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Treatment outcomes from community-based drug resistant tuberculosis treatment programs: a systematic… Weiss, Pamela; Chen, Wenjia; Cook, Victoria J; Johnston, James C Jun 17, 2014

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RESEARCH ARTICLE Open AccessTreatment outcomes from community-baseddrug resistant tuberculosis treatment programs:a systematic review and meta-analysisPamela Weiss1, Wenjia Chen2, Victoria J Cook3,4 and James C Johnston3,4*AbstractBackground: There is increasing evidence that community-based treatment of drug resistant tuberculosis (DRTB) isa feasible and cost-effective alternative to centralized, hospital-based care. Although several large programs havereported favourable outcomes from community-based treatment, to date there has been no systematic assessmentof community-based DRTB treatment program outcomes. The objective of this study was to synthesize availableevidence on treatment outcomes from community based multi-drug resistant (MDRTB) and extensively drugresistant tuberculosis (XDRTB) treatment programs.Methods: We performed a systematic review and meta-analysis of the published literature to examine treatmentoutcomes from community-based MDRTB and XDRTB treatment programs. Studies reporting outcomes fromprograms using community-based treatment strategies and reporting outcomes consistent with WHO guidelineswere included for analysis. Treatment outcomes, including treatment success, default, failure, and death werepooled for analysis. Meta-regression was performed to examine for associations between treatment outcomesand program or patient factors.Results: Overall 10 studies reporting outcomes on 1288 DRTB patients were included for analysis. Of thispopulation, 65% [95% CI 59-71%] of patients had a successful outcome, 15% [95% CI 12-19%] defaulted, 13%[95% CI 9-18%] died, and 6% [95% CI 3-11%] failed treatment for a total of 35% [95% CI 29-41%] with unsuccessfultreatment outcome. Meta-regression failed to identify any factors associated with treatment success, including studyyear, age of participants, HIV prevalence, XDRTB prevalence, treatment regimen, directly observed therapy (DOT)location or DOT provider.Conclusions: Outcomes of community-based MDRTB and XDRTB treatment outcomes appear similar to overalltreatment outcomes published in three systematic reviews on MDRTB therapy. Work is needed to delineateprogram characteristics associated with improved treatment outcomes.Keywords: Tuberculosis, Multidrug-resistant, Treatment, Community basedBackgroundDrug resistant tuberculosis (DRTB) is a global health con-cern that undermines recent successes in tuberculosis(TB) control [1]. DRTB includes both multidrug-resistant(MDR) and extensively drug-resistant (XDR) TB; MDRTBstrains are resistant to the two most-effective first-lineanti-TB drugs, while XDRTB is resistant to four highlyeffective anti-TB drugs [2]. Worldwide there are approxi-mately 650,000 cases of MDRTB of which 10% areXDRTB [3,4]. Without significant scale-up in diagnosticand treatment capacity for DRTB, MDRTB and XDRTBcould become the dominant forms of TB worldwide [1].Treatment of MDRTB and XDRTB requires second-line anti-TB drugs that are more costly, less effica-cious and more toxic than first-line drugs [4,5], andrequire ≥20 months of medical therapy [6]. Treatmentis typically delivered using the WHO DOTS-Plus modeland traditionally involves prolonged inpatient treatment* Correspondence: james.johnston@bccdc.ca3Division of Respirology, University of British Columbia, Vancouver, Canada4The British Columbia Center for Disease Control, 655 West 12th Avenue,Vancouver, BC V5Z4R4, CanadaFull list of author information is available at the end of the article© 2014 Weiss et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited.Weiss et al. BMC Infectious Diseases 2014, 14:333http://www.biomedcentral.com/1471-2334/14/333that enables enhanced monitoring of adverse drug reac-tions, ensures adherence, and may prevent spread withinthe community [7,8]. Unfortunately, resource limitationsoften force patients to wait months for inpatient therapy,during which time they can spread to other people in theircommunity. Inpatient therapy also increases the risk ofnosocomial transmission, particularly in low-resourcesettings.To address these challenges, many DRTB treatmentprograms have incorporated community participation inthe DRTB treatment. Community-based directly observedtherapy (cb-DOTS) programs