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.

Read free Nature article here

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.

Read free PLOS article here

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.

Read free Lancet article here

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.

Read abstract here 

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).

Read free PLOS article here 

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.
Read free PMC article here

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.


Adverse effects of oral second-line antituberculosis drugs in children.
Schaaf HS, Thee S, van der Laan L, Hesseling AC, Garcia-Prats AJ
INTRODUCTION: Increasing numbers of children with drug-resistant tuberculosis are accessing second-line antituberculosis drugs; these drugs are more toxic than first-line drugs. Little is known about the safety of new antituberculosis drugs  in children. Knowledge of adverse effects, and how to assess and manage these, is important to ensure good adherence and treatment outcomes.
AREAS COVERED: A Pubmed search was performed to identify articles addressing adverse effects of second-line antituberculosis drugs; a general search was done for the new drugs delamanid and bedaquiline. This review discusses adverse effects associated with oral second-line antituberculosis drugs, including delamanid and bedaquiline. The spectrum of adverse effects caused by antituberculosis drugs is wide; the majority are mild or moderate, but even these are important to manage as it could lead to non-adherence to treatment. Adverse effects may be more common in HIV-infected than in HIV-uninfected children.
EXPERT OPINION: Although children may experience fewer adverse effects from oral second-line antituberculosis drugs than adults, evidence from prospective studies of the incidence of adverse events in children is still limited. Higher doses of second-line drugs, new antituberculosis drugs, and new drug regimens are being evaluated in children: these call for strict pharmacovigilance in children treated in the near future, as adverse effect profiles may change.

Delamanid co-administered with antiretroviral drugs or anti-TB drugs shows no clinically relevant drug-drug interactions in healthy subjects. 
Mallikaarjun S, Wells C, Petersen C, Paccaly A, Shoaf SE, Patil S, Geiter L
OBJECTIVES: Delamanid is a medicinal product approved for treatment of MDR-TB. Three studies were conducted to evaluate the potential drug-drug interactions between delamanid and antiretroviral drugs including ritonavir, a strong inhibitor of CYP3A4 and selected anti-TB drugs, including rifampicin, a strong inducer of cytochrome P450 (CYP) isozymes.
METHODS: Multiple-dose studies were conducted in parallel groups of healthy subjects. Plasma samples were analysed for delamanid, delamanid metabolite, and coadministered drug concentrations, and pharmacokinetic (PK) parameters were determined. The magnitude of the interaction was assessed by the ratio of the geometric means (GMR) and 90% CIs.
RESULTS: Coadministration of delamanid with tenofovir or efavirenz did not affect the PK of delamanid. Coadministration of Kaletra® [lopinavir/ritonavir] with delamanid resulted in about 25% higher delamanid AUCτ. Tenofovir, efavirenz, lopinavir, and ritonavir exposure were not affected by delamanid. Coadministration of delamanid with the TB drugs [ethambutol + Rifater® (rifampicin, pyrazinamide, and isoniazid)] resulted in lower delamanid exposure (47% and 42% for AUCτ and Cmax, respectively), as well as decreased exposure of three primary metabolites (about 30 to 50% lower AUCτ). Delamanid did not affect rifampicin, pyrazinamide, and isoniazid exposure; ethambutol AUCτ and Cmax were about 25% higher with delamanid coadministration.
CONCLUSIONS: The lack of clinically significant drug-drug interactions between delamanid and selected antiretroviral agents (including the strong CYP inhibitor ritonavir) and a combination of anti-TB drugs was demonstrated. While there was a decrease in delamanid concentrations when coadministered with [ethambutol + Rifater], this is likely related to decreased delamanid absorption and not CYP induction.

Prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of Mycobacterium tuberculosis.
Whitfield MG, Streicher EM, Dolby T, Simpson JA, Sampson SL, Van Helden PD, Van Rie A, Warren RM
Pyrazinamide resistance is largely unknown in the spectrum of drug resistant phenotypes. We summarize data on PZA resistance in clinical isolates from South Africa. PZA DST should be performed when considering its inclusion in treatment of patients with rifampicin-resistant TB or MDR-TB.

Development, roll-out and impact of Xpert MTB/RIF for tuberculosis: what lessons  have we learnt and how can we do better?
Albert H, Nathavitharana RR, Isaacs C, Pai M, Denkinger CM, Boehme CC
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 newtechnologies, as well as quality impact data from programmatic settings.



Sequence analysis of fluoroquinolone resistance associated genes gyrA and gyrB in clinical Mycobacteriumtberculosis isolates fromsuspected multidrug-resistant tuberculosis patients in New Delhi, India.
Singhal R, Reynolds PR, Marola J, Epperson LE, Arora J, Sarin R, Myneedu VP, Strong M, Salfinger M. J Clin Microbiol. 2016 Jun 22. pii: JCM.00670-16.
Fluoroquinolones (FQ) are broad-spectrum antibiotics recommended for treatment of multidrug-resistant tuberculosis (MDR-TB) patients. FQ resistance, caused by mutations in the gyrA and gyrB genes of Mycobacterium tuberculosis (MTB), is increasingly reported world-wide; however, information on mutations occurring in strains from the Indian sub-continent is scarce. Hence, in this study we aimed to characterize mutations in the gyrA and gyrB genes of acid-fast bacilli (AFB) smear positive sediments or MTB isolates from AFB smear negative TB suspects from India. A total of 152 samples from suspected MDR-TB patients were included in the study. Of these, 146 strains detected were characterized by sequencing of thegyrA and gyrB genes. The extracted DNA was subjected to successive amplification using a nested PCR protocol, followed by sequencing.
A total of 27 mutations were observed in 25 strains in the gyrA gene, while no mutations were observed in the gyrB gene. The most common mutation occurred at amino-acid position 94 (13/27; 48.1%) of which the D94G mutation was the most prevalent. The gyrA mutations were significantly associated with rifampin (RIF) resistant-TB patients in comparison with non-RIF resistant patients. Heterozygosity was seen in 4/27 (14.8%) mutations, suggesting the occurrence of mixed populations with different antimicrobial susceptibilities.
A high rate of FQ-resistant mutations (17.1%), were obtained among the isolates of TB patients suspected of MDR-TB. These observations emphasize the need for accurate and rapid molecular tests for the detection of FQ-resistant mutations at the time of MDR-TB diagnosis.

