Treatment of tuberculosis: update 2010.

Currently, the standard short-course chemotherapy for tuberculosis comprises a 6-month regimen, with a four-drug intensive phase and a two-drug continuation phase. Alternative chemotherapy using more costly and toxic drugs, often for prolonged durations generally >18 months, is required for multidrug-resistant and extensively drug-resistant tuberculosis. Directly observed treatment, as part of a holistic care programme, is a cost-effective strategy to ensure high treatment success and curtail development of drug resistance in tuberculosis. New antituberculosis drugs are urgently needed to improve the present standard short-course and alternative chemotherapies, by shortening administration durations and increasing cure rates, through the greater potency of these agents. At the same time, the role of adjunctive surgery for drug-resistant tuberculosis has to be better defined. Immunotherapy might improve treatment outcomes of both drug-susceptible and -resistant tuberculosis, and warrants further exploration.

Treatment of latent infection with Mycobacterium tuberculosis: update 2010.

Much remains unknown about latent infection with Mycobacterium tuberculosis. Existing immunodiagnostic tools for this condition have various limitations, most importantly in their ability to predict disease. Randomised controlled trials have established protective efficacy of isoniazid therapy for 6-12 months among non-HIV-infected and HIV-infected subjects. While efficacy may reach 90%, acceptance and adherence to prolonged therapy are less than desired. Rifampicin plus pyrazinamide for 2 months, though efficacious, has been associated with excess hepatotoxicity in non-HIV-infected persons. Isoniazid plus rifampicin for 3 months has proven efficacy, but adverse effects may be more frequent than isoniazid or rifampicin monotherapy. Rifampicin monotherapy for 3-4 months is well tolerated, but efficacy data are currently limited, and concerns remain over possible selection of rifampicin-resistant mutants. For contacts of patients with multidrug-resistant tuberculosis, expert opinions differ on whether to treat with at least two drugs or just a fluoroquinolone, and for how long. With the existing diagnostic and treatment tools, efficacy of preventive therapy does not necessarily translate into field effectiveness. A targeted approach is required to maximise cost-effectiveness. Each geographic region needs to set its own priority after taking into account available scientific data and local circumstances.

Global lung health: the colliding epidemics of tuberculosis, tobacco smoking, HIV and COPD.

Tuberculosis (TB), smoking, HIV and chronic obstructive pulmonary disease (COPD) are burgeoning epidemics in developing countries. The link between TB and HIV is well established. Less well recognised is the strong relationship between tobacco smoking and the development and natural history of TB. These associations are of considerable relevance to public health and disease outcomes in individuals with TB. Moreover, tobacco smoking, a modifiable risk factor, is associated with poorer outcomes in HIV-associated opportunistic infections, of which TB is the commonest in developing countries. It is now also becoming clear that TB, like tobacco smoke, besides its known consequences of bronchiectasis and other pulmonary morbidity, is also a significant risk factor for the development of COPD. Thus, there is a deleterious and synergistic interaction between TB, HIV, tobacco smoking and COPD in a large proportion of the world's population. Further work, specifically mechanistic and epidemiological studies, is required to clarify the role of tobacco smoke on the progression of TB and HIV infection, and to assess the impact of smoking cessation interventions. These interactions deserve urgent attention and have major implications for coordinated public health planning and policy recommendations in the developing world.

Newer fluoroquinolones for treating respiratory infection: do they mask tuberculosis?

Possible masking of tuberculosis (TB) in treatment of community-acquired respiratory infection by newer fluoroquinolones has not been examined in randomised controlled trials. We undertook a randomised, open-label controlled trial involving adults with community-acquired pneumonia or infective exacerbation of bronchiectasis encountered in government chest clinics in Hong Kong. 427 participants were assigned by random permutated blocks of 20 to receive either amoxicillin clavulanate (n = 212) or moxifloxacin (n = 215). Participants were followed for 1 yr for active pulmonary TB. Excluding three participants with positive baseline culture, 13 developed active pulmonary TB: 10 (4.8%) out of 210 were given amoxicillin clavulanate, and three (1.4%) out of 214 were given moxifloxacin. The difference was significant by both proportion and time-to-event analysis. Post hoc analysis showed a significant decrease in the proportion with active pulmonary TB from 4.8% to 2.4% and 0% among participants given amoxicillin clavulanate (n = 210), moxifloxacin for predominantly 5 days (n = 127) and 10 days (n = 87), respectively. The log rank test for trend also showed a significant difference between the three subgroups. Regression models reaffirmed the linear effect; the adjusted odds ratio (95% confidence interval) of active pulmonary TB after moxifloxacin exposure up to predominantly 10 days was 0.3 (0.1-0.9). Newer fluoroquinolones appear to mask active pulmonary TB.

