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New drugs and shorter treatments for drug-resistant tuberculosis (DR-TB) have become available in recent years and active pharmacovigilance (PV) is recommended by the World Health Organization (WHO) at least during the early phases of implementation, with active drug safety monitoring and management (aDSM) proposed for this. We conducted a literature review of papers reporting on aDSM. Up to 18 April, 2019, results have only been published from one national aDSM programme. Because aDSM is being introduced in many low- and middle-income countries, we also report experiences in introducing it into DR-TB treatment programmes, targeting the reporting of a restricted set of adverse events (AEs) as per WHO-recommended aDSM principles for the period 2014-2017. Early beneficial effects of active PV for TB patients include increased awareness about the occurrence, detection and management of AEs during TB treatment, and the increase of spontaneous reporting in some countries. However, because PV capacity is low in most countries and collaboration between national TB programmes and national PV centres remains weak, parallel and coordinated co-development of the capacities of both TB programmes and PV centres is needed., Competing Interests: Conflict of interest: E. Tiemersma reports grants from USAID under the Challenge TB Project, during the conduct of the study. Conflict of interest: S. van den Hof has nothing to disclose. Conflict of interest: G. Dravniece has nothing to disclose. Conflict of interest: F. Wares reports grants from USAID under the Challenge TB Project, during the conduct of the study. Conflict of interest: Y. Molla reports grants from the USAID under the Challenge TB Project, during the conduct of the study. Conflict of interest: Y. Permata has nothing to disclose. Conflict of interest: E. Lukitosari has nothing to disclose. Conflict of interest: M. Quelapio has nothing to disclose. Conflict of interest: S.T. Aung has nothing to disclose. Conflict of interest: K.M. Aung has nothing to disclose. Conflict of interest: H.T. Thuy has nothing to disclose. Conflict of interest: V.D. Hoa has nothing to disclose. Conflict of interest: M. Sulaimanova has nothing to disclose. Conflict of interest: S. Sagyndykova has nothing to disclose. Conflict of interest: M. Makhmudova has nothing to disclose. Conflict of interest: A. Soliev has nothing to disclose. Conflict of interest: M. Kimerling has nothing to disclose., (Copyright ©ERS 2019.)

Background: In many countries, regular monitoring of the emergence of resistance to anti-tuberculosis drugs is hampered by the limitations of phenotypic testing for drug susceptibility. We therefore evaluated the use of genetic sequencing for surveillance of drug resistance in tuberculosis., Methods: Population-level surveys were done in hospitals and clinics in seven countries (Azerbaijan, Bangladesh, Belarus, Pakistan, Philippines, South Africa, and Ukraine) to evaluate the use of genetic sequencing to estimate the resistance of Mycobacterium tuberculosis isolates to rifampicin, isoniazid, ofloxacin, moxifloxacin, pyrazinamide, kanamycin, amikacin, and capreomycin. For each drug, we assessed the accuracy of genetic sequencing by a comparison of the adjusted prevalence of resistance, measured by genetic sequencing, with the true prevalence of resistance, determined by phenotypic testing., Findings: Isolates were taken from 7094 patients with tuberculosis who were enrolled in the study between November, 2009, and May, 2014. In all tuberculosis cases, the overall pooled sensitivity values for predicting resistance by genetic sequencing were 91% (95% CI 87-94) for rpoB (rifampicin resistance), 86% (74-93) for katG, inhA, and fabG promoter combined (isoniazid resistance), 54% (39-68) for pncA (pyrazinamide resistance), 85% (77-91) for gyrA and gyrB combined (ofloxacin resistance), and 88% (81-92) for gyrA and gyrB combined (moxifloxacin resistance). For nearly all drugs and in most settings, there was a large overlap in the estimated prevalence of drug resistance by genetic sequencing and the estimated prevalence by phenotypic testing., Interpretation: Genetic sequencing can be a valuable tool for surveillance of drug resistance, providing new opportunities to monitor drug resistance in tuberculosis in resource-poor countries. Before its widespread adoption for surveillance purposes, there is a need to standardise DNA extraction methods, recording and reporting nomenclature, and data interpretation., Funding: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development., (© 2018 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Introduction: Despite the close link between tuberculosis (TB) and poverty, most mathematical models of TB have not addressed underlying social and structural determinants., Objective: To review studies employing mathematical modelling to evaluate the epidemiological impact of the structural determinants of TB., Methods: We systematically searched PubMed and personal libraries to identify eligible articles. We extracted data on the modelling techniques employed, research question, types of structural determinants modelled and setting., Results: From 232 records identified, we included eight articles published between 2008 and 2015; six employed population-based dynamic TB transmission models and two non-dynamic analytic models. Seven studies focused on proximal TB determinants (four on nutritional status, one on wealth, one on indoor air pollution, and one examined overcrowding, socio-economic and nutritional status), and one focused on macro-economic influences., Conclusions: Few modelling studies have attempted to evaluate structural determinants of TB, resulting in key knowledge gaps. Despite the challenges of modelling such a complex system, models must broaden their scope to remain useful for policy making. Given the intersectoral nature of the interrelations between structural determinants and TB outcomes, this work will require multidisciplinary collaborations. A useful starting point would be to focus on developing relatively simple models that can strengthen our knowledge regarding the potential effect of the structural determinants on TB outcomes.

