Catastrophic costs of tuberculosis care in a population with internal migrants in China.

BACKGROUND: The internal rural-to-urban migration is one of the major challenges for tuberculosis (TB) control in China. Patient costs incurred during TB diagnosis and treatment could cause access and adherence barriers, particularly among migrants. Here, we estimated the prevalence of catastrophic costs of TB patients and its associated factors in an urban population with internal migrants in China. METHODS: A cross-sectional survey was conducted to enroll culture-confirmed pulmonary TB patients in Songjiang district, Shanghai, between December 1, 2014, and December 31, 2015. Consenting participants completed a questionnaire, which collected direct and indirect costs before and after the diagnosis of TB. The catastrophic cost was defined as the annual expenses of TB care that exceeds 20% of total household disposable income. We used logistic regression to identify factors associated with catastrophic costs. RESULTS: Overall, 248 drug-susceptible TB patients were enrolled, 70% (174/248) of them were from migrants. Migrant patients were significantly younger compared to resident patients. The total costs were 25,824 ($3689) and 13,816 ($1974) Chinese Yuan (RMB) in average for resident and migrant patients, respectively. The direct medical cost comprised about 70% of the total costs among both migrant and resident patients. Overall, 55% (132 of 248) of patients experienced high expenses (>10% of total household income), and 22% (55 of 248) experienced defined catastrophic costs. The reimbursement for TB care only reduced the prevalence of catastrophic costs to 20% (49 of 248). Meanwhile, 52% (90 of 174) of the internal migrants had no available local health insurance. Hospitalizations, no available insurance, and older age (> 45-year-old) contributed significantly to the occurrence of catastrophic costs. CONCLUSIONS: The catastrophic cost of TB service cannot be overlooked, despite the free policy. Migrants have difficulties benefiting from health insurance in urban cities. Interventions, including expanded medical financial assistance, are needed to secure universal TB care.

Transmission of Mycobacterium tuberculosis in China: a population-based molecular epidemiologic study.

BACKGROUND: Understanding the transmission of Mycobacterium tuberculosis is essential for the development of efficient tuberculosis control strategies. China has the second-largest tuberculosis burden in the world. Recent transmission and infection with M. tuberculosis, particularly drug-resistant strains, may account for many new tuberculosis cases. METHODS: We performed a population-based molecular epidemiologic study of pulmonary tuberculosis in China during 1 July 2009 to 30 June 2012. We defined clusters as cases with identical variable number tandem repeat genotype patterns and identified the risk factors associated with clustering, by logistic regression. Relative transmission rates were estimated by the sputum smear status and drug susceptibility status of tuberculosis patients. RESULTS: Among 2274 culture-positive tuberculosis patients with genotyped isolates, there were 705 (31.0%) tuberculosis patients in 287 clusters. Multidrug-resistant (MDR) tuberculosis (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.25-2.63) and infection with a Beijing family strain (aOR, 1.56; 95% CI, 1.23-2.96) were associated with clustering. Eighty-four of 280 (30.0%) clusters had a putative source case that was sputum smear negative, and 30.6% of their secondary cases were attributed to transmission by sputum smear-negative patients. The relative transmission rate for sputum smear negative compared with sputum smear-positive patients was 0.89 (95% CI, .68-1.10), and was 1.51 (95% CI, 1.00-2.24) for MDR tuberculosis vs drug-susceptible tuberculosis. CONCLUSIONS: Recent transmission of M. tuberculosis, including MDR strains, contributes substantially to tuberculosis disease in China. Sputum smear-negative cases were responsible for at least 30% of the secondary cases. Interventions to reduce the transmission of M. tuberculosis should be implemented in China.

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens.

Factors associated with presence of pharmacies and pharmacies that sell syringes over-the-counter in Los Angeles County.