Role of oxidative stress in clofazimine-induced cardiac dysfunction in a zebrafish model.

BACKGROUND: Clofazimine (CFZ), a riminophenazine, is now commonly used in the treatment of multidrug-resistant tuberculosis. However, its use may be potentially associated with cardiac dysfunction in some individuals. In this study, the zebrafish heart, by merit of its developmental and genetic characteristics being in homology with that of human, was chosen as an animal model for evaluation of such dysfunction. METHODS: Morphological and physiological parameters were used to assess cardiac dysfunction. Transcriptome analysis was performed, followed by validation with real-time quantitative PCR, for delineation of the relevant genomics. RESULTS: Exposure of 2 dpf zebrafish to 4 mg/L CFZ for 2 days, adversely affected cardiac functions including significant decreases in HR, SV, CO, and FS, with observable pathophysiological developments of pericardial effusion and blood accumulation in the heart, in comparison with the control group. In addition, genes which respond to xenobiotic stimulus, related to oxygen transport, glutathione metabolism and extracellular matrix -receptor interactions, were significantly enriched among the differentially up-regulated genes. Antioxidant response element motif was enriched in the 5000 base pair upstream regions of the differentially expressed genes. Co-administration of N-acetylcysteine was shown to protect zebrafish against the development of CFZ-induced cardiac dysfunction. CONCLUSIONS: This study suggests an important role of oxidative stress as a major pathogenetic mechanism of riminophenazine-induced cardiac dysfunction.

Analyses of fluoroquinolones and Clostridium difficile-associated diarrhoea in tuberculosis patients.

SETTING: Systematic studies of fluoroquinolones (FQs) and Clostridium difficile-associated diarrhoea (CDAD) are scarce among tuberculosis (TB) patients, in whom fluoroquinolones (FQs) are increasingly used. OBJECTIVE: To evaluate the relationship between FQs and CDAD among TB patients. DESIGN: Retrospective cohort and nested case-control analyses were conducted among 3319 hospital patients on anti-tuberculosis treatment from 1999 to 2005. Each case of CDAD was matched by three sex- and age-matched controls randomly selected from the rest of the cohort. Not every case was confirmed by C. difficile cytotoxins. RESULTS: Among 38 cases studied, the incidence of CDAD, which was 28.2 (95%CI 20.3-38.3) per 100 000 patient-days overall, increased from 12.9 (95%CI 5.8-25.3) for patients aged <60 years to 26.6 (95%CI 15.5-42.8) for those aged between 60 and 79 years, and 66.9 (95%CI 39.8-106.1) for those aged >79 years. Univariate analysis showed a significant association between CDAD and age, FQs, non-FQ antibiotics, serum albumin level, duration of hospital stay and nasogastric feeding. Only duration of hospital stay and nasogastric feeding remained significant on multivariable analysis. CONCLUSION: The risk of CDAD due to FQs among TB patients is probably modest after controlling for sex, age, non-FQ antibiotics, serum albumin level, duration of hospital stay and nasogastric feeding.

Detection of novel mutations associated with independent resistance and cross-resistance to isoniazid and prothionamide in Mycobacterium tuberculosis clinical isolates.

OBJECTIVES: Prothionamide, a structural analogue of isoniazid, is used mainly for treating multidrug-resistant tuberculosis (MDR-TB). Both drugs have a common target InhA, so prothionamide can be ineffective against isoniazid-resistant (INHR) Mycobacterium tuberculosis. We aimed to investigate the prevalence of mutations in katG, ethA, ndh, ethR, mshA, inhA and/or its promoter associated with independent resistance and cross-resistance to INHR and/or prothionamide-resistant (PTOR) M. tuberculosis isolates. METHODS: We sequenced the above genes in 206 M. tuberculosis isolates with susceptibility testing against ten drugs. RESULTS: Of the 173 INHR PTOR isolates, 170 (98.3%) harboured mutations in katG, 111 (64.2%) in ethA, 58 (33.5%) in inhA or its promoter, 5 (2.9%) in ndh, 3 (1.7 %) in ethR and 2 (1.2%) in mshA. Among the 18 INHR PTOS isolates, mutations in katG were found in all of them; one had a mutation in the inhA promoter and another in ndh. Of the five INHS PTOR isolates, four showed mutations in ethA and two in the inhA promoter. Notably, 55 novel non-synonymous mutations were found in them and 20.2% of the PTORM. tuberculosis isolates harboured no known mutations. CONCLUSIONS: This is the first report to investigate cross-resistance between INHR and/or PTOR isolates. Among INHR (94.4% MDR-TB) M. tuberculosis isolates, the high diversity of mutations for independent resistance and cross-resistance with prothionamide highlight the importance of both phenotypic susceptibility and genotypic diagnosis when using it to treat patients with INHR-TB. The high proportion (one-fifth) of PTORM. tuberculosis isolates showed no known mutation related to PTOR genes, so uncovered resistance mechanism(s) of prothionamide exist.

