Tuberkulose

Immigration from areas of high incidence is thought to have fueled the resurgence of tuberculosis (TB) in areas of low incidence. To reduce the risk of disease in low-incidence areas, the main countermeasure has been the screening of immigrants on arrival. This measure is based on the assumption of a prompt decline in the incidence of TB in immigrants during their first few years of residence in a country with low overall incidence. We have documented that this assumption is not true for 619 Somali immigrants reported in Denmark as having TB. The annual incidence of TB declined only gradually during the first 7 years of residence, from an initial 2,000 per 100,000 to 700 per 100,000. The decline was described by an exponential function with a half-time of 5.7 (95% confidence interval 4.0 to 9.7) years. This finding seriously challenges the adequacy of the customary practice of screening solely on arrival.

As countries approach the elimination phase of tuberculosis, specific problems and challenges emerge, due to the steadily declining incidence in the native population, the gradually increasing importance of the importation of latent tuberculosis infection and tuberculosis from other countries and the emergence of groups at particularly high risk of tuberculosis. Therefore, a Working Group of the World Health Organization (WHO), the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) have developed a new framework for low incidence countries based on concepts and definitions consistent with those of previous recommendations from WHO/IUATLD Working Groups. In low-incidence countries, a broader spectrum of interventions is available and feasible, including: 1) a general approach to tuberculosis which ensures rapid detection and treatment of all the cases and prevention of unnecessary deaths; 2) an overall control strategy aimed at reducing the incidence of tuberculosis infection (risk-group management and prevention of transmission of infection in institutional settings) and 3) a tuberculosis elimination strategy aimed at reducing the prevalence of tuberculosis infection (outbreak management and provision of preventive therapy for specified groups and individuals). Government and private sector commitment towards elimination, effective case detection among symptomatic individuals together with active case finding in special groups, standard treatment of disease and infection, access to tuberculosis diagnostic and treatment services, prevention (e.g. through screening and bacille Calmette-Guéria immunization in specified groups), surveillance and treatment outcome monitoring are prerequisites to implementing the policy package recommended in this new framework document.

Infliximab is a humanized antibody against tumor necrosis factor alpha (TNF-alpha) that is used in the treatment of Crohn's disease and rheumatoid arthritis. Approximately 147,000 patients throughout the world have received infliximab. Excess TNF-alpha in association with tuberculosis may cause weight loss and night sweats, yet in animal models it has a protective role in the host response to tuberculosis. There is no direct evidence of a protective role of TNF-alpha in patients with tuberculosis.

Does immigration from a high-prevalence area contribute to an increased risk of tuberculosis in a low-incidence country? The tuberculosis incidence in Somalia is among the highest ever registered. Due to civil war and starvation, nearly half of all Somalis have been forced from their homes, causing significant migration to low-incidence countries. In Denmark, two-thirds of all tuberculosis patients are immigrants, half from Somalia. To determine the magnitude of Mycobacterium tuberculosis transmission between Somalis and Danes, we analyzed DNA fingerprint patterns of isolates collected in Denmark from 1992 to 1999, comprising >97% of all culture-positive patients (n = 3,320). Of these, 763 were Somalian immigrants, 55.2% of whom shared identical DNA fingerprint patterns; 74.9% of these were most likely infected before their arrival in Denmark, 23.3% were most likely infected in Denmark by other Somalis, and 1.8% were most likely infected by Danes. In the same period, only 0.9% of all Danish tuberculosis patients were most likely infected by Somalis. The Somalian immigrants in Denmark could be distributed into 35 different clusters with possible active transmission, of which 18 were retrieved among Somalis in the Netherlands. This indicated the existence of some internationally predominant Somalian strains causing clustering less likely to represent recent transmission. In conclusion, M. tuberculosis transmission among Somalis in Denmark is limited, and transmission between Somalis and Danes is nearly nonexistent. The higher transmission rates between nationalities found in the Netherlands do not apply to the situation in Denmark and not necessarily elsewhere, since many different factors may influence the magnitude of active transmission.