Background: Pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available., Methods: In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system., Findings: Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3·0-42·1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0-16·6% for ofloxacin, to 0·5-12·4% for levofloxacin, and 0·9-14·6% for moxifloxacin when tested at 0·5 μg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 μg/mL was low in all countries., Interpretation: Although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness., Funding: Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

To accelerate the fight against tuberculosis, major diagnostic challenges need to be addressed urgently. Post-2015 targets are unlikely to be met without the use of novel diagnostics that are more accurate and can be used closer to where patients first seek care in affordable diagnostic algorithms. This article describes the efforts by the stakeholder community that led to the identification of the high-priority diagnostic needs in tuberculosis. Subsequently target product profiles for the high-priority diagnostic needs were developed and reviewed in a World Health Organization (WHO)-led consensus meeting. The high-priority diagnostic needs included (1) a sputum-based replacement test for smear-microscopy; (2) a non-sputum-based biomarker test for all forms of tuberculosis, ideally suitable for use at levels below microscopy centers; (3) a simple, low cost triage test for use by first-contact care providers as a rule-out test, ideally suitable for use by community health workers; and (4) a rapid drug susceptibility test for use at the microscopy center level. The developed target product profiles, along with complimentary work presented in this supplement, will help to facilitate the interaction between the tuberculosis community and the diagnostics industry with the goal to lead the way toward the post-2015 global tuberculosis targets., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Existing approaches to tuberculosis (TB) control have been no more than partially successful in areas with high human immunodeficiency virus (HIV) prevalence. In the context of increasingly constrained resources, mathematical modelling can augment understanding and support policy for implementing those strategies that are most likely to bring public health and economic benefits. In this paper, we present an overview of past and recent contributions of TB modelling in this key area, and suggest a way forward through a modelling research agenda that supports a more effective response to the TB-HIV epidemic, based on expert discussions at a meeting convened by the TB Modelling and Analysis Consortium. The research agenda identified high-priority areas for future modelling efforts, including 1) the difficult diagnosis and high mortality of TB-HIV; 2) the high risk of disease progression; 3) TB health systems in high HIV prevalence settings; 4) uncertainty in the natural progression of TB-HIV; and 5) combined interventions for TB-HIV. Efficient and rapid progress towards completion of this modelling agenda will require co-ordination between the modelling community and key stakeholders, including advocates, health policy makers, donors and national or regional finance officials. A continuing dialogue will ensure that new results are effectively communicated and new policy-relevant questions are addressed swiftly.

Background: The World Health Organization recommends the screening of all people living with HIV for tuberculosis (TB) disease, followed by TB treatment, or isoniazid preventive therapy (IPT) when TB is excluded. However, the difficulty of reliably excluding TB disease has severely limited TB screening and IPT uptake in resource-limited settings. We conducted an individual participant data meta-analysis of primary studies, aiming to identify a sensitive TB screening rule., Methods and Findings: We identified 12 studies that had systematically collected sputum specimens regardless of signs or symptoms, at least one mycobacterial culture, clinical symptoms, and HIV and TB disease status. Bivariate random-effects meta-analysis and the hierarchical summary relative operating characteristic curves were used to evaluate the screening performance of all combinations of variables of interest. TB disease was diagnosed in 557 (5.8%) of 9,626 people living with HIV. The primary analysis included 8,148 people living with HIV who could be evaluated on five symptoms from nine of the 12 studies. The median age was 34 years. The best performing rule was the presence of any one of: current cough (any duration), fever, night sweats, or weight loss. The overall sensitivity of this rule was 78.9% (95% confidence interval [CI] 58.3%-90.9%) and specificity was 49.6% (95% CI 29.2%-70.1%). Its sensitivity increased to 90.1% (95% CI 76.3%-96.2%) among participants selected from clinical settings and to 88.0% (95% CI 76.1%-94.4%) among those who were not previously screened for TB. Negative predictive value was 97.7% (95% CI 97.4%-98.0%) and 90.0% (95% CI 88.6%-91.3%) at 5% and 20% prevalence of TB among people living with HIV, respectively. Abnormal chest radiographic findings increased the sensitivity of the rule by 11.7% (90.6% versus 78.9%) with a reduction of specificity by 10.7% (49.6% versus 38.9%)., Conclusions: Absence of all of current cough, fever, night sweats, and weight loss can identify a subset of people living with HIV who have a very low probability of having TB disease. A simplified screening rule using any one of these symptoms can be used in resource-constrained settings to identify people living with HIV in need of further diagnostic assessment for TB. Use of this algorithm should result in earlier TB diagnosis and treatment, and should allow for substantial scale-up of IPT.

