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In a Collection Review, Patrick Phillips and colleagues discuss developments in clinical trial design for the evaluation of TB therapeutics. [ABSTRACT FROM AUTHOR]

Extensively drug-resistant tuberculosis (XDR TB) has extremely poor treatment outcomes in adults. Limited data are available for children. We report on clinical manifestations, treatment, and outcomes for 37 children (<15 years of age) with bacteriologically confirmed XDR TB in 11 countries. These patients were managed during 1999-2013. For the 37 children, median age was 11 years, 32 (87%) had pulmonary TB, and 29 had a recorded HIV status; 7 (24%) were infected with HIV. Median treatment duration was 7.0 months for the intensive phase and 12.2 months for the continuation phase. Thirty (81%) children had favorable treatment outcomes. Four (11%) died, 1 (3%) failed treatment, and 2 (5%) did not complete treatment. We found a high proportion of favorable treatment outcomes among children, with mortality rates markedly lower than for adults. Regimens and duration of treatment varied considerably. Evaluation of new regimens in children is required. [ABSTRACT FROM AUTHOR]

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) continue to challenge physicians and public health specialists. Global treatment outcomes continue to be unsatisfactory, positive outcomes being achieved in only 54% of patients. Overall outcomes are even worse in patients infected with highly resistant strains. Treating MDR-/XDR-TB is difficult because of frequent adverse events, the long duration of drug regimens, the high costs of second-line drugs, chronic post-infectious sequelae, and loss of organ function. Ongoing research efforts (studies and trials) have various aims: increasing the rates of treatment success; understanding the potentialities of new and repurposed drugs; shortening the treatment duration; and reducing the rates of adverse events. It is hoped that better access to rapid diagnostics, increased awareness, and treatments that are more effective will reduce the rate of complications and of lung function impairment. This article aims to discuss the management of severe tuberculosis (defined as that which is potentially life threatening, requiring higher levels of care) and its sequelae, from intensive care to the postoperative period, rehabilitation, and recovery. We also discuss the nonpharmacological interventions available to manage chronic sequelae and improve patient quality of life. Because the majority of MDR-/ XDR-TB cases evolve to lung function impairment (typically obstructive but occasionally restrictive), impaired quality of life, and low performance status (as measured by walk tests or other metrics), other interventions (e.g., smoking cessation, pulmonary rehabilitation, vaccination/prevention of secondary bacterial infections/exacerbations, complemented by psychological and nutritional support) are required. [ABSTRACT FROM AUTHOR]

The cascade of care is a model for evaluating patient retention across sequential stages of care required to achieve a successful treatment outcome. This approach was first used to evaluate HIV care and has since been applied to other diseases. The tuberculosis (TB) community has only recently started using care cascade analyses to quantify gaps in quality of care. In this article, we describe methods for estimating gaps (patient losses) and steps (patients retained) in the care cascade for active TB disease. We highlight approaches for overcoming challenges in constructing the TB care cascade, which include difficulties in estimating the population-level burden of disease and the diagnostic gap due to the limited sensitivity of TB diagnostic tests. We also describe potential uses of this model for evaluating the impact of interventions to improve case finding, diagnosis, linkage to care, retention in care, and post-treatment monitoring of TB patients. [ABSTRACT FROM AUTHOR]

Rationale: Treatment of multi-drug resistant Tuberculosis (MDR-TB) is challenging because it mostly relies on drugs with lower efficacy and greater toxicity than those used for drug-susceptible TB. Objectives: Aim of the study was to describe the frequency and type of adverse drug reactions in a cohort of MDR-TB patients and their potential impact on treatment outcome. Methods: We conducted a retrospective study in a cohort of MDR-TB patients enrolled at a tertiary referral hospital in Italy from January 2008 to December 2016. The records of patients were reviewed for epidemiological, clinical, microbiological and adverse drug reactions data. Results: Seventy-four MDR-TB patients (mean age 32 years, 58.1% males, 2 XDR, 12 pre-XDR TB) were extracted from the Institute data base and included in the retrospective study cohort in the evaluation period (January 2008—December 2016). Median length of treatment duration was 20 months (IQR 14–24). Treatment outcome was successful in 57 patients (77%; 51 cured, 6 treatment completed); one patient died and one failed (2.7% overall); 15 patients were lost to follow-up (20.3%). Sixty-six (89.2%) presented adverse drug reactions during the whole treatment period. Total number of adverse drug reactions registered was 409. Three hundred forty-six (84.6%) were classified as adverse events (AEs) and 63 (15.4%) were serious AEs (SAEs). One third of the total adverse drug reactions (134/409; 32.8%) was of gastrointestinal origin, followed by 47/409 (11.5%) ototoxic drug reactions, thirty-five (8.6%) regarded central nervous system and 33 (8.1%) affected the liver. All 63 SAEs required treatment suspension with 61 SAEs out of 63 (96.8%) occurring during the first six months of treatment. Factors associated with unsuccessful treatment outcome were smoking (p = 0.039), alcohol abuse (p = 0.005) and homeless condition (p = 0.044). Neither the number of antitubercular drugs used in different combinations nor the number of AEs showed significant impact on outcome. Patients who completed the treatment experienced a greater number of AEs and SAEs (p < 0.001) if compared to lost to follow-up patients. Conclusions: Our data demonstrate that, despite the high frequency of adverse drug reactions and long term therapy, the clinical management of MDR-TB patients in a referral center could reach successful treatment according to WHO target, by implementing active and systematic clinical and laboratory assessment to detect, report and manage suspected and confirmed adverse drug reactions. [ABSTRACT FROM AUTHOR]