The whole-genome fingerprinting technique, fluorescent amplified-fragment length polymorphism (FAFLP) analysis, was applied to Mycobacterium tuberculosis. Sixty-five clinical isolates were analyzed to determine the value of FAFLP as a stand-alone genotyping technique and to compare it with the well-established IS6110 typing system. The genome sequence of M. tuberculosis strain H37Rv (S. T. Cole et al., Nature 393:537-544, 1998) was used to model computer-generated informative primer combination(s), and the precision and reproducibility of FAFLP were evaluated by comparing the results of in vitro and computer-generated experiments. Multiplex FAFLP was used to increase resolving power in a predictable and systematic fashion. FAFLP analysis was broadly congruent with IS6110 typing for those strains with multiple IS6110 copies. It was also able to resolve an epidemiologically unlinked group of strains with only one copy of IS6110; up to 10% of clinical isolates may fall into this category. For certain epidemiological investigations, it was concluded that a combination of FAFLP and IS6110 typing would give higher resolution than would either alone. FAFLP data were digital, precise, reproducible, and suitable for rapid electronic dissemination, manipulation, interlaboratory comparison, and storage in national or international epidemiological databases. Because FAFLP samples and analyzes base substitution across the genome as a whole, FAFLP could generate new information about the microevolution of the M. tuberculosis complex.

To estimate the risk and prevalence of Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) incidence, prevalence, and mortality, including disease attributable to human immunodeficiency virus (HIV), for 212 countries in 1997.

The present study is based on notified cases of tuberculosis (TB) in the National tbc. register 1972-1996. A decline in Tb incidence was seen from 1972 and until the mid-1980's. Subsequently the trend has reversed due to an increasing number of TB cases in foreigners. In 1996, 60% of all cases of TB in Denmark were found in foreigners reflecting the rising number of refugees and their families arriving in Denmark from highly endemic areas, mainly Somalia. Among native Danes the TB incidence fell from 14 per 100,000 in 1972 to 4 per 100,000 in the 1980's and stabilized at this very low level. The unchanged incidence in Danes covers a falling incidence in the older and a rising incidence in the younger and middle-aged adult population, mainly in the capital. Approximately half of the cases occur in high-risk groups. The TB-epidemic is close to elimination in the indigenous Danish population, but the disease is maintained at a low level probably due to increased patient and doctor delay and resulting microepidemics primarily in high-risk populations.

Yang, D., Li, S., Stabenow, J., Zalduondo, L., Kong, Y.

Mycobacterium tuberculosis (Mtb) Rv3775 (LipE) was annotated as a putative lipase. However, its lipase activity has never been characterized and its precise role in tuberculosis (TB) pathogenesis has not been thoroughly studied to date. We overexpressed and purified the rLipE protein and demonstrated that LipE has a lipase/esterase activity. rLipE prefers medium-chain ester substrates, with the maximal activity on hexanoate. Its activity is the highest at 40 °C and pH=9. We determined that rLipE hydrolyzes trioctanoate. Using site-directed mutagenesis, we confirmed that the predicted putative activity triad residues Ser97, Gly342, and His363 are essential for the lipase activity of rLipE. Expression of lipE gene was induced under stressed conditions mimicking Mtb's intracellular niche. The gene-disrupting mutation of lipE led to significantly reduced bacterial growth inside THP-1 cells and human peripheral blood mononuclear cell derived macrophages, and attenuated Mtb infection in mice (with ~8-fold bacterial load reduction in mouse lungs). Our data suggest that LipE functions as a lipase and is important for Mtb intracellular growth and in vivo infection.…

Abstract Background Tuberculosis is an important health concern in Iraq, but limited research has examined the quality of tuberculosis care and the survival of the patients. This study aimed to assess the 12-month survival of tuberculosis patients and evaluate the effect of the associated risk factors on patients’ survival. Methods We reviewed the records of 728 patients with tuberculosis who were registered and treated at the Chest and Respiratory Disease Center in Erbil, Iraqi Kurdistan Region, from January 2012 to December 2017. Demographic data, the site of the disease, and treatment outcomes were retrieved from patients’ records. Data analysis included the use of the Kaplan–Meier method and the log-rank test to calculate the estimates of the survival and assess the differences in the survival among the patients. The Cox regression model was used for univariate and multivariate analysis. Results The mean period of the follow-up of the patients was 7.6 months. Of 728 patients with tuberculosis, 50 (6.9%) had died. The 12-month survival rate of our study was 93.1%. A statistically significant difference was detected in the survival curves of different age groups (P 

Koenig S, Kim A, Shepherd B, et al.

