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Vaccination with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended for all pregnant women to protect infants who are too young for vaccination from severe pertussis-related outcomes (1-3). However, Tdap vaccine coverage among pregnant women remains suboptimal in California (4). California mothers whose infants developed pertussis in 2016 and their prenatal care providers were interviewed to ascertain possible reasons for low Tdap vaccine coverage. Mothers who were offered Tdap vaccination on-site during a routine prenatal visit were more likely to be vaccinated than were mothers who were referred off-site for vaccination. Mothers insured by Medicaid were less likely to receive Tdap vaccine than were mothers with private insurance, even when the vaccine was stocked on-site. Nearly all vaccinated mothers received Tdap vaccine in their prenatal clinic. Incorporating Tdap vaccination into routine prenatal care visits is an effective means to increase prenatal Tdap vaccination coverage.

b ABSTRACT California's state and local tuberculosis (TB) programs collaborated to develop the Tuberculosis Indicators Project (TIP), a program evaluation and improve- ment process. In TIP, local and state staff review data, identify program gaps, implement plans to improve local TB program performance, and evaluate outcomes. After 10 years of project implementation, indicator performance changes and patient outcomes were measured. Eighty-seven percent of participating programs showed a performance increase in targeted indicators after three years compared with 57% of comparison groups. Statistically signifi - cant performance change was more common in the intervention local health departments (LHDs) than in comparison groups. The most notable performance changes were in the contact investigation and case management indicators. These results indicate that this systematic evaluation and program improve- ment project was associated with improved LHD TB control performance and may be useful to inform improvement projects in other public health programs.

California state and local tuberculosis (TB) programs used a systematic process to develop a set of indicators to measure and improve program performance in controlling TB. These indicators were the basis for a quality improvement process known as the TB Indicators Project. Indicators were derived from guidelines and legal mandates for clinical, case management, and surveillance standards and were assessed using established criteria. The indicators were calculated using existing surveillance data. The indicator set was field tested by local programs with high TB morbidity and subsequently revised. Collaboration with key stakeholders at all stages was crucial to developing useful and accepted indicators. Data accessibility was a critical requirement for indicator implementation. Indicators most frequently targeted for performance improvement were those perceived to be amenable to intervention. Indicators based on surveillance data can complement other public health program improvement efforts by identifying program gaps and successes and monitoring performance trends.

The role of so-called “group 5” second-line drugs as a part of antibiotic therapy for multidrug-resistant tuberculosis (MDR-TB) is widely debated. We performed an individual patient data meta-analysis to evaluate the effectiveness of several group 5 drugs including amoxicillin/clavulanic acid, thioacetazone, the macrolide antibiotics, linezolid, clofazimine and terizidone for treatment of patients with MDR-TB.Detailed individual patient data were obtained from 31 published cohort studies of MDR-TB therapy. Pooled treatment outcomes for each group 5 drug were calculated using a random effects meta-analysis. Primary analyses compared treatment success to a combined outcome of failure, relapse or death.Among 9282 included patients, 2191 received at least one group 5 drug. We found no improvement in treatment success among patients taking clofazimine, amoxicillin/clavulanic acid or macrolide antibiotics, despite applying a number of statistical approaches to control confounding. Thioacetazone was associated with increased treatment success (OR 2.6, 95% CI 1.1–6.1) when matched controls were selected from studies in which the group 5 drugs were not used at all, although this result was heavily influenced by a single study.The development of more effective antibiotics to treat drug-resistant TB remains an urgent priority.

New World Health Organization guidelines recommend initial treatment of active tuberculosis (TB) with a 6-month regimen utilising rifampin throughout. We have modelled expected treatment outcomes, including drug resistance, with this regimen, compared to an 8-month regimen with rifampin for the first 2 months only, followed by standardised retreatment. A deterministic model was used to predict treatment outcomes in hypothetical cohorts of 1,000 new smear-positive cases from seven countries with varying prevalence of initial drug resistance. Model inputs were taken from published systematic reviews. Predicted outcomes included number of deaths, failures and relapses, plus the proportion with drug resistance. Sensitivity analyses examined different risks of acquired drug resistance. Compared to use of the standardised 8-month regimen, for every 1,000 new TB cases treated with the 6-month regimen we predict that 48-86 fewer persons will require retreatment, and 3-12 deaths would be avoided. However, the proportion failing or relapsing after retreatment is predicted to be higher, because with the 6-month regimen 50-94% of failures and 3-56% of relapses will have multidrug-resistant TB. We predict substantial public health benefits from changing from the 8-month to the 6-month regimen. However in almost all settings the current standardised retreatment regimen will no longer be adequate.