Background: Rifampicin-resistant tuberculosis (RR-TB) is largely underdetected in Indonesia. Xpert MTB/RIF (Xpert) has recently been introduced, prioritizing patients at risk of RR-TB, followed by phenotypic drug-susceptibility (DST) if rifampicin resistance is detected. Objective: This study investigated Xpert-based management of presumptive RR-TB cases under routine practice in West Java, Indonesia. Methods: We examined all records of patients tested with Xpert in the referral hospital for West Java in 2015–2016. We measured loss across a limited cascade of care, time to Xpert diagnosis and the commencement of initial second-line treatment, and identified factors associated with diagnostic and treatment delay. Additionally, we analyzed the appropriateness of treatment according to DST results. Results: Of 3415 patients with presumptive RR-TB, 3215 (94%) were tested by Xpert, of whom 339 (10.5%) were diagnosed as RR-TB. 288 (85%) of 339 RR-TB patients started initial second-line TB treatment, with 48 (14%) patients being lost between diagnosis and pre-treatment assessment. Second-line treatment was commenced at a median of 41 days (IQR 29–70) after RR-TB diagnosis. Delays in both diagnosis and treatment initiation were observed in 104 (52%) of 201 RR-TB patients with identifiable referral date. Rural residence was associated with delay to diagnosis (adjusted OR 2.7; 95%CI 1.5–5.2) and treatment initiation (adjusted OR 2.0; 1.2–3.4). Of 162 patients with available DST result, 107 (66%) had multidrug-resistant tuberculosis (MDR-TB) and 32 (20%) had either pre-extensively drug resistant (pre-XDR) or extensively drug resistant tuberculosis (XDR-TB). We estimated that with the current algorithm 41% of pre-XDR or XDR-TB patients are diagnosed, and 33% of them started on an appropriate treatment regimen. Conclusions: Many patients with Xpert-diagnosed RR-TB either do not start MDR-TB treatment or encountered diagnostic and treatment delays under programmatic conditions in Indonesia, and most pre-XDR and XDR-TB cases remain undiagnosed. Further expansion and ongoing quality improvement of RR-TB services are urgently needed. [ABSTRACT FROM AUTHOR]

We have previously reported the inhibition of bacterial topoisomerase I activity by a fluoroquinophenoxazine compound (FP-11g) with a 6-bipiperidinyl lipophilic side chain that exhibited promising antituberculosis activity (MIC = 2.5 μM against Mycobacterium tuberculosis, SI = 9.8). Here, we found that the compound is bactericidal towards Mycobacterium smegmatis, resulting in greater than 5 Log10 reduction in colony-forming units [cfu]/mL following a 10 h incubation at 1.25 μM (4X MIC) concentration. Growth inhibition (MIC = 50 μM) and reduction in cfu could also be observed against a clinical isolate of Mycobacterium abscessus. Stepwise isolation of resistant mutants of M. smegmatis was conducted to explore the mechanism of resistance. Mutations in the resistant isolates were identified by direct comparison of whole-genome sequencing data from mutant and wild-type isolates. These include mutations in genes likely to affect the entry and retention of the compound. FP-11g inhibits Mtb topoisomerase I and Mtb gyrase with IC50 of 0.24 and 27 μM, respectively. Biophysical analysis showed that FP-11g binds DNA as an intercalator but the IC50 for inhibition of Mtb topoisomerase I activity is >10 fold lower than the compound concentrations required for producing negatively supercoiled DNA during ligation of nicked circular DNA. Thus, the DNA-binding property of FP-11g may contribute to its antimycobacterial mechanism, but that alone cannot account for the observed inhibition of Mtb topoisomerase I. [ABSTRACT FROM AUTHOR]

Background: Routine surveillance is required to monitor the performance of tuberculosis diagnostic programme and is essential for the rapid detection of drug resistance. The main objective of this study was to explore the effectiveness and stakeholder perception of the current routine surveillance system for previously treated tuberculosis cases in Tanzania with a view to identify interventions to improve and accelerate positive patient outcomes. Methods: A study using quantitative and qualitative methods of data collection including in-depth interviews and focus group discussions with health care service providers was conducted in four regions. Quantitative data were extracted from the routine databases to assess performance. Results: Quantitative findings from 2011 to 2013 showed 2,750 specimens from previously treated TB cases were received at the reference laboratory. The number increased year on year, but even in the most recent year was only 61% of that expected. The median and interquartile range of turnaround time in days from specimen reception to results reported for smear microscopy, culture and drug susceptibility testing were 1(1, 1), 61(43, 71) and 129(72, 170) respectively. Contaminated specimens were reported in 3.6% of cases. The qualitative analysis showed the system of sending specimens using postal services was seen to be efficient by participants. However, there were many challenges and significant delays in specimens reaching the reference laboratory associated with lack of funds to transfer specimens, weak form completion, inadequate training and poor supervision. These all adversely affected the implementation of the routine surveillance system. Conclusions: Many issues limit the effectiveness of the routine surveillance system in Tanzania. Priority areas for strengthening are; specimen transportation, supervision and availability of commodities. A pilot study of a revised routine surveillance system that takes into account the observations from this study alongside improved access to drug susceptibility testing using Xpert MTB/RIF should be considered. [ABSTRACT FROM AUTHOR]

Recurrence of TB in an individual can occur due to relapse of the same strain or reinfection by a different strain. The contribution of reinfection and relapse to TB incidence, and the factors associated with each are unknown. We aimed to quantify and describe cases attributable to relapse or reinfection, and identify associated risk factors in order to reduce recurrence. We categorised recurrent TB cases from notifications in London (2002–2015) as relapse or reinfection using molecular (MIRU VNTR strain type) and epidemiological information (hierarchical approach using time since notification, site of disease and method of case finding). Factors associated with each outcome were determined using logistic regression in Stata Version 13.1 (2009–2015 only). Of 43,465 TB cases, 1.4% (618) were classified as relapse and 3.8% (1,637) as reinfection. The proportion with relapse decreased from 2002 (2.3%) to 2015 (1.3%), while the proportion of reinfection remained around 4%. Relapse was more common among recent migrants (<1 year, odds ratio (OR) = 1.99, p = 0.005), those with a social risk factor (OR = 1.51, p = 0.033) and those with central nervous system, spinal, miliary or disseminated TB (OR = 1.75, p = 0.001). Reinfection was more common among long term migrants (>11 years, OR = 1.67, p = <0.001), those with a social risk factor (OR = 1.96, p = <0.001) and within specific areas in London. Patients with social risk factors were at increased risk of both relapse and reinfection. Characterising those with relapsed disease highlights patients at risk and factors associated with reinfection suggest groups where transmission is occurring. This will inform TB control programs to target appropriate treatment and interventions in order to reduce the risk of recurrence. [ABSTRACT FROM AUTHOR]