We aimed to evaluate the incremental cost-effectiveness of engaging private practitioners (PPs) to refer tuberculosis (TB) suspects to public health centers in Jogjakarta, Indonesia. Effectiveness was assessed for TB suspects notified between May 2004 and April 2005. Private practitioners referred 1,064 TB suspects, of which 57.5% failed to reach a health center. The smear-positive rate among patients reaching a health center was 61.8%. Two hundred eighty (280) out of a total of 1,306 (21.4%) new smear-positive cases were enrolled through the PPs strategy. The incremental cost-effectiveness ratio per smear-positive case successfully treated for the PPs strategy was US$351.66 (95% CI 322.84-601.33). On the basis of an acceptability curve using the National TB control program's willingness-to-pay threshold (US$448.61), we estimate the probability that the PPs strategy is cost-effective at 66.8%. The strategy of engaging PPs was incrementally cost-effective, although under specific conditions, most importantly a well-functioning public directly observed treatment, short-course (DOTS) program.

Standard short course chemotherapy is recommended by the World Health Organization to control tuberculosis worldwide. However, in settings with high drug resistance, first line standard regimens are linked with high treatment failure. We evaluated treatment outcomes after standardized chemotherapy with the WHO recommended category II retreatment regimen in a prison with a high prevalence of drug resistant tuberculosis (TB). A cohort of 233 culture positive TB patients was followed through smear microscopy, culture, drug susceptibility testing and DNA fingerprinting at baseline, after 3 months and at the end of treatment. Overall 172 patients (74%) became culture negative, while 43 (18%) remained positive at the end of treatment. Among those 43 cases, 58% of failures were determined to be due to treatment with an inadequate drug regimen and 42% to either an initial mixed infection or re-infection while under treatment. Overall, drug resistance amplification during treatment occurred in 3.4% of the patient cohort. This study demonstrates that treatment failure is linked to initial drug resistance, that amplification of drug resistance occurs, and that mixed infection and re-infection during standard treatment contribute to treatment failure in confined settings with high prevalence of drug resistance.

Setting: The current study evaluates one of four pilot sites initiated in Cambodia to establish feasible and effective ways to manage patients with human immunodeficiency virus (HIV) infection and tuberculosis (TB)., Objective: To measure the costs of intensified case finding (ICF) and isoniazid preventive therapy (IPT) services for HIV-infected patients in Battambang Province, Cambodia., Design: We analyzed cost data retrospectively from September 2003 to February 2006 using a microcosting or ingredients-based approach and interviewed clinic personnel to determine the cost of ICF and IPT per person., Results: Adherence to IPT at Battambang IPT clinic was high (86%) relative to other reported studies of IPT among HIV patients in developing countries. The estimated cost per TB case averted through ICF was US$363, while the estimated cost per TB case averted through IPT was US$955., Conclusion: Economic evaluations of TB-HIV integrated services are necessary as countries move to establish or scale-up these services. Based upon the estimated effectiveness of ICF and IPT used by other studies examining the provision of integrated HIV-TB services, the cost per TB case prevented by ICF and IPT in Battambang, Cambodia, is less than the reported cost of treating a new smear-positive TB case.