are low-cost treatmentprograms that utilize family members, neighbours, co-workers, local health care workers (HCWs) or former pa-tients to directly observe treatment rather than requiringhospitalizations or frequent visits to a health care facility.For drug-susceptible TB, cb-DOTS appears comparable orbetter than hospital-based approaches [9-11]. Many re-search groups have examined treatment outcomes ofcommunity-based DRTB treatment models and reportgood results, however to date no systematic evaluation ofcb-DRTB programs has been reported in the literature.Our objective was to synthesize available evidence ontreatment outcomes from community based multi-drugresistant (MDRTB) and extensively drug resistant tubercu-losis (XDRTB) treatment programs.We performed a systematic review and meta-analysisto investigate treatment outcomes in community-basedMDRTB and XDRTB treatment programs. For the pur-pose of this study, community-based refers to treatmentthat occurs on an outpatient basis, and includes partici-pation by community members in treatment delivery.Treatment outcomes were examined and pooled for ana-lysis. Program and patient characteristics were also ana-lyzed to determine the effect these variables had ontreatment success.MethodsThe present review have been reported according to thepreferred reporting items for systematic reviews andmeta-analyses (PRISMA) (Additional file 1).Search strategyA methodical strategy was used to identify relevant publi-cations. Our search strategy was modeled after Johnstonet al. [12] and Orenstein et al. [13] with slight modifica-tion. The search was limited to English language pub-lications in the EMBASE, MEDLINE, InternationalPharmaceutical Abstracts and BIOSIS databases and theWeb of Science that were published between January1990 and August 2012. Keyword searches were conductedon both titles and abstracts to identify relevant publica-tions using combinations of the keywords “MDR*”,“XDR*”, “drug resistant”, “drug-resistant”, “multidrug”,“multi-drug”, “extensively”, “TB”, “tuberculosis”, “directlyobserved”, “DOTS”, “DOTS-Plus”, “cb-DOTS”, “treat-ment”, “community”, “outpatient”, “public participation”,“community-based”, “decentralized”, “home-based”, “am-bulatory”, “clinic”, “community health worker”, and“CHW”. A search of EBM reviews was also conducted todetermine existing systematic reviews on this topic. Thisincluded Database of Abstracts of Reviews and Effects,Cochrane Central Register of Controlled Trials andCochrane Database of Systematic Reviews. Citationswere all thoroughly reviewed and it was determined thatno systematic reviews were published on this subject.Online archives of several journals were also methodicallysearched manually from January 1990 (when available).Journals searched included American Journal of Respira-tory and Critical Care Medicine, Clinical InfectiousDisease, Chest, International Journal of Tuberculosis andLung Disease, and Journal of Infectious Disease. Biblio-graphic searches of identified articles were conducted toidentify other relevant studies.Selection of studiesRelevant articles were reviewed and examined for eligi-bility beginning with the abstract and followed by fulltext review. The following inclusion criteria were ap-plied: original study; published in English after January1990; reported treatment outcomes on patients withculture-confirmed MDRTB or XDRTB; utilized directlyobserved treatment on an outpatient basis; employedcommunity-based treatment strategies; reported treat-ment outcomes that would allow for comparison withother studies. Studies were excluded if they utilized onlysurgical interventions, reported only preliminary out-comes, routinely hospitalized patients for ≥ six months,or did not report data in a format enabling extraction.Methodological assessmentTwo authors (P.W. and J.J.) independently assessed themethodological quality of the selected studies consideredin the current review. Randomized controlled-trials, pro-spective cohorts, retrospective cohorts or consecutivecase control studies were assessed. Publications includedin this analysis reported treatment outcomes for ≥ fivepatients, reported results on at least 50% of patients, re-ported general demographic information on patients,and included community-based treatment ≥ six monthsin duration and total treatment duration of ≥18 months.In the case of duplicate data, the publication with themore detailed reports on treatment outcomes was in-cluded for meta-analysis. Studies were selected