The effect of surgery on the outcome of treatment for multidrug-resistant tuberculosis: a systematic reviewand meta-analysis.
Harris RC, Khan MS, Martin LJ, Allen V, Moore DA, Fielding K, Grandjean L; LSHTM MDR-TB surgery systematic review group. BMC Infect Dis. 2016; 16: 262. Published online 2016 Jun 10.
BACKGROUND: In 2014 only 50 % of multidrug-resistant tuberculosis (MDR-TB) patients achieved a successful treatment outcome. With limited options for medical treatment, surgery has re-emerged as an adjuvant therapeutic strategy. We conducted a systematic review and meta-analysis to assess the evidence for the effect of surgery as an adjunct to chemotherapy on outcomes of adults treated for MDR-TB.
METHODS: Databases and grey literature sources were searched using terms incorporating surgery and MDR-TB. No language or publication type limits were applied. Articles published pre-1990, without a comparator group, or reporting <10 surgical participants were excluded. Two-stage sifting in duplicate was employed. Data on WHO-defined treatment outcomes were abstracted into a standardised database. Study-level risk of bias was evaluated using standardised tools. Outcome-level evidence quality was assessed using GRADE. Forest plots were generated, random effects meta-analysis conducted, and heterogeneity assessed using the I2 statistic.
RESULTS: Of 1024 unique citations identified, 62 were selected for full-text review and 15 retained for inclusion. A further four articles were included after bibliography/citation searching, and one additional unpublished manuscript was identified, giving 20 articles for final inclusion. Six were meta-analyses/systematic reviews and 14 were primary research articles (observational studies).
From the 14 primary research articles, a successful outcome (cured/treatment completed) was reported for 81.9 % (371/453) and 59.7 % (1197/2006) in the surgical and non-surgical group respectively, giving a summary odds ratio of 2.62 (95 % confidence interval 1.94–3.54). Loss to follow-up and treatment failure were lower in the surgery group (both p = 0.01). Overall GRADE quality of evidence for all outcomes considered was “very low”.
CONCLUSIONS: This meta-analysis suggests that surgery as an adjunct to chemotherapy is associated with improved treatment outcomes in MDR-TB patients. However, inherent limitations in observational study design, insufficient reporting, and lack of adjustment for confounders, led to grading of the evidence as very low quality. Data on rationale for surgical referral, subsequent outcomes and resource-limited settings are scarce, precluding evidence-based recommendations on the suitability of surgery by patient characteristics or setting. It is hoped that highlighted methodological and reporting gaps will encourage improved design and reporting of future surgical studies for MDR-TB.

A cross-sectional study about knowledge and attitudes toward multidrug-resistant and extensively drug-resistant tuberculosis in a high-burden drug-resistant country.
Javed H, Tahir Z, Hashmi HJ, Jamil N. Int J Mycobacteriol. 2016 Jun;5(2):128-34.
OBJECTIVE/BACKGROUND: Tuberculosis (TB) is a leading cause of death worldwide, with new threats of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Pakistan is the fifth highest among high-burden TB countries and the fourth highest among high-burden drug-resistant-TB countries. Pakistan is the sixth most populous country in the world, and Pakistani youth is the highest population group in Pakistan and second in the world. This study was aimed at assessing the understanding, awareness, and mindset of university students toward TB, MDR TB, and XDR TB in Lahore.
METHODS: A cross-sectional questionnaire-based study was performed on 1137 individuals from three major public-sector universities in Lahore, Pakistan. Information regarding their knowledge and attitude toward MDR and XDR TB was gathered using a structured questionnaire. Data collected was analyzed using SPSS version 20.
RESULTS: Male (531) and female (606) students were asked about different aspects of MDR and XDR TB. Although 80.47% students had good knowledge about simple TB, a very small fraction had awareness and appropriate knowledge about MDR/XDR-TB. Considering TB as a stigma, only 9.3% students disclosed that they had household TB contact. Only 25% students knew about XDR TB.
CONCLUSION: Our results indicated that a small fraction of people knew the exact definition and treatment duration of MDR TB and XDR TB in our society. There is a need to increase the awareness and knowledge status of university students about MDR and XDR TB.

Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda.
Mitnick CD, Rodriguez CA, Hatton ML, Brigden G, Cobelens F, Grobusch MP, Horsburgh R, Lange C, Lienhardt C, Oren E, Podewils LJ, Seaworth B, van den Hof S, Daley CL, Gebhard AC, Wares F; RESIST-TB (Research Excellence to Stop TB Resistance) and GDI (Global Drug Resistant TB Initiative). PLoS One. 2016 May 25;11(5):e0155968. doi: 10.1371/journal.pone.0155968. eCollection 2016.
INTRODUCTION: There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey.
METHODS: Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings.
RESULTS: Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR−TB patients were also top priorities in their respective categories. Results were internally consistent and robust.
DISCUSSION: Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data.
CONCLUSION: There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.


New WHO recommendations aim to speed up detection and improve treatment outcomes for multidrug resistant tuberculosis (MDR-TB) through use of a novel rapid diagnostic test and a shorter, cheaper treatment regimen.

Shorter treatment with better outcomes
At less than US$ 1000 per patient, the new treatment regimen can be completed in 9–12 months. Not only is it less expensive than current regimens, but it is also expected to improve outcomes and potentially decrease deaths due to better adherence to treatment and reduced loss to follow-up. The shorter regimen is recommended for patients diagnosed with uncomplicated MDR-TB, for example those individuals whose MDR-TB is not resistant to the most important drugs used to treat MDR-TB (fluoroquinolones and injectables), known as “second-line drugs”. It is also recommended for individuals who have not yet been treated with second line drugs.

Rapid diagnostic test to identify second-line drug resistance
A newly recommended diagnostic test for use in national TB reference laboratories– called MTBDRsl – is a DNA-based test that identifies genetic mutations in MDR-TB strains, making them resistant to fluoroquinolones and injectable second-line TB drugs.

This test yields results in just 24-48 hours, down from the 3 months or longer currently required. The much faster turnaround time means that MDR-TB patients with additional resistance are not only diagnosed more quickly, but can quickly be placed on appropriate second-line regimens. The MTBDRsl test is also a critical prerequisite for identifying MDR-TB patients who are eligible for the newly recommended shorter regimen, while avoiding placing patients who have resistance to second-line drugs on this regimen (which could fuel the development of extensively drug-resistant TB or XDR-TB).