In Mycobacterium tuberculosis (Mtb) the detection of single nucleotide polymorphisms (SNPs) is of high importance both for diagnostics, since drug resistance is primarily caused by the acquisition of SNPs in multiple drug targets, and for epidemiological studies in which strain typing is performed by SNP identification. To provide the necessary coverage of clinically relevant resistance profiles and strain types, nucleic acid-based measurement techniques must be able to detect a large number of potential SNPs. Since the Mtb problem is pressing in many resource-poor countries, requiring low-cost point-of-care biosensors, this is a non-trivial technological challenge. This paper presents a proof-of-concept in which we chose simple DNA-DNA hybridization as a sensing principle since this can be transferred to existing low-cost hardware platforms, and we pushed the multiplex boundaries of it. With a custom designed probe set and a physicochemical-driven data analysis it was possible to simultaneously detect the presence of SNPs associated with first- and second-line drug resistance and Mtb strain typing. We have demonstrated its use for the identification of drug resistance and strain type from a panel of phylogenetically diverse clinical strains. Furthermore, reliable detection of the presence of a minority population (<5%) of drug-resistant Mtb was possible. [ABSTRACT FROM AUTHOR]

The incidence of tuberculosis (TB) in some countries increases continuously, especially caused by mycobacterial strains resistant to various anti-tuberculotic drugs (AT). The emergence and spread of drug-resistant tuberculosis (multidrugresistant - MDR-TB, and extensively drug-resistant - XDR-TB) suggest the crucial role of pharmacotherapy protocol tailored to the respective patient with MDR-TB or XDR-TB (a personalized approach) and requirements for fast and precise diagnostics of the degree of resistance. The aim of this study was to characterize a molecular basis of resistance to AT, and to identify the presence of the resistance using conventional susceptibility testing and molecular genetic methods using PCR tests in Slovakia during years 2009 – 2017. Furthermore, we focused on evaluation of the relationship between the level of resistance, the clinical status, and some laboratory markers of patients with drugresistant TB. Totally 1157 strains isolated from patients in 2009 – 2017 were tested for resistance using classical methods and in resistant strains, the molecular-genetic tests were performed. Increased incidence of recurrence, prolonged time required to culture conversion, increased mortality during treatment, plasma C-reactive protein concentrations and sedimentation rate, broader spectrum of AT used, as well as higher incidence of adverse effects (sufficiently controlled with symptomatic treatment) were observed with higher degree of resistance. Contrary, the number of patients who achieved remission decreased. Rapid and precise identification of MDR-TB or XDR-TB strains using both classical and molecular-genetic testing is an essential tool for personalized drug treatment and prevention of resistance spread and worsening. Both tests should be used for correct diagnosis of resistant TB. Higher level of resistance required more aggressive therapeutic approach, associated with adverse effects and prolongation of the culture conversion time, as well as increased risk of relapse. Effective pharmacotherapy led to significant decrease of CRP levels in all groups of patients. The most frequent adverse effects of ATs - impairment of liver and kidney functions - were effectively managed by symptomatic treatment. [ABSTRACT FROM AUTHOR]

Background: Given the inherent characteristics of the Hajj pilgrimage, the event is a risk for tuberculosis (TB) infection. Early diagnosis and appropriate management of TB cases by knowledgeable and skilled healthcare workers (HCWs) are key in improving patients’ outcome and preventing transmission during the Hajj mass gathering and globally. Method: We conducted a cross-sectional study to assess knowledge, attitude and practice (KAP) of HCWs deployed during the 2016 Hajj regarding TB and its management using an anonymous self-administered questionnaire. Results: Data was collected from 540 HCWs from 13 hospitals. HCWs originated from 17 countries and included physicians, nurses and other non-administrative HCWs. Nearly half of HCWs declared having experience dealing with TB patients. In general, HCWs had average knowledge (mean knowledge score of 52%), above average attitude (mean attitude score of 73%) and good practice (mean practice score of 85%) regarding TB, based on our scoring system and cut-off points. Knowledge gaps were identified in relation to the definition of MDR-/XDR-TB and LTBI, smear microscopy results, length of standard TB treatment for drug-sensitive TB, 2nd line anti-TB drugs, BCG vaccination, and appropriate PPE to be used with active PTB patients. Poor attitudes were found in relation to willingness to work in TB clinic/ward and to the management and treatment of TB patients. Poor practices were reported for commencing anti-TB treatment on suspected TB cases before laboratory confirmation and not increasing natural ventilation in TB patients’ rooms. Age, gender, nationality, occupation, length of work experience and experience dealing with TB patients were associated with knowledge scores. Age and occupation were associated with attitude scores while length of work experience and occupation were associated with practice scores. There was a weak but statistically significant positive correlation between score for knowledge and attitude (rs = 0.11, p = 0.009) and attitude and practice (rs = 0.13, p = 0.002). Conclusions: While the results of the study are encouraging, important knowledge gaps and some poor attitudes and practices regarding TB were identified among HCWs during Hajj. This calls for multifaceted interventions to improve HCWs KAP regarding TB including tailored, periodic TB education and training aimed at boosting knowledge and improving behaviour. [ABSTRACT FROM AUTHOR]

South Africa has the highest tuberculosis (TB) disease incidence rate in the world, and TB is the leading infectious cause of death. Decisions on, and funding for, TB prevention and care policies are decentralised to the provincial governments and therefore, tools to inform policy need to operate at this level. We describe the use of a mathematical model planning tool at provincial level in a high HIV and TB burden country, to estimate the impact on TB burden of achieving the 90-(90)-90 targets of the Stop TB Partnership Global Plan to End TB. “TIME Impact” is a freely available, user-friendly TB modelling tool. In collaboration with provincial TB programme staff, and the South African National TB Programme, models for three (of nine) provinces were calibrated to TB notifications, incidence, and screening data. Reported levels of TB programme activities were used as baseline inputs into the models, which were used to estimate the impact of scale-up of interventions focusing on screening, linkage to care and treatment success. All baseline models predicted a trend of decreasing TB incidence and mortality, consistent with recent data from South Africa. The projected impacts of the interventions differed by province and were greatly influenced by assumed current coverage levels. The absence of provincial TB burden estimates and uncertainty in current activity coverage levels were key data gaps. A user-friendly modelling tool allows TB burden and intervention impact projection at the sub-national level. Key sub-national data gaps should be addressed to improve the quality of sub-national model predictions. [ABSTRACT FROM AUTHOR]

