Microscopic-observation drug-susceptibility assay for the diagnosis of TB.

BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on Löwenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for Löwenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used

Drug-Resistant Tuberculosis--Current Dilemmas, Unanswered Questions, Challenges and Priority Needs

Tuberculosis was declared a global emergency by the World Health Organization (WHO) in 1993. Following the declaration and the promotion in 1995 of directly observed treatment short course (DOTS), a cost-effective strategy to contain the tuberculosis epidemic, nearly 7 million lives have been saved compared with the pre-DOTS era, high cure rates have been achieved in most countries worldwide, and the global incidence of tuberculosis has been in a slow decline since the early 2000s. However, the emergence and spread of multidrug-resistant (MDR) tuberculosis, extensively drug-resistant (XDR) tuberculosis, and more recently, totally drug-resistant tuberculosis pose a threat to global tuberculosis control. Multidrug-resistant tuberculosis is a man-made problem. Laboratory facilities for drug susceptibility testing are inadequate in most tuberculosis-endemic countries, especially in Africa; thus diagnosis is missed, routine surveillance is not implemented, and the actual numbers of global drug-resistant tuberculosis cases have yet to be estimated. This exposes an ominous situation and reveals an urgent need for commitment by national programs to health system improvement because the response to MDR tuberculosis requires strong health services in general. Multidrug-resistant tuberculosis and XDR tuberculosis greatly complicate patient management within resource-poor national tuberculosis programs, reducing treatment efficacy and increasing the cost of treatment to the extent that it could bankrupt healthcare financing in tuberculosis-endemic areas. Why, despite nearly 20 years of WHO-promoted activity and >12 years of MDR tuberculosis–specific activity, has the country response to the drug-resistant tuberculosis epidemic been so ineffectual? The current dilemmas, unanswered questions, operational issues, challenges, and priority needs for global drug resistance screening and surveillance, improved treatment regimens, and management of outcomes and prevention of DR tuberculosis are discussed

Drug Susceptibility Patterns in MDR-TB Patients:Challenges for Future Regimen Design. A Cross-Sectional Study

Globally, there is substantial concern regarding the challenges of treating complex drug resistance patterns in multidrug resistant tuberculosis cases. Utilising data from three different settings (Estonia, Latvia, Romania) we sought to contrast drug susceptibility profiles for multidrug resistant tuberculosis cases, highlight the difficulties in designing universal regimen, and inform future regimen selection. Demographic and microbiological surveillance data for multidrug resistant tuberculosis cases from 2004-13 were analysed. High levels of additional resistance to currently recommended second line drugs were seen in all settings, with extensive variability between countries. Accurate drug susceptibility testing and drug susceptibility testing data are vital to inform the development of comprehensive, flexible, multidrug resistant tuberculosis guidance

Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients

AbstractBackgroundFluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan.ObjectiveTo evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients.MethodsThis was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients’ socio-demographic, microbiological, and clinical data. SPSS 16 was used for data analysis.ResultsHigh degree of drug resistance (median 5 drugs, range 2–8) was observed. High proportion of patients was resistant to all five first-line anti-tuberculosis drugs (62.6%), and more than half were resistant to second line drugs (55.1%). The majority of the patients were ofloxacin resistant (52.7%). Upon multivariate analysis previous tuberculosis treatment at private (OR=1.953, p=0.034) and public private mix (OR=2.824, p=0.046) sectors were predictors of ofloxacin resistance.ConclusionThe high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public–private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains

Double infection with a resistant and a multidrug-resistant strain of Mycobacterium tuberculosis.

An immunocompetent patient was dually infected with a resistant and a multidrug-resistant strain of Mycobacterium tuberculosis (TB). The multidrug-resistant strain, which belongs to the W- strain/Beijing family, was first isolated after 3 months of therapy. Inappropriate treatment led to further drug resistance and unsuccessful therapy. Thus, additional infections with resistant M. tuberculosis strains should be considered when tuberculosis therapy fails

Global burden of drug-resistant tuberculosis in children: a mathematical modelling study