Supervised and induced sputum among patients with smear-negative pulmonary tuberculosis.

Sputum culture is essential for monitoring drug resistance. Although sputum induction may optimise culture yield, better selection criteria and simpler algorithms are needed for countries with intermediate tuberculosis burdens. From a cohort of 660 patients who registered for antituberculosis treatment in a government chest clinic from May 21, 2005 to February 28, 2007, 187 patients with pulmonary disease and a negative smear in two unsupervised sputum specimens were enrolled prospectively for collection of one specimen each of supervised and induced sputum in succession. Among enrolled patients, induced sputum significantly improved ease of expectoration on a subjective five-point scale. Among 78 patients with culture-proven pulmonary tuberculosis, analysis of matched sputum culture results showed that: 1) induced sputum outperformed supervised sputum; 2) the second unsupervised sputum was significantly inferior to the first and redundant in the presence of the others; 3) adding one specimen each of supervised and induced sputum to two unsupervised specimens increased culture yield significantly; and 4) patients with either extent of disease less than right upper lobe or no respiratory symptoms were more likely to benefit. In summary, it may be practical to collect a sample of unsupervised, supervised and induced sputum for smear-negative patients with extent of disease less than the right upper lobe, especially when respiratory symptoms are absent.

Comparison of T-Spot.TB and tuberculin skin test among silicotic patients.

In the present study, T-Spot.TB and the tuberculin skin test (TST) were compared in the screening of latent tuberculosis infection among silicotic patients. A conditional probability model was used to compare the potential clinical utilities of T-Spot.TB and TST performed on 134 silicotic subjects from December 1, 2004 to January 31, 2007. Data from a historical cohort were also reanalysed for further comparison. Agreement with T-Spot.TB was best using a TST cut-off of 10 mm. Age >or=65 yrs independently predicted a tuberculin reaction <10 mm (odds ratio = 3), but not a negative T-Spot.TB response. Lower measures of agreement were observed among current smokers and those aged >or=65 yrs. Tuberculin reaction size was well correlated with both early secretary antigenic target 6 and culture filtrate protein 10 spot counts, except among current smokers. Within the current estimates of sensitivity (88-95%) and specificity (86-99%) for T-Spot.TB, the positive likelihood ratio for T-Spot.TB test would be substantially higher (6.29-95.0 versus 1.65-1.94) and negative likelihood ratio substantially lower (0.05-0.14 versus 0.32-0.41) than the corresponding ratios for the tuberculin test. A low tuberculosis risk differential was similarly observed between tuberculin-negative and untreated tuberculin-positive subjects in the historical cohort. T-Spot.TB is likely to perform better than tuberculin test in the screening of latent tuberculosis infection among silicotic subjects.

Risk factors for multidrug-resistant tuberculosis in Hong Kong.

SETTING: Previous anti-tuberculosis treatment is a widely reported risk factor for multidrug-resistant tuberculosis (MDR-TB), whereas other risk factors are less well described. In Hong Kong, the clinical characteristics of MDR-TB have not been systematically evaluated. OBJECTIVE: To explore the risk factors for MDR-TB in Hong Kong. DESIGN: MDR-TB patients treated between 1999 and 2003 were compared with non-MDR-TB patients by stratification of previous anti-tuberculosis treatment. RESULTS: One hundred and fifty-six MDR-TB patients, including 93 with and 63 without a previous history of anti-tuberculosis treatment, were identified. Among the 322 non-MDR-TB controls, respectively 192 and 130 patients did and did not have a previous history of anti-tuberculosis treatment. Using logistic regression analysis, non-permanent residents (OR 6.85, 95%CI 1.38-34.09), frequent travel (OR 2.48, 95%CI 1.07-5.74) and younger age were found to be independent predictors of MDR-TB in previously treated patients, whereas living on financial assistance just failed to reach statistical significance (OR 2.75, 95%CI 0.98-7.68, P=0.05). In the treatment-naïve group, despite significant differences in baseline characteristics among MDR-TB and non-MDR-TB patients, no independent predictor variables could be identified. CONCLUSION: In Hong Kong, non-permanent residents, frequent travel and young age were independent predictors of MDR-TB among previously treated patients.