by oneauthor (P.W.), with selected studies reviewed for inclu-sion/exclusion by two authors (P.W, J.J.).Weiss et al. BMC Infectious Diseases 2014, 14:333 Page 2 of 9http://www.biomedcentral.com/1471-2334/14/333Treatment outcome definitionsWe used treatment outcome measures defined by Lasersonet al. and the WHO [5,14]. Patients that met the criteria forcure or treatment completed were classified as having suc-cessful treatment outcomes. Patients that met criteria fordeath, treatment default, treatment failure or transfer outwere classified as having unsuccessful treatment outcomes.For data analysis, patients whose results were not availableor patients that met transfer out criteria were placed in thetreatment default category.Study characteristicsThe association between treatment success and severalstudy characteristics was examined among several sub-groups. Factors examined included study year (enroll-ment started before 2002 versus after 2002), patient age(>14 years versus ≤14), HIV prevalence (in the cohortdescribed) (0-2%; >2%), XDRTB infection (0%; >0%),treatment regimen (individualized; standardized), DOTlocation (home-based; clinic/PHC-based) and DOT pro-vider (CHWs/HCWs only; included family/friends).Data analysisData extraction was performed by one author (P.M.) andcross-checked by a second author (J.J.). Data was ana-lyzed using Microsoft Excel (version 14 · 1 · 0) and Stats-Direct (version 2 · 7 · 9) and STATA/IC v12 · 0. Treatmentoutcome data (successful, default, death and failure) acrossall studies were pooled to measure overall treatment out-comes associated with community-based treatment. TheHeterogeneity between these studies was assessed with bycalculating I2 test. A calculated value of I2 > 50% indicatedsubstantial heterogeneity. For pooling of these results, weused a more conservative random-effect model. An Eggertest was used to assess for publication bias, and funnelplots were created.To examine sources of heterogeneity, a random-effectsmeta-regression was performed. The dependent variablewas logit-transformed DRTB treatment success (ES). All10 studies were included in this analysis. For ES = 0 or 1,to avoid generating missing data, a small adjustment term(2n)−1 was applied to the logit-transformation [15]. Stand-ard errors were adjusted in accordance. This analysis wasbased on a significance level at p = 0 · 05. Predictors wereexamined using univariate meta-regression models.ResultsFigure 1 shows the study selection process. The initialdatabase search yielded 584 articles, while manual searchand bibliographic search yielded 33 additional articles.Of these articles, 103 were retained for full text review;88 studies were excluded for various reasons, leaving 10articles for analysis (Figure 1) [16-25]. Overall the dates ofenrollment for studies ranged from 1996–2011 and exam-ined populations in six different countries (Table 1). Eightstudies were retrospective and two were prospective.Study heterogeneityThere was a high degree of heterogeneity between stud-ies. This was not unexpected, as each study differed interms of population characteristics and treatment model.Studies involved a mean 129 participants with a broadrange of sample sizes (5–651) (Table 1). Two studiesonly included children under ≤15 years [19,25]. Twostudies reported and included patients infected withXDRTB, with a mean of 4 · 4% (1–7). Four studies re-ported and included patients co-infected with HIV, witha mean of 28 · 2% (1–60). Of the eight studies that re-ported on previous TB therapy, 94 · 3% (65–100) of pa-tients received previous treatment. Eight studies reportedon retrospective cohorts, while two studies reported onprospective cohorts.In terms of treatment models, six studies utilized an in-dividualized regimen and four studies utilized a standard-ized regimen (Table 2). Treatment duration was expressedin different ways and varied between studies. All studiesexcept two reported the DOTS location; these two studiesdescribed outpatient treatment. The other studies involvedtreatment at local health centers or decentralized clinics,local hospitals or in patient homes. The DOTS providerwas reported in all studies and consisted of CHWs,HCWs, local nurses, friends, neighbours or householdmembers. Some studies reported additional communityinvolvement in the form of community education andsupport programs, the nomination of treatment supportindividuals and community teams that tracked patientsand did home visits if any treatments were missed.Treatment