Background Extensively drug-resistant (XDR) tuberculosis (TB) is a global public health emergency. We investigated the characteristics and extent of XDR TB in California to inform public health interventions. Methods XDR TB was defined as TB with resistance to at least isoniazid, rifampin, a fluoroquinolone, and 1 of 3 injectable second-line drugs (amikacin, kanamycin, or capreomycin). Pre-XDR TB was defined as TB with resistance to isoniazid and rifampin and either a fluoroquinolone or second-line injectable agent but not both. We analyzed TB case reports submitted to the state TB registry for the period 1993-2006. Local health departments and the state TB laboratory were queried to ensure complete drug susceptibility reporting. Results Among 424 multidrug-resistant (MDR) TB cases with complete drug susceptibility reporting, 18 (4.2%) were extensively drug resistant, and 77 (18%) were pre-extensively drug resistant. The proportion of pre-XDR TB cases increased over time, from 7% in 1993 to 32% in 2005 (P = .02)). Among XDR TB cases, 83% of cases involved foreign-born patients, and 43% were diagnosed in patients within 6 months after arrival in the United States. Mexico was the most common country of origin. Five cases (29%) of XDR TB were acquired during therapy in California. All patients with XDR TB had pulmonary disease, and most had prolonged infectious periods; the median time for conversion of sputum culture results was 195 days. Among 17 patients with known outcomes, 7 (41.2%) completed therapy, 5 (29.4%) moved, and 5 (29.4%) died. One patient continues to receive treatment. Conclusions XDR TB and pre-XDR TB cases comprise a substantial fraction of MDR TB cases in California, indicating the need for interventions that improve surveillance, directly observed therapy, and rapid drug susceptibility testing and reporting.

OBJECTIVE. We undertook a decision analysis to evaluate the economic and health effects and incremental cost-effectiveness of using targeted tuberculin skin testing, compared with universal screening or no screening, before kindergarten.METHODS. We constructed a decision tree to determine the costs and clinical outcomes of using targeted testing compared with universal screening or no screening. Baseline estimates for input parameters were taken from the medical literature and from California health jurisdiction data. Sensitivity analyses were performed to determine plausible ranges of associated outcomes and costs. We surveyed California health jurisdictions to determine the prevalence of mandatory universal tuberculin skin testing.RESULTS. In our base-case scenario, the cost to prevent an additional case of tuberculosis by using targeted testing, compared with no screening, was $524897. The cost to prevent an additional case by using universal screening, compared with targeted testing, was $671398. The incremental cost of preventing a case through screening remained above $100000 unless the prevalence of tuberculin skin testing positivity increased to >10%. More than 51% of children entering kindergarten in California live where tuberculin skin testing is mandatory.CONCLUSIONS. The cost to prevent a case of tuberculosis by using either universal screening or targeted testing of kindergarteners is high. If targeted testing replaced universal tuberculin skin testing in California, then $1.27 million savings per year would be generated for more cost-effective strategies to prevent tuberculosis. Improving the positive predictive value of the risk factor tool or applying it to groups with higher prevalence of latent tuberculosis would make its use more cost-effective. Universal tuberculin skin testing should be discontinued, and targeted testing should be considered only when the prevalence of risk factor positivity and the prevalence of tuberculin skin testing positivity among risk factor–positive individuals are high enough to meet acceptable thresholds for cost-effectiveness.

In 2010, 30 countries with anti-tuberculosis drug resistance surveillance data were each estimated to have more than 700 multidrug-resistant tuberculosis (MDR-TB) cases among their notified TB cases. New TB patients comprised a median of 54% (interquartile range 45-67) of the MDR-TB cases. The occurrence of MDR-TB in a new TB patient is a warning sign that MDR-TB is spreading in a community. While MDR-TB case-finding efforts should first prioritize previously treated patients, reaching universal access requires rapidly adding other risk groups, and then all new TB patients. Epidemiological data as presented in this paper can help inform country scale-up plans.

Prompt laboratory reporting of tuberculosis (TB) test results is necessary for TB control. To understand the extent of and factors contributing to laboratory reporting delays and the impact of reporting delays on initiation of treatment of TB patients, we analyzed data from 300 consecutive culture-positive TB cases reported in four California counties in 1998. Laboratory reporting to the specimen submitter was delayed for 26.9% of smear-positive patients and 46.8% of smear-negative patients. Delays were associated with the type of laboratory that performed the testing and with delayed transport of specimens. Referral laboratories (public health and commercial) had longer median reporting time frames than hospital and health maintenance organization laboratories. Among patients whose treatment was not started until specimens were collected, those with delayed laboratory reporting were more likely to have delayed treatment than patients with no laboratory reporting delays (odds ratio [OR] of 3.9 and 95% confidence interval [CI] of 1.6 to 9.7 for smear-positive patients and OR of 13.1 and CI of 5.3 to 32.2 for smear-negative patients). This relation remained after adjustment in a multivariate model for other factors associated with treatment delays (adjusted OR of 25.64 and CI of 7.81 to 83.33 for smear-negative patients). These findings emphasize the need to reduce times of specimen transfer between institutions and to ensure rapid communication among laboratories, health care providers, and health departments serving TB patients.

