Global burden of MDR-TB and XDR-TB attributable to high fasting plasma glucose from 1990 to 2019: a retrospective analysis based on the global burden of disease study 2019.

PURPOSE: High fasting plasma glucose (HFPG) has been identified as a risk factor for drug-resistant tuberculosis incidence and mortality. However, the epidemic characteristics of HFPG-attributable multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) remain unclear. We aimed to analyze the global spatial patterns and temporal trends of HFPG-attributable MDR-TB and XDR-TB from 1990 to 2019. METHODS: Utilizing data from the Global Burden of Disease 2019 project, annual deaths and disability-adjusted life years (DALYs) of HFPG-attributable MDR-TB and XDR-TB were conducted from 1990 to 2019. Joinpoint regression was employed to quantify trends over time. RESULTS: From 1990 to 2019, the deaths and DALYs due to HFPG-attributable MDR-TB and XDR-TB globally showed an overall increasing trend, with a significant increase until 2003 to 2004, followed by a gradual decline or stability thereafter. The low sociodemographic index (SDI) region experienced the most significant increase over the past 30 years. Regionally, Sub-Saharan Africa, Central Asia and Oceania remained the highest burden. Furthermore, there was a sex and age disparity in the burden of HFPG-attributable MDR-TB and XDR-TB, with young males in the 25-34 age group experiencing higher mortality, DALYs burden and a faster increasing trend than females. Interestingly, an increasing trend followed by a stable or decreasing pattern was observed in the ASMR and ASDR of HFPG-attributable MDR-TB and XDR-TB with SDI increasing. CONCLUSION: The burden of HFPG-attributable MDR-TB and XDR-TB rose worldwide from 1990 to 2019. These findings emphasize the importance of routine bi-directional screening and integrated management for drug-resistant TB and diabetes.

Comparative genomic analyses of multi-drug resistant Mycobacterium tuberculosis from Nepal and other geographical locations.

Nepal exhibits a tuberculosis (TB) incidence rate that is comparable to neighbouring high TB incidence countries. In addition, it records >500 cases of multi-drug resistant (MDR) TB each year. The objective of this study was to perform whole-genome bioinformatic analysis on MDR-TB isolates from Nepal (n = 19) to identify the specific mutations underlying their phenotypic resistance. In addition, we examined the dominant genotype among the Nepal MDR-TB isolates, the East-Asian Beijing sub-lineage, to determine its relatedness to a panel of 1274 genomes of international strains available from public databases. These analyses provided evidence that the XDR-TB isolates in our collection were not derived from importation of primary XDR-TB to Nepal but were more likely the result of acquisition of second-line drug resistance in Nepal. Resistance to fluoroquinolones was detected among a high proportion of the Nepal isolates. This has implications for the management of TB, including appropriate antimicrobial stewardship and susceptibility testing for fluoroquinolones and other second-line TB drugs, to minimise the development of XDR-TB among Nepal TB cases.

Adverse effects of bedaquiline in patients with extensively drug-resistant tuberculosis.

BACKGROUND: The World Health Organisation (WHO) guidelines recommend that, because of the resistance patterns of extensively drug-resistant (XDR) tuberculosis (TB) and its unique mechanism of action, bedaquiline be included in the regimen. Although the results of clinical trials have shown bedaquiline to be beneficial, it also carries the risk of adverse effects, some potentially life-threatening. The aim of the study was to determine the incidence of adverse effects caused by bedaquiline in patients diagnosed with XDR-TB. The subsequent management of these adverse effects was also analysed. METHODS: The medical records of patients aged 18 years or older living with XDR-TB who were prescribed bedaquiline in combination with a background regimen at a public-sector drug-resistant TB hospital in the Eastern Cape were reviewed. RESULTS: Thirty records were reviewed in September 2016. Female patients constituted 66.67% (n = 20) of the sample. Nearly half (46.67%; n = 14) of the patients were living with human immunodeficiency virus, and six (42.86%) of them were female. Adverse effects were recorded for 26 patients (86.67%) including corrected QT prolongation (40%; n = 12), skin rash (33.33%; n = 10) and hyperlactataemia (33.33%; n = 10) as the most common. There were no treatment discontinuations or deaths. The management of adverse effects varied from omitting doses of bedaquiline to pharmacological intervention. CONCLUSION: All patients completed bedaquiline treatment, indicating that the adverse effects did not require discontinuation of the drug. However, when pharmacological intervention is required for the management of adverse effects, care should be taken to ensure that there is minimal interaction with other TB drugs and a low risk of further adverse effects.

Long-term Follow-up Reveals High Posttreatment Mortality Rate Among Patients With Extensively Drug-Resistant Tuberculosis in the Country of Georgia.

BACKGROUND: Given very limited data, we assessed the long-term outcomes among patients with extensively drug-resistant (XDR) tuberculosis (TB). METHODS: A retrospective population-based cohort study was performed in patients with XDR-TB diagnosed during 2011-2013 in the country of Georgia. Data were abstracted from the National TB Program, medical charts, interviews, and the national Georgian death registry. RESULTS: Among 111 patients starting treatment for XDR-TB, 59 (53.2%) had newly diagnosed tuberculosis, and 3 (2.9%) had human immunodeficiency virus (HIV) coinfection. The median length of follow-up from diagnosis of XDR-TB to death or the end of study was 53.9 months (interquartile range, 27.2-66.3 months). End-of-treatment outcomes were available for 106 patients; 35 (33.0%) had a favorable outcome, and 71 (67.0%) had an unfavorable outcome, including death in 16 (15.1%). An additional 20 patients died after cessation of initial treatment, increasing the overall mortality rate to 34.0%. In multivariable analysis, an unfavorable initial end-of-treatment outcome was associated with posttreatment death (adjusted odds ratio, 14.41; 95% confidence interval, 1.78-117.13). CONCLUSIONS: The overall mortality rate and specifically the posttreatment mortality rate were high among patients with XDR-TB. Patients with an unfavorable end-of-treatment outcome had an increased risk of death during follow-up. Our findings highlight the need for improved adherence, better-tolerated and shorter therapies, and enhanced posttreatment surveillance among patients treated for XDR-TB.