Design: Retrospective data analysis of human immunodeficiency virus (HIV) infected patients attending an HIV clinic (referral hospital), Cambodia. Chest X-rays (CXRs) were read independently by onsite and offsite physicians., Results: Data on 881 patients were analyzed (smear-negative = 776, smear-positive = 105). Overall, the prevalence of culture-confirmed pulmonary tuberculosis (PTB) was 17% (150/881, smear-negative = 62/150). For those with any positive culture, a smear-negative case was four times more likely to be mycobacteria other than tuberculosis (MOTT) than Mycobacterium tuberculosis (P = 0.001). Median CD4 count was higher in smear-negative than smear-positive PTB patients (92.5 vs. 42, P = 0.24). Age, symptoms (cough >3 weeks or hemoptysis or fever >1 month) (aOR 2.6, P = 0.02) and an abnormal CXR (offsite reading) (aOR 4.9, P < 0.001) were significant predictors of smear-negative PTB. CXR was no longer significant in the model using the onsite reading (aOR 1.6, P = 0.11). The combination of age >or=30 years plus symptoms had a sensitivity of 100% but a positive predictive value (PPV) of 9%. CXR (offsite), as the next diagnostic test, had a sensitivity of 50% and specificity of 83%. The sensitivity of smear microscopy was 59% and its specificity 97%., Conclusions: While age and symptoms are useful both in screening smear-negative PTB suspects and in predicting smear-negative PTB cases, they have limited PPV. Given the limitations of smear microscopy, culture is required to diagnose smear-negative disease. Where culture is unavailable, CXR is an important adjunct for diagnosis. However, inaccurate CXR interpretation can impact case detection.

Background: Zambia faces overlapping tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics; however, care for co-infected patients often occurs through separate, vertical programs., Objective: To establish a program to integrate TB and HIV services in Lusaka primary care centers., Methods: In collaboration with the Zambian Ministry of Health, TB-HIV integration activities began in December 2005 and were expanded to seven health centers by March 2007. Principal activities included developing staff capacity to manage co-infected patients, implementing HIV testing within TB departments and establishing referral systems between departments., Results: Using a provider-initiated approach, 2053 TB patients were offered HIV testing. Seventy-seven per cent agreed to be tested; 69% of those tested were HIV-infected. Of these, 59% were enrolled in HIV care. The proportion of antiretroviral treatment (ART) program enrollees who were TB-HIV co-infected increased by 38% after program implementation. The median CD4 count among co-infected patients was 161 cells/microl, with 88% eligible for ART., Conclusion: Integration of HIV testing and referral services into urban primary care centers identified many co-infected patients and significantly increased the proportion of TB patients among people accessing HIV care. Ongoing challenges include maximizing the number of patients accepting HIV testing and overcoming barriers to enrollment into HIV care.

Setting: Voluntary counseling and confidential testing center (VCCT), Battambang District, Cambodia., Objectives: To determine newly diagnosed pulmonary tuberculosis (PTB) prevalence and predicting factors, and assess the utility of TB-related symptoms and yield of sputum microscopy and culture., Design: Cross-sectional survey using interview, sputum smears and cultures and human immunodeficiency virus (HIV) testing., Results: Of 496 participants, 29 (5.8%) had culture-confirmed PTB while 19 (65.5%) were acid-fast bacilli (AFB) smear-positive. PTB prevalence was higher (P < 0.001) in HIV-positives (20/124, 16.1%) than in HIV-negatives (9/372, 2.4%). On multivariable analysis, being HIV-positive, underweight (body mass index <18.5 kg/m(2)), rapid weight loss and age > or =35 years were predictors of PTB. Fever (93%) and hemoptysis (86%) had the highest sensitivity and specificity, respectively. The symptom complex of rapid weight loss, fever and hemoptysis detected all PTB cases (sensitivity 100%). Examination of three sputum smears with culture of the first sample detected 95% (19/20) of the HIV-associated PTB cases and 90% (26/29) overall., Conclusions: TB is common in the VCCT setting, regardless of HIV status. The high prevalence of HIV and PTB among the participants warrants consideration of TB screening for all HIV suspects. Such screening through VCCT is feasible. Adding a single culture test to the evaluation of an initial sputum sample set will substantially increase case detection.

Background: To accelerate DOTS expansion, the hospital sector and specialized chest clinics must be engaged., Objective: To develop a model for public-private partnership through DOTS expansion into public and private hospitals in Indonesia., Design: Model development included gaining commitment from stakeholders, stepwise training of hospital staff, and developing unified networks for case management, patient referral, laboratory quality assurance, supervision and evaluation., Results: The number of notified tuberculosis (TB) cases (all forms and new smear-positive) increased dramatically from baseline. Together, hospitals and chest clinics accounted for a significant proportion of the total cases notified by the province (51% of total TB cases and 56% of new smear-positive cases in 2004). Compared to health centers and chest clinics, hospitals reported lower cure and success rates. Despite the option for referral to health centers, the majority of patients diagnosed in hospitals and chest clinics in 2002-2004 opted to be fully managed by the diagnosing facility., Conclusion: The roles and strengths of hospitals differ with regard to health centers, providing a rational basis for linkage of these health service components. In Yogyakarta, linkage became effective only after establishing a stakeholder-based provincial coordinating (DOTS) committee as the recognized interface between the National Tuberculosis Programme and various providers.