Less than one in five of the world’s multidrug-resistant tuberculosis (MDR-TB) cases was estimated to have been diagnosed and reported to health authorities in 2012.{{600 World Health Organization 2012;}} Incomplete coverage of drug susceptibility testing (DST) is a major contributor to this gap, and strategies to expand testing are a global priority.{{436 World Health Organization 2011;}} When drug resistance is not detected, MDR-TB patients cannot access life-saving treatment; this puts their communities at risk of ongoing MDR-TB transmission. In Cambodia, only one-third (74/218) of previously-treated patients – a priority group for MDR-TB case finding – notified in the second half of 2011 had DST results.{{622 Khann, S. 2013;}} Cambodia’s guidelines recommend that previously-treated patients have sputum specimens tested by Xpert MTB/RIF (available in four provincial laboratories), followed by culture and species identification using liquid and solid media (available in three regional laboratories) and conventional DST at the national reference laboratory. If patients cannot travel to the laboratory, specimens may be collected in patients’ homes or health centres by trained TB staff. Previously treated patients were defined as those who received one month or more of anti-TB drugs in the past.{{623 World Health Organization 2009;}} In Cambodia, patients classified as relapse or returning after treatment failure or loss to follow up are smear-positive, while “other” refers to retreatment patients who have smear-negative pulmonary or extrapulmonary disease. The present study builds upon prior studies {{616 Chadha, S.S. 2011;615 Yagui, M. 2006;625 Noeske, J. 2012;626 Kilale, AM. 2013;}} to explore the perceptions of frontline health workers and program staff in order to better understand modifiable factors contributing to gaps in MDR-TB case finding among previously-treated patients. However, this is the first study of this kind conducted in Cambodia, and as such, it should be considered a pilot study. The objectives were to quantify the gaps in MDR-TB case finding, and elicit health workers’ perspectives on barriers, facilitators, and potential interventions.

Background: In spring 1993, four students in a high school were diagnosed with tuberculosis resistant to isoniazid, streptomycin, and ethionamide. Methods: To investigate potential transmission of drug-resistant tuberculosis, a retrospective cohort study with case investigation and screening by tuberculin skin tests and symptom checks was conducted in a high school of approximately 1400 students. Current and graduated high-school students were included in the investigation. DNA fingerprinting of available isolates was performed. Results: Eighteen students with active tuberculosis were identified, Through epidemiologic and laboratory investigation, 13 cases were linked; 8 entered 12th grade in fall 1993; 9 of 13 had positive cultures for Mycobacterium tuberculosis with isoniazid, streptomycin, and ethionamide resistance, and all 8 available isolates had identical DNA fingerprints. No staff member had tuberculosis. One student remained infectious for 29 months, from January 1991 to June 1993, and was the source case for the outbreak. Another student was infectious for 5 months before diagnosis in May 1993 and was a treatment failure in February 1994 with development of rifampin and ethambutol resistance in addition to isoniazid, streptomycin, and ethionamide. In the fall 1993 screening, 292 of 1263 (23%) students tested had a positive tuberculin skin test. Risk of infection was highest among 12th graders and classroom contacts of the two students with prolonged infectiousness. An additional 94 of 928 (10%) students tested in spring 1994 had a positive tuberculin skin test; 22 were classroom contacts of the student with treatment failure and 21 of these had documented tuberculin skin test conversions. Conclusion: Extensive transmission of drug-resistant tuberculosis was documented in this high school, along with missed opportunities for prevention and control of this outbreak. Prompt identification of tuberculosis cases and timely interventions should help reduce this public health problem. (J Pediatr 1997;131:863-8)

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis., Background Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. Methods and Findings Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]). Conclusions In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary., Editors' Summary Background In 2010, 8.8 million people developed tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs. Why Was This Study Done? Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called “individual patient data meta-analysis.” In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB. What Did the Researchers Do and Find? The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1–8.5 months and with the total duration of treatment up to 18.6–21.5 months. What Do These Findings Mean? These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300. The World Health Organization provides information on all aspects of tuberculosis, including MDR-TB; its guidelines for the programmatic management of drug-resistant tuberculosis are available The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the treatment of tuberculosis and on MDR-TB The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis, including a drug-resistant tuberculosis visual tour MedlinePlus has links to further information about tuberculosis (in English and Spanish) TB & ME, a collaborative blogging project run by patients being treated for multidrug-resistant tuberculosis and Medecins sans Frontieres, provides information about MDR-TB and patient stories about treatment for MDR-TB The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, also provides personal stories about treatment for tuberculosis