Smoking and tuberculosis: the epidemiological association and immunopathogenesis.

There is increasing evidence of a link between tuberculosis and smoking. This paper reviews the epidemiological evidence from the UK, China, India and the USA, summarizing some of the main papers which indicate an association. Where an association has been found there seems to be an increase in tuberculosis case rates of between two- and four-fold for those smoking in excess of 20 cigarettes a day, but it may be difficult to control for other factors, particularly alcohol consumption. The final part of the paper reviews possible mechanisms. A likely possibility is that nicotine turns off the production of TNF-alpha by the macrophages in the lungs, rendering the patient more susceptible to the development of progressive disease from latent Mycobacterium tuberculosis infection.

Socio-demographic and geographic indicators and distribution of tuberculosis in Hong Kong: a spatial analysis.

OBJECTIVE: To determine the socio-demographic and geographic indicators responsible for the distribution and transmission of tuberculosis (TB) in Hong Kong using geographical information system (GIS) technology. MATERIALS AND METHODS: All patients with bacteriologically proven TB over a period of 3 years (May 1999-April 2002) residing within Hong Kong Island were studied. Molecular characterisation of their sputum isolates by IS6110-based restriction fragment length polymorphism (RFLP) technique was performed. Socio-demographic data were derived from the 2001 Hong Kong population census. Geographic coordinates of patients' addresses were linked to the GIS; large street block groups (LSBGs) were the units of analysis. RESULTS: Of 2387 patients with bacteriologically confirmed TB, 2332 had valid addresses distributed in 430 LSBGs in Hong Kong Island. Of the five socio-demographic indicators studied, significant correlations were found between the rate of TB in an LSBG and low educational attainment, elderly population and low-income household, but not population density or unemployment. The five socio-demographic indicators were not different between LSBG with clustered cases and those with unique cases. CONCLUSION: Low educational attainment, old age and poverty were significant determinants of the rate of TB in different parts of Hong Kong, while none of the socio-demographic indicators was related to disease transmission.

Chest radiograph screening for tuberculosis in a Hong Kong prison.

SETTING: Long-stay prisoners are not regularly screened for TB in Hong Kong. OBJECTIVE: To evaluate tuberculosis (TB) screening in prison. METHOD: All prisoners in a maximum security prison as of 31 October 2001 were screened by chest radiograph (CXR), except for those being followed up for TB or examined by CXR in the last 6 months. RESULTS: A total of 814 male prisoners aged 34.6 +/- 9.6 (mean +/- SD) years were successfully screened. Of 53 cases (6.51%) with radiographic abnormalities, 10 active TB cases (8 culture-negative, 2 culture-positive) were diagnosed, giving an overall yield of 1.23% (95%CI 0.59-2.26). There was no statistical difference in age, ethnicity, place of birth or residency status between those with and those without TB (all P > 0.05). Incarceration > or = 2 years, being in current prison > or = 2 years and not having CXR in last 2 years were associated with TB in univariate analysis (all P < 0.05), but only the last remained an independent predictor in multiple logistic regression (OR 16.8, 95%CI 2.1-132.9, P = 0.008). In that group, the yield was 3.1% (95%CI 1.42-5.89). No further cases were detected in the subsequent 2 years. CONCLUSION: CXR screening of long-stay prisoners gave a high yield in this study.

Do patients with obstructive sleep apnea wake up with headaches?