Setting: Prisons throughout Honduras., Objective: To assess the strengths, weaknesses, and opportunities to improve non-standardized tuberculosis (TB) educational campaign materials utilized in prisons., Design: A qualitative assessment was conducted. Prison staff completed a survey describing development and implementation of educational activities at each prison (n=25). Completed surveys with photographs or copies of educational materials were collected and cataloged. The content, literacy demand, illustrations, learning stimulation, and cultural appropriateness of cataloged items were assessed using an adapted version of the Suitability Assessment of Materials Instrument. Results from this assessment were examined in conjunction with information collected through focus groups conducted with prisoners and interviews with prison staff., Results: Campaign strengths included the development and dissemination of print materials appropriate for individuals with low literacy levels. By actively engaging prisoners in the campaigns, materials often incorporated the language, values, and experiences encountered within prison culture. Content of print materials and presentations focused on correcting misperceptions and facilitating acceptance of TB control activities. Campaign weaknesses included the creation of illustrations that could perpetuate the stigma associated with TB and use of some materials in which the purpose was not apparent., Conclusions: The campaigns were generally suitable, and the evaluation allowed for their improvement.

Setting: The State of Alabama Department of Public Health Division of Tuberculosis Control., Objective: To standardize contact investigation protocols and implement an intervention to increase TB field worker adherence to the protocols with the goal of promoting efficiency and effectiveness in contact investigations., Design: A process evaluation of existing data collection and management systems and protocols was performed. Standardized protocols and an intervention to increase TB field worker adherence to the protocols were created and pilot tested. These were then implemented and formative evaluation data were collected., Results: The process evaluation revealed considerable variance among field workers with regard to protocols and definitions of variables related to contact investigations. Protocols were standardized and an intervention targeted at TB field workers was developed. The intervention consisted of a training workshop and the development of a computer-based contact investigation module. This was successfully implemented throughout the state., Conclusions: To perform effective contact investigations and conduct studies to improve the effectiveness of these investigations, TB control programs must pay careful attention to precisely defining variables and concepts related to the contact investigation. Furthermore, protocols must be standardized and resources devoted to training of TB field workers to ensure adherence to protocols.

Setting: Tomsk, Siberia, Russian Federation., Objective: To evaluate the relationship between TB susceptibility patterns and risk factors among a civilian cohort of new cases in Tomsk city in 1999., Design: Population-based study. The association between MDR-TB or PROMDR-TB, defined as resistance to isoniazid and rifampicin (MDR) or to isoniazid, ethambutol, and streptomycin (rifampicin mono-sensitive), and hypothesized risk factors was determined. Univariable analysis with and without stratification for history of incarceration and stepwise logistic regression modeling were used., Results: Overall, 49.6% of participants were infected with a Mycobacterium tuberculosis strain resistant to at least one prescribed anti-tuberculosis medication. PROMDR-TB and MDR-TB were prevalent in 17.2% and 13.1% of participants, respectively. Logistic regression modeling indicated that good residence (OR 3.1, 95%CI 1.4-6.9), treatment default (OR 4.4, 95%CI 2.1-9.3) and psychological disorder (OR 3.3, 95%CI 1.0-10.9) were associated with PROMDR-TB. Both good residence (OR 2.6, 95%CI 1.1-6.0) and treatment default (OR 5.3, 95%CI 2.4-11.6) were associated with MDR-TB. History of incarceration was not found to be significant., Conclusion: Our findings support the hypothesis that drug-resistant disease among the Tomsk city population is not directly linked to history of incarceration, nor is it an extension of drug resistance in prisons. Rather, drug resistance in the civil sector reflects problems specific to the sector itself.

Setting: Phnom Penh, Cambodia., Objective: To determine the burden of active pulmonary tuberculosis among an HIV-infected cohort and the proportion of drug-resistant strains, using active case-finding adapted to a home care setting., Design: Cross-sectional study. Measures include the prevalence of culture-confirmed Mycobacterium tuberculosis, utilizing a single spot sputum specimen; the proportion of pulmonary TB, detected and undetected; proportion of cases resistant to isoniazid, rifampicin, ethambutol, streptomycin; and the diagnostic value of symptoms., Results: Of 441 persons surveyed, 41 (9%) had active pulmonary TB by culture; 29 were smear-positive (71%), and only one case was on treatment. The total burden of pulmonary TB was 12% (54/441), with a ratio of undetected to detected cases of 3:1. Primary isoniazid resistance was detected in six new cases (15%); no MDR-TB was identified. Symptoms were not predictive of active pulmonary disease. Mortality was high among those not surveyed (20%) and those found to have TB (49%)., Conclusions: Tuberculosis is epidemic in this HIV-infected population. Active case-finding yielded three times the number of cases already detected and should be considered where resources allow. However, effective passive case detection and improved coordination of TB and HIV care programs are required to address HIV-associated TB morbidity and mortality.