Introduction: Isoniazid-resistant, rifampin susceptible tuberculosis (INHR-TB) is the most common form of drug resistant TB globally. Treatment of INHR-TB with standard first-line therapy is associated with high rates of multidrug resistant TB (MDR-TB). We modelled the potential impact of INHR-TB detection and appropriate treatment on MDR-TB prevalence. Methods: A decision analysis model was developed to compare three different strategies for the detection of TB (AFB smear, Xpert MTB/RIF, and Line-Probe Assays (LPA)), combined with appropriate treatment. The population evaluated were patients with a globally representative prevalence of newly diagnosed, drug-susceptible (88.6%), isoniazid-resistant (7.3%), and multidrug resistant (4.1%) pulmonary TB. Our primary outcome was the proportion of patients with MDR-TB after initial attempt at diagnosis and treatment within a 2-year period. Secondary outcomes were the proportion of i) individuals with detected TB who acquired MDR-TB ii) individuals who died after initial attempt at diagnosis and treatment. Results: After initial attempt at diagnosis and treatment, LPA combined with appropriate INHR-TB therapy resulted in a lower proportion of prevalent MDR-TB (1.61%; 95% Uncertainty Range (UR: 2.5th and 97.5th percentiles generated from 10 000 Monte Carlo simulation trials) 1.61–1.65), when compared to Xpert (1.84%; 95% UR 1.82–1.85) and AFB smear (3.21%; 95% UR 3.19–3.26). LPA also resulted in fewer cases of acquired MDR-TB in those with detected TB (0.35%; 95% UR 0.34–0.35), when compared to Xpert (0.67%; 95% UR 0.65–0.67) and AFB smear (0.68%; 95% UR 0.67–0.69). The majority of acquired MDR-TB arose from the treatment of INHR-TB in all strategies. Xpert-based strategies resulted in a lower proportion of death (2.89%; 95% UR 2.87–2.90) compared to LPA (2.93%; 95% UR 2.91–2.94) and AFB smear (3.21%; 95% UR 3.19–3.23). Conclusion: Accurate diagnosis and tailored treatment of INHR-TB with LPA led to an almost 50% relative decrease in acquired MDR-TB when compared with an Xpert MTB/RIF strategy. Continued reliance on diagnostic and treatment protocols that ignore INHR-TB will likely result in further generation of MDR-TB. [ABSTRACT FROM AUTHOR]

Introduction: The Indian Tuberculosis (TB) Programme currently faces the dual challenges of tackling increasing numbers of drug resistant (DR) TB cases and regulating practices of a pluralistic private sector catering to TB patients. A study of health seeking behaviour of DR-TB patients in such a situation, offers an opportunity to understand the problems patients face while interacting with health systems. Methodology: Forty-six DR-TB patients drawn from 15 high TB burden wards in Mumbai were interviewed using an open ended interview tool. Interviews were audio recorded and transcribed. Pathway schematics developed from analysis of patient records, were linked to transcripts. Open coding was used to analyse these units and themes were derived after collating the codes. Results and discussion: The paper presents themes interwoven with narratives in the discussions. These include awareness-action gap among patients, role of neighbourhood providers, responsiveness of health systems, the not-such a ‘merry go round’ that patients go/are made to go on while seeking care, costs of diagnostics and treatment, and how DR-TB is viewed as the ‘big TB’. Conclusion: The recommendations are based on a preventative ethos which is sustainable, compared to interventions with top-down approaches, which get piloted, but fail to sustain impact when scaled up. [ABSTRACT FROM AUTHOR]

Background: The prevalence of drug-resistant tuberculosis (DR-TB) has brought severe challenges to the prevention and control of tuberculosis. Studies have explored the status of antituberculosis drug (ATD) resistance in different regions of China. However, few studies have focused on DR-TB in Sichuan to date. Due to the large population in Sichuan, detailed investigations of the DR-TB burden in Sichuan are needed. The objective of this study was to investigate the drug resistance characteristics of TB isolates from tuberculosis patients with and without HIV (TB-HIV patients and TBw/oHIV patients) in Chengdu, Sichuan, China. Methods: Isolates from respiratory samples of TBw/oHIV patients and TB-HIV patients hospitalized between January 2014 and December 2017 were collected. Nontuberculosis mycobacteria (NTM) were excluded. Drug sensitivity testing (DST) was performed according to the dilution method in microplates with 4 first-line ATDs and 8 second-line ATDs. TB strains were separated according to patient treatment history, patient age, calendar year and GeneXpert MTB/RIF (GeneXpert) assay results for further analysis. Results: For the 7470 patients recruited, the multidrug-resistant tuberculosis (MDR-TB) rate was 2.1-fold (14.6% vs. 6.8%) higher than the national baseline level. The repeatedly admitted patients were more likely to have a resistance profile than the first-time-admitted cases in both the TB-only group (P<0.05) and the TB-HIV corresponding group (P<0.05). Among the 7273 TBw/oHIV cases and 197 TB-HIV cases, the positivity rates of acid-fast bacilli (AFB) in the TB-HIV group were significantly lower than those in the TBw/oHIV group (P<0.05). The repeatedly admitted TB-HIV patients had lower resistance rates to INH than the repeatedly admitted TBw/oHIV patients (24.4% vs. 41.5%, P<0.05). The Rifampicin-resistant TB strains in the TBw/oHIV group were more likely to be resistant to INH in the repeatedly admitted group than those in the first-time admitted patients (P<0.05). The proportions of XDR (3.6% vs. 1.3%, P<0.05) and XDR-TB/MDR-TB (7.3% vs. 2.2%, P<0.05) in all TB-HIV patients were significantly higher than those in all TBw/oHIV patients. The ratio of XDR-TB was significantly higher in the TB-HIV group than in the TBw/oHIV group (30.4% vs. 9.0%, P<0.05) and the all TB group (9.0% vs. 10.1%, P<0.05). Regarding age, the <25-year-old TB-HIV patients (9.1% vs. 0.7%, P<0.05) and 25~44-year-old TB-HIV patients (5.2% vs. 2.4%, P<0.05) were more likely to have a higher XDR proportion than their TBw/oHIV counterparts. The ATD-resistance profile in terms of different years from high to low was 2014>2015>2016≈2017 for TBw/oHIV patients. The same trend was also observed for TB-HIV patients: 2014>2015>2016≈2017. The GeneXpert TB-positive rate in the TBw/oHIV group was higher than that in the TB-HIV group [81%(639/792) vs. 65% (13/20), P<0.05]. In TBw/oHIV cases, the agreement was 92.3% and the Kappa value was 0.75. In TB-HIV cases, the agreement was 85.0% and the Kappa value was 0.32. Conclusion: In Sichuan, ATD resistance has improved since 2014, but to date, it remains severe. The different resistance profiles of TBw/oHIV patients and TB-HIV patients indicates the need for personalized treatment plans. Specifically, the GeneXpert assay might be more suitable for TBw/oHIV patients than for TB-HIV patients. [ABSTRACT FROM AUTHOR]

