eur Respir J. 2016 Aug;48(2):516-25. doi: 10.1183/13993003.00543-2016. Epub 2016 Jul 13.
Albert H, Nathavitharana RR, Isaacs C, Pai M, Denkinger CM, Boehme CC.

ABSTRACT: The global roll-out of Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) has changed the diagnostic landscape of tuberculosis (TB). More than 16 million tests have been performed in 122 countries since 2011, and detection of multidrug-resistant TB has increased three- to eight-fold compared to conventional testing. The roll-out has galvanised stakeholders, from donors to civil society, and paved the way for universal drug susceptibility testing. It has attracted new product developers to TB, resulting in a robust molecular diagnostics pipeline. However, the roll-out has also highlighted gaps that have constrained scale-up and limited impact on patient outcomes. The roll-out has been hampered by high costs for under-funded programmes, unavailability of a complete solution package (notably comprehensive training, quality assurance, implementation plans, inadequate service and maintenance support) and lack of impact assessment. Insufficient focus has been afforded to effective linkage to care of diagnosed patients, and clinical impact has been blunted by weak health systems. In many countries the private sector plays a dominant role in TB control, yet this sector has limited access to subsidised pricing. In light of these lessons, we advocate for a comprehensive diagnostics implementation approach, including increased engagement of in-country stakeholders for product launch and roll-out, broader systems strengthening in preparation for new technologies, as well as quality impact data from programmatic settings.
Read free PMC article here

4. Comparison of TaqMan(®) Array Card and MYCOTB(TM) with conventional phenotypic susceptibility testing in MDR-TB.
Int J Tuberc Lung Dis. 2016 Aug;20(8):1105-12. doi: 10.5588/ijtld.15.0896.
Foongladda S, Banu S, Pholwat S, Gratz J, O-Thong S, Nakkerd N, Chinli R, Ferdous SS, Rahman SM, Rahman A, Ahmed S, Heysell S, Sariko M, Kibiki G, Houpt E.

BACKGROUND: Although phenotypic drug susceptibility testing (DST) is endorsed as the standard for second-line drug testing of Mycobacterium tuberculosis, it is slow and laborious.
METHODS: We evaluated the accuracy of two faster, easier methodologies that provide results for multiple drugs: a genotypic TaqMan(®) Array Card (TAC) and the Sensititre(®) MYCOTB(TM) plate. Both methods were tested at three central laboratories in Bangladesh, Tanzania, and Thailand with 212 multidrug-resistant tuberculosis (MDR-TB) isolates and compared with the laboratories’ phenotypic method in use.
RESULTS: The overall accuracy for ethambutol, streptomycin, amikacin, kanamycin, ofloxacin, and moxifloxacin vs. the phenotypic standard was 87% for TAC (range
70-99) and 88% for the MYCOTB plate (range 76-98). To adjudicate discordances, we re-defined the standard as the consensus of the three methods, against which the
TAC and MYCOTB plate yielded 94-95% accuracy, while the phenotypic result yielded 93%. Some isolates with genotypic mutations and high minimum inhibitory concentration (MIC) were phenotypically susceptible, and some isolates without mutations and low MIC were phenotypically resistant, questioning the phenotypic standard.
CONCLUSIONS: In our view, the TAC, the MYCOTB plate, and the conventional phenotypic method have similar performance for second-line drugs; however, the former methods offer speed, throughput, and quantitative DST information.
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5. Tuberculosis Treatment Outcome and Drug Resistance in Lambaréné, Gabon: A Prospective Cohort Study.
Am J Trop Med Hyg. 2016 Aug 3;95:472-80. doi: 10.4269/ajtmh.15-0668. Epub 2016 Jun 27.
Bélard S, Remppis J, Bootsma S, Janssen S, Kombila DU, Beyeme JO, Rossatanga EG, Kokou C, Osbak KK, Obiang Mba RM, Kaba HM, Traoré AN, Ehrhardt J, Bache EB, Flamen A, Rüsch-Gerdes S, Frank M, Adegnika AA, Lell B, Niemann S, Kremsner PG, Loembé MM, Alabi AS, Grobusch MP.

ABSTRACT: Despite overall global progress in tuberculosis (TB) control, TB remains one of the deadliest communicable diseases. This study prospectively assessed TB epidemiology in Lambaréné, Gabon, a Central African country ranking 10th in terms of TB incidence rate in the 2014 World Health Organization TB report. In Lambaréné, between 2012 and 2014, 201 adult and pediatric TB patients were enrolled and followed up; 66% had bacteriologically confirmed TB and 95% had pulmonary TB. The human immunodeficiency virus (HIV) coinfection rate was 42% in adults and 16% in children. Mycobacterium tuberculosis and Mycobacterium
africanum were identified in 82% and 16% of 108 culture-confirmed TB cases, respectively. Isoniazid (INH) and streptomycin yielded the highest resistance rates (13% and 12%, respectively). The multidrug resistant TB (MDR-TB) rate was
4/91 (4%) and 4/13 (31%) in new and retreatment TB cases, respectively. Treatment success was achieved in 53% of patients. In TB/HIV coinfected patients, mortality rate was 25%. In this setting, TB epidemiology is characterized by a high rate of TB/HIV coinfection and low treatment success rates. MDR-TB is a major public health concern; the need to step-up in-country diagnostic capacity for culture and drug susceptibility testing as well as access to second-line TB drugs urgently requires action.
Read abstract here.

6. Rapid Drug Susceptibility Testing of Drug-Resistant Mycobacterium tuberculosis Isolates Directly from Clinical Samples by Use of Amplicon Sequencing: a Proof-of-Concept Study.
J Clin Microbiol. 2016 Aug;54(8):2058-67. doi: 10.1128/JCM.00535-16. Epub 2016
May 25.
Colman RE, Anderson J, Lemmer D, Lehmkuhl E, Georghiou SB, Heaton H, Wiggins K, Gillece JD, Schupp JM, Catanzaro DG, Crudu V, Cohen T, Rodwell TC, Engelthaler DM.

ABSTRACT: Increasingly complex drug-resistant tuberculosis (DR-TB) is a major global health concern and one of the primary reasons why TB is now the leading infectious cause of death worldwide. Rapid characterization of a DR-TB patient’s complete drug resistance profile would facilitate individualized treatment in place of empirical treatment, improve treatment outcomes, prevent amplification of resistance, and reduce the transmission of DR-TB. The use of targeted next-generation sequencing (NGS) to obtain drug resistance profiles directly from patient sputum samples has the potential to enable comprehensive evidence-based treatment plans to be implemented quickly, rather than in weeks to months, which is currently needed for phenotypic drug susceptibility testing (DST) results. In this pilot study, we evaluated the performance of amplicon sequencing of Mycobacterium tuberculosis DNA from patient sputum samples using a tabletop NGS technology and automated data analysis to provide a rapid DST solution (the Next Gen-RDST assay). One hundred sixty-six out of 176 (94.3%) sputum samples from the Republic of Moldova yielded complete Next Gen-RDST assay profiles for 7 drugs of interest. We found a high level of concordance of our Next Gen-RDST assay results with phenotypic DST (97.0%) and pyrosequencing (97.8%) results from the same clinical samples. Our Next Gen-RDST assay was also able to estimate the proportion of resistant-to-wild-type alleles down to mixtures of ≤1%, which demonstrates the ability to detect very low levels of resistant variants not detected by pyrosequencing and possibly below the threshold for phenotypic growth methods. The assay as described here could be used as a clinical or surveillance tool.
Read abstract here.