Summary WHO has previously recommended sputum-smear examination at the end of the second month of treatment in patients with recently diagnosed pulmonary tuberculosis, and, if positive, extension of the intensive therapy phase. We did a systematic review and meta-analysis to assess the accuracy of a positive sputum smear or culture during treatment for predicting failure or relapse in pulmonary tuberculosis. We searched PubMed, Embase, and the Cochrane Library for studies published in English through December, 2009. We included randomised controlled trials, cohort, and case-control studies of previously untreated pulmonary tuberculosis patients who had received a standardised regimen with rifampicin in the initial phase. Accuracy results were summarised in forest plots and pooled by use of a hierarchical regression approach. 15 papers (28 studies) met the inclusion criteria. The pooled sensitivities for both 2-month smear (24% [95% CI 12–42%], six studies) and culture (40% [95% CI 25–56%], four studies) to predict relapse were low. Corresponding specificities (85% [95% CI 72–90%] and 85% [95% CI 77–91%]) were higher, but modest. For failure, 2-month smear (seven studies) had low sensitivity (57% [95% CI 41–73%]) and higher, although modest, specificity (81% [95% CI 72–87%]). Both sputum-smear microscopy and mycobacterial culture during tuberculosis treatment have low sensitivity and modest specificity for predicting failure and relapse. Although we pooled a diverse group of patients, the individual studies had similar performance characteristics. Better predictive markers are needed.

BACKGROUND: Patients with human immunodeficiency virus (HIV) infection and tuberculosis have an increased risk of death, treatment failure, and relapse. METHODS: A systematic review and meta-analysis of randomized, controlled trials and cohort studies was conducted to evaluate the impact of duration and dosing schedule of rifamycin and use of antiretroviral therapy in the treatment of active tuberculosis in HIV-positive patients. In included studies, the initial tuberculosis diagnosis, failure, and/or relapse were microbiologically confirmed, and patients received standardized rifampin- or rifabutin-containing regimens. Pooled cumulative incidence of treatment failure, death during treatment, and relapse were calculated using random-effects models. Multivariable meta-regression was performed using negative binomial regression. RESULTS: After screening 5158 citations, 6 randomized trials and 21 cohort studies were included. Relapse was more common with regimens using 2 months rifamycin (adjusted risk ratio, 3.6; 95% confidence interval, 1.1-11.7) than with regimens using rifamycin for at least 8 months. Compared with daily therapy in the initial phase (n=3352 patients from 35 study arms), thrice-weekly therapy (n=211 patients from 5 study arms) was associated with higher rates of failure (adjusted risk ratio, 4.0; 95% confidence interval, 1.5-10.4) and relapse [adjusted risk ratio, 4.8; 95% confidence interval, 1.8-12.8). There were trends toward higher relapse rates if rifamycins were used for only 6 months, compared with > or =8 months, or if antiretroviral therapy was not used. CONCLUSIONS: This review raises serious concerns regarding current recommendations for treatment of HIV-tuberculosis coinfection. The data suggest that at least 8 months duration of rifamycin therapy, initial daily dosing, and concurrent antiretroviral therapy might be associated with better outcomes, but adequately powered randomized trials are urgently needed to confirm this.