Molecular fingerprinting with the IS6110 insertion sequence is useful for tracking transmission of Mycobacterium tuberculosis within a population or confirming specimen contamination in the laboratory or through instrumentation. Secondary typing with other molecular methods yields additional information as to the relatedness of strains with similar IS6110 fingerprints. Isolated, relatively rare, random events within the M. tuberculosis genome alter molecular fingerprinting patterns with any of the methods; therefore, strains which are different by two or more typing methods are usually not considered to be closely related. In this report, we describe two strains of M. tuberculosis, obtained from the same bronchoscope 2 days apart, that demonstrated unique molecular fingerprinting patterns by two different typing methods. They were closely linked through the bronchoscope by a traditional epidemiologic investigation. Genetic analysis of the two strains revealed that a single event, the transposition of an IS6110 insertion sequence in one of the strains, accounted for both the differences in the IS6110 pattern and the apparent deletion of a spacer in the spoligotype. This finding shows that a single event can change the molecular fingerprint of a strain in two different molecular typing systems, and thus, molecular typing cannot be the only means used to track transmission of this organism through a population. Traditional epidemiologic techniques are a necessary complement to molecular fingerprinting so that radical changes within the fingerprint pattern can be identified.

Unlabelled: Childhood tuberculosis (TB) cases indicate recent community transmission and thus reflect the effectiveness of TB control efforts, particularly the contact investigation., Objective: To evaluate all preventable childhood TB cases and implications in the context of TB morbidity trends., Design: Statewide morbidity trends are presented from 1983 to 1997. Since 1992, each child TB case is classified as either preventable or not preventable, based on a standard definition., Main Outcome Measures: Case characteristics (preventable and not preventable), TB disease rates over time, and reasons for preventable case classification., Setting: Alabama TB control program, from January 1, 1983 through December 31, 1997., Results: For the period 1983-1997, nonwhite children had a higher disease rate (rate ratio: 5.7; 95% confidence interval: 4.3,7.6) than white children. Since 1990, the overall child rate has increased significantly despite a decline in the adult rate. Among 120 child cases diagnosed from 1992 to 1997, 25 (21%) were classified as preventable. The causes were contact investigation interview failure (12/25 = 48%), delay to evaluation (16%), source case noncompliance with previously prescribed preventive therapy (16%), and source case diagnosed out of state (16%) with no initial investigation performed in Alabama. All preventable cases identified were black children; the proportion of preventable cases did not vary by age group or sex. During 1996, the case rate for nonwhite children exceeded that of adult whites., Conclusions: Childhood TB in Alabama for nonwhites is rising despite a national downward trend. TB is clearly a disproportionate disease burden for the state's African American population, and the median case age is falling. Additional research and improved training in contact investigation are required to assess this situation and effectively intervene.

Setting: Two homeless shelters in Birmingham, Alabama., Objective: To interrupt tuberculosis transmission and evaluate the utility of spot sputum screening., Design: Two shelters participated in the study between May 1996 and February 1997. A spot sputum specimen was collected on a given evening from each overnight client. Information was obtained regarding symptoms and tuberculin skin test (TST) status. There were four screenings during two rounds, with TST in round one only., Results: Of 127 persons involved in the study, 120 (95%) provided specimens, and four tuberculosis cases were identified (4/127, 3.1%). Symptoms were infrequently reported. RFLP analysis (IS6110) confirmed a two-band cluster in three of the four cases; another matching two-band strain was found in a drug rehabilitation client staying in one shelter. Secondary RFLP typing (pTBN12) confirmed the homeless cluster. Costs were $1311 per case identified. Among 92 clients with a prior TST, 40% reported a positive result (37/92). Of 21 PPD tests read, 11 were > or =10 mm (52%)., Conclusion: Spot sputum screening is effective in identifying unsuspected tuberculosis cases in shelters. It has acceptable costs, is logistically simple and efficient. Symptom screening was not useful in this general homeless population. RFLP analysis showed cloning of the two-band strain. Given the evidence for ongoing transmission, sputum screening should be considered in shelter settings.