AbstractWe assessed association between cured tuberculosis and mortality among persons with HIV in Latin America. We compared survival among persons with and without tuberculosis at enrollment in HIV care, starting 9 months after clinic enrollment. In multivariable analysis, tuberculosis was associated with higher long-term mortality (hazard ratio=1.57; 95% confidence interval=1.25-1.99).

Chaisson, Lelia H.; Saraceni, Valeria; Cohn, Silvia; Seabrook, Dena; Cavalcante, Solange; Chaisson, Richard E.; Golub, Jonathan; Durovni, Betina

Objectives: In 2018, Brazilian guidelines changed to recommend tuberculosis (TB) preventive therapy for all people with HIV and a CD4≤350 cells/μL, but only for those with a positive tuberculin skin test (TST) if CD4> 350 cells/μL. We determined the potential effectiveness of CD4-based guidelines for TB testing and preventive therapy. Design: Secondary analysis of the stepped-wedge, cluster-randomized THRio trial for isoniazid preventive therapy (IPT). Methods: We analyzed data from 4,114 newly-registered patients with HIV in 29 clinics followed until TB diagnosis, death, or administrative censoring. We compared incidence rates of TB and TB/death between CD4, TST, IPT, and antiretroviral therapy (ART) categories. Results: Initial CD4 count was ≤350 in 2,138 (52%) and > 350 in 1,976 (48%) patients. TST was performed for 2,922 (71%), of whom 657 (16%) were TST-positive (278 [13%] CD4≤350 vs. 379 [19%] CD4> 350). A total of 619 (15%) received IPT and 2,806 (68%) received ART. For patients with CD4≤350 who did not receive IPT, the incidence rate of TB was 1.79/100 person-years (pys) and TB/death was 3.89/100pys. For patients with CD4> 350 who did not receive IPT, the incidence rates of TB and TB/death were 0.57/100pys and 1.49/100pys for TST-negatives, and 1.05/100pys and 1.64/100pys for TST-unknowns. Conclusions: TB incidence was high among all patients who did not receive IPT, including those with CD4> 350 and negative or unknown TST results. TB preventive therapy should be provided to all PLWH in medium burden settings, regardless of CD4 count and TST status. Correspondence to Jonathan Golub, PhD, Johns Hopkins University Center for Tuberculosis Research, 1550 Orleans Street, Cancer Research Building-2, Baltimore, MD 21287. Tel: +43-287-2969; e-mail: jgolub@jhmi.edu Received 13 August, 2019 Revised 3 September, 2019 Accepted 13 September, 2019 Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com). Copyright © 2019 Wolters Kluwer Health, Inc.

Naidoo K, Hassan-Moosa R, Mlotshwa P, et al.

AbstractBackgroundNew onset or worsening drug-induced liver injury challenges coinfected patients on antiretroviral therapy (ART) initiation during antituberculosis (TB) treatment.MethodsPost hoc analysis within a randomized trial, the Starting Antiretroviral Therapy at Three Points in Tuberculosis trial, was conducted. Patients were randomized to initiate ART either early or late during TB treatment or after TB treatment completion. Liver enzymes were measured at baseline, 6-month intervals, and when clinically indicated.ResultsAmong 642 patients enrolled, the median age was 34 years (standard deviation, 28–40), and 17.6% had baseline CD4+ cell counts

Abstract Background Tuberculosis (TB) remains one of the infectious diseases with a leading cause of death among adults worldwide. Metformin, a first-line medication for the treatment of type 2 diabetes, may have potential for treating TB. The aims of the present systematic review were to evaluate the impact of metformin prescription on the risk of tuberculosis diseases, the risk of latent TB infection (LTBI) and treatment outcomes of tuberculosis among patients with diabetic mellitus. Methods Databases were searched through March 2019. Observational studies reporting the effect of metformin prescription on the risk and treatment outcomes of TB were included in the systematic review. We qualitatively analyzed results of included studies, and then pooled estimate effects with 95% confidence intervals (CIs) of different outcome using random-effect meta-analyses. Results This systematic review included 6980 cases from 12 observational studies. The meta-analysis suggested that metformin prescription could decrease the risk of TB among diabetics (pooled odds ratio [OR], 0.38; 95%CI, 0.21 to 0.66). Metformin prescription was not related to a lower risk of LTBI (OR, 0.73; 95%CI, 0.30 to 1.79) in patients with diabetes. Metformin medication during the anti-tuberculosis treatment is significantly associated with a smaller TB mortality (OR, 0.47; 95%CI, 0.27 to 0.83), and a higher probability of sputum culture conversion at 2 months of TB disease (OR, 2.72; 95%CI, 1.11 to 6.69) among patients with diabetes. The relapse of TB was not statistically reduced by metformin prescription (OR, 0.55; 95%CI, 0.04 to 8.25) in diabetics. Conclusions According to current observational evidence, metformin prescription significantly reduced the risk of TB in patients with diabetes mellitus. Treatment outcomes of TB disease could also be improved by the metformin medication among diabetics.…