In a systematic review of randomized controlled trials on tuberculosis treatment, Dick Menzies and colleagues find shorter courses of rifampin to be associated with poorer treatment outcomes., Background Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes. Methods and Findings PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1–2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy. Conclusions TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy. Please see later in the article for the Editors' Summary, Editors' Summary Background Tuberculosis—a contagious infection, usually of the lungs—kills nearly two million people annually. It is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with tuberculosis cough. Most people infected with M. tuberculosis do not become ill—their immune system contains the infection. However, the bacteria remain dormant within the body and can cause tuberculosis years later if immunity declines because of, for example, infection with HIV (the virus that causes AIDS). The symptoms of tuberculosis include a persistent cough, weight loss and night sweats. The disease can usually be cured by taking several powerful antibiotics regularly for several months although drug-resistant tuberculosis is increasingly widespread. The standardized drug regimen recommended by the World Health Organization (WHO) for previously uninfected patients consists of an initial treatment phase, in which rifampin, isoniazid, ethambutol, and pyrazinamide are taken daily or thrice weekly for 2 months, and a continuation phase, in which two antibiotics are taken for a further 4–6 months. Why Was This Study Done? Resistance to rifampicin, which can develop if this drug is not taken regularly, is associated with poor treatment outcomes, particularly in patients infected with isoniazid-resistant M. tuberculosis. WHO recommends, therefore, that health-care workers watch patients take all their doses of rifampicin (“directly observed therapy”). Treatment regimens for tuberculosis that use rifampicin only during the initial phase and/or give rifampicin several times a week (intermittently) rather than daily would make direct observation of treatment much easier but are such regimens effective? In this study (which, together with two similar studies, was commissioned by WHO to provide the evidence needed for a revision of their treatment guidelines), the researchers undertook a systematic review (a search using specific criteria to identify relevant research studies, which are then appraised and analyzed according to an explicit protocol) and a meta-analysis (a statistical approach that pools the results of several studies) of published trials of various rifampicin-containing regimens for the treatment of tuberculosis in previously untreated patients. What Did the Researchers Do and Find? The researchers identified 57 randomized controlled trials (studies in which groups of patients are randomly assigned to different interventions) that reported the treatment failure and/or relapse rates (determined by seeing whether M. tuberculosis could be grown from sputum brought up from the lungs by coughing, so-called bacteriologically confirmed tuberculosis) associated with various rifampicin-containing treatment regimens. In their statistical analysis of the results of these trials (which involved more than 21,000 previously untreated patients), the researchers found that regimens that used rifampicin during only the first 1–2 months of treatment had higher rates of failure, relapse, and acquired drug resistance than regimens that used rifampicin for 6 months. Indeed, relapse rates decreased with the duration of rifampicin treatment up to 8 months of treatment. Furthermore, outcomes were particularly bad with regimens that included rifampicin during only the first 1–2 months of treatment if there was initial resistance to isoniazid and/or streptomycin (another antibiotic). Outcomes were similar, however, in regimens in which rifampicin was given daily throughout treatment, daily during the initial phase then twice or thrice weekly, or thrice weekly throughout treatment; insufficient evidence was available to evaluate the efficacy of regimens in which rifampicin was given twice weekly throughout treatment. What Do These Findings Mean? These findings suggest that tuberculosis treatment regimens for previously untreated patients who use rifampicin during only the first two months of treatment should be phased out and replaced by regimens that use rifampicin for 6 months, particularly in settings where there is likely to be resistance to isoniazid and/or streptomycin. This recommendation will be made in the planned 2009 revision of the WHO tuberculosis treatment guidelines. In addition, these findings suggest that giving rifampicin thrice weekly is as effective as giving it daily during the initial phase or throughout treatment. Importantly, these findings also indicate that more trials are needed to investigate other dosing schedules, to determine the optimal duration of treatment, and to determine the best way to manage patients infected with isoniazid-resistant bacteria. Finally, since very few of the trials identified in the systematic review included HIV-positive participants, trials designed to test drug regimens in people infected with both HIV and M. tuberculosis are urgently needed to reduce global deaths from tuberculosis. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000146. The results of another WHO-commissioned study into the treatment of tuberculosis are presented in a separate PLoS Medicine Research Article by Menzies et al. (Menzies D, Benedetti A, Paydar A, Royce S, Pai M, et al. (2009) Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis. PLoS Med 6(9): e1000150. doi:10.1371/journal.pmed.1000150) The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis The US Centers for Disease Control and Prevention provide several facts sheets and other information resources about tuberculosis The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America have published guidelines on TB treatment The 2003 (2004 revision) WHO guidelines for national programs for the treatment of tuberculosis are available; WHO also provides information on efforts to reduce the global burden of tuberculosis (in several languages) and its 2009 annual report on global control of tuberculosis describes the current situation (key points are available in several languages) The WHO publishes guidelines on TB treatment

Nucleophilic substitution reactions of small rings incorporating selenium are examined using computational methods. The potential energy surfaces of HS- and HSe- with 1,2-diselenirane, 1,2-diselenetane, 1,2-diselenolane, and 1,2-diselenane were computed at B3LYP/6-31+G(d) and MP2/6-31+G(d). The reactions of three-, four-, five-, and six-membered rings incorporating the S-Se bond with HS- were computed at B3LYP/6-31+G(d). The strained three- and four-membered diselenides and selenenyl sulfide rings undergo SN2 reactions, while the five- and six-membered rings react via the addition-elimination pathway, a path that invokes a hypercoordinate selenium intermediate. The strain in the small rings precludes the addition of a further ligand to either heteroatom. Substitution at selenium is both kinetically and thermodynamically favored over attack at sulfur.