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Possible impact of the standardized Category IV regimen on multidrug-resistant tuberculosis patients in Mumbai.
Udwadia ZF, Mullerpattan JB, Shah KD, Rodrigues CS. Lung India. 2016 May-Jun;33(3):253-6. doi: 10.4103/0970-2113.180800.
BACKGROUND: Treatment of multidrug-resistant tuberculosis (MDR-TB) in the Programmatic Management of Drug-resistant TB program involves a standard regimen with a 6-month intensive phase and an 18-month continuation phase. However, the local drug resistance patterns in high MDR regions such as Mumbai may not be adequately reflected in the design of the regimen for that particular area.
OBJECTIVE: To analyze the impact of prescribing the standardized Category IV regimen to all patients receiving a DST at our mycobacteriology laboratory.
MATERIALS AND METHODS: All samples confirmed to be MDR-TB and tested for the second-line drugs at Hinduja Hospital’s Mycobacteriology Laboratory in the year 2012 were analyzed.
RESULTS: A total of 1539 samples were analyzed. Of these, 464 (30.14%) were MDR-TB, 867 (56.33%) were MDR with fluoroquinolone resistance, and 198 (12.8%) were extensively drug-resistant TB. The average number of susceptible drugs per sample was 3.07 ± 1.29 (assuming 100% cycloserine susceptibility). Taking 4 effective drugs to be the cut or an effective regimen, the number of patients receiving 4 or more effective drugs from the standardized directly observed treatment, short-course plus regimen would be 516 (33.5%) while 66.5% of cases would receive 3 or less effective drugs.
CONCLUSION: Our study shows that a high proportion of patients will have resistance to a number of the first- and second-line drugs. Local epidemiology must be factored in to avoid amplification of resistance.

Mutations in pepQ Confer Low-level Resistance to Bedaquiline and Clofazimine inMycobacterium tuberculosis.
Almeida D, Ioerger T, Tyagi S, Li SY, Mdluli K, Andries K,Grosset J, Sacchettini J, Nuermberger E. Antimicrob Agents Chemother. 2016 May 16. pii: AAC.00753-16. [Epub ahead of print]
The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, upward shifts of ≥4-fold inbedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than parental H37Rv strain. Co-incubation with efflux inhibitors verapamil/reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, qPCR revealed no significant differences in expression of Rv0678, mmpS5 or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with wild-type gene restored susceptibility, indicating loss of pepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.

Aggressive Regimens Reduce Risk of Recurrence After Successful Treatment ofMDR-TB.
Ahmad Khan F, Gelmanova IY, Franke MF, Atwood S, Zemlyanaya NA,Unakova IA, Andreev YG, Berezina VI, Pavlova VE, Shin S,Yedilbayev AB, Becerra MC, Keshavjee S. Clin Infect Dis. 2016 May 8. pii: ciw276. [Epub ahead of print]
BACKGROUND: We sought to determine whether treatment with a “long aggressive regimen” was associated with lower rates of relapse among patients successfully treated for pulmonary multidrug-resistant tuberculosis (MDR-TB) in Tomsk, Russia.
METHODS: We conducted a retrospective cohort study of adult patients that initiated MDR-TB treatment with individualized regimens between September 2000 and November 2004, and were successfully treated. Patients were classified as having received “aggressive regimens” if their intensive phase consisted of at least 5 likely effective drugs (including a second-line injectable and a fluoroquinolone) used for at least 6 months post culture conversion, and their continuation phase included at least 4 likely effective drugs. Patients that were treated with aggressive regimens for a minimum duration of 18 months post culture conversion were classified as having received “long aggressive regimens”. We used recurrence as a proxy for relapse because genotyping was not performed. After treatment, patients were classified as having disease recurrence if cultures grew MDR-TB or they re-initiated MDR-TB therapy. Data were analyzed using Cox proportional hazard regression.
RESULTS: Of 408 successfully treated patients, 399 (97.5%) with at least one follow-up visit were included. Median duration of follow-up was 42.4 months (interquartile range: 20.5-59.5), and there were 27 recurrence episodes. In a multivariable complete case analysis (n=371 [92.9%]) adjusting for potential confounders, long aggressive regimens were associated with a lower rate of recurrence (adjusted hazard ratio: 0.22, 95% CI: 0.05-0.92).
CONCLUSIONS: Long aggressive regimens for MDR-TB treatment are associated with lower risk of disease recurrence. © The Author 2016. Published by Oxford University Press for the InfectiousDiseases Society of America. All rights reserved. For permissions, e-mailjournals.permissions@oup.com.

Neuroleptic drugs in the treatment of tuberculosis: Minimal inhibitoryconcentrations of different phenothiazines against Mycobacterium tuberculosis.
Vesenbeckh S, Krieger D, Bettermann G, Schönfeld N, Bauer TT,Rüssmann H, Mauch H. Tuberculosis (Edinb). 2016 May;98:27-9. doi: 10.1016/j.tube.2016.02.003. Epub 2016 Feb 26.
Due to an increase of drug resistant TB, alternative drugs that are not currently listed in the WHO guidelines on MDR TB treatment are currently being evaluated. Our group tested 100 susceptible, 20 MDR and 2 XDR Mtb strains against the phenothiazine derivatives thioridazine, trifluoperazine and triflupromazine. MIC testing was performed on Middlebrook7H10 agar and was defined as the lowest drug concentration that inhibits ≥99% of the bacterial population. We confirm very good in vitro activity of phenothiazines against Mycobacterium tuberculosis. In >77% of all strains MICs of ≤10 μg/ml were found.


April eNewsletter

The affordability for patients of a new universal MDR-TB coverage model in China.