Background: After infection with Mycobacterium tuberculosis, children are at an increased risk of progression to tuberculosis disease; a condition that can be challenging to diagnose. New estimation approaches for children have highlighted the gap between incidence and notifications of M tuberculosis, and suggest there are more cases of isoniazid-resistant and multidrug-resistant (MDR) disease than are identified. No work has yet quantified the burden of drug-resistant infection, or accounted for other types of drug resistance or sampling uncertainty. Methods: We combined a mathematical model of tuberculosis in children with an analysis of drug-resistance patterns to produce country-level, regional, and global estimates of drug-resistant infection and disease. We determined drug resistance using data from the Global Project on Antituberculosis Drug Resistance Surveillance at WHO, from surveys and surveillance reported between 1988 and 2014. We combined 1000 sampled proportions for each country from a Bayesian approach with 10 000 sampled country estimates of tuberculosis disease incidence and M tuberculosis infection prevalence. We estimated the proportions of tuberculosis cases at a country level with isoniazid monoresistance, rifampicin monoresistance, multidrug resistance (MDR), fluoroquinolone-resistant multidrug resistance, second-line injectable-resistant multidrug resistance, and extensive multidrug resistance with resistance to both a fluoroquinolone and a second-line injectable (XDR). Findings: We estimated that 850 000 children developed tuberculosis in 2014; 58 000 with isoniazid-monoresistant tuberculosis, 25 000 with MDR tuberculosis, and 1200 with XDR tuberculosis. We estimate 67 million children are infected with M tuberculosis; 5 million with isoniazid monoresistance, 2 million with MDR, and 100 000 with XDR. Africa and southeast Asia have the highest numbers of children with tuberculosis, but the WHO Eastern Mediterranean region, European region, and Western Pacific region also contribute substantially to the burden of drug-resistant tuberculosis because of their much higher proportions of resistance. Interpretation: Far more drug-resistant tuberculosis occurs in children than is diagnosed, and there is a large pool of drug-resistant infection. This finding has implications for approaches to empirical treatment and preventive therapy in some regions of the world

Multidrug and extensively drug-resistant tuberculosis from a general practice perspective

Despite intensive efforts to eradicate the disease, tuberculosis continues to be a major threat to Indian society, with an estimated prevalence of 3.45 million cases in 2006. Emergence of multidrug-resistant tuberculosis has complicated eradication attempts in recent years. Incomplete and/inadequate treatment are the main causes for development of drug resistance. Directly observed therapy, short-course (DOTS) is the World Health Organization (WHO) strategy for worldwide eradication of tuberculosis, and our country achieved 100% coverage for DOTS through the Revised National Tuberculosis Control Program in 2006. For patients with multidrug-resistant tuberculosis, the WHO recommends a DOTS-Plus treatment strategy. Early detection and prompt treatment of multidrug-resistant tuberculosis is crucial to avoid spread of the disease and also because of the chances of development of potentially incurable extensively drug-resistant tuberculosis in these cases. This review discusses the epidemiologic, diagnostic, and therapeutic aspects of multidrug-resistant tuberculosis, and also outlines the role of primary care doctors in the management of this dangerous disease

Adverse effects profile of multidrug-resistant tuberculosis treatment in a South African outpatient clinic

Background: Highly active antiretroviral therapy (HAART) and drugs that are used to treat multidrug-resistant tuberculosis have potentially overlapping adverse effects. Few South African studies have documented adverse effects in the multidrugresistant tuberculosis population. This study examined the adverse effects profile in a sample of the outpatient population at the King George V Hospital Multidrug-Resistant Tuberculosis Clinic in Durban, KwaZulu-Natal.Method: The method was an anonymous, retrospective record review of 350 patients with multidrug-resistant tuberculosis, who were attending the King George V Hospital Multidrug-Resistant Tuberculosis Clinic (2010-2011). Adverse effect profiles in patients with multidrug-resistant tuberculosis only, and those who were co-infected with the human immunodeficiency virus (HIV) who were on and not on HAART, were documented and analysed.Results: Adverse events were recorded for 80.6% of patients. These included hearing loss (28.7%); peripheral neuropathy (23.2%); diarrhoea, nausea and vomiting (20.5%); arthralgia (15.9%); rashes and dermatological effects (excluding Stevens-Johnson syndrome) (14%); abdominal pain and dyspepsia (10.3%); and psychoses and confusion (8.3%). In this study population, 72.6% of patients were HIV positive, and 85% were concomitantly on HAART and multidrug-resistant tuberculosis treatment. Adverse events were significantly more common in patients who were HIV positive than in patients who were HIV negative with regard to peripheral neuropathy (p-value &lt; 0.001), psychosis and confusion (p-value = 0.04), hearing loss (p-value = 0.047), and thyroid disease (p-value &lt; 0.001). The use of HAART in patients who were HIV positive and on multidrug-resistant tuberculosis treatment was not significantly associated with the overall incidence of adverse events (p-value = 0.432). However, the calculated likelihood ratios of several individual adverse events occurring in these patients was greater. Patients who were HIV negative experienced the least adverse events.Conclusion: The high percentage of patients in the sample population (45%) who was found to be multidrug-resistant tuberculosis positive de novo or while on standard tuberculosis treatment suggests that drug sensitivity testing for all patients with tuberculosis should be considered. The findings of  this study support the current national policy that all patients with tuberculosis should be tested for HIV, and that all patients who are HIV positive and with multidrug-resistant tuberculosis should be on HAART. Clinicians should be supported in their function of examining, managing and recording adverse events. Reporting adverse events to the Department of Health should be encouraged. The development of a standardised recording instrument may mitigate the under-reporting of adverse events. The adverse effects profile in this study population differs from that reported in other studies