Background Immigrants to the U.S. are required to undergo overseas screening for tuberculosis (TB), but the value of evaluation and treatment following entry to the U.S. is not well understood. We determined the cost-effectiveness of domestic follow-up of immigrants identified as tuberculosis suspects through overseas screening. Methods Using a stochastic simulation for tuberculosis reactivation, transmission, and follow-up for a hypothetical cohort of 1000 individuals, we calculated the incremental cost-effectiveness of follow-up and evaluation interventions. We utilized published literature, California Reports of Verified Cases of Tuberculosis (RVCTs), demographic estimates from the California Department of Finance, Medicare reimbursement, and Medi-Cal reimbursement rates. Our target population was legal immigrants to the United States, our time horizon is twenty years, and our perspective was that of all domestic health-care payers. We examined the intervention to offer latent tuberculosis therapy to infected individuals, to increase the yield of domestic evaluation, and to increase the starting and completion rates of LTBI therapy with INH (isoniazid). Our outcome measures were the number of cases averted, the number of deaths averted, the incremental dollar cost (year 2004), and the number of quality-adjusted life-years saved. Results Domestic follow-up of B-notification patients, including LTBI treatment for latently infected individuals, is highly cost-effective, and at times, cost-saving. B-notification follow-up in California would reduce the number of new tuberculosis cases by about 6–26 per year (out of a total of approximately 3000). Sensitivity analysis revealed that domestic follow-up remains cost-effective when the hepatitis rates due to INH therapy are over fifteen times our best estimates, when at least 0.4 percent of patients have active disease and when hospitalization of cases detected through domestic follow-up is no less likely than hospitalization of passively detected cases. Conclusion While the current immigration screening program is unlikely to result in a large change in case rates, domestic follow-up of B-notification patients, including LTBI treatment, is highly cost-effective. If as many as three percent of screened individuals have active TB, and early detection reduces the rate of hospitalization, net savings may be expected.

David Horne and colleagues’ systematic review and meta-analysis, of sputum monitoring during tuberculosis treatment for predicting outcomes, deals with an important topic. However, we disagree with some methodological aspects, which might have introduced important biases. We believe, on the basis of relevant references on systematic reviews and meta-analysis, that the search strategy used was not the most appropriate; it led to the high number of studies selected in the initial search (n=12 369) and makes reproducibility of the search questionable. Moreover, a one-by-one selection of relevant trials among 12 369 titles or abstracts is much more prone to mistakes. In our opinion, the strategy could have been more specifi c (including more terms or restrictions), without loss of search sensitivity. Another concern is about the fi gure used to show the study selection process. From the description of the included studies, how 15 papers resulted in 28 studies was unclear; the study selection information was not clearly explained during the development of the paper either, which allows for diff erent potential interpretations by readers. It was also unclear as to how the authors dealt with non-English papers. Initially exclusion criteria included a language restriction (only English), but in the second search round no language restrictions were used. The results of this second look, without language restrictions, were not mentioned. Considering that the studied disease largely aff ects underdeveloped non-Englishspeaking countries, relevant papers were probably not included in the meta-analysis. Finally, there was no information about whether the investigators attempted to contact the authors of studies to complete missing data, to avoid the exclusion of these studies. How unpublished studies were searched for (grey literature search) and handled were not mentioned either. Since the results of unpublished studies can systematically diff er from published and widely available studies, we believe this search is very important to prevent selection (publication) bias and ensure the systematic review’s quality.

Objectives. To describe the epidemiology and clinical characteristics of tuberculosis (TB) among children and adolescents and to define children at risk for TB. Setting. 4607 children 0 to 14 years of age and 1615 adolescents 15 to 19 years of age reported with TB in California. Methods. We analyzed surveillance data reported to the California Department of Health Services TB Control Branch from 1985 through 1995. Results. TB cases increased 22% among children 0 to 4 years of age and 66% among children 5 to 14 from 1985 through 1995. Case rates were highest among children 0 to 4 years of age (13/100 000 children), but declined from 1993 to 1995, except for black children 0 to 4 years of age. Minority children 0 to 14 years of age had case rates 6- to 34-fold higher than did white children. Pulmonary TB was the most common site of disease in all age groups (71 to 82%). TB meningitis was most common in children 0 to 4 years of age (5%). Most children (64%) did not have cultures done; however, among culture-proved cases isoniazid-resistant Mycobacterium tuberculosis was isolated in 7%. Adolescents were more likely to have cavitary pulmonary disease (24%), to be foreign-born (78%) or homeless (4%) and to have an isoniazid-resistant strain isolated (13%) than were children 0 to 14 years of age (P Conclusions. TB in children and adolescents increased substantially in the mid-1980s and early 1990s. Pediatric TB remains a serious health problem, especially among minority children and adolescents. Our findings indicate that TB control programs need improved strategies to prevent infection and detect disease in this population.

Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen., Background A standardized regimen recommended by the World Health Organization for retreatment of active tuberculosis (TB) is widely used, but treatment outcomes are suspected to be poor. We conducted a systematic review of published evidence of treatment of patients with a history of previous treatment or documented isoniazid mono-resistance. Methods and Findings PubMed, EMBASE, and the Cochrane Central database for clinical trials were searched for randomized trials in previously treated patients and/or those with with mono-resistance to isoniazid, published in English, French, or Spanish between 1965 and June 2008. The first two sources were also searched for cohort studies evaluating specifically the current retreatment regimen. In studies selected for inclusion, rifampin-containing regimens were used to treat patients with bacteriologically confirmed pulmonary TB, in whom bacteriologically confirmed failure and/or relapse had been reported. Pooled cumulative incidences and 95% CIs of treatment outcomes were computed with random effects meta-analyses and negative binomial regression. No randomized trials of the currently recommended retreatment regimen were identified. Only six cohort studies were identified, in which failure rates were 18%–44% in those with isoniazid resistance. In nine trials, using very different regimens in previously treated patients with mono-resistance to isoniazid, the combined failure and relapse rates ranged from 0% to over 75%. From pooled analysis of 33 trials in 1,907 patients with mono-resistance to isoniazid, lower failure, relapse, and acquired drug resistance rates were associated with longer duration of rifampin, use of streptomycin, daily therapy initially, and treatment with a greater number of effective drugs. Conclusions There are few published studies to support use of the current standardized retreatment regimen. Randomized trials of treatment of persons with isoniazid mono-resistance and/or a history of previous TB treatment are urgently needed. Please see later in the article for the Editors' Summary, Editors' Summary Background Every year, nearly ten million people develop tuberculosis—a contagious infection, usually of the lungs—and about 2 million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, fever, weight loss, and night sweats. Diagnostic tests for tuberculosis include chest X-rays and sputum slide exams and cultures in which bacteriologists try to grow M. tuberculosis from mucus brought up from the lungs by coughing. The disease can be cured by taking several powerful antibiotics regularly (daily or several times a week) for at least 6 months. However, 10%–20% of patients treated for tuberculosis in low- and middle-income countries need re-treatment because the initial treatment fails to clear M. tuberculosis from their body or because their disease returns after they have apparently been cured (treatment relapse). Patients who need re-treatment are often infected with bacteria that are resistant to one or more of the antibiotics commonly used to treat tuberculosis. Why Was This Study Done? As part of its strategy to reduce the global burden of tuberculosis, the World Health Organization (WHO) recommends standardized treatment regimens for tuberculosis. For re-treatment, WHO recommends an 8-month course of isoniazid, rifampin, and ethambutol with pyrazinamide and streptomycin added for the first 3 and 2 months, respectively. All these drugs are given daily (the preferred regimen) or three times a week. Unfortunately, although this regimen is now used to treat about 1 million patients each year, it yields poor results, particularly in regions where drug resistance is common. In this study (which was commissioned by WHO to provide the evidence needed for a revision of its treatment guidelines), the researchers undertake a systematic review (a search using specific criteria to identify relevant research studies, which are then appraised) and a meta-analysis (a statistical approach that pools the results of several studies) of randomized trials and cohort studies (two types of study that investigate the efficacy of medical interventions) of re-treatment regimens in previously treated tuberculosis patients, and in patients with infection that was resistant to isoniazid (“mono-resistance”). What Did the Researchers Do and Find? The researchers' systematic search for published reports of randomized trials and cohort studies of the currently recommended re-treatment regimen identified no relevant randomized trials and only six cohort studies. In the three cohort studies in which the participants carried M. tuberculosis strains that were sensitive to all the antibiotics in the regimen, failure rates were generally low. However, in the studies in which the participants carried drug-resistant bacteria, failure rates ranged from 9% to 45%. The researchers also identified and analyzed the results of nine trials in which several re-treatment regimens, all of which deviated from the standardized regimen, were used in previously treated patients with isoniazid mono-resistance. In these trials, the combined failure and relapse rates ranged from 0% to more than 75%. Finally, the researchers analyzed the pooled results of 33 trials that investigated the effect of various regimens on nearly 2,000 patients (some receiving their first treatment for tuberculosis, some being re-treated) with isoniazid mono-resistance. This meta-analysis showed that lower relapse, failure, and acquired drug resistance rates were associated with longer duration of rifampicin treatment, use of streptomycin, daily therapy early in the treatment, and regimens that included a greater number of drugs to which the M. tuberculosis carried by the patient were sensitive. What Do These Findings Mean? These findings reveal that there is very little published evidence that supports the regimen currently recommended by WHO for the re-treatment of tuberculosis. Furthermore, this limited body of evidence is a patchwork of results gleaned from a few cohort studies and a set of randomized trials not specifically designed to test the efficacy of the standardized regimen. There is an urgent need, therefore, for a concerted international effort to initiate randomized trials of potential treatment regimens in both previously untreated and previously treated patients with all forms of drug-resistant tuberculosis. Because these trials will take some time to complete, the limited findings of the meta-analysis presented here may be used in the meantime to redesign and, hopefully, improve the current standardized re-treatment regimen. In fact, the revised WHO TB treatment guidelines will provide updated recommendations for patients with previously treated TB. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000150. The results of another WHO-commissioned study into the treatment of tuberculosis are presented in a separate PLoS Medicine Research Article by Menzies et al. (Menzies D, Benedetti A, Paydar A, Martin I, Royce S, et al. (2009) Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis. PLoS Med 6(9): e1000146.) The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America offer guidelines on TB treatment The US Centers for Disease Control and Prevention provide several facts sheets and other information resources about tuberculosis The 2003 (2004 revision) WHO guidelines for national programs for the treatment of tuberculosis are available; WHO also provides information on efforts to reduce the global burden of tuberculosis (in several languages) and its 2009 annual report on global control of tuberculosis describes the current situation (key points are available in several languages) The WHO publishes guidelines on TB treatment For guidelines on drug susceptibility testing (DST) and other information on TB diagnostic tests, the Stop TB Partnership's New Diagnostics Working Group has created a new Web site called Evidence-Based Tuberculosis Diagnosis