Ruan YZ, Li RZ, Wang XX, Wang LX, Sun Q, Chen C, Xu CH, Su W, Zhao J, Pang Y, Cheng J, Wang Q, Fu YT, Huan ST, Chen MT, Scano F,Floyd K, Chin DP, Fitzpatrick C.
Int J Tuberc Lung Dis. 2016 May;20(5):638-44. doi: 10.5588/ijtld.15.0413.
BACKGROUND: China has piloted a new model of universal coverage for multidrug-resistant tuberculosis (MDR-TB), designed to rationalize hospital use of drugs and tests and move away from fee-for-service payment towards a standard package with financial protection against catastrophic health costs.
OBJECTIVE: To evaluate the affordability to patients of this new model.
DESIGN: This was an observational study of 243 MDR-TB cases eligible for enrolment on treatment under the project. We assessed the affordability of the project from the perspective of households, with a focus on catastrophic costs.
RESULTS: Of the 243 eligible cases, 172 (71%) were enrolled on treatment; of the 71 cases not enrolled, 26 (37%) cited economic reasons. The 73 surveyed cases paid an average of RMB 5977 (US$920) out-of-pocket in search costs incurred outside the pilot model. Within the pilot, they paid another RMB 2094 (US$322) in medical fees and RMB 5230 (US$805) in direct non-medical costs. Despite 90% reimbursement of medical fees, 78% of households experienced catastrophic costs, including indirect costs.
CONCLUSION:The objectives of the pilot model are aligned with health reform in China and universal health coverage globally. Enrollment would almost certainly be higher with 100% reimbursement of medical fees, but patient enablers will be required to truly eliminate catastrophic costs.


 A performance evaluation of MTBDRplus version 2 for the diagnosis of multidrug-resistant tuberculosis.

Seifert M, Ajbani K, Georghiou SB, Catanzaro D, Rodrigues C, Crudu V, Victor TC, Garfein RS, Catanzaro A, Rodwell TC.
Int J Tuberc Lung Dis. 2016 May;20(5):631-7. doi: 10.5588/ijtld.15.0788.
OBJECTIVE:To evaluate the performance of a recently updated rapid molecular diagnostic test, GenoType(®) MTBDRplus version 2, designed to detect drug resistance in both acid-fast bacilli (AFB) smear-negative and -positive specimens.
DESIGN: Sputum samples from 1128 patients at risk for multidrug-resistant tuberculosis (MDR-TB) were tested using MTBDRplus v2 and compared with reference standard MGIT™ 960™ drug susceptibility testing. The relationship of participant human immunodeficiency virus (HIV) status, diabetic status, previous treatment, and smear gradation to the likelihood of obtaining an interpretable result was assessed using logistic regression.
RESULTS:The sensitivity and specificity of MTBDRplus v2 for detecting MDR-TB, when compared to a reference standard, were respectively 96.0% (95%CI 93.5-97.6) and 99.2% (95%CI 97.0-99.9) in AFB smear-positive specimens and 82.8% (95%CI 63.5-93.5) and 98.3% (95%CI 89.9-99.9) in AFB smear-negative specimens. A dose-response relationship was observed between the proportion of interpretable test results and AFB smear bacterial load after adjusting for age, sex, body mass index, HIV status, previous treatment and diabetic status.
CONCLUSION:While MTBDRplus v2 performs well among both AFB smear-positive and -negative specimens, smear gradation appears to influence both the probability of obtaining an interpretable result and test sensitivity, indicating a significant association between bacillary load and test performance.


A Multi-Center Non-inferiority Evaluation of Hain GenoType MTBDRplus Version 2 and Nipro NTM+MDRTB line probe assays for the diagnosis of Rifampin and Isoniazid Resistance.

Nathavitharana RR, Hillemann D, Schumacher SG, Schlueter B, Ismail N, Vally Omar S, Sikhondze W, Havumaki J, Valli E, Boehme C, Denkinger CM.
J Clin Microbiol. 2016 Apr 13. pii: JCM.00251-16. [Epub ahead of print]
INTRODUCTION:Under 30% of MDR-TB patients are currently diagnosed due to laboratory constraints. Molecular diagnostics enable rapid and simplified diagnosis. Newer version line probe assays have not been evaluated against the WHO-endorsed GenoType® MTBDRplus(HainV1) for the rapid detection of rifampin (RIF) and isoniazid (INH) resistance.
METHODS:A two-phase non-inferiority study was conducted in two supra-national reference laboratories to allow head-to-head comparisons of two new tests (HainV2, Nipro) to HainV1. In phase 1, results for 379 test strains were compared to a composite reference standard using phenotypic DST and targeted sequencing. In phase 2, results for 644 sputum samples were compared to phenotypic DST.
RESULTS:Using a challenging set of strains in phase 1, sensitivity and specificity for HainV1, HainV2 and Nipro for RIF resistance detection were 90.3%/98.5%, 90.3%/98.5% and 92.0%/98.5% respectively and 89.1%/99.4%, 89.1%/99.4% and 89.6%/100.0% for INH resistance detection. Testing of sputa in phase 2 yielded a sensitivity and specificity of 97.1%/97.1%, 98.2%/97.8% and 96.5%/97.5% for RIF and 94.4%/96.4%, 95.4%/98.8% and 94.9%/97.6% for INH. Overall indeterminate rates were low but there was a higher rate of indeterminate results with Nipro compared to HainV1 and V2 in samples with low smear-grade.
CONCLUSION:Non-inferiority of HainV2 and Nipro to HainV1 was demonstrated for RIF and INH resistance detection in isolates and sputum specimens. These results support WHO endorsement of HainV2 and Nipro assays for MDR-TB detection.


Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

Tiberi S, Sotgiu G, D’Ambrosio L, Centis R, Abdo Arbex M, Alarcon Arrascue E, Alffenaar JW, Caminero JA, Gaga M, Gualano G, Skrahina A, Solovic I, Sulis G, Tadolini M, Alarcon Guizado V, De Lorenzo S, Roby Arias AJ, Scardigli A, Akkerman OW, Aleksa A, Artsukevich J, Auchynka V,Bonini EH, Chong Marín FA, Collahuazo López L, de Vries G, Dore S, Kunst H, Matteelli A, Moschos C, Palmieri F, Papavasileiou A, Payen MC,Piana A, Spanevello A, Vargas Vasquez D, Viggiani P, White V, Zumla A, Migliori GB.
Eur Respir J. 2016 Apr 13. pii: ERJ-00214-2016. doi: 10.1183/13993003.00214-2016. [Epub ahead of print]
No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanateversusmeropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanateversusmeropenem/clavulanate added to background regimens to treat MDR- and XDR-TBcases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8versus8) but more fluoroquinolone resistance (79.0%versus48.9%, p<0.0001) and higher XDR-TB prevalence (67.9%versus49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428)versus85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7%versus94.8%, p=0.02 and 71.9%versus94.8%, p<0.0001, respectively) and on success rates (59.7%versus77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating M/XDR-TB patients.


The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia.