Community pharmacies serve as key locations for public health services including interventions to enhance the availability of syringes sold over-the-counter (OTC), an important strategy to prevent injection-mediated HIV transmission. Little is known about the community characteristics associated with the availability of pharmacies and pharmacies that sell syringes OTC. We conducted multivariable regression analyses to determine whether the sociodemographic characteristics of census tract residents were associated with pharmacy presence in Los Angeles (LA) County during 2008. Using a geographic information system, we conducted hot-spot analyses to identify clusters of pharmacies, OTC syringe-selling pharmacies, sociodemographic variables, and their relationships. For LA County census tracts (N = 2,054), population size (adjusted odds ratio [AOR], 1.22; 95 % confidence interval [CI], 1.16, 1.28), median age of residents (AOR, 1.03; 95 % CI, 1.01, 1.05), and the percent of households receiving public assistance (AOR, 0.97; 95 % CI, 0.94, 0.99) were independently associated with the presence of all pharmacies. Only 12 % of census tracts had at least one OTC syringe-selling pharmacy and sociodemographic variables were not independently associated with the presence of OTC syringe-selling pharmacies. Clusters of pharmacies (p < 0.01) were located proximally to clusters of older populations and were distant from clusters of poorer populations. Our combined statistical and spatial analyses provided an innovative approach to assess the sociodemographic and geographic factors associated with the presence of community pharmacies and pharmacies that participate in OTC syringe sales.

Mycobacterium tuberculosis Beijing strains favor transmission but not drug resistance in China.

BACKGROUND: The Mycobacterium tuberculosis Beijing strains are widespread globally. We aimed to determine whether Beijing strains in China are more likely than other strains to spread, and whether they are more likely to become drug resistant. We also sought to determine whether different Beijing sublineages have distinct phenotypic characteristics. METHODS: We conducted a population-based molecular epidemiologic study in 6 provinces in China from 2009 to 2010. We analyzed data and specimens from culture-confirmed pulmonary tuberculosis patients. Each patient's isolate was genotyped using 16-loci variable number of tandem repeats and 6 single-nucleotide polymorphisms. RESULTS: By genotyping, 75.0% (1031/1375) of the strains of M. tuberculosis were Beijing strains. Beijing strains were more likely than non-Beijing strains to be in a genotypic cluster (odds ratio, 2.40, P < .001), and were significantly associated with younger age (P(trend) < .05). There was no significant difference in the proportion of Beijing strains and non-Beijing strains that were drug resistant, even when stratified by new vs retreatment patients. We identified 6 sublineages of Beijing strains in the study population. The modern sublineage of Beijing strains were more likely than the ancient sublineages to be clustered (odds ratio, 2.27, P < .001). CONCLUSIONS: Beijing strains of M. tuberculosis were significantly associated with genotypic clustering, reflecting recent transmission, and younger age, but were not associated with drug resistance. Future studies of Beijing family strains should avoid assuming and attributing characteristics to the entire family and should assess strains of specific sublineages and/or settings.

Demographic, risk, and spatial factors associated with over-the-counter syringe purchase among injection drug users.

Since 2005, California law allowed over-the-counter (OTC) syringe sales pending local authorization. Although pharmacy sales of OTC syringes are associated with reduced injection-mediated risks and decreases in human immunodeficiency virus infection rates, little is known about the factors associated with syringe purchase among injection drug users (IDUs). Using a cross-sectional design, the authors applied targeted sampling to collect quantitative survey data from IDUs (n = 563) recruited in San Francisco, California, during 2008. They also compiled a comprehensive list of retail pharmacies, their location, and whether they sell OTC syringes. They used a novel combination of geographic information system and statistical analyses to determine the demographic, behavioral, and spatial factors associated with OTC syringe purchase by IDUs. In multivariate analyses, age, race, injection frequency, the type of drug injected, and the source of syringe supply were independently associated with OTC syringe purchases. Notably, the prevalence of OTC syringe purchase was 53% lower among African-American IDUs (adjusted prevalence ratio = 0.47, 95% confidence interval: 0.33, 0.67) and higher among injectors of methamphetamine (adjusted prevalence ratio = 1.35, 95% confidence interval: 1.07, 1.70). Two neighborhoods with high densities of IDUs had limited access to OTC syringes. Increased access to OTC syringes would potentially prevent blood-borne infectious diseases among IDUs.

Non-Beijing strains of Mycobacterium tuberculosis in China.

In a 2-year prospective study of tuberculosis (TB) patients in China, the prevalences of non-Beijing strains of Mycobacterium tuberculosis varied between Shandong Province (20.6%), Shanghai (27.6%), and Sichuan Province (45.9%) (P < 0.005). These differences may be due to factors such as human migration, transmission, or diversification and adaptation of the mycobacteria to different hosts.