outcomesOverall, the 10 studies examined the treatment outcomesof 1288 DRTB patients (Table 3; Figure 2). Of this popula-tion, 65% [95% CI 59-71%] had a successful outcome(Figure 2). A total of 15% [95% CI 12-19%] of patientsdefaulted, 13% [95% CI 9-18%] of patients died, and 6%[95% CI 3-11%] failed treatment for a total of 35% [95%CI 29-41%] with an unsuccessful treatment outcome. Het-erogeneity between studies was high (I2 > 50%) for alltreatment outcomes except default. All pooled treatmentoutcome results were statistically significant (p < 0 · 05).Based on the funnel plot, there was no evidence of publi-cation bias (Additional file 2) (Egger test p = 0 · 69).Subgroup treatment successTreatment success among study subgroups was pooledand analyzed (Table 4). The univariate meta-regressionanalysis was performed to explain the source of hetero-geneity. Treatment success did not differ significantlyWeiss et al. BMC Infectious Diseases 2014, 14:333 Page 3 of 9http://www.biomedcentral.com/1471-2334/14/333Table 1 Baseline characteristics of the included studiesStudy Location Date Study type* Sample size XDR (%) HIV (%) Previous therapy (%) Mean resistanceDrobac et al [19] Peru 1999-2003 RC 27 - - - -Joseph et al [17] India 2006-2007 PC 38 0 0 100 3 · 6Malla et al [22] Nepal 2005-2006 RC 175 - - 93 3 · 7Mitnick et al. [20] Peru 1996-1999 RC 75 - 1 · 3 100 Median 6Mitnick et al. [21] Peru 1999-2002 RC 651 7 · 4 1 · 4 65 5 · 3, 8 · 4Oyieng’o et al. [24] Kenya 2008-2010 RC 8 0 50 100 3 · 1Satti et al. [25] Lesotho 2007-2011 RC 5 0 60 - 2.8Singla et al. [16] India 2002-2006 RC 126 - 0 100 3Thomas et al. [18] India 1999-2003 PC 66 1 · 5 - 100 3 · 4Tupasi et al. [23] Philippines 1999-2002 RC 117 - - 96 -*RC = retrospective cohort; PC = prospective cohort.Figure 1 Literature search and study selection process.Weiss et al. BMC Infectious Diseases 2014, 14:333 Page 4 of 9http://www.biomedcentral.com/1471-2334/14/333based on study year, age of participants, HIV prevalence,XDRTB prevalence, treatment regimen, DOTS locationor DOT provider (Additional file 3).DiscussionOver the past decade, evidence has amassed from treat-ment programs in low-income regions to demonstratethe feasibility, safety and cost-effectiveness of cb-DRTBtherapy. Our findings provide further evidence to sup-port this once controversial model of care. Overall, treat-ment success was 65% [95% CI 59–71] in a populationof MDRTB and XDRTB patients. The results from thisstudy are comparable to outcomes reported in two pre-vious meta-analyses of published MDRTB literature andone individual patient data meta-analysis (Figure 2)[12,13,26]. When compared with all treatment outcomesTable 2 Description of the treatment in the included studiesStudy Model* Treatmentduration(months)Drugs inregimen†DOTS location DOTS provider AdditionalcommunityinvolvementDrobac et al. [19] I 18-24 n/a Local health centre CHWs, nurses CHWs provided dosesoutside centre hoursJoseph et al. [17] S 6-9, 18 6,4 Local health centre HCWs, friends/neighboursHealth educationprovided for familyMalla et al. [22] S 8-12,16-24 5,4 Decentralized clinics Health workers Nominated treatmentsupport person requiredMitnick et al. [20] I Median 23 (0 · 4-35 · 9) Median 6 (5-9) Outpatient CHWs, nurses -Mitnick et al. [21] I ≥18 ≥5 Health centre or patient home CHWs Group therapy as neededOyieng’o et al. [24] S ≥6, 18 5,4 Local health centreor patient homeLocal nurse, HCW,household memberHousehold membersupervised evening doseSatti et al. [25] I ≥18 6 Outpatient CHWs Community teamtracked patients andprovided supportSingla et al. [16] S 6-9, 18 5,3 Peripheral healthcentre or patient homeHCW, household member Household membersupervised evening doseThomas et al. [18] I ≥18 5, ≥2 Village health centres,clinics or hospitalAnganwadi workers,village HCWs,private practitioners-Tupasi et al. [26] I ≥6, ≥18 5, 4 Local health centre,or patient homeHCWs Treatment partnernominated by the patient*I = Individualized, S = Standardized.