BACKGROUND: There is a controversy regarding the association of obstructive sleep apnea (OSA) and morning headaches. This study investigates whether this relationship exists. METHODS: This is a retrospective study of 80 consecutive patients with OSA who underwent sleep polysomnography from December 1996 to March 1997. Patients were interviewed about their headache history. Headaches were classified according to International Headache Society criteria and the severity graded by the Chronic Pain Index. Headache characteristics were compared with those of 22 control patients with periodic limb movement disorder. Headache response to continuous positive airway pressure or uvulopalatopharyngoplasty in the patients with OSA was also assessed. RESULTS: Forty-eight (60%) patients had headaches in the year prior to study. Twenty-five of the 48 patients had headaches that did not fit any category. Of these 25 patients, 23 (48% of total group) reported awakening headaches. These awakening headaches were significantly more common in the OSA group compared with the periodic limb movement disorder group, 9 (41%) of whom had headaches, none of which occurred on awakening. The proportion of common types of headaches in both groups was similar. The awakening headaches were brief (shorter than 30 minutes), and their occurrence and severity correlated with OSA severity. Of the 29 patients with OSA who were treated with continuous positive airway pressure or uvulopalatopharyngoplasty, awakening headaches improved by a mean of 80% compared with minimal improvement of migraine, tension, and cervicogenic headaches. CONCLUSIONS: Awakening headaches are associated with OSA. These headaches are of brief duration, and their occurrence and severity increase with increasing OSA severity. Treatment of OSA with continuous positive airway pressure or uvulopalatopharyngoplasty can reduce these headaches.

Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015.

Drug-resistant tuberculosis (DR-TB), including multi- and extensively drug-resistant TB, is posing a significant challenge to effective treatment and TB control worldwide. New progress has been made in our understanding of the mechanisms of resistance to anti-tuberculosis drugs. This review provides an update on the major advances in drug resistance mechanisms since the previous publication in 2009, as well as added information on mechanisms of resistance to new drugs and repurposed agents. The recent application of whole genome sequencing technologies has provided new insight into the mechanisms and complexity of drug resistance. However, further research is needed to address the significance of newly discovered gene mutations in causing drug resistance. Improved knowledge of drug resistance mechanisms will help understand the mechanisms of action of the drugs, devise better molecular diagnostic tests for more effective DR-TB management (and for personalised treatment), and facilitate the development of new drugs to improve the treatment of this disease.

Clinical research in the treatment of tuberculosis: current status and future prospects.

To supplement previous state-of-art reviews on anti-tuberculosis treatment and to pave the way forward with reference to the current status, we systematically reviewed published literature on clinical research on tuberculosis (TB) over the past decade in the treatment of drug-susceptible and multidrug-resistant TB (MDR-TB), with a focus on drugs, dosing factors and regimens. Our review was restricted to Phase II/III clinical trials, cohort and case-control studies, and systematic reviews of clinical studies. TB programmatic and patient behavioural factors, non-TB drugs, adjunctive surgery, new vaccines, immunotherapy, antiretroviral therapy and management of latent tuberculous infection are outside the scope of this review. An algorithm was used to systematically search PubMed for relevant articles published in English from 1 January 2005 to 31 December 2014. Articles without evaluated factors (drugs, dosing factors and regimens) or comparative analysis of specified anti-tuberculosis treatment outcomes were excluded. Of the 399 articles initially identified, 294 were excluded. The main findings of the remaining 105 articles are described under two categories: presumed drug-susceptible TB and MDR-TB. Fifty-nine articles included under drug-susceptible TB were divided into 12 subcategories: isoniazid, rifampicin, pyrazinamide, fluoroquinolones, fixed-dose combination drugs, dosing frequency, treatment phases, treatment duration, experimental regimens for pulmonary (surrogate markers vs. clinical outcomes) and extra-pulmonary TB. Forty-nine articles included under MDR-TB were divided into seven subcategories: fluoroquinolones, pyrazinamide, second-line injectable drugs, World Health Organization Group 4 and Group 5 drugs, MDR-TB regimens and novel drugs. Clinical research in the last decade and ongoing trials might furnish new paradigms for improving the treatment of this recalcitrant ancient disease.

Western Pacific Regional Green Light Committee: progress and way forward.

The Western Pacific Regional Green Light Committee (rGLC WPR) was established in 2011 to promote the rational scale-up of programmatic management of drug-resistant tuberculosis (PMDT). We reflect on its achievements, consider the challenges faced, and explore its potential future role. Achievements include the supervision and support of national PMDT action plans, increased local ownership, contextualized guidance, and a strong focus on regional capacity building, as well as a greater awareness of regional challenges. Future rGLC activities should include (1) advocacy for high-level political commitment; (2) monitoring, evaluation, and supervision; (3) technical support and contextualized guidance; and (4) training, capacity building, and operational research. Regional activities require close collaboration with both national and global efforts, and should be an important component of the new Global Drug-resistant TB Initiative.