Quantification of multidrug-resistant M. tuberculosis bacilli in sputum during the first 8 weeks of treatment.

SETTING: Mulago Hospital, Kampala, Uganda.OBJECTIVE: To quantify Mycobacterium tuberculosis in sputum during the first 8 weeks of pulmonary multidrug-resistant TB (MDR-TB) treatment.DESIGN: We enrolled consecutive adults with pulmonary MDR-TB treated according to national guidelines. We collected overnight sputum samples before treatment and weekly. Sputum samples were cultured on Middlebrook 7H11S agar to measure colony-forming units per mL (cfu/mL) and in MGIT™ 960™ media to measure time to detection (TTD). Linear mixed-effects regression was used to estimate the relational change in log10 cfu/mL and TTD.RESULTS: Twelve adults (median age: 27 years) were enrolled. Half were women, and two-thirds were HIV-positive. At baseline, median log10 cfu/mL was 5.1, decreasing by 0.29 log10 cfu/mL/week. The median TTD was 116.5 h, increasing in TTD by 36.97 h/week. The weekly change was greater in the first 2 weeks (-1.04 log10 cfu/mL/week and 120.02 h/week) than in the remaining 6 weeks (-0.17 log10 cfu/mL/week and 26.11 h/week).CONCLUSION: Serial quantitative culture measures indicate a slow, uneven rate of decline in sputum M. tuberculosis over 8 weeks of standardized pulmonary MDR-TB treatment.

What will it take to eliminate drug-resistant tuberculosis?

Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

Low body mass index and latent tuberculous infection: a systematic review and meta-analysis.

BACKGROUND: The well-documented association between underweight and increased incidence of active tuberculosis (TB) has not been extended to incidence or prevalence of latent tuberculous infection (LTBI). DESIGN: After identifying studies that reported a categorical measure of body mass index (BMI) and used the tuberculin skin test (TST) or QuantiFERON®-TB Gold In-Tube (QFT) to measure LTBI, a maximum likelihood random-effects model was used to examine the pooled association between LTBI and low BMI (<18.5 kg/m2), compared with 1) normal BMI (18.5-25 kg/m2) and 2) a complementary group of all others, i.e., non-underweight subjects (BMI 18.5 kg/m2). RESULTS: Among studies using TST, the odds ratios (ORs) showed a slight, non-statistically significant decrease in the odds of TST positivity in underweight persons compared with both groups (non-underweight, OR 0.88, 95%CI 0.73-1.05; normal weight, OR 0.96, 95%CI 0.77-1.20). Among studies using QFT, the OR suggested slightly decreased, yet non-significant, odds of QFT positivity in underweight compared with non-underweight subjects (OR 0.92, 95%CI 0.68-1.26), and significantly decreased odds of QFT positivity in underweight compared with normal weight subjects (OR 0.84, 95%CI 0.73-0.98). CONCLUSION: These results suggest that underweight persons are not at an increased risk of LTBI. Screening this population for LTBI would not increase the yield of identified LTBI.

Loss to follow-up among patients receiving anti-tuberculosis treatment, Haiti, 2011-2015.

Setting: Tuberculosis (TB) treatment facilities in Haiti. Objective: To assess factors associated with loss to follow-up (LTFU) among patients receiving treatment for tuberculosis (TB) in Haiti. Design: We analyzed Haiti's national surveillance data for patients started on anti-tuberculosis treatment from 2011 to 2015 to determine factors associated with LTFU using multivariable logistic regression and describe LTFU in terms of subnational units to target future intervention strategies. We also conducted a survival analysis to estimate hazard ratios of factors associated with time to LTFU. Results: Of 81 490 TB cases reported, 7423 (9.1%) were LTFU during anti-tuberculosis treatment, increasing from 7.1% in 2011 to 10.3% in 2015. Six high-volume facilities had significantly higher rates of LTFU (14.3-31.9%) than the rest of the country, accounting for 18.8% of all TB cases reported, but 41.7% of all LTFU patients. Male sex, previous treatment history, and human immunodeficiency virus infection were associated with higher rates of LTFU. The median time to LTFU was 94 days. Conclusion: A small number of facilities accounted for disproportionately high rates of LTFU. These results identify characteristics of facilities and individuals leading to concentrated interventions to reduce LTFU and improve treatment success.