‡Duration of intensive phase and continuation phase are separated by a comma. Otherwise duration represents length of treatment. †Number of drugs inintensive and continuation regimens separated by a comma.Table 3 Outcomes at the end of treatmentAuthors SamplesizeSuccessfuloutcome (n)Unsuccessful outcomeDefault (n) Death (n) Failure (n)Drobac et al. [19] 27 21 5 1 0Joseph et al. [17] 38 25 5 3 5Malla et al. [22] 175 123 29 14 9Mitnick et al. [20] 75 55 14 5 1Mitnick et al. [21] 651 429 70 134 18Oyieng’o et al. [24] 8 6 0 2 0Satti et al. [25] 5 5 0 0 0Singla et al. [16] 126 76 22 24 4Thomas et al. [18] 66 25 16 8 17Tupasi et al. [26] 117 71 16 18 12Summary 129 65% 15% 13% 6%95% CI - [59-71] [12-19] [9-18] [3-11]I2 Statistic - 73% 49% 74% 81%p value - 0.0001 0.0381 <0.0001 <0.0001Weiss et al. BMC Infectious Diseases 2014, 14:333 Page 5 of 9http://www.biomedcentral.com/1471-2334/14/333reported by Johnston et al., results were similar for treat-ment default (15% [95% CI 12–19] versus 13% [95% CI9–17]), death (13% [95% CI 9–18] versus 11% [95% CI9–13]) and treatment failure (6% [95% CI 3–11] versus8% [95% CI 5–11]) [12].The success of cb-DOTS programs for treatment ofdrug-susceptible TB has been the subject of a previoussystematic review. Kangovi et al. evaluated 24 programsand reported an overall treatment success rate of 80 · 1%[95% CI 77.1-83.2%] [27]. Their definition for community-based therapy included DOT by a community member ‘ina location other than a health facility or TB club’. Our in-clusion criteria were less rigid and included programs thatdelivered medication from health care facilities when asso-ciated with a form of community support.More recently, a systematic review by Bassili et al. ex-amined outcomes in ambulatory MDRTB treatment pro-grams, comparing outcomes to those from hospital-basedprograms [28]. Outcomes were similar between ambula-tory and hospital-based outcomes. Studies included for re-view did not maintain a requirement for communitysupport. Related to inclusion/exclusion criteria, this studyincluded only 8 studies in the ambulatory care arm, anddid not include large cohorts by Mitnick, Tupasi, Singla[16,21,23]. In addition, two treatment cohorts, includingthe largest analyzed, were from high income countries[29,30]. Thus, findings from this review may not necessar-ily reflect the majority of community-based MDR-TBmanagement.Study limitationsThe programs analyzed in this review varied in terms ofDOT delivery site and community support. DOT sitesincluded hospitals, clinics, community health centres andpatient homes. Meanwhile, community support varied,and included intense educational sessions for patients andfamilies, working with a nominated community supportperson, food supplementation, and transportation support.DOTS delivery was provided by various groups, includingnurses, health care workers (HCWs), community mem-bers, and family members. The variability in communitydelivery and community supports makes the evaluationFigure 2 Forest plot representing treatment success with results from meta-analyses.Weiss et al. BMC Infectious Diseases 2014, 14:333 Page 6 of 9http://www.biomedcentral.com/1471-2334/14/333and comparison of individual community programs diffi-cult. However, this variability likely stems from thecommunity-responsive design of such programs, and islikely essential for the success of cb-MDRTB programs.We attempted to identify elements of cb-MDRTB pro-grams associated with improved outcomes, such as DOTSlocation or DOTS provider. Based on this analysis, how-ever, there were no significant associations with improvedtreatment outcomes, possibly related to the limited samplesize.The community impact of cb-MDRTB was difficult tocapture in this study. We captured individual patient out-comes associated with cb-MDRTB programs, but the ef-fect of cb-MDRTB on treatment wait times, communityand hospital MDRTB transmission, community engage-ment and stigma, and overall cost were not analyzed.These outcomes, however, are beginning to emerge in theMDRTB literature. For example, in South Africa, Helleret al. reported decreased waiting times in cb-MDRTBwhen compared to a traditional, hospital based program[31]. Meanwhile, Fitzpatrick and Floyd examined cost-effectiveness of four MDRTB treatment programs andfound that the cost per DALY averted favours cb-MDRTB therapy [32]. Further assessments will be re-quired to better understand the influence of cb-MDRTBprograms on transmission dynamics, community per-ception, and other population-based aspects of TB con-trol. In addition, the stability of cb-MDRTB treatmentprograms during rapid scale-up will also be an import-ant issue given the recent expansion in MDRTB point ofcare diagnostic capacity [33].We should emphasize that up to four studies from ouranalysis were included in previous systematic reviews,which partially accounts for their similar outcomes.These four studies, however, contribute to less than 20%of the outcomes reported in all previous analyses. Weconsidered comparing