Selection of mutations to detect multidrug-resistant Mycobacterium tuberculosis strains in Shanghai, China.

Novel tools are urgently needed for the rapid, reliable detection of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. To develop such tools, we need information about the frequency and distribution of the mycobacterial mutations and genotypes that are associated with phenotypic drug resistance. In a population-based study, we sequenced specific genes of M. tuberculosis that were associated with resistance to rifampin and isoniazid in 242 phenotypically MDR isolates and 50 phenotypically pan-susceptible isolates from tuberculosis (TB) cases in Shanghai, China. We estimated the sensitivity and specificity of the mutations, using the results of conventional, culture-based phenotypic drug susceptibility testing as the standard. We detected mutations within the 81-bp core region of rpoB in 96.3% of phenotypically MDR isolates. Mutations in two structural genes (katG and inhA) and two regulatory regions (the promoter of mabA-inhA and the intergenic region of oxyR-ahpC) were found in 89.3% of the MDR isolates. In total, 88.0% (213/242 strains) of the phenotypic MDR strains were confirmed by mutations in the sequenced regions. Mutations in embB306 were also considered a marker for MDR and significantly increased the sensitivity of the approach. Based on our findings, an approach that prospectively screens for mutations in 11 sites of the M. tuberculosis genome (rpoB531, rpoB526, rpoB516, rpoB533, and rpoB513, katG315, inhA-15, ahpC-10, ahpC-6, and ahpC-12, and embB306) could detect 86.8% of MDR strains in Shanghai. This study lays the foundation for the development of a rapid, reliable molecular genetic test to detect MDR strains of M. tuberculosis in China.

Prevalence of fluoroquinolone resistance among tuberculosis patients in Shanghai, China.

We determined the prevalence of fluoroquinolone resistance among the isolates of Mycobacterium tuberculosis from 605 pulmonary tuberculosis patients in Shanghai, China. Mutations in gyrA were found in 81.5% of phenotypically fluoroquinolone-resistant isolates and were used as a molecular marker of fluoroquinolone resistance. gyrA mutations were detected in 1.9% of strains pan-susceptible to first-line drugs and 25.1% of multidrug-resistant strains. Fluoroquinolone resistance was independently associated with resistance to at least one first-line drug and prior tuberculosis treatment.

Use of spoligotyping and large sequence polymorphisms to study the population structure of the Mycobacterium tuberculosis complex in a cohort study of consecutive smear-positive tuberculosis cases in The Gambia.

Mycobacterium africanum, first described in Senegal in 1968, causes up to half of the smear-positive pulmonary tuberculosis cases in West Africa, but it has not been found in other geographical areas except among recent West African migrants. The reasons for the geographic restriction of M. africanum are unknown. We used molecular tools to determine the population structure of the Mycobacterium tuberculosis complex in a cohort study of consecutive smear-positive tuberculosis cases in The Gambia. We collected and genotyped 386 clinical isolates using spoligotype analysis and PCRs for large sequence polymorphisms (LSPs) and compared the genotype patterns to the patterns in an international database. The results of spoligotyping and LSP analysis for the study population were also compared to determine the correlation between them. The main lineages within the Mycobacterium tuberculosis complex identified in The Gambia included M. africanum type I (38.4%), characterized by an LSP in region of difference 702 (RD702; West African type 2). Among the M. tuberculosis sensu stricto isolates, lineages characterized by RD182 and by RD174 were the most common. We also detected a gradient in the prevalence of M. africanum that extended from neighboring Guinea-Bissau. The genotypic diversity of the spoligotype patterns was greater among the isolates of M. africanum than among the isolates of M. tuberculosis. We postulate that M. africanum became endemic in West Africa first, before the introduction of different lineages within M. tuberculosis sensu stricto.

Deaths among tuberculosis cases in Shanghai, China: who is at risk?