Eliseev P, Balantcev G, Nikishova E, Gaida A, Bogdanova E, Enarson D, Ornstein T, Detjen A, Dacombe R, Gospodarevskaya E, Phillips PP, Mann G,Squire SB, Mariandyshev A.
PLoS One. 2016 Apr 7;11(4):e0152761. doi: 10.1371/journal.pone.0152761. eCollection 2016.
BACKGROUND: In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy.
STUDY AIM: The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes.
METHODS: A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm.
RESULTS: Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time toMDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms.
CONCLUSION:The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.


External Quality Assessment for Tuberculosis Diagnosis and Drug Resistance in the European Union: A Five Year Multicentre Implementation Study.

Nikolayevskyy V, Hillemann D, Richter E, Ahmed N, van der Werf MJ, Kodmon C, Drobniewski F, Ruesch-Gerdes S; ERLTB-Net Network.
PLoS One. 2016 Apr 7;11(4):e0152926. doi: 10.1371/journal.pone.0152926. eCollection 2016.
BACKGROUND: External quality assurance (EQA) systems are essential to ensure accurate diagnosis of TB and drug-resistant TB. The implementation of EQA through organising regular EQA rounds and identification of training needs is one of the key activities of the European TB reference laboratory network (ERLTB-Net). The aim of this study was to analyse the results of the EQA rounds in a systematic manner and to identify potential benefits as well as common problems encountered by the participants.
METHODS: The ERLTB-Net developed seven EQA modules to test laboratories’ proficiency for TB detection and drug susceptibility testing using both conventional and rapid molecular tools. All National TB Reference laboratories in the European Union and European Economic Area (EU/EEA) Member States were invited to participate in the EQA scheme.
RESULTS: A total of 32 National TB Reference laboratories participated in six EQA rounds conducted in 2010-2014. The participation rate ranged from 52.9% – 94.1% over different modules and rounds. Overall, laboratories demonstrated very good proficiency proving their ability to diagnose TB and drug-resistant TB with high accuracy in a timely manner. A small number of laboratories encountered problems with identification of specific Non-tuberculous Mycobacteria (NTMs) (N = 5) and drug susceptibility testing to Pyrazinamide, Amikacin, Capreomycin, and Ethambutol (N = 4).
CONCLUSIONS: The European TB Reference laboratories showed a steady and high level of performance in the six EQA rounds. A network such as ERLTB-Net can be instrumental in developing and implementing EQA and in establishing collaboration between laboratories to improve the diagnosis of TB in the EU/EEA.

Comparison of Xpert MTB/RIF Assay and GenoType MTBDRplus DNA Probes for Detection of Mutations Associated with Rifampicin Resistance in Mycobacterium tuberculosis.

Rahman A, Sahrin M, Afrin S, Earley K, Ahmed S, Rahman SM, Banu S.
PLoS One. 2016 Apr 7;11(4):e0152694. doi: 10.1371/journal.pone.0152694. eCollection 2016.
BACKGROUND: GeneXpert MTB/RIF (Xpert) and Genotype MTBDRplus (DRplus) are two World Health Organization (WHO) endorsed probe based molecular drug susceptibility testing (DST) methods for rapid diagnosis of drug resistant tuberculosis. Both methods target the same 81 bp Rifampicin Resistance Determining Region (RRDR) of bacterial RNA polymerase β subunit (rpoB) for detection of Rifampicin (RIF) resistance associated mutations using DNA probes. So there is a correspondence of the probes of each other and expected similarity of probe binding.
METHODS: We analyzed 92 sputum specimens by Xpert, DRplus and LJ proportion method (LJ-DST). We compared molecular DSTs with gold standard LJ-DST. We wanted to see the agreement level of two molecular methods for detection of RIF resistance associated mutations. The 81bp RRDR region of rpoB gene of discrepant cases between the two molecular methods was sequenced by Sanger sequencing.
RESULTS: The agreement of Xpert and DRplus with LJ-DST for detection of RIF susceptibility was found to be 93.5% and 92.4%, respectively. We also found 92.4% overall agreement of two molecular methods for the detection of RIF susceptibility. A total of 84 out of 92 samples (91.3%) had agreement on the molecular locus of RRDR mutation by DRplus and Xpert. Sanger sequencing of 81bp RRDR revealed that Xpert probes detected seven of eight discrepant cases correctly and DRplus was erroneous in all the eight cases.
CONCLUSION: Although the overall concordance with LJ-DST was similar for both Xpert and DRplus assay, Xpert demonstrated more accuracy in the detection of RIF susceptibility for discrepant isolates compared with DRplus. This observation would be helpful for the improvement of probe based detection of drug resistance associated mutations especially rpoB mutation in M. tuberculosis.


Management and treatment outcomes of patients enrolled in MDR-TB treatment in Viet Nam.

Phuong NT, Nhung NV, Hoa NB, Thuy HT, Takarinda KC, Tayler-Smith K, Harries AD.
Public Health Action. 2016 Mar 21;6(1):25-31. doi: 10.5588/pha.15.0068. Epub 2016 Feb 11.
SETTING: The programmatic management of drug-resistant tuberculosis (TB) in Viet Nam has been rapidly scaled up since 2009.
OBJECTIVES: To document the annual numbers of patients enrolled for multidrug-resistant tuberculosis (MDR-TB) treatment during 2010-2014and to determine characteristics and treatment outcomes of patients initiating treatment during 2010-2012.
DESIGN: A retrospective cohort study using national reports and data from the national electronic data system for drug-resistant TB.
RESULTS: The number of patients enrolled annually for MDR-TB treatment increased from 97 in 2010 to 1522 in 2014. The majority of patients were middle-aged men who had pulmonary disease and had failed a retreatment regimen; 77% had received ⩾2 courses of TB treatment. Favourable outcomes (cured and treatment completed) were attained in 73% of patients. Unfavourable outcomes included loss to follow-up (12.5%), death (8%) and failure (6.3%). Having had ⩾2 previous treatment courses and being human immunodeficiency virus-positive were associated with unfavourable outcomes.
CONCLUSION: Increasing numbers of patients are being treated for MDR-TB each year with good treatment outcomes under national programme management in Viet Nam. However, there is a need to increase case detection-currently at 30% of the estimated 5100 MDR-TBcases per year, reduce adverse outcomes and improve monitoring and evaluation.


Assessing Local Risk of Rifampicin-Resistant Tuberculosis in KwaZulu-Natal, South Africa Using Lot Quality Assurance Sampling.