A 34-year-old chemical manufacturing worker had new onset of work-related asthma after several years of exposure to the fungicide, captafol. On specific bronchial challenge testing, he demonstrated a marked and persistent fall in FEV1. Cessation of exposure resulted in improved symptoms and pulmonary function. The delay in symptoms after several years of workplace exposure and the dual reaction demonstrated on specific bronchial challenge testing suggest sensitization to some component of technical-grade captafol, but an IgE response was not detected.

Objectives. Childhood tuberculosis (TB) is an important indicator of public health success in interrupting and preventing TB transmission. To determine the frequency and types of missed opportunities for preventing TB among children Methods. We collected data from the public health records of child TB cases and their adult source cases. These children were from health jurisdictions where TB case rates in children were higher than the California average for this age group. Results. We reviewed the records for 165 children reported with TB (20% confirmed by culture). These children were evaluated for TB because of signs or symptoms of illness (32%), a contact investigation (26%), screening (22%), a source case investigation (4%), and unknown reasons (16%). Excluding 4 children infected byMycobacterium bovis, only 59 of 161 children (37%) had a source case found. Children found in a contact investigation, born in the United States, Conclusions. Important missed opportunities to prevent TB in children include the failure to find and appropriately manage adult source cases and failure to completely evaluate and properly treat children exposed to TB. Improvements in case detection, case management, and contact investigations are necessary to eliminate TB in children.

Context. —Patient with tuberculosis (TB) who are persistently nonadherent to treatment present a public health risk. In 1993, California created a new civil detention process and allowed detention of noninfectious but persistently nonadherent patients. Objectives. —To determine (1) which patients TB controllers attempt to detain, (2) how often and where patients are detained, and (3) how many of these patients complete TB treatment. Design. —Case series with cross-sectional comparison to other adult TB patients in the study counties. Setting. —Twelve California counties with the largest number of new TB cases reported in 1994. Subjects. —All patients whom TB controllers sought to detain during 1994 and 1995 because of persistent nonadherence to treatment. Data Sources. —Public health records, interviews with county TB officials, and Reports of Verified Cases of Tuberculosis to the California Tuberculosis Control Branch. Results. —Tuberculosis controllers sought the civil detention or arrest of 67 patients during the study period (1.3% of adult TB patients with the same disease sites). Forty-six percent of these patients were homeless, 81% had drug or alcohol abuse, and 28% had mental illness. Tuberculosis controllers sought civil detention of 15 patients. Fourteen patients were detained (median length of detention, 14.5 days). Tuberculosis controllers sought to arrest 62 patients during the study period. Fifty-three patients were arrested (median time in jail, 83 days). In 10 cases, both civil and criminal detention were attempted. We analyzed completion of therapy after excluding patients who were not detained or who died or moved. Overall, 41 (84%) of the remaining 49 detained patients completed therapy. Of the patients who completed therapy, only 17 were detained until treatment was completed. Compared with other TB patients in these counties, detained patients had 4 times the proportion lost to follow-up and half the proportion completing therapy within 12 months. Conclusion. —Further improvements in the care of persistently nonadherent patients may require more psychosocial services, appropriate facilities for civil detention, and detaining patients long enough to assure completion of treatment.