Following publication of the original article [1]. The authors reported that there is a mistake in Fig. 1: the number of patients in the control group its 449 patients, instead of 455.…

Stabel, J. R., Bannantine, J. P.

Infection of the host with Mycobacterium avium subsp. paratuberculosis (MAP) results in a chronic and progressive enteritis that traverses both subclinical and clinical stages. The mechanism(s) for the shift from asymptomatic subclinical disease state to advanced clinical disease are not fully understood. In the present study, naturally infected dairy cattle were defined as subclinical and clinical infection groups, along with noninfected control cows of similar parity to study host immune responses in different stages of infection. Both infection groups had higher secretion of IFN-, TNF-α, and IL-2 than control cows, whereas only clinical cows had increased secretion of IL-10, IL-12 and IL-18 upon stimulation of PBMCs with antigen. Conversely, secretion of IL-17A was decreased for clinical cows compared to subclinical and control cows. Pro-inflammatory cytokine genes were upregulated only for subclinical cows, whereas increased IL-10 and IL-17 gene expression were observed for both infection groups. Increased CD4+, CD8+ and TCR+ T cells were observed for subclinical cows compared to clinical cows. Although clinical cows expressed antigen-specific immune responses, the profile for subclinical cows was one of a dominant pro-inflammatory response to infection. We reason that a complex coordination of immune responses occurs during MAP infection, with these responses shifting as the host transitions through the different stages of infection and disease (subclinical to clinical). Further understanding of the series of events characterized by Th1/Th2/Th17 responses will provide mechanisms for disease progression and may direct insightful intervention strategies.…

M. Fellag et al.

Abstract Background In Lao People’s Democratic Republic (PDR), tuberculosis (TB) prevalence was estimated at 540/100,000 in 2011. Nevertheless, little is known about the genetic characteristics and anti-TB drug resistance of the Mycobacterium tuberculosis population. The main objective of this work was to study the genetic characteristics and drug resistance of M. tuberculosis population collected during the first National TB Prevalence Survey (TBPS) of Lao PDR (2010–2011). Methods Two hundred and twenty two isolates collected during TBPS (2010–2011) were analyzed with the GenoType MTBDRplus test for M. tuberculosis identification and drug resistance detection. Then, 206 of the 222 isolates were characterized by spoligotyping and MIRU-VNTR typing. Results Among the 222 M. tuberculosis isolates, 11 were mono-resistant to isoniazid and 2 were resistant to isoniazid and rifampicin (MDR-TB), using the GenoType MTBDRplus test. Among the 202 genetically characterized isolates, the East African-Indian (EAI) family was predominant (76.7%) followed by the Beijing (14.4%) and T (5.5%) families. EAI isolates came from all the country provinces, whereas Beijing isolates were found mainly in the northern and central provinces. A higher proportion of Beijing isolates was observed in people younger than 35 years compared to EAI. Moreover, the percentage of drug resistance was higher among Beijing (17.2%) than EAI (5.2%) isolates, and the two MDR-TB isolates belonged to the Beijing family. Combined analysis of the MIRU-VNTR and spoligotyping results (n = 202 isolates) revealed an estimated clustering rate of 11% and the occurrence of mini-outbreaks of drug-resistant TB caused by Beijing genotypes. Conclusions The EAI family, the ancient and endemic family in Asia, is predominant in Lao PDR whereas the prevalence of Beijing, the most harmful M. tuberculosis family for humans, is still low, differently from neighboring countries. However, its association with drug resistance, its presence in young patients and its potential association with recent transmission suggest that the Beijing family could change TB epidemiological pattern in Lao PDR. Therefore, efficient TB control and surveillance systems must be maintained and reinforced to prevent the emergence of highly transmissible and drug-resistant strains in Lao PDR, as observed in neighboring countries.…