We analyzed data for a retrospective cohort of patients treated for extensively drug-resistant tuberculosis in 2 provinces in South Africa and compared predictors of treatment outcome in HIV-positive patients who received or had not received antiretroviral drugs with those for HIV-negative patients. Overall, 220 (62.0%) of 355 patients were HIV positive. After 2 years, 34 (10.3%) of 330 patients with a known HIV status and known outcome had a favorable outcome. Multivariate analysis showed that predictors of favorable outcome were negative results for acid-fast bacilli by sputum microscopy at start of treatment and weight >50 kg. HIV-positive patients were more likely to have an unfavorable outcome. The strongest predictor of unfavorable outcome was weight

We report 20 cases of extensively drug-resistant tuberculosis managed in France. Treatment was individualized and included bedaquiline and linezolid for most patients and surgery in 8 patients. At last follow-up (22 months), 19 patients had achieved conversion from positive to negative on culture testing. These promising results of comprehensive management obtained in a small series deserve confirmation.

Developing a fast, inexpensive, and specific test that reflects the mutations present in Mycobacterium tuberculosis isolates according to geographic region is the main challenge for drug-resistant tuberculosis (TB) control. The objective of this study was to develop a molecular platform to make a rapid diagnosis of multidrug-resistant (MDR) and extensively drug-resistant TB based on single nucleotide polymorphism (SNP) mutations present in therpoB, katG, inhA,ahpC, and gyrA genes from Colombian M. tuberculosis isolates. The amplification and sequencing of each target gene was performed. Capture oligonucleotides, which were tested before being used with isolates to assess the performance, were designed for wild type and mutated codons, and the platform was standardised based on the reverse hybridisation principle. This method was tested on DNA samples extracted from clinical isolates from 160 Colombian patients who were previously phenotypically and genotypically characterised as having susceptible or MDR M. tuberculosis. For our method, the kappa index of the sequencing results was 0,966, 0,825, 0,766, 0,740, and 0,625 forrpoB, katG, inhA,ahpC, and gyrA, respectively. Sensitivity and specificity were ranked between 90-100% compared with those of phenotypic drug susceptibility testing. Our assay helps to pave the way for implementation locally and for specifically adapted methods that can simultaneously detect drug resistance mutations to first and second-line drugs within a few hours.

Despite the recent advances in the diagnosis of tuberculosis, treatment of the disease, for the most part, remains the same as it was half a century ago. In recent years only two new anti-tuberculosis drugs have been approved by the European Medicines Agency and Food and Drug Administration. Though the prevalence of this disease is slowly decreasing all over Europe, new challenges appear. One of them is multidrug-resistant tuberculosis (MDR-TB). This problem is especially prominent in Lithuania, which is one of the 27 high MDR-TB burden countries in the world and falls behind neighboring countries in terms of the prevalence of the disease. The objective of this paper was to review the situation of tuberculosis and MDR-TB in Lithuania, and current available methods of treatment, control and diagnosis of this disease.

Objective/Background: Tuberculosis (TB) is a leading cause of death worldwide, with new threats of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Pakistan is the fifth highest among high-burden TB countries and the fourth highest among high-burden drug-resistant-TB countries. Pakistan is the sixth most populous country in the world, and Pakistani youth is the highest population group in Pakistan and second in the world. This study was aimed at assessing the understanding, awareness, and mindset of university students toward TB, MDR TB, and XDR TB in Lahore. Methods: A cross-sectional questionnaire-based study was performed on 1137 individuals from three major public-sector universities in Lahore, Pakistan. Information regarding their knowledge and attitude toward MDR and XDR TB was gathered using a structured questionnaire. Data collected was analyzed using SPSS version 20. Results: Male (531) and female (606) students were asked about different aspects of MDR and XDR TB. Although 80.47% students had good knowledge about simple TB, a very small fraction had awareness and appropriate knowledge about MDR/XDR-TB. Considering TB as a stigma, only 9.3% students disclosed that they had household TB contact. Only 25% students knew about XDR TB. Conclusion: Our results indicated that a small fraction of people knew the exact definition and treatment duration of MDR TB and XDR TB in our society. There is a need to increase the awareness and knowledge status of university students about MDR and XDR TB.