Contexte : Structures de traitement de la tuberculose (TB) en Haïti.Objectif : Evaluer les facteurs associés à la perte de vue (LTFU) parmi les patients recevant un traitement de TB en Haïti.Schéma : Nous avons analysé les données de surveillance nationale de Haïti pour les patients mis sous traitement de TB entre 2011 et 2015, afin de déterminer les facteurs associés aux LTFU grâce à une régression logistique multivariée, et nous avons décrit les LTFU par unités sous-nationales afin de cibler les stratégies d'intervention futures. Nous avons également réalisé une analyse de survie afin d'estimer les ratios de risque des facteurs associés au délai de LTFU.Résultats : Sur 81 490 cas de TB rapportés, 7423 (9,1%) ont été perdus de vue pendant le traitement de TB, augmentant de 7,1% en 2011 à 10,3% en 2015. Six structures à haut débit de patients ont eu des taux de LFTU significativement plus élevés (14,3­31,9%) que le reste du pays, représentant 18,8% de tous les cas de TB rapportés, mais 41,7% de tous les patients perdus de vue. Le sexe masculin, des antécédents de traitement préalable, et une infection au virus de l'immunodéficience humaine ont été associés à des taux plus élevés de LTFU. Le délai médian de LTFU a été de 94 jours.Conclusion : Un petit nombre de structures ont des taux disproportionnellement élevés de LTFU. Ces résultats identifient les caractéristiques des structures et des individus aboutissant à des interventions ciblées afin de réduire les LTFU et d'améliorer le taux de succès du traitement.

Marco de referencia: Establecimientos de tratamiento de la tuberculosis (TB) en Haití.Objetivo: Evaluar los factores que se asocian con la pérdida durante el seguimiento (LTFU) de los pacientes que reciben tratamiento antituberculoso en Haití.Método: Se analizaron los datos nacionales de vigilancia de los pacientes que iniciaron tratamiento antituberculoso del 2011 al 2015 en Haití, con el objeto de determinar los factores asociados con la LTFU mediante modelos de regresión logística multivariante y se describieron estas pérdidas por unidades subnacionales, con el fin de orientar las futuras estrategias de intervención. Se practicó además un análisis de supervivencia con el fin de estimar los cocientes de riesgos instantáneos de los factores asociados con el tiempo transcurrido hasta la LTFU.Resultados: De los 81 490 casos de TB notificados, se perdieron durante el seguimiento del tratamiento antituberculoso 7423 (9,1%) y se observó un aumento del 7,1% en el 2011 al 10,3% en el 2015. En seis establecimientos con alta carga asistencial se encontraron tasas significativamente más altas de LTFU (14,3­31,9%) que en el resto del país y correspondieron al 18,8% de todos los casos de TB notificados, pero al 41,7% de todos los pacientes pérdidas. Los factores que se asociaron con tasas más altas de LTFU fueron el sexo masculino, el antecedente de tratamiento y la infección por el virus de la inmunodeficiencia humana. La mediana del lapso transcurrido hasta la LTFU fue 94 días.Conclusión: Un número pequeño de establecimientos contribuyó con tasas desproporcionadamente altas de LTFU. Estos resultados ponen de manifiesto las características de las instalaciones y de las personas que deben orientar las intervenciones dirigidas, encaminadas a disminuir la LTFU y mejorar el éxito terapéutico.

Annual risk of tuberculous infection measured using serial skin testing, Orel Oblast, Russia, 1991-2005.

OBJECTIVE: To compare trends in direct annual risk of tuberculous infection (ARTI) during 1991-2005 in relation to tuberculosis (TB) incidence and to indirect estimates of ARTI derived from the prevalence of tuberculin skin test (TST) positivity in schoolchildren in Orel Oblast, Russia. DESIGN: In 2005, we abstracted annual TST results and vaccination histories from a representative sample of schoolchildren in Orel Oblast, Russia, where bacille Calmette-Guerin (BCG) vaccination and annual TST of children are nearly universal. We calculated direct ARTI based on the percentage of children tested with TST conversions each year, excluding conversions following BCG vaccination. RESULTS: We analysed records from 13 206 children, with a median of 10 recorded TST results per child. The ARTI increased from 0.2% in 1991 to 1.6% in 2000, paralleling trends in TB incidence. Similar results were observed when the ARTI was estimated based on prevalence of infection among children aged 3-5 years using a 12 mm cut-off to define TST positivity. Results differed substantially when 10 or 15 mm cut-offs were used or when prevalence was determined among children aged 6-8 years. CONCLUSION: ARTI measured through TST conversion increased as TB incidence increased in Orel Oblast. ARTI measured through serial TSTs can thus provide an indicator of changing trends in TB incidence.