Multidrug-resistant tuberculosis (MDR-TB) threatens the progress of global control efforts. Prisons represent a high risk setting for development and transmission of MDR-TB. In a Siberian TB referral prison (Kemerovo region), the treatment failure rate is 35% (June 1996-March 1997), despite implementation of a strict DOTS program and use of the World Health Organization Category 2 re-treatment regimen for all new cases. Among 164 patients (December 1997-March 1998), initial resistance to isoniazid and rifampin is 22.6%. Such a rate is a warning call to reconsider prison control strategies, and importantly, to address the treatment regimens necessary to combat an institutional epidemic of MDR-TB.

Setting: Alabama State Tuberculosis Control Program, USA., Objective: To combine molecular screening data with routine information to assess transmission of Mycobacterium tuberculosis and improve control efforts., Design: Since January 1994, samples from tuberculosis cases statewide have been systematically analyzed by IS6110 restriction fragment length polymorphism (RFLP). All cases during 1994-1995 with a predominate RFLP pattern were evaluated and risk factors assessed. pTBN12 was used to evaluate a large cluster in the Birmingham-Jefferson County (BJC) area., Results: Statewide, a common two-band pattern was found, named JH2 (99/566, 17.5%). The most important risk associated with this pattern was homelessness (odds ratio, 8.9; P < 0.001). In the BJC area, the homeless accounted for 29% (51/175) of new cases diagnosed during the study period. For the BJC homeless, there were 13 unique RFLP patterns, and JH2 was predominant (29/33, 88%) among three clusters. Secondary analysis of the homeless JH2 cluster revealed a large group that included 19 of 24 (79%) isolates analyzed. Compared with the BJC non homeless (n = 124), the homeless were younger (P < 0.001), of male gender (P < 0.001), black race (P = 0.002), and were heavy alcohol (P < 0.001) and non-injection drug (P = 0.001) users., Conclusions: By screening tuberculosis cases statewide, a common two-band RFLP pattern was identified. Its predominance is explained by an ongoing tuberculosis epidemic among Birmingham's homeless population, highlighting RFLP as a tool for population surveillance. The pattern differences observed by pTBN12 typing clearly demonstrate that the isolates might be related but are not clonal.

Background: Despite the use of directly observed therapy (DOT) by tuberculosis control programs, patient treatment failure, relapse, and acquired drug resistance remain problematic in a small number. We investigated serum drug levels in non-HIV-infected tuberculosis patients who were receiving DOT by the health department and did not respond to treatment as expected., Methods: The indications for checking levels were as follows: (1) slow clinical response or failure to convert the sputum culture within 12 weeks; (2) treatment failure, early disease relapse < 13 months since being declared cured; (3) relapse, late disease reactivation > or = 13 months since being declared cured; and (4) acquired drug resistance while receiving DOT. Baseline characteristics of control subjects who responded to therapy as expected were compared. Venous blood for analysis was obtained at 2 h after directly observed ingestion and measured by high-performance liquid chromatography., Results: Twenty-four patients receiving daily or twice-weekly standard therapy with isoniazid (INH, 300 or 900 mg) and rifampin (RMP, 600 mg) were identified; 22 had drug levels evaluated at 2 h. For INH, 15 of 22 patients (68%) had levels less than the reported target range. For RMP, 14 of 22 patients (64%) had low levels. Among the 14 patients receiving INH, 900 mg, and RMP, 600 mg, 4 (29%) had very low levels of both. Use of a combination INH/RMP tablet was associated with lower INH levels (p=0.04); however, RMP levels were higher (p<0.02). Alcohol use was associated with significantly higher RMP (p<0.01) serum concentrations., Conclusions: Important questions remain concerning the utility and timing of serum drug measurements. However, if a patient is not responding to therapy as expected and one is assured that the Mycobacterium tuberculosis organism is susceptible to the drugs given and that the patient is taking the medication as prescribed, drug level monitoring should be considered.

Through systematic evaluation of information contained in tuberculosis patients treatment cards, we present an example of a rapid operations evaluation method for identifying issues important to a national tuberculosis programme (NTP). Analysis of all 279 treatment cards of patients scheduled to attend one specific clinic day was made ((Kinondoni district in Dar es Salaam, Tanzania). Two hundred and twenty five patients (81%) were diagnosed as having pulmonary tuberculosis. Males accounted for 61% of cases. Ninety two per cent were cases without prior history of treatment. Of all patients, those under 15 years and those aged 25 to 54 years were more likely to be sputum smear-negative compared with other age groups. A chest radiograph was obtained as recommended to support the diagnosis in only 61 (38%) of 160 cases diagnosed as sputum smear-negative pulmonary tuberculosis. Initial drug dosing based on weight (mg/kg) revealed frequent dosing errors of isoniazid (97%) and pyrazinamide (65%), almost exclusively overdosing, in sputum smear-positive patients. Systematic examination of patient treatment cards provided usefull information and raises issues important to NTP planning and operations. Weaknesses in the execution of the national programme in Dar es Salaam were identified: the under-utilisation of chest radiography to diagnose sputum smear-negative tuberculosis and overdosing of certain drugs.