ABSTRACT Here, we report the cases of three patients diagnosed with extensively drug-resistant tuberculosis and admitted to a referral hospital in the state of São Paulo, Brazil, showing the clinical and radiological evolution, as well as laboratory test results, over a one-year period. Treatment was based on the World Health Organization guidelines, with the inclusion of a new proposal for the use of a combination of antituberculosis drugs (imipenem and linezolid). In the cases studied, we show the challenge of creating an acceptable, effective treatment regimen including drugs that are more toxic, are more expensive, and are administered for longer periods. We also show that treatment costs are significantly higher for such patients, which could have an impact on health care systems, even after hospital discharge. We highlight the fact that in extreme cases, such as those reported here, hospitalization at a referral center seems to be the most effective strategy for providing appropriate treatment and increasing the chance of cure. In conclusion, health professionals and governments must make every effort to prevent cases of multidrug-resistant and extensively drug-resistant tuberculosis.

Background: The South African Electronic Drug-Resistant Tuberculosis Register (EDRweb) is the national database of registered drug-resistant tuberculosis (DR-TB) cases. Methods: This study was a retrospective, de-identified secondary analysis of EDRweb patients initiating treatment for rifampicin-resistant TB (January 2009 to September 2011). The relative risks of death and treatment success were estimated using modified Poisson regression with robust error estimation. Results: Seventeen thousand six hundred and ninety-seven cases of DR-TB were registered and met the inclusion criteria; 52.0% (n = 9207) were male and the median age was 35 years (interquartile range 27–43 years). Of the 9419 cases with HIV infection (53.2%), 7157 (76.0%) were on antiretroviral therapy. Most had undergone previous TB treatment (76.5%, n = 13 531). Multidrug-resistant TB was the most common diagnosis, at 80.6% (n = 14 272). No treatment outcome was available for 6934 patients (39.2%). For patients with outcomes, 4227 (39.4%) were successfully treated, 2987 (27.8%) died, 2533 (23.7%) were lost to follow-up, and 996 (9.3%) failed. Second-line drug resistance was the strongest predictor of death during DR-TB treatment; extensively drug-resistant TB patients were more likely to have died during treatment (adjusted relative risk 2.63, 95% confidence interval 2.45–2.84). Conclusions: Testing for second-line drug resistance at initiation of DR-TB treatment can identify patients most at risk of treatment failure and death and most in need of individualized treatment.

Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non–MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010–2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe.

Tubercidin is an adenosine analogue that has been shown to exhibit good activity against some tumours and parasites. In this study, the in vitro activity of tubercidin was evaluated against Mycobacterium tuberculosis (Mtb) and nontuberculosis Mycobacteria (NTM). For determining the MICs of tubercidin, 23 fully drug-sensitive (DS) Mtb strains, 33 multi-drug resistance tuberculosis (MDR-TB) strains, 29 pre-extensively drug-resistant tuberculosis (pre-XDR-TB) strains, 21 extensively drug-resistant tuberculosis (XDR-TB) strains, 17 rapidly growing mycobacteria (RGM) and nine slowly growing mycobacteria (SGM) references strains were tested by microplate-based Alamar Blue assay (MABA) method. The results indicate that tubercidin has high in vitro activity against some drug-resistance Mtb strains and NTM reference strains, which warrants further investigation on the actions of tubercidin and its derivatives as potential drugs for mycobacterial infections.

Background: Tuberculosis is a major cause of morbidity and mortality in the developing world. Drug resistance, which is predicted to rise in many countries worldwide, threatens tuberculosis treatment and control. Objective: To identify features associated with treatment failure and to predict which patients are at highest risk of treatment failure. Methods: On a multi-country dataset managed by the National Institute of Allergy and Infectious Diseases we applied various machine learning techniques to identify factors statistically associated with treatment failure and to predict treatment failure based on baseline demographic and clinical characteristics alone. Results: The complete-case analysis database consisted of 587 patients (68% males) with a median (p25-p75) age of 40 (30–51) years. Treatment failure occurred in approximately one fourth of the patients. The features most associated with treatment failure were patterns of drug sensitivity, imaging findings, findings in the microscopy Ziehl-Nielsen stain, education status, and employment status. The most predictive model was forward stepwise selection (AUC: 0.74), although most models performed at or above AUC 0.7. A sensitivity analysis using the 643 original patients filling the missing values with multiple imputation showed similar predictive features and generally increased predictive performance. Conclusion: Machine learning can help to identify patients at higher risk of treatment failure. Closer monitoring of these patients may decrease treatment failure rates and prevent emergence of antibiotic resistance. The use of inexpensive basic demographic and clinical features makes this approach attractive in low and middle-income countries. [ABSTRACT FROM AUTHOR]

As current treatment of tuberculosis is burdensomely long, provoking non-adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis. [ABSTRACT FROM AUTHOR]