BACKGROUND: Information about the risk factors associated with death caused by tuberculosis (TB) or death with TB would allow improvements in the clinical care of TB patients and save lives. The present study sought to identify characteristics associated with increased risk of death during anti-TB treatment in Shanghai, a city in China with one of the country's highest TB mortality rates. METHODS: We evaluated deaths among culture positive pulmonary TB cases that were diagnosed in Shanghai during 2000-2004 and initiated anti-TB therapy. Demographic, clinical, mycobacteriological information and treatment outcomes were routinely collected through a mandatory reporting system. RESULTS: There were 7,999 culture positive pulmonary cases reported during the study period. The overall case fatality rate was 5.5% (440 cases), and approximately half (50.5%) of the deaths were attributed to causes other than TB. Eighty-six percent of the deaths were among TB cases age > or = 60 years. The significant independent risk factors for mortality during anti-TB treatment were advancing age, male sex, sputum smear positivity, and the presence of a comorbidity. CONCLUSION: More vigorous clinical management and prevention strategies by both the TB control program and other public health programs are essential to improve TB treatment outcomes. Earlier suspicion, diagnosis and treatment of TB, especially among persons older than 60 years of age and those with a comorbid condition, could reduce deaths among TB patients.

Impact of bacterial genetics on the transmission of isoniazid-resistant Mycobacterium tuberculosis.

Understanding the ecology of drug-resistant pathogens is essential for devising rational programs to preserve the effective lifespan of antimicrobial agents and to abrogate epidemics of drug-resistant organisms. Mathematical models predict that strain fitness is an important determinant of multidrug-resistant Mycobacterium tuberculosis transmission, but the effects of strain diversity have been largely overlooked. Here we compared the impact of resistance mutations on the transmission of isoniazid-resistant M. tuberculosis in San Francisco during a 9-y period. Strains with a KatG S315T or inhA promoter mutation were more likely to spread than strains with other mutations. The impact of these mutations on the transmission of isoniazid-resistant strains was comparable to the effect of other clinical determinants of transmission. Associations were apparent between specific drug resistance mutations and the main M. tuberculosis lineages. Our results show that in addition to host and environmental factors, strain genetic diversity can influence the transmission dynamics of drug-resistant bacteria.

Genomic interrogation of ancestral Mycobacterium tuberculosis from south India.

Mycobacterium tuberculosis is a very important global pathogen. One quarter of the world's TB cases occur in India. The tuberculosis strains isolated from south Indian patients exhibit certain phenotypic characteristics like low virulence in guinea-pigs, resistance to isoniazid, thiophene-2-carboxylic acid hydrazide (TCH) and para-amino salicylic acid (PAS), and enhanced susceptibility to H2O2. Besides this, a large percentage of the isolates harbor only a single copy of IS 6110 which makes these strains distinct. Hence, we have studied the genotypic characteristics of these strains by using advanced techniques like Deletion Micro array, deletion PCR, allelic discrimination RT-PCR using several lineage specific markers and KatG G1388T (non-synonymous) polymorphism along with spoligotyping. The analysis of 1215 tuberculosis patient isolates from south India revealed that 85.2% belonged to the ancestral lineage of M. tuberculosis. Comparative whole-genome hybridization identified six new genomic regions within this lineage that were variably deleted.

Highly polymorphic variable-number tandem repeats loci for differentiating Beijing genotype strains of Mycobacterium tuberculosis in Shanghai, China.

The PCR-based variable-number tandem repeats (VNTR) typing method is a very promising tool for the molecular epidemiological study of Mycobacterium tuberculosis. The discriminatory power of the VNTR loci that were optimized in many previous studies has not been evaluated in Shanghai, an area where Beijing genotype strains dominate. In the present study, we first performed a literature search to identify VNTR loci that were at least 45 bp in length. Second, we determined the Hunter-Gaston discriminatory index (HGI) values of each of the 45 VNTR loci that we identified, using Beijing genotype strains from a 'test set' of isolates from a population with low migration in Chongming Island, Shanghai, China. Third, we optimized two sets of VNTR loci, which we named VNTR-7 and VNTR-16. The HGI value of VNTR-7 was slightly lower than that of IS6110 restriction fragment length polymorphisms (RFLP), and the HGI values of VNTR-16 and IS6110 RFLP were comparable. Our results suggest that VNTR-7, followed by VNTR-16 and IS6110 RFLP, can be used routinely as a tool to discriminate between M. tuberculosis isolates in population-based epidemiologic studies of M. tuberculosis transmission in Shanghai, China.