Heidebrecht CL, Podewils LJ, Pym A, Mthiyane T, Cohen T.
PLoS One. 2016 Apr 6;11(4):e0153143. doi: 10.1371/journal.pone.0153143. eCollection 2016.
BACKGROUND: KwaZulu-Natal (KZN) has the highest burden of notified multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant (XDR) TB cases in South Africa. A better understanding of spatial heterogeneity in the risk of drug-resistance may help to prioritize local responses.
METHODS: Between July 2012 and June 2013, we conducted a two-way Lot Quality Assurance Sampling (LQAS) study to classify the burden of rifampicin (RIF)-resistant TB among incident TB cases notified within the catchment areas of seven laboratories in two northern and one southern district of KZN. Decision rules for classification of areas as having either a high- or low-risk of RIF resistant TB (based on proportion of RIF resistance among all TB cases) were based on consultation with local policy makers.
RESULTS: We classified five areas as high-risk and two as low-risk. High-risk areas were identified in both Southern and Northern districts, with the greatest proportion of RIF resistance observed in the northernmost area, the Manguzi community situated on the Mozambique border.
CONCLUSION: Our study revealed heterogeneity in the risk of RIF resistant disease among incident TB cases in KZN. This study demonstrates the potential for LQAS to detect geographic heterogeneity in areas where access to drug susceptibility testing is limited.


Presumptive treatment of multidrug-resistant tuberculosis in household contacts.

Parr JB, Rich ML, Keshavjee S, Franke MF, Mitnick CD, Bayona J, Becerra MC.
Int J Tuberc Lung Dis. 2016 Mar;20(3):370-5. doi: 10.5588/ijtld.15.0433.
SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing global health threat that often requires presumptive treatment in the absence of drug susceptibility testing (DST) results.
OBJECTIVE: To compare two approaches to the treatment of MDR-TB contacts with no DST results who develop TB disease.
DESIGN: We conducted a retrospective cohort study of adults treated for TB disease who were contacts of patients living with MDR-TB. Subjects had been treated according to one of two presumptive treatment strategies: 1) regimens containing exclusively first-line drugs, and 2) regimens that included both first- and second-line drugs that were adjusted if and when DST results became available. The primary endpoint was a composite of death and treatment failure.
RESULTS: Household contacts of MDR-TB patients who developed TB disease and were treated with first-line regimens were significantly more likely to experience unfavorable end-of-treatment outcomes than those treated with presumptive MDR-TB regimens (RR 2.88, 95%CI 1.24-6.68).
CONCLUSION: Household contacts of MDR-TB patients who develop TB disease but have no DST results should receive regimens containing second-line drugs selected based on the infecting strain of the index patient. Regimens containing only first-line anti-tuberculosis drugs significantly increase the risk of unfavorable outcomes.


Direct tuberculosis drug susceptibility testing: time-saving and cost-effective in detecting MDR-TB.

Zhang T, Lv CF, Wang J, Zheng WB, Lu LZ, Liu SJ, Bao J.
Int J Tuberc Lung Dis. 2016 Mar;20(3):323-8. doi: 10.5588/ijtld.15.0637.
BACKGROUND: Recent advances have made molecular diagnosis of tuberculosis (TB) and drug susceptibility testing (DST) possible, but the high costs involved present a huge challenge. The refinement and improvement of affordable methods therefore remain a priority. Conventional indirect DST is inexpensive and reliable, but time-consuming. A direct DST method for the direct testing of sputum samples without culture has been developed to reduce the time required for DST, but there have been conflicting results.
METHODS AND RESULTS: Direct and indirect DST against isoniazid and rifampicin were performed on 208 sputum smear-positive specimens, 186 from newly diagnosed patients and 22 from previously treated patients; respectively 169 and 180 of the direct and indirect DST results were reportable. In comparison with indirect DST, direct DST resulted in a saving of on average 10.5 days. The time to direct DST results was inversely correlated with the number of acid-fast bacilli in the sputum samples.
CONCLUSION: Direct DST is highly sensitive, reliable, cost-effective and time-saving in comparison with indirect DST.

Dilemma of managing asymptomatic children referred with ‘culture-confirmed’ drug-resistant tuberculosis.

Loveday M, Sunkari B, Marais BJ, Master I, Brust JC.
Arch Dis Child. 2016 Apr 4. pii: archdischild-2015-310186. doi: 10.1136/archdischild-2015-310186. [Epub ahead of print]
BACKGROUND: The diagnosis of drug-resistant tuberculosis (DR-TB) in children is challenging and treatment is associated with many adverse effects.
OBJECTIVE: We aimed to assess if careful observation, without initiation of second-line treatment, is safe in asymptomatic children referred with ‘culture-confirmed’ DR-TB.
SETTING: KwaZulu-Natal, South Africa-an area with high burdens of HIV, TB and DR-TB.
DESIGN, INTERVENTION AND MAIN OUTCOME MEASURES: We performed an outcome review of children with ‘culture-confirmed’ DR-TB who were not initiated on second-line TB treatment, as they were asymptomatic with normal chest radiographs on examination at our specialist referral hospital. Children were followed up every other month for the first year, with a final outcome assessment at the end of the study.
RESULTS: In total, 43 asymptomatic children with normal chest radiographs were reviewed. The median length of follow-up until final evaluation was 549 days (IQR 259-722 days); most (34; 83%) children were HIV uninfected. Resistance patterns included 9 (21%) monoresistant and 34 (79%) multidrug-resistant (MDR) strains. Fifteen children (35%) had been treated with first-line TB treatment, prior to presentation at our referral hospital. At the final evaluation, 34 (80%) children were well, 7 (16%) were lost to follow-up, 1 (2%) received MDR-TB treatment and 1 (2%) died of unknown causes. The child who received MDR-TB treatment developed new symptoms at the 12-month review and responded well to second-line treatment.
CONCLUSIONS: Bacteriological evaluation should not be performed in the absence of any clinical indication. If drug-resistant Mycobacterium tuberculosis is detected in an asymptomatic child with a normal chest radiograph, close observation may be an appropriate strategy, especially in settings where potential laboratory error and poor record keeping are constant challenges.


Migration-related tuberculosis: epidemiology and characteristics of tuberculosis cases originating outside the European Union and European Economic Area, 2007 to 2013.