Title: Provision of guideline-based care for drug-resistant tuberculosis in South Africa: Level of concordance between prescribing practices and guidelines. Objective: We examined the influence of individual and site characteristics on the concordance between prescribed treatment regimens and recommended standardized regimen according to national guidelines for patients with drug-resistant tuberculosis (DR-TB) in South Africa. Methods: Participants were 337 youth and adults treated for DR-TB between November 2014 and August 2016 at ten DR-TB treatment sites in Eastern Cape and KwaZulu Natal provinces, South Africa. Logistic regression was used to determine individual and system characteristics related to concordance at treatment initiation between the prescribed treatment regimens in terms of medication composition, dosage, and frequency and guideline-based standardized regimen that included four oral and one injectable medications. Results: The sample was 19% (n = 64) youth (15–24 years), 53% (n = 179) male, 73% (n = 243) HIV coinfected, and 51% (n = 169) with prior history of TB treatment. Guideline medications were correctly prescribed for 88% (n = 295) of patients, but only 33% (n = 103) received the correct medications and doses. Complete guideline adherence to medications, doses, and frequency was achieved for 30% (n = 95) of patients. Younger age, HIV coinfection, and rural treatment setting were associated with the prescription of correct medications. Conclusion: Most individuals are prescribed the correct DR-TB medications, yet few individuals receive correct medications, dosages, and frequencies. Further study is needed to examine the root causes for treatment guideline deviations and opportunities for improvement. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization drug-resistant tuberculosis (DR-TB) 2016 guidelines reclassified para-aminosalicylic acid (PAS) as Group D3 “add-on" drug. We studied our DR-TB data wherein PAS was widely and preferably used as a substitute in the standardized regimen in varied situations and report its utility in DR-TB. Methodology: This retrospective observational study enrolled both pulmonary and extrapulmonary DR-TB patients receiving PAS in the programmatic management of DR-TB from March 2012 to June 2013. They were divided into seven subgroups on the basis of indication for PAS substitution in the standardized regimen for DR-TB cases. The clinical profile and outcomes were analyzed. Results: PAS was substituted in 250 cases (225 - pulmonary DR-TB and 25 - extrapulmonary DR-TB). PAS was used in (1) pre-extensively drug-resistant TB (XDR-TB) fluoroquinolones (FQs) - 136 (54.4%), (2) XDR-TB - 15 (6%), (3) substitute drug for serious adverse events - 3 (1.2%), (4) pregnant DR-TB patients - 5 (2%), (5) patients on successful private-based second-line therapy adopted under the Revised National Tuberculosis Control Program - 10 (4%), (6) substitute drug for previous FQ exposure - 5 (2%), and (7) Category V - 76 (30.4%). Although 51.2% had an unfavorable response (UFR) against 48.8% with FR, wide disparity was noted in subgroups. FR was observed in 68.4% pre-XDR-TB (FQ), 80% pregnant patients, 90% adopted from private on successful second-line therapy, 80% previous FQ exposure against 40% XDR-TB, 7.9% Category V, and 0% PAS substitution for adverse drug reactions (ADRs). UFR was seen in 31.6% pre-XDR-TB (FQ), 20% pregnant patients, 10% adopted from private on successful second-line therapy, 20% of previous FQ exposure against 60% XDR-TB, 92.1% Category V, and 100% on PAS substitution for ADR. Conclusion: In view of the safety and efficacy of PAS in our DR-TB patients except for XDR and Category V group, we recommend larger studies with PAS and consider its reclassification into Group C rather than Group D3. [ABSTRACT FROM AUTHOR]

Background: Drug-resistant tuberculosis (TB) is a global public health issue. To monitor this in Canada, surveillance systems have been in place for the last 20 years.Objective: To describe drug resistance patterns among TB isolates in Canada in 2017 by type of resistance as well as geographic location, demographic data and origin and to compare current data to those of the previous 10 years.Methods: Data were derived and analyzed from two sources. The Canadian Tuberculosis Laboratory Surveillance System (CTBLSS) is an isolate-based laboratory surveillance system and was used to obtain information on the results of drug susceptibility testing (DST) as well as province or territory, sex and age of the individual from which the sample originated. The Canadian Tuberculosis Reporting System (CTBRS) is a case-based surveillance system with information on active and retreatment TB cases in Canada and was used to derive origin data, which is defined as either foreign-born, Canadian-born Indigenous or Canadian-born non-Indigenous. Analysis was descriptive and compared with data from these two sources for 2007-2016.Results: In 2017, 1,515 TB isolates were tested for resistance to anti-TB drugs, with 123 (8.1%) demonstrating resistance to any first-line anti-TB drug. Of these, 103 were monoresistant, six were polyresistant and 14 were multidrug-resistant tuberculosis (MDR-TB). No extensively drug-resistant tuberculosis (XDR-TB) isolates were reported. Drug resistance was reported in seven provinces/territories (British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and New Brunswick). There were 63 isolates from females with drug resistance (9.5%) and 60 isolates from males with drug resistance (7.0%). Drug resistance was found in a greater percentage of isolates among those aged 25-34 (n=29, 23.6%). By origin, 1,072 (11%) foreign-born TB cases reported between 2005 and 2015 were drug-resistant. Among the Canadian-born non-Indigenous and Canadian-born Indigenous TB cases, 143 (9%) and 54 (2%) were drug-resistant, respectively. Compared with previous years, the number of isolates tested increased slightly (from 1,267 to 1,515); however, there was a decrease in the percentage of isolates with reported drug resistance (from 10.5% in 2007 to 8.1% in 2017).Conclusion: In 2017, TB drug resistance rates remained low in Canada. [ABSTRACT FROM AUTHOR]

Background: Although it is a preventable and treatable disease, tuberculosis remains a major medical and public health problem throughout the world. The control and elimination of tuberculosis is currently challenged by the development and spread of antituberculosis drug resistance. The resistance is often correlated to the absence of properly implemented control measures that lead to poor treatment outcomes. Therefore, the aim of the current study was to assess poor treatment outcomes and its determinants among tuberculosis patients in selected health facilities in East Wollega zone, Western Ethiopia. Method: A five-year retrospective cross-sectional study design was employed. Data were collected from patients’ medical record from January to March 2017. Data were entered and analyzed using SPSS version 20. Descriptive statistics were used to generate and summarize frequencies. Univariate and multivariate logistic regression analysis were used to associate the potential determinants of poor treatment outcomes. Results: From 995 patients with documented treatment outcomes, 58.9% were males with a mean age of 31.9±16.3 years and 58% lived in rural areas. Majorities of cases (95.7%) were newly treated ones. Nearly half of the cases had extrapulmonary tuberculosis and 6.8% were co-infected with HIV. Nearly three-quarter of patients had completed their treatment while 17.2%, 2.9%, 4.8%, 0.4% patients were cured, defaulted, died, and failed, respectively. The overall treatment success rate was 91.9%. Being treated in Anger Gute health center (adjusted odds ratio (AOR): 2.27; 95% confidence interval (CI): 1.18–4.38); male (AOR: 1.81; 95% CI: 1.06–3.10); lived in rural areas (AOR: 1.73; 95% CI: 1.02–2.91); previously treated (AOR: 2.72; 95% CI: 1.16–6.39) and unknown HIV status (AOR: 4.56; 95% CI: 1.98–10.50) were determinants of poor treatment outcomes. Conclusion: The current treatment success rate was exceeded the recommended target. However, special attention and strict follow up is required for tuberculosis patients with high risk of unsuccessful treatment outcomes including male, rural resident, previously treated and unknown in HIV status patients throughout their treatment periods. [ABSTRACT FROM AUTHOR]

The article offers information on pathogen based precision medicine for drug resistant tuberculosis. Topics discussed include prevention and treatment strategies take information from systems biology and individual variability into account; model example of precision medicine in infectious diseases is multidrug-resistant tuberculosis (MDR-TB); and molecular tests to quickly identify genotypic drug resistance successfully implemented in daily practice.