Clinical characteristics, drug resistance, and treatment outcomes among tuberculosis patients with diabetes in Peru.

OBJECTIVES: Diabetes is a risk factor for active tuberculosis (TB). Data are limited regarding the association between diabetes and TB drug resistance and treatment outcomes. We examined characteristics of TB patients with and without diabetes in a Peruvian cohort at high risk for drug-resistant TB. Among TB patients with diabetes (TB-DM), we studied the association between diabetes clinical/management characteristics and TB drug resistance and treatment outcomes. METHODS: During 2005-2008, adults with suspected TB with respiratory symptoms in Lima, Peru, who received rapid drug susceptibility testing (DST), were prospectively enrolled and followed during treatment. Bivariate and Kaplan-Meier analyses were used to examine the relationships of diabetes characteristics with drug-resistant TB and TB outcomes. RESULTS: Of 1671 adult TB patients enrolled, 186 (11.1%) had diabetes. TB-DM patients were significantly more likely than TB patients without diabetes to be older, have had no previous TB treatment, and to have a body mass index (BMI) >18.5 kg/m(2) (p<0.05). In patients without and with previous TB treatment, the prevalence of multidrug-resistant TB was 23% and 26%, respectively, among patients without diabetes, and 12% and 28%, respectively, among TB-DM patients. Among 149 TB-DM patients with DST results, 104 (69.8%) had drug-susceptible TB and 45 (30.2%) had drug-resistant TB, of whom 29 had multidrug-resistant TB. There was no association between diabetes characteristics and drug-resistant TB. Of 136 TB-DM patients with outcome information, 107 (78.7%) had a favorable TB outcome; active diabetes management was associated with a favorable outcome. CONCLUSIONS: Diabetes was common in a cohort of TB patients at high risk for drug-resistant TB. Despite prevalent multidrug-resistant TB among TB-DM patients, the majority had a favorable TB treatment outcome.

Performance of Cepheid ® Xpert MTB/RIF ® and TB-Biochip ® MDR in two regions of Russia with a high prevalence of drug-resistant tuberculosis.

The purpose of this study was to assess the performance of Cepheid® Xpert MTB/RIF® ("Xpert") and TB-Biochip® MDR ("TB-Biochip"). Sputum specimens from adults with presumptive tuberculosis (TB) were homogenized and split for: (1) direct Xpert and microscopy, and (2) concentration for Xpert, microscopy, culture [Lowenstein-Jensen (LJ) solid media and Mycobacteria Growth Indicator Tube® (MGIT)], indirect drug susceptibility testing (DST) using the absolute concentration method and MGIT, and TB-Biochip. In total, 109 of 238 (45.8 %) specimens were culture-positive for Mycobacterium tuberculosis complex (MTBC), and, of these, 67 isolates were rifampicin resistant (RIF-R) by phenotypic DST and 64/67 (95.5 %) were isoniazid resistant (INH-R). Compared to culture of the same specimen, a single direct Xpert was more sensitive for detecting MTBC [95.3 %, 95 % confidence interval (CI), 90.0-98.3 %] than direct (59.6 %, 95 % CI, 50.2-68.5 %) or concentrated smear (85.3 %, 95 % CI, 77.7-91.1 %) or LJ culture (80.8 %, 95 % CI, 72.4-87.5 %); the specificity was 86.0 % (95 % CI, 78.9-91.3 %). Compared with MGIT DST, Xpert correctly identified 98.2 % (95 % CI, 91.5-99.9 %) of RIF-R and 95.5 % (95 % CI, 85.8-99.2 %) of RIF-susceptible (RIF-S) specimens. In a subset of 104 specimens, the sensitivity of TB-Biochip for MTBC detection compared to culture was 97.3 % (95 % CI, 91.0-99.5 %); the specificity was 78.1 % (95 % CI, 61.5-89.9 %). TB-Biochip correctly identified 100 % (95 % CI, 94.2-100 %) of RIF-R, 94.7 % (95 % CI, 76.7-99.7 %) of RIF-S, 98.2 % (95 % CI, 91.4-99.9 %) of INH-R, and 78.6 % (95 % CI, 52.1-94.2 %) of INH-S specimens compared to MGIT DST. Xpert and Biochip were similar in accuracy for detecting MTBC and RIF resistance compared to conventional culture methods.