Ködmön C, Zucs P, van der Werf MJ.
Euro Surveill. 2016;21(12). doi: 10.2807/1560-7917.ES.2016.21.12.30164.
Migrants arriving from high tuberculosis (TB)-incidence countries may pose a significant challenge to TB control programmes in the host country. TB surveillance data for 2007-2013 submitted to the European Surveillance System were analysed. Notified TB cases were stratified by origin and reporting country. The contribution of migrant TB cases to the TB epidemiology in EU/EEA countries was analysed. Migrant TB cases accounted for 17.4% (n = 92,039) of all TB cases reported in the EU/EEA in 2007-2013, continuously increasing from 13.6% in 2007 to 21.8% in 2013. Of 91,925 migrant cases with known country of origin, 29.3% were from the Eastern Mediterranean, 23.0% from south-east Asia, 21.4% from Africa, 13.4% from the World Health Organization European Region (excluding EU/EEA), and 12.9% from other regions. Of 46,499 migrant cases with known drug-susceptibility test results, 2.9% had multidrug-resistant TB, mainly (51.7%) originating from the European Region. The increasing contribution of TB in migrants from outside the EU/EEA to the TB burden in the EU/EEA is mainly due to a decrease in native TB cases. Especially in countries with a high proportion of TB cases in non-EU/EEA migrants, targeted prevention and control initiatives may be needed to progress towards TB elimination.


What can we offer to 3 million MDRTB household contacts in 2016?

Moore DA.
BMC Med. 2016 Apr 1;14(1):64. doi: 10.1186/s12916-016-0610-x.
The diagnosis of multidrug resistant tuberculosis (MDR-TB) in any individual is the beginning of a prolonged and difficult therapeutic journey. It also marks the moment from which to begin consideration of how to manage close contacts. Preventive therapy for drug-susceptible latent tuberculosis infection has been demonstrated to be effective at reducing the risk of future disease; the stakes are higher when considering prevention of MDR-TB because treatment of active disease is more prolonged and toxic and much less effective. This has encouraged exploration of the potential utility of preventive therapy, with second-line agents, in reducing future incident drug-resistant TB.Three clinical trials of preventive therapy for contacts of patients with MDR-TB are starting in 2015/16; results will not be available until at least 2020, so what should be offered to exposed contacts in the interim?A recent policy brief, arising from a global consultation meeting of international experts, recommended preventive therapy based upon very limited available observational data. However the many known unknowns associated with this approach, include the high proportion of index-contact pairs with discordant drug susceptibility profiles and (even if susceptibilities are shared) the lack of data supporting the use of the selected agents in the treatment of latent infection (rather than active disease).It is important to acknowledge that the alternative to offering preventive therapy is not doing nothing. On the contrary, identified contacts should be maintained under close, active surveillance for 24 months, enabling early detection of active disease in the small proportion amongst whom this may occur. Such patients should benefit from less extensive disease at diagnosis and early access to individualized therapeutic regimens with improved treatment outcomes. Moreover the vast majority of contacts that do not develop disease will benefit from avoidance of potentially toxic, unnecessary therapy.Whether preventive therapy or close observation are implemented, national programmes should maintain a register of all contacts, interventions and 24 month outcomes; these will provide important performance metrics for programmatic management of MDRTB. If harmonized and standardized internationally, such a register could rapidly yield a wealth of observational data, to complement the trial results of the future.


A call to action: Addressing the reproductive health needs of women with drug-resistant tuberculosis.

Schnippel K, Ndjeka N, Conradie F, Berhanu R, Claasen Z, Banoo S, Firnhaber C.
S Afr Med J. 2016 Mar 17;106(4):333-4. doi: 10.7196/SAMJ.2016.v106i4.10205.
Although there is substantial risk to maternal and neonatal health in the situation of pregnancy during treatment for rifampicin-resistant tuberculosis (RR-TB), there is little evidence to guide clinicians as to how to manage this complexity. Of the 49 680 patients initiated on RR-TB treatment from 2009 to 2014 in South Africa, 47% were women and 80% of them were in their reproductive years (15 – 44). There is an urgent need for increased evidence of the safety of RR-TB treatment during pregnancy, increased access to contraception during RR-TB treatment, and inclusion of reproductive health in research on the prevention and treatment of TB.


Assessment of treatment response in tuberculosis.

Rockwood N, du Bruyn E, Morris T, Wilkinson RJ.
Expert Rev Respir Med. 2016 Mar 31:1-12. [Epub ahead of print]
Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.

Propensity Score-Based Approaches to Confounding by Indication in Individual Patient Data Meta-Analysis: Non-Standardized Treatment for Multidrug Resistant Tuberculosis.

Fox GJ, Benedetti A, Mitnick CD, Pai M, Menzies D; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB.
PLoS One. 2016 Mar 29;11(3):e0151724. doi: 10.1371/journal.pone.0151724. eCollection 2016.
In the absence of randomized clinical trials, meta-analysis of individual patient data (IPD) from observational studies may provide the most accurate effect estimates for an intervention. However, confounding by indication remains an important concern that can be addressed by incorporating individual patient covariates in different ways. We compared different analytic approaches to account for confounding in IPD from patients treated for multi-drug resistant tuberculosis (MDR-TB).
METHODS: Two antibiotic classes were evaluated, fluoroquinolones-considered the cornerstone of effective MDR-TB treatment-and macrolides, which are known to be safe, yet are ineffective in vitro. The primary outcome was treatment success against treatment failure, relapse or death. Effect estimates were obtained using multivariable and propensity-score based approaches.
RESULTS: Fluoroquinolone antibiotics were used in 28 included studies, within which 6,612 patients received a fluoroquinolone and 723 patients did not. Macrolides were used in 15 included studies, within which 459 patients received this class of antibiotics and 3,670 did not. Both standard multivariable regression and propensity score-based methods resulted in similar effect estimates for early and late generation fluoroquinolones, while macrolide antibiotics use was associated with reduced treatment success.
CONCLUSIONS:In this individual patient data meta-analysis, standard multivariable and propensity-score based methods of adjusting for individual patient covariates for observational studies yielded produced similar effect estimates. Even when adjustment is made for potential confounding, interpretation of adjusted estimates must still consider the potential for residual bias.


Rationing tests for drug-resistant tuberculosis – who are we prepared to miss?