Introduction: Treatment success rates of rifampicin resistant (RR)/multi-drug resistant (MDR) tuberculosis (TB) in South Africa range from 43–48%, falling short of the World Health Organization’s target of ≥75%. We present rates and assess predictors of attrition by 12 months on treatment. Methods: Prospective observational cohort analysis of adults (≥18 years) initiating RR/MDR-TB treatment from 01 March 2013 to 30 September 2016. Attrition was defined as a combination of death and loss to follow-up (LTFU; treatment interruption ≥2 months) by 12 months on treatment. Predictors of attrition were identified using Cox Proportional Hazards models to estimate crude (HR) and adjusted hazard ratios (aHR) with corresponding 95% confidence intervals. Results: By 12 months on treatment, 75/240 (31.3%) patients had either died (37/240; 15.4%) or been LTFU (38/240; 15.8%). Patients with moderate/severe anaemia (aHR: 2.10; 95% CI 1.00–4.39), and those who were smear positive at baseline (aHR: 2.04; 95% CI 1.01–4.12) were significantly more likely to die or be lost from care. Conclusion: At this outpatient DR-TB treatment site, there was a high rate of attrition halfway through the standard treatment course at 12 months of 31%. High rates of attrition by 12 months on treatment may continue during the second-half of therapy. [ABSTRACT FROM AUTHOR]

Tuberculosis in infants is a clinical case difficult to diagnose by regular testing which often yield negative results; additionally, the source of transmission is difficult to identify. This work presents the case of a one-month old nursing boy presenting irritability, tachypnea, fever, poor gain weight from birth, and hepatomegaly. Additionally, he had the maternal history of pre-extensively drug- resistant tuberculosis and tuberculoid granulomatosis reaction with positive auramine tincture for acid-alcohol resistant bacilli at histopathology of the placenta. With a suspected congenital tuberculosis, he was referred to the National Children's Health Institute for diagnosis and treatment. The patient showed a favorable clinical evolution and no adverse reactions to treatment. The diagnosis of congenital tuberculosis must be considered in infants with suggestive clinical signs of the disease and such suspicion must be maintained with the presence of a maternal history of Mycobacterium tuberculosis infection. [ABSTRACT FROM AUTHOR]

Background: Fatty acid synthase 1 (FAS I) from Mycobacterium tuberculosis (Mtb) is an essential protein and a promising drug target. FAS I is a multi-functional, multi-domain protein that is organized as a large (1.9 MDa) homohexameric complex. Acyl intermediates produced during fatty acid elongation are attached covalently to an acyl carrier protein (ACP) domain. This domain is activated by the transfer of a 4'-Phosphopantetheine (4'-PP, also termed P-pant) group from CoA to ACP catalyzed by a 4'-PP transferase, termed acyl carrier protein synthase (AcpS). Methods: In order to obtain an activated FAS I in E. coli, we transformed E. coli with tagged Mtb fas1 and acpS genes encoded by a separate plasmid. We induced the expression of Mtb FAS I following induction of AcpS expression. FAS I was purified by Strep-Tactin affinity chromatography. Results: Activation of Mtb FAS I was confirmed by the identification of a bound P-pant group on serine at position 1808 by mass spectrometry. The purified FAS I displayed biochemical activity shown by spectrophotometric analysis of NADPH oxidation and by CoA production, using the Ellman reaction. The purified Mtb FAS I forms a hexameric complex shown by negative staining and cryo-EM. Conclusion: Purified hexameric and active Mtb FAS I is required for binding and drug inhibition studies and for structure-function analysis of this enzyme. This relatively simple and short procedure for Mtb FAS I production should facilitate studies of this enzyme. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest the burden of pulmonary tuberculosis (PTB) in Ethiopia may be greater in university students relative to the overall population. However, little is known about the transmission dynamics of PTB among students and members of the communities surrounding university campuses in Eastern Ethiopia. Methods: A cross sectional study was conducted in Eastern Ethiopia among prevalent culture-confirmed PTB cases from university students (n = 36) and community members diagnosed at one of four hospitals (n = 152) serving the surrounding area. Drug susceptibility testing (DST) was performed on Mycobacterium tuberculosis complex (MTBC) isolates using BD Bactec MGIT 960 and molecular genotyping was performed using spoligotyping and 24-loci MIRU-VNTR. MTBC strains with Identical genotyping patterns were assigned to molecular clusters as surrogate marker for recent transmission and further contact tracing was initiated among clustered patients. Results: Among all study participants, four MTBC lineages and 11 sub-lineages were identified, with Ethiopia_3 (Euro-American lineage) being most common sub-lineage (29.4%) in both cohorts and associated with strain clustering (P = 0.016). We further identified 13 (8.1%) strains phylogenetically closely related to Ethiopia_3 but with a distinct Spoligotyping pattern and designated as Ethiopia_4. The clustering rate of MTBC strains was 52.9% for university students and 66.7% for community members with a Recent Transmission Index (RTI) of 17.6% and 48.4%, respectively. Female gender, urban residence, and new TB cases were significantly associated with strain clustering (P<0.05). Forty-eight (30%) of the study participants were resistant to one or more first line anti TB drugs, three patients were classified as multidrug resistant (MDR). Conclusion: We found evidence for recent transmission of PTB among Ethiopian university students and the local community in Eastern Ethiopia, mainly linked to strains classified as Ethiopia_3 sub lineage. Drug resistance didn’t have a major impact on recent transmission but comprehensive molecular surveillance in combination with drug resistance profiling of MTBC strains is desirable to better characterize TB transmission dynamics in high risk congregate living environments such as university campuses and guide regional TB control programs. [ABSTRACT FROM AUTHOR]

In a Perspective on the research article from Jacobson and colleagues, Amitabh Suthar and colleagues from the Centers for Disease Control and Prevention discuss the importance of and considerations for developing real-time and large-scale reporting systems for tracking and controlling antimicrobial resistance. [ABSTRACT FROM AUTHOR]