Predictors of sputum culture conversion among patients treated for multidrug-resistant tuberculosis.

OBJECTIVE: To identify predictors of initial sputum culture conversion, estimate the usefulness of persistent positive cultures at different time points in predicting treatment failure, and evaluate different definitions of culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. METHODS: Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'culture conversion' on the balance between sensitivity and specificity. RESULTS: Overall, 1209/1416 (85%) of patients with baseline positive cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative cultures. CONCLUSION: Patients with identified risk factors were less likely to achieve sputum culture conversion during MDR-TB treatment.

Impact of rapid drug susceptibility testing for tuberculosis: program experience in Lima, Peru.

SETTING: Programmatic implementation of decentralized rapid drug susceptibility testing (DST) in Lima, Peru. OBJECTIVE: Pre-post analysis compared time to diagnosis, treatment outcome and survival among patients tested with direct nitrate reductase assay (NRA) vs. indirect conventional methods. DESIGN: From 2005 to 2009, we prospectively followed all patients referred for DST before (control) and after (intervention) NRA implementation. Among those referred for DST, NRA was used for smear-positive samples of patients with no prior history of multidrug resistance or treatment for multidrug-resistant tuberculosis (TB). Data were abstracted from patient charts and laboratory registers. Endpoints were favorable outcomes, time to result and time to death. RESULTS: Of those patients who met the criteria for NRA, 740 underwent NRA and 621 underwent conventional DST. NRA yielded test results for 78.4% of cases vs. 68.8% for conventional DST (P < 0.0001); the median time to result was 44 vs. 133 days, respectively (adjusted HR 0.64, 95%CI 0.56-0.73). Among individuals without previous anti-tuberculosis treatment, NRA was associated with a favorable treatment outcome (adjusted OR 1.39, 95%CI 1.01-1.90) and prolonged survival (adjusted HR 0.53, 95%CI 0.31-0.90). CONCLUSION: Direct NRA significantly shortened time to test result and improved treatment outcomes and survival in certain groups.

Impact of second-line drug resistance on tuberculosis treatment outcomes in the United States: MDR-TB is bad enough.

SETTING: The worldwide emergence of extensively drug-resistant tuberculosis (TB) has focused attention on treatment with second-line drugs (SLDs). OBJECTIVE: To determine the impact on outcomes of resistance to individual SLDs, we analyzed successful treatment completion and death among drug-resistant TB cases in the US national TB surveillance system, 1993-2007 (N = 195 518). DESIGN: We defined four combinations of first-line drug (FLD) resistance based on isoniazid (INH) and rifamycin, and three patterns of SLD resistance: fluoroquinolones, injectable SLDs and other oral SLDs. We compared treatment outcomes of cases by FLD resistance, with and without each pattern of SLD resistance. RESULTS: In all but one instance, cases with FLD resistance but no SLD resistance had better outcomes than cases with SLD resistance. Rifamycin resistance, alone or with INH, resulted in a greater decline in treatment completion and greater increase in deaths than resistance to SLDs. Among patients with multidrug-resistant TB, additional resistance to injectable SLDs was statistically significant. Outcomes were better for human immunodeficiency virus (HIV) negative than HIV-positive cases for all resistance patterns, but improved among HIV-infected cases after 1998, when highly active antiretroviral treatment became widely available. CONCLUSION: These results suggest that the effect of rifamycin resistance may outweigh the more modest effects of resistance to specific SLDs.

Outcomes and follow-up of patients treated for multidrug-resistant tuberculosis in Orel, Russia, 2002-2005.