Quantitative impact of human immunodeficiency virus infection on tuberculosis dynamics.

RATIONALE: Human immunodeficiency virus (HIV) infection has a major but unquantified impact on the risk of tuberculosis. OBJECTIVES: To quantify the impact of HIV infection on the number of tuberculosis cases in San Francisco. METHODS: We studied all patients reported with tuberculosis in San Francisco from 1991 to 2002. The initial isolates of Mycobacterium tuberculosis were genotyped using IS6110 restriction fragment-length polymorphism genotyping as the primary method, and clustered cases (identical genotype patterns) were identified. MEASUREMENTS AND MAIN RESULTS: We determined the case number, case rate, and the fraction of tuberculosis attributable to HIV infection. Of 2,991 reported tuberculosis cases, 2,193 (73.3%) had a genotype pattern of M. tuberculosis available. Genotypic clusters with at least one HIV-positive person were larger, lasted longer, and had a shorter time between successive cases relative to clusters with only HIV-uninfected persons (P < 0.00005, P = 0.0009, P = 0.018, respectively). Overall, 13.7% of the tuberculosis cases were attributable to HIV infection and an estimated 405 excess tuberculosis cases occurred. CONCLUSIONS: During a period encompassing the resurgence and decline of tuberculosis in San Francisco, a substantial number of the tuberculosis cases were attributable to HIV infection. Coinfection with HIV amplified the local tuberculosis epidemic.

Internal migration and transmission dynamics of tuberculosis in Shanghai, China: an epidemiological, spatial, genomic analysis.

BACKGROUND: Massive internal migration from rural to urban areas poses new challenges for tuberculosis control in China. We aimed to combine genomic, spatial, and epidemiological data to describe the dynamics of tuberculosis in an urban setting with large numbers of migrants. METHODS: We did a population-based study of culture-positive Mycobacterium tuberculosis isolates in Songjiang, Shanghai. We used whole-genome sequencing to discriminate apparent genetic clusters of M tuberculosis sharing identical variable-number-tandem-repeat (VNTR) patterns, and analysed the relations between proximity of residence and the risk of genomically clustered M tuberculosis. Finally, we used genomic, spatial, and epidemiological data to estimate time of infection and transmission links among migrants and residents. FINDINGS: Between Jan 1, 2009, and Dec 31, 2015, 1620 cases of culture-positive tuberculosis were recorded, 1211 (75%) of which occurred among internal migrants. 150 (69%) of 218 people sharing identical VNTR patterns had isolates within ten single-nucleotide polymorphisms (SNPs) of at least one other strain, consistent with recent transmission of M tuberculosis. Pairs of strains collected from individuals living in close proximity were more likely to be genetically similar than those from individuals who lived far away-for every additional km of distance between patients' homes, the odds that genotypically matched strains were within ten SNPs of each other decreased by about 10% (OR 0·89 [95% CI 0·87-0·91]; p<0·0001). We inferred that transmission from residents to migrants occurs as commonly as transmission from migrants to residents, and we estimated that more than two-thirds of migrants in genomic clusters were infected locally after migration. INTERPRETATION: The primary mechanism driving local incidence of tuberculosis in urban centres is local transmission between both migrants and residents. Combined analysis of epidemiological, genomic, and spatial data contributes to a richer understanding of local transmission dynamics and should inform the design of more effective interventions. FUNDING: National Natural Science Foundation of China, National Science and Technology Major Project of China, and US National Institutes of Health.

Transmission of multidrug-resistant Mycobacterium tuberculosis in Shanghai, China: a retrospective observational study using whole-genome sequencing and epidemiological investigation.