Abstract Background The dual challenge of low diagnostic sensitivity of microscopy test and technical challenge of performing a TB culture test poses a problem for case detection and initiation of Tuberculosis (TB) second-line treatment. There is thus need for a rapid, reliable and easily accessible assay. This comparative analysis was performed to assess diagnostic performance characteristics of GeneXpert MTB/RIF and Line Probe Assay (LPA). Methods Three hundred twenty nine sputum samples of patients across the 47 counties in Kenya suspected to have drug resistant TB were picked and subjected to GeneXpert, LPA and Culture MGIT at the National TB Reference Laboratory. Sensitivity, specificity and predictive values were then determined to assess the performance characteristics of the various assays. Results Against culture MGIT as the gold standard for TB diagnosis, GeneXpert had a sensitivity, specificity, positive predictive value, and negative predictive value of 78.5, 64.9, 59.4 and 82.2% respectively while LPA had 98.4, 66.0, 65.4 and 98.4%. For diagnosis of rifampicin mono-resistance GeneXpert had a moderate agreement (Kappa 0.59, P 

Abstract Background In settings such as China, where universal implementation of directly observed therapy (DOT) is not feasible, innovative approaches are needed to support patient adherence to TB treatment. The electronic medication monitor (EMM) is one of the digital technologies recommended by the World Health Organization (WHO), but evidence from implementation studies remains sparse. In this study, we evaluated acceptance of the EMM among health care workers and patients while implementing the device for differential TB patient management at the community level. Methods Zhenjiang City in Jiangsu Province was purposively selected for the study. All participating patients were allowed to select their preferred management approach. If patients declined to use the EMM, DOT was offered. The EMM was designed to hold 1 month of anti-TB drugs for once-daily dosing of fixed-dose combination (FDC) tablets. Patient EMM records were monitored monthly by a physician; if 20 to 50% of doses were missed twice, or more than 50% of doses were missed once, the patient was switched to DOT. The four physicians and five nurses involved in the study at four designated hospitals were surveyed using a structured questionnaire to assess their acceptance of the EMM. Results From October 2017 through January 2018, 316 pulmonary TB patients were notified in the TB information management system, and 231 (73.1%) met the study enrollment criteria. Although 186 patients (80.5%) initially consented to use the EMM, 17 later refused to use it. Among the 169 patients who used the EMM, 15 (8.9%) were switched to DOT due to poor adherence, and the other 154 completed the treatment course. The median adherence rate was 99.3%. Surveyed health care workers from designated hospitals found the EMM acceptable, although eight of nine felt use of the device moderately increased their workload. However, the EMM program significantly reduced the workload of community physicians by reducing patient visits by 87.9%. Conclusions This study demonstrated the acceptability of using an indigenously developed EMM for differential management of TB patients at the community level. However, more operational research should be conducted before introducing and scaling the technology throughout China.…

Donnellan, S., Aljayyoussi, G., Moyo, E., Ardrey, A., Martinez-Rodriguez, C., Ward, S. A., Biagini, G. A.

Clinical studies of new anti-tubercular drugs are costly and time consuming. Owing to the extensive TB treatment periods, the ability to identify drug candidates based on their predicted clinical efficacy is vital to accelerate the pipeline of new therapies. Recent failures of pre-clinical models in predicting the activity of fluoroquinolones underlines the importance of developing new and more robust predictive tools that will optimise the design of future trials. Here, we have used high-content imaging screening and pharmacodynamic intracellular modelling (PDi) to identify and prioritise fluoroquinolones for TB treatment. In a set of studies designed to validate this approach, we show moxifloxacin to be the most effective fluoroquinolone, and PDi modelling-based Monte Carlo simulations accurately predict negative culture conversion (sputum sterilisation) rates when compared against 8-independent clinical trials. Additionally, PDi-based simulations were used to predict the risk of relapse. Our analyses show that the duration of treatment following culture conversion can be used to predict relapse rate. These data further support that PDi-based modelling offers a much-needed decision making tool for the TB drug development pipeline.…