Martin LJ, Roper MH, Grandjean L, Gilman RH, Coronel J, Caviedes L, Friedland JS, Moore DA.
BMC Med. 2016 Mar 23;14(1):30. doi: 10.1186/s12916-016-0576-8.
BACKGROUND:Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss.
METHODS: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB.
RESULTS: Overall, 147/1,545 (9.5 %) subjects had culture-positive TB, of which 32 (21.8 %) had DR-TB (MDR, 13.6 %; isoniazid mono-resistant, 7.5 %; rifampicin mono-resistant, 0.7 %). A total of 553 subjects (35.8 %) reported one or more MDR-TB risk factors; of these, 506 (91.5 %; 95 % CI, 88.9-93.7 %) did not have TB, 32/553 (5.8 %; 95 % CI, 3.4-8.1 %) had drug-susceptible TB, and only 15/553 (2.7 %; 95 % CI, 1.5-4.4 %) hadDR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2 %; 95 % CI, 34.7-70.9).
CONCLUSIONS: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority.

Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance.

Phelan J, Coll F, McNerney R, Ascher DB, Pires DE, Furnham N, Coeck N, Hill-Cawthorne GA, Nair MB, Mallard K, Ramsay A, Campino S,Hibberd ML, Pain A, Rigouts L, Clark TG.
BMC Med. 2016 Mar 23;14(1):31. doi: 10.1186/s12916-016-0575-9.
BACKGROUND: Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance.
METHODS: To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods.
RESULTS: The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites.
CONCLUSIONS: Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management.



The Burden of Drug-Resistant Tuberculosis in Papua New Guinea: Results of a Large Population-Based Survey.

Aia P, Kal M, Lavu E, John LN, Johnson K, Coulter C, Ershova J, Tosas O, Zignol M, Ahmadova S, Islam T.
PLoS One. 2016 Mar 22;11(3):e0149806. doi: 10.1371/journal.pone.0149806. eCollection 2016.
BACKGROUND: Reliable estimates of the burden of multidrug-resistant tuberculosis (MDR-TB) are crucial for effective control and prevention of tuberculosis (TB). Papua New Guinea (PNG) is a high TB burden country with limited information on the magnitude of the MDR-TB problem.
METHODS: A cross-sectional study was conducted in four PNG provinces: Madang, Morobe, National Capital District and Western Province. Patient sputum samples were tested for rifampicin resistance by the Xpert MTB/RIF assay and those showing the presence of resistance underwent phenotypic susceptibility testing to first- and second-line anti-TB drugs including streptomycin, isoniazid, rifampicin, ethambutol, pyrazinamide, ofloxacin, amikacin, kanamycin and capreomycin.
RESULTS: Among 1,182 TB patients enrolled in the study, MDR-TB was detected in 20 new (2.7%; 95% confidence intervals [CI] 1.1-4.3%) and 24 previously treated (19.1%; 95%CI: 8.5-29.8%) TB cases. No case of extensively drug-resistant TB (XDR-TB) was detected. Thirty percent (6/20) of new and 33.3% (8/24) of previously treated cases with MDR-TB were detected in a single cluster in Western Province.
CONCLUSION: In PNG the proportion of MDR-TB in new cases is slightly lower than the regional average of 4.4% (95%CI: 2.6-6.3%). A large proportion of MDR-TB cases were identified from a single hospital in Western Province, suggesting that the prevalence of MDR-TB across the country is heterogeneous. Future surveys should further explore this finding. The survey also helped strengthening the use of smear microscopy and Xpert MTB/RIF testing as diagnostic tools for TB in the country.


Linezolid as a potentially effective drug for the treatment of multidrug-resistant tuberculosis in Japan.

Yi L, Yoshiyama T, Okumura M, Morimoto K, Sasaki Y, Shiraishi Y, Ogata H, Mitarai S.
Jpn J Infect Dis. 2016 Mar 18. [Epub ahead of print]
Linezolid (LZD) is classified as a WHO group 5 drug used in the treatment of tuberculosis (TB). Although its efficacy and long-term safety have not yet been established, it is being increasingly used in the treatment of multidrug resistant tuberculosis (MDR-TB) and extensive multidrug-resistant tuberculosis (XDR-TB). The current study is a single-center retrospective clinical analysis of hospitalized M/XDR-TB patients in Fukujuji Hospital involving 26 patients (18 males and 8 females) consecutively treated with combinations of anti-TB drugs including LZD from 2009 to 2015. The sputum culture results were negative after using LZD for an average period of 28.0 ± 12.0 (average ± SD) days. LZD was reduced or withdrawn in eleven cases due to adverse effects. Nineteen cases including three XDR-TB cases were operated on, and their TB was healed following surgery. The average time from the initiation of LZD therapy to surgery was 87.6 ± 38.7 (average ± SD) days. Favorable clinical outcome was maintained in twenty-three surviving patients, while three patients died during treatment because of end stage cancer and aspiration pneumonia. Our study showed that LZD might be clinically effective in the treatment of M/XDR-TB cases in Japan.


Rights and Responsibilities of Tuberculosis Patients, and the Global Fund: A Qualitative Study.

PLoS One. 2016 Mar 21;11(3):e0151321. doi: 10.1371/journal.pone.0151321. eCollection 2016.
BACKGROUND: Implementation of the Charter to protect patients’ rights is an important criterion to achieve patient-centered approach and receive financial support from the Global Fund. Our study aims to explore the knowledge of tuberculosis (TB) patients about their rights and responsibilities at the Chest Disease Unit of the Bahawal Victoria Hospital, Bahawalpur, Pakistan.
METHODS: This was a qualitative study. The data from purposefully selected TB patients was collected by in-depth interviews. Eligibility criteria included confirmed diagnosis of TB and enrollment in the TB program. A pilot tested interview protocol was based upon the objectives of the study, and was used uniformly in each interview to maintain the consistency. The sample size was limited by applying the saturation criteria. All interviews were audiotaped and transcribed verbatim. Inductive thematic content analysis was applied to analyze the data and draw conclusions.
RESULTS: Out of the total 16 patients, four were female, and seven were illiterate. Eight patients were known cases of multi-drug resistant TB. Analysis of the data yielded seven themes; tuberculosis care services, moral support and stigmatization, dignity and privacy, complaints, fear of losing job, information sharing and compliance to the treatment plan, and contribution to eradicate TB. First five represented the rights section while latter two were related to the responsibilities section of the Charter.
CONCLUSION: Discriminatory access to TB care services and the right to privacy were two major concerns identified in this study. However, the respondents recognized their responsibilities as a TB patient. To ensure uninterrupted investment from the Global Fund, there is a need to implement fair TB care policies which support human rights-based approach.