BACKGROUND: Multidrug-resistance is a substantial threat to global elimination of tuberculosis. Understanding transmission patterns is crucial for control of the disease. We used a genomic and epidemiological approach to assess recent transmission of multidrug-resistant (MDR) tuberculosis and identify potential risk factors for transmission. METHODS: We did a population-based, retrospective study of patients who tested positive for tuberculosis between Jan 1, 2009, and Dec 31, 2012, in Shanghai, China. We did variable-number-of-tandem-repeat genotyping and whole-genome sequencing of isolates. We measured strain diversity within and between genomically clustered isolates. Genomic and epidemiological data were combined to construct transmission networks. FINDINGS: 367 (5%) of 7982 patients with tuberculosis had MDR tuberculosis and 324 (88%) of these had isolates available for genomic analysis. 103 (32%) of the 324 MDR strains were in 38 genomic clusters that differed by 12 or fewer single nucleotide polymorphisms (SNPs), indicating recent transmission of MDR strains. Patients who had delayed diagnosis or were older than 45 years had high risk of recent transmission. 235 (73%) patients with MDR tuberculosis probably had transmission of MDR strains. Transmission network analysis showed that 33 (87%) of the 38 clusters accumulated additional drug-resistance mutations through emergence or fixation of mutations during transmission. 68 (66%) of 103 clustered MDR strains had compensatory mutations of rifampicin resistance. INTERPRETATION: Recent transmission of MDR tuberculosis strains, with increasing drug-resistance, drives the MDR tuberculosis epidemic in Shanghai, China. Whole-genome sequencing can measure of the heterogeneity of drug-resistant mutations within and between hosts and help to determine the transmission patterns of MDR tuberculosis. FUNDING: National Science and Technology Major Project, National Natural Science Foundation of China, and US National Insitutes of Health.

Recurrent tuberculosis in an urban area in China: Relapse or exogenous reinfection?

Recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. We conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of HIV infection. Genotyping the Mycobacterium tuberculosis from clinical isolates was used to distinguish between relapse and reinfection. In total, 5.3% (710/13,417) of successfully treated cases had a recurrence, a rate of 7.55 (95% CI 7.01-8.13) episodes per 1000 person-years, more than 18 times the rate of tuberculosis in the general population. Patients who were male, age 30-59, retreatment cases, had cavitation, diabetes, drug-resistant or multidrug-resistant tuberculosis in their initial episode of tuberculosis, were at high risk for a recurrence. Among 141 recurrent cases that had paired isolates, 59 (41.8%) had different genotypes, indicating reinfection with a different strain. Patients who completed treatment were still at high risk of another episode of tuberculosis and exogenous reinfection contributed a significant proportion of the recurrent tuberculosis cases. Targeted control strategies are needed to prevent new tuberculosis infections in this setting.

Does DOTS work in populations with drug-resistant tuberculosis?

BACKGROUND: Directly observed therapy (DOTS) is the main strategy for prevention and control of tuberculosis worldwide. However, its effect on tuberculosis transmission in populations with moderate rates of drug-resistant disease is not known. METHODS: This population-based prospective study in southern Mexico between March, 1995, and February, 2000, was based on passive case finding and detection of acid-fast bacilli in sputum samples to diagnose pulmonary tuberculosis. We also used cultures, drug-susceptibility testing, bacterial genotyping, and monitoring of treatment outcomes. FINDINGS: We enrolled 436 patients; the HIV seroprevalence rate was 2%. We used three indicators to monitor continuing tuberculosis transmission: the incidence rate of pulmonary tuberculosis, which decreased by 54.4% between 1995 and 2000, from 42.1 to 19.2 per 10(5) population (p=0.00048); the percentage of clustered pulmonary tuberculosis cases, which decreased by 62.6% from 22% to 8% (p=0.02); and the rate of primary drug resistance, which decreased by 84.0% from 9.4 to 1.5 per 10(5) population (p=0.004). Rates of multidrug-resistant (MDR) tuberculosis also decreased (p<0.0001). The case-fatality ratio was 12% for MDR tuberculosis (five of 41), 7% for strains resistant to at least one drug after exclusion of MDR (four of 55), and 3% for pansusceptible strains (nine of 272). There were 13 treatment failures (11%) in 1995 and one (2%) in 2000 (p=0.012). INTERPRETATION: Even in settings with moderate rates of MDR tuberculosis, DOTS can rapidly reduce the transmission and incidence of both drug-susceptible and drug-resistant tuberculosis. However, further interventions, such as drug-susceptibility testing and standardised or individualised treatment regimens, are needed to reduce mortality rates for MDR tuberculosis.