Abstract Background Household contact tracing of index TB cases has been advocated as a key part of TB control for many years, but has not been widely implemented in many low-resource setting because of the current dearth of high quality evidence for effectiveness. Innovative strategies for earlier, more effective treatment are particularly important in contexts with hyper-endemic levels of HIV, where levels of TB infection remain extremely high. Methods We present the design of a household cluster-randomised controlled trial of interventions aimed at improving TB-free survival and reducing childhood prevalence of Mycobacterium tuberculosis infection among household contacts of index TB cases diagnosed in two provinces of South Africa. Households of index TB cases will be randomly allocated in a 1:1 ratio to receive either an intensified home screening and linkage for TB and HIV intervention, or enhanced standard of care. The primary outcome will compare between groups the TB-free survival of household contacts over 15 months. All participants, or their next-of-kin, will provide written informed consent to participate. Discussion Evidence from randomised trials is required to identify cost-effective approaches to TB case-finding that can be applied at scale in sub-Saharan Africa. Trial registration ISRCTN16006202 (01/02/2017: retrospectively registered) and NHREC4399 (11/04/2016: prospectively registered). Protocol version: 4.0 (date: 18th January 2018).…

Abstract Background Tuberculosis (TB) is a major public health problem in developing countries like Bangladesh. Female sex workers (FSWs) and their clients are active sources for spreading TB. The purpose of this study was to assess the knowledge of TB among FSWs in Rajshahi city, Bangladesh. Methods It was a cross-sectional study with a sample size of 225 FSWs. The knowledge on TB was measured by six different questions. Chi-square test and multinomial logistic regression model were used in this study to find the associated factors of lack of general knowledge on TB among FSWs. Results Out of 225 FSWs, 43.1, 34.7 and 22.2% came from urban, rural and slum areas respectively. More than 41% FSWs perceived that TB is a non-communicable disease. A large number of FSWs (76.4%) did not know the spread of TB. It was found that more than 90% FSWs did not have knowledge on latent TB. The χ2-test demonstrated that FSWs’ education, monthly family income, age, currently marital status and sex trading place were significantly associated with their knowledge on TB. A remarkable number of FWSs (42.2%) had poor knowledge on TB. It was found that comparatively higher educated FWSs were more likely to have good or fair knowledge on TB than lower educated ones (p 

Kempker, R. R., Alghamdi, W. A., Al-Shaer, M. H., Burch, G., Peloquin, C. A.

Tuberculosis (TB) and hepatitis C virus (HCV) infection are both major public health problems. Despite high rates of co-infection there is scarce literature addressing the convergence of the two diseases. One particularly unexplored area is the potential for simultaneous treatment of TB and HCV which would allow for leveraging an extensive global TB treatment infrastructure to help scale up HCV treatment. We review the drug metabolism of anti-TB and HCV drugs and the known and potential drug-drug interactions between recommended HCV regimens and individual anti-TB drugs. Rifampin is the only anti-TB drug to have been formally studied for potential drug interactions with anti-HCV direct-acting antivirals (DAAs) and existing data precludes these combinations. However, based on known pathways of drug metabolism and enzyme effects, the combination of HCV DAA regimens with all other anti-TB drugs may be feasible. Pharmacokinetic studies are needed next to help move co treatment regimens forward for clinical use among patients coinfected with TB and HCV.…

Singh N.

Mariana Bento Tatara, João Perdigão, Miguel Viveiros, Afrânio Kritski, Kesia Esther da Silva, Flávia Patussi Correia Sacchi, Camila Camioli de Lima, Paulo César Pereira dos Santos, Jaciara de Lourdes do Carmo Guimarães Diniz, Pedro Eduardo Almeida Silva, Pedro Gomes, Mônica Maria Quirino Gomes, Eunice Atsuko Totumi Cunha, José Roberto Lapa e Silva, Isabel Portugal, Julio Croda and Monica Kramer de N. Andrade