cb-MDRTB studies to studiesreporting on other types of treatment programs. Unfor-tunately, treatment protocols are not well-described inmost studies, preventing strict classification and com-parison between treatment programs. In addition, ourinclusion of more recent publications may bias our re-sults towards improved MDRTB outcomes in this co-hort. Indeed, our subgroup analysis demonstrates non-significant improvement in treatment outcomes betweenstudies starting before and after 2002. However, the fivestudies published in or after 2009 did not demonstratesignificant differences in outcomes (data not shown).Lastly, we were limited by the number of studies avail-able for analysis; with only ten studies and 1288 patientsavailable for comparison, subgroup analysis was quitelimited.ConclusionIn conclusion, this systematic review and meta-analysis ofcb-DRTB therapy demonstrates that the published resultsof community-based MDRTB and XDRTB treatment pro-grams appear to have adequate treatment outcomes.These results help strengthen the evidence base to supportthe WHO’s conditional recommendation for cb-MDRTBtherapy and support recent calls for decentralizedMDRTB care [34]. More research is required to examineindividual and population-based effects of cb-MDRTBcare: How do outcomes from home-based care comparewith clinic-based ambulatory care? What community sup-ports are essential to maintaining adherence and success-ful outcomes in financially strapped MDRTB treatmentprograms? What aspects of MDRTB diagnosis and treat-ment can a national TB treatment program safelydecentralize? On a population level the effect of commu-nity engagement and education should be analyzed moreclosely, along with careful epidemiological study onMDRTB transmission. In our opinion, the call forTable 4 Treatment success among study subgroupsSubgroups Studies Treatment success(n) (95% CI)Year study began2002 or later 5 68% (59-75)Before 2002 5 63% (52-73)Patient’s ageIncluded patients ≤14 years old 6 67% (54-78)All patients >14 years old 4 65% (62-68)HIV prevalence0-2% 4 72% (61-81)HIV > 2% 2 85% (55-100)Not specified or unknown 4 61% (46-75)XDRTB prevalence0% 3 75% (55-91)>0% 2 53% (26-78)Not specified or unknown 5 67% (61-73)Treatment modelIndividualized 6 65% (54-75)Standardized 4 66% (60-71)DOTS locationIncluded home-based option 4 64% (61-68)Clinic or public health centre only 4 63% (45-79)Not specified 2 82% (54-98)DOTS providerFamily members, neighbours orhousehold members sometimes utilized3 62% (55-69)Only CHWs, HCWs and othermedical practitioners7 66% (57-74)Weiss et al. BMC Infectious Diseases 2014, 14:333 Page 7 of 9http://www.biomedcentral.com/1471-2334/14/333decentralized MDRTB treatment requires a rapid butwell-considered response.Additional filesAdditional file 1: Prisma 2009 checklist.Additional file 2: Funnel Plot with pseudo 95% confidence intervals.Additional file 3: Univariate meta-regression of DRTB treatmentsuccess.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsPW contributed to study design, data acquisition, data analysis, manuscriptpreparation and editing. WC contributed to study design, data analysis,manuscript preparation and editing. VC contributed to study design,manuscript preparation and editing. JJ contributed to study design, dataacquisition, data analysis, manuscript preparation and editing. All authorsread and approved the final manuscript.Author details1School of Humanitarian Studies, Royal Roads University, 2005 Sooke Rd,Victoria, British Columbia. 2Collaboration for Outcomes Research andEvaluation, University of British Columbia, 2405 Wesbrook Mall, Vancouver,Canada. 3Division of Respirology, University of British Columbia, Vancouver,Canada. 4The British Columbia Center for Disease Control, 655 West 12thAvenue, Vancouver, BC V5Z4R4, Canada.Received: 4 September 2013 Accepted: 28 May 2014Published: 17 June 2014References1. Gandhi NR, Nunn P, Dheda K, Schaaf HS, Zignol M, van Soolingen D,Jensen P, Bayona J: Multidrug-resistant and extensively drug-resistanttuberculosis: a threat to global control of tuberculosis. Lancet 2010,375(9728):1830–1843.2. World Health Organization: Global Tuberculosis Report. Geneva: WHO; 2012.3. 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BMC Infectious Diseases 2014 14:333.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitWeiss et al. BMC Infectious Diseases 2014, 14:333 Page 9 of 9http://www.biomedcentral.com/1471-2334/14/333

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