SETTING: Multidrug-resistant tuberculosis (MDR-TB) treatment facility, Orel Oblast, Russian Federation. OBJECTIVES: To determine factors associated with poor outcome and to document status of patients after recording of TB outcomes. DESIGN: Retrospective review of prospective single cohort. RESULTS: Among 192 patients, factors significantly associated with poor outcome in multivariate analysis include three or more treatment interruptions during the intensive phase of therapy and alcohol or drug addiction (adjusted OR [aOR] 2.1, 95%CI 1.0-4.3 and aOR 1.9, 95%CI 1.0-3.7). Previous treatment was associated with poor outcome, but only among smear-positive patients (aOR 3.1, 95%CI 1.3-7.3). Ten patients (5%) developed extensively drug-resistant TB (XDR-TB) during treatment; of 115 patients with at least 6 months of follow-up data after outcomes were recorded, 13 (11%) developed XDR-TB. CONCLUSION: Interventions focused on supporting patient adherence during the intensive phase of treatment; the management of drug and alcohol addiction should be developed and studied. A substantial proportion of patients developed XDR-TB during and after treatment. Longer term follow-up data of patients treated for MDR-TB are needed to better inform programmatic policy.

Rifampicin-resistant Mycobacterium tuberculosis: susceptibility to isoniazid and other anti-tuberculosis drugs.

Based on data from 14 Supranational Tuberculosis (TB) Reference Laboratories worldwide, the proportion of rifampicin (RMP) resistant isolates that were isoniazid (INH) susceptible by phenotypic drug susceptibility testing varied widely (0.5-11.6%). RMP-resistant isolates that were INH-susceptible had significantly lower rates of resistance to other first- and second-line anti-tuberculosis drugs (except rifabutin) compared to multidrug-resistant isolates. RMP resistance is not always a good proxy for a presumptive diagnosis of multidrug-resistant TB, which has implications for use of molecular assays that identify only RMP resistance-associated DNA mutations.

Global isoniazid resistance patterns in rifampin-resistant and rifampin-susceptible tuberculosis.

Following the World Health Organization's endorsement of the Xpert® MTB/RIF assay, which rapidly and simultaneously diagnoses tuberculosis (TB) and detects resistance to rifampin (RMP), the question arises to what extent RMP resistance is an adequate marker for multidrug-resistant TB (MDR-TB). A retrospective analysis of data from >81 countries and subnational settings demonstrated that >40% of RMP-resistant isolates from new TB cases did not display resistance to isoniazid (INH) in settings with relatively low MDR-TB prevalence (one third of all countries and subnational settings). Results indicated the need for INH susceptibility testing in addition to RMP susceptibility testing.

Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment.

Monthly culture is usually recommended to monitor treatment of multidrug-resistant tuberculosis (MDR-TB). As mycobacterial laboratory capacity is limited in many settings, TB programs need evidence to decide whether monthly cultures are necessary compared to other approaches. We simulated three alternative monitoring strategies (culture every 2 or 3 months, and monthly smears alone) in a cohort of MDR-TB patients in Estonia, Latvia, Philippines, Russia and Peru from 2000 to 2004. This retrospective analysis illustrated that less frequent testing delays confirmation of bacteriological conversion. This would prolong intensive treatment, hospitalization and respiratory isolation, increasing cost and toxicity. After conversion, less frequent testing could delay diagnosis of possible treatment failure.

Global policies and practices for managing persons exposed to multidrug-resistant tuberculosis.

SETTING: In the 1960s, treatment for latent tuberculosis infection (LTBI) with isoniazid proved to be so effective, safe, and inexpensive that research into alternative treatments virtually ceased. Now that multidrug-resistant tuberculosis (MDR-TB) is widespread, no data are available to guide the management of persons exposed to MDR-TB (contacts). METHODS: We surveyed National TB Program directors and MDR-TB program managers about current practices for managing MDR-TB contacts in countries with an MDR-TB prevalence of >2% in new patients and those with programs for managing MDR-TB. RESULTS: Of 35 countries that met the survey criteria, 25 (71%) responded; 24 of these (96%) have a guideline for managing TB contacts. Of these, 19 (76%) usually or always evaluated contacts and treated LTBI. In contrast, 10 (40%) countries reported having a guideline for managing MDR-TB contacts, 11 (44%) usually or always evaluated MDR-TB contacts, and 9 (36%) treated LTBI. Only two (8%) used a regimen that has activity against MDR-TB. Lack of evidence or guidelines was the main reason for not treating MDR-TB contacts. CONCLUSIONS: Management of MDR-TB contacts is inconsistent and ineffective due to lack of evidence-based guidelines. There is an urgent need to generate evidence to guide policy.