Abstract. National border areas are special places for the spread of Mycobacterium tuberculosis (MTB). These regions concentrate vulnerable populations and constant population movements. Understanding the dynamics of the transmission of MTB is fundamental to propose control measures and to monitor drug resistance. We conducted a population-based prospective study of tuberculosis (TB) to evaluate molecular characteristics of MTB isolates circulating in Roraima, a state on the border of Venezuela and Guyana. Eighty isolates were genotyped by IS6110-RFLP (restriction fragment length polymorphism), spoligotyping, and 24-locus mycobacterial interspersed repetitive unit-variable number of repeats tandem (MIRU-VNTR). Drug susceptibility tests were performed by using the proportion method and GeneXpert® MTB/RIF (Cepheid, Sunnyvale, CA). Isolates showing a phenotypic resistance profile were submitted to polymerase chain reaction (PCR) and sequencing. Spoligotyping showed 40 distinct patterns with a high prevalence of Latin-American and Mediterranean (LAM), Haarlem (H), and the “ill-defined” T clades. Mycobacterial interspersed repetitive unit -VNTR and IS6110-RFLP showed clustering rates of 21.3% and 30%, respectively. Drug resistance was detected in 11 (15.1%) isolates, and all were found to have primary resistance; among these, six (8.2%) isolates were streptomycin mono-resistant, four (5.4%) isoniazid mono-resistant, and one (1.3%) multidrug resistant. This is the first study on the molecular epidemiology and drug resistance profile of MTB from Roraima. Herein, we describe high diversity of genetic profiles circulating in this region that may be driven by the introduction of new strain types because of large population flow in this region. In summary, our results showed that analyses of these circulating strains can contribute to a better understanding of TB epidemiology in the northern Brazilian border and be useful to establish public health policies on TB prevention.…

Lyons, M. A.

Pretomanid (PA-824) is a nitroimidazole in clinical testing for the treatment of tuberculosis. A population pharmacodynamic model for pretomanid was developed using a Bayesian analysis of efficacy data from two early bactericidal activity (EBA) studies, PA-824-CL-007 and PA-824-CL-010, conducted in Cape Town, South Africa. The two studies included 122 adult male and female participants with newly diagnosed pulmonary tuberculosis who received once daily oral pretomanid doses of either 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The structural model described capacity-limited growth and saturable drug-induced bacterial killing with separate rate equations for sputum solid culture colony forming unit (CFU) counts and liquid culture time to positivity (TTP) that were linked through a time constant. The posterior population geometric means and interindividual variability percent coefficients of variation were, respectively; 0.152±0.013 log10 CFU/mL sputum/day and 54%±6% for the maximum kill rate constant, 20.4±1.0 h and 20.8%±0.1% for the time constant of proportionality between the CFU and TTP rate equations, and 770±140 ng/mL and 48%±17% for the pretomanid half-maximum effect plasma concentration. Model simulations showed once daily pretomanid at 100 mg, 200 mg, and 300 mg, attained 58%, 73%, and 80%, respectively, of an expected maximum 14-day EBA of 0.136 log10CFU/mL sputum/day. These results establish a pretomanid exposure-efficacy relationship with dual outcomes for CFU counts and TTP, and with potential applications to dose optimization of pretomanid-containing regimens.…

Mase S, Chorba T, Parks S, et al.

AbstractBackgroundIn 2012, the Food and Drug Administration approved the use of bedaquiline fumarate as part of combination therapy for treatment of multidrug-resistant tuberculosis (MDR TB). We describe the treatment outcomes, safety, and tolerability of bedaquiline in our case series.MethodsData on patients started on bedaquiline for MDR TB between September 2012 and August 2016 were collected retrospectively through four TB programs using a standardized abstraction tool. Data were analyzed using univariate methods. Adverse events were graded using the Common Terminology Criteria for Adverse Events.ResultsOf 14 patients in this case series, 7/14 (50%) had MDR, 4/14 (29%) had pre-extensively-drug-resistant (XDR), and 3/14 (21%) had XDR. All had pulmonary TB, 5/14 (36%) had pulmonary and extrapulmonary TB, and 9/13 (69%) were smear-positive. One patient (7%) had HIV co-infection, 5/14 (36%) had diabetes mellitus, and 5 (36%) had been previously treated for TB. All patients were non-U.S.-born and 5 (36%) had private insurance. All patients achieved sputum culture conversion within a mean of 71 days (26-116); 6/14 after starting bedaquiline. Twelve (86%) completed treatment and 1/14 (7%) moved out of the country. One patient (7%) had QTc prolongation >500 milliseconds and died 20 months after discontinuing bedaquiline of a cause not attributable to the drug. The most common adverse events were peripheral neuropathy (50%), not customarily associated with bedaquiline use, and QTc prolongation (43%).ConclusionsOf 14 patients, one had an adverse event necessitating bedaquiline discontinuation. Safety, culture conversion, and treatment completion in this series support use of bedaquiline for the treatment of MDR/XDR TB.