February 2017 e-Newsletter

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

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

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

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

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

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

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

Read free Lancet article here 

January 2017 e-Newsletter

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

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

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

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

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

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

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

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

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

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

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December eNewsletter

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

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

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

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

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

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

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

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

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

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

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November eNewsletter

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

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

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

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

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

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

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

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

Read abstract here

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.

Read abstract here 

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.

Read free BioMed Central article here

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.

Read abstract here

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).

Read free editorial here 

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.

JULY ENEWSLETTER

Adverse effects of oral second-line antituberculosis drugs in children.
Schaaf HS, Thee S, van der Laan L, Hesseling AC, Garcia-Prats AJ
Abstract
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
Abstract
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
Abstract
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
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 newtechnologies, as well as quality impact data from programmatic settings.

 

JUNE ENEWSLETTER

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.
Abstract
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.
Abstract
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.
Abstract
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.
Abstract
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.

MAY ENEWSLETTER

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.
Abstract:
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]
Abstract:
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]
Abstract:
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.
Abstract:
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.