Chuk district hospital is centrally located in a rural malarious region in southern Cambodia. It was the site of a hospital-based evaluation (KAP assessment and in vivo i.v. quinine/oral tetracycline drug study) done to identify relevant issues for establishing a rational malaria control strategy. The KAP assessment identified the young, male forest worker as the highest risk group. Of 112 study patients, 73% were male and 82% reported various forest activities. The primary reason found for patient delay (8.9 days) in seeking hospital care was self-treatment at home (N = 102, 91%) with drugs purchased through private sellers (104/105). Using the 7-day WHO field test methodology, resistance rates were calculated (N = 22); S1/R1, 73%; R1, 9%; R2, 0%; R3, 18%. A modified version of the 7-day test was used to calculate its utility in this particular rural setting. It showed a negative predictive value of 93% and a positive predictive value of 71%. The case fatality rate for the study period was 2.7%. Information from this study, which correlates a confirmed malaria diagnosis with prior patient behavior and response to anti-malarial therapy, is intended for realizing the goals set forth by the national malaria control program.

An 11-year review of childhood tuberculosis in Alabama was made in order to define indicators of program effectiveness in interrupting community transmission. Minority (nonwhite) children, 96% of whom were black, had the highest risk of disease (odds ratio, 5.5; 95% confidence interval, 3.9, 7.7). Of 171 cases, 71% (n = 122) occurred in blacks and 2% (n = 3) occurred in Asian-Pacific islanders. Age 0 to 4 years (107 of 171) compared with age 5 to 14 years (64 of 171) was an additional risk factor for the development of tuberculosis (odds ratio, 3.4; 95% confidence interval 2.5, 4.7)), whereas gender was not. Males accounted for 49% of cases (83 of 171). During the period 1983 to 1993 there was no trend of increasing or decreasing numbers among child cases (trend test P = 0.94) despite significant changes by year. The purified protein derivative test had a 9% (8 of 89) false negative rate and was significantly more likely to be negative in children younger than 1 year (4 of 12 vs. 4 of 77; P = 0.01). During the 2-year interval 1992 to 1993, 19% of cases were thought to be preventable. We believe that the PPD skin test is useful and an improved contact investigation is essential to preventing childhood tuberculosis. Miniepidemics of transmission of tuberculosis from adults to a large group of children partially explain the observed disease pattern.

Setting: The rural Cambodian district of Banteay Meas, population 74,464., Objective: To evaluate the effectiveness of a district based tracing program developed to improve tuberculosis control program treatment results. Specifically, to assess factors affecting patient non-adherence to therapy and return of patients to treatment., Design: All patients started on treatment during 1992 were included. Standardized cohort analysis methods were applied to assess treatment outcome for all tuberculosis cases registered during Trimesters I-III. Absconders for the year were traced and followed as a separate cohort. Those returning to therapy were followed until the end of the study period in October 1993., Results: Activity in 1992 included 171 admissions and 46 absconders. Of the 46, 57% were met at home. Among those met, 81% returned to treatment. Males absconded more than females even though females accounted for a majority of admissions. Socioeconomic factors (68%) were cited most often as the reason for non-adherence. Distance was not a factor. Cohort analysis showed improvement in the treatment completion rate (54.8% vs 69.2% vs 64%) coupled with a drop in the absconding rate (35.5% vs 25% vs 20%). Of the 21 patients returning, 76% have either completed or nearly completed treatment., Conclusion: These results support tracing as an effective means to improve patient adherence in rural Cambodia, thereby strengthening tuberculosis control programs at district level.

In recent years, several outbreaks of drug-resistant tuberculosis have occurred in U.S. hospitals. In response to this recognized risk of tuberculosis exposure in health care facilities, the Centers for Disease Control and the Occupational Safety and Health Administration have issued guidelines or policy procedures for minimizing risks of tuberculosis transmission within these facilities. Some of the recommendations outlined in these governmental documents have been controversial. In this review the guidelines/policies and the debate surrounding them are discussed as they affect the health care worker who cares for adult patients with tuberculosis.