A systematic review on extensively drug-resistant tuberculosis from 2009 to 2020: special emphases on treatment outcomes / Una revisión sistemática sobre la tuberculosis extremadamente resistente de 2009 a 2020: énfasis especial sobre los resultados del tratamiento

Objectives: Extensively drug-resistant tuberculosis (XDR-TB) has raised a great threat to human health globally, especially in developing countries. The objective of the present study is to collate and contrast the proportions of treatment outcome in the previously published XDR-TB articles. Material and methods: By considering inclusion criteria and search engines, a total of 22 articles were enrolled. Results. Our findings revealed that the overall favorable treatment outcome was 24.04%. From the cohort of enrolled studies 19.76% (397) and 43.35% (871) patients were cured and died respectively. In 90.9% of enrolled articles, the investigators performed drug-susceptibility testing at the baseline. The overall treatment outcome was improved by the use of new drugs (linezolid, bedaquiline, ciprofloxacin, clofazimine) in the treatment regimen of XDR-TB showing linezolid and bedaquiline better results i.e. 59.44 and 78.88%, respectively. Moreover, use of antiretroviral treatment in XDR-TB patients with HIV infection have not shown any significant difference in the treatment outcome. Conclusions: XDR-TB treatment success can be achieved by implying standardized definitions, upgraded diagnostic procedures, and novel drugs. (AU)

Objetivos: La tuberculosis extremadamente resistente (XDR-TB) ha planteado una gran amenaza para la salud humana a nivel mundial, especialmente en los países en desarrollo. El objetivo del estudio es recopilar y contrastar las proporciones del resultado del tratamiento en los artículos de XDR-TB publicados.Material y métodos: Teniendo en cuenta los criterios de inclusión y los motores de búsqueda un total de 22 artículos fueron incluidos. Resultados. Nuestros hallazgos revelaron que el resultado total del tratamiento favorable fue del 24,04%. De la cohorte de estudios inscritos, el 19,76% (397) y el 43,35% (871) de los pacientes se curaron y murieron, respectivamente. En el 90,9% de los artículos, los investigadores realizaron pruebas de sensibilidad. El resultado total del tratamiento mejoró mediante el uso de nuevos medicamentos (linezolid, bedaquilina, ciprofloxacino, clofazimina) en el régimen de tratamiento de XDR-TB, mostrando linezolid y bedaquilina los mejores resultados, 59,44 y 78,88%, respectivamente. Además, el uso del tratamiento antirretroviral en pacientes con XDR-TB y con infección por VIH no mostró ninguna diferencia significativa en el resultado del tratamiento. Conclusiones: El éxito del tratamiento de la XDR-TB se puede lograr implicando definiciones estandarizadas, procedimientos de diagnóstico mejorados y nuevos medicamentos. (AU)

A patient with central nervous system tuberculomas and a history of disseminated multi-drug-resistant tuberculosis.

Tuberculosis (TB) is one of the leading causes of death worldwide, particularly in low- and middle-income countries. The global rates and numbers of drug resistant TB are rising. With increasing globalization, the spread of drug-resistant strains of TB has become a mounting global public health concern. We present a case of a young man previously treated for multi-drug resistant (MDR) TB in India who presented with neurological symptoms and central nervous system TB in the United States. His case highlights unique diagnostic and treatment challenges that are likely to become more commonplace with the increase of patients infected with drug-resistant TB and complicated extrapulmonary disease.

Delamanid and bedaquiline to treat multidrug-resistant and extensively drug-resistant tuberculosis in children: a systematic review.

The new drugs delamanid and bedaquiline are increasingly used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). As evidence is lacking, the World Health Organization recommends their use under specific conditions in adults, delamanid only being recommended in children ≥6 years of age. No systematic review has yet evaluated the efficacy, safety and tolerability of the new drugs in children. A search of peer-reviewed, scientific evidence was performed, to evaluate the efficacy/effectiveness, safety, and tolerability of delamanid or bedaquiline-containing regimens in children with confirmed M/XDR-TB. We used PubMed and Embase to identify any relevant manuscripts in English until 31 December 2016, excluding editorials and reviews. Three out of 96 manuscripts retrieved satisfied the inclusion criteria, while 93 were excluded because dealing exclusively with adults (12: 4 on delamanid and 8 on bedaquiline), being recommendations or guidelines (8 manuscripts), reviews (17 papers) or other studies (56 papers). One of the studies retrieved reported evidence on 19 M/XDR-TB children, 16 of them treated under compassionate use with delamanid (13 achieving consistent bacteriological conversion) and 3 candidates for the drug. Two studies reported details on the first paediatric case treated (and cured) with a delamanid-containing regimen. Eight trials including children were also retrieved (clinicaltrials.gov). Although the methodology used in the study was rigorous, the results are limited by the paucity of the studies available in the literature on the use of new anti-TB drugs in children. In conclusion, more evidence is needed on the use of delamanid and bedaquiline in paediatric patients.

Extensively Drug-resistant Tuberculosis (XDR-TB): A daunting challenge to the current End TB Strategy and policy recommendations.

Extensively Drug-resistant Tuberculosis (XDR-TB) has emerged as one of the most formidable challenges to the End TB Strategy that has targeted a 95% reduction in TB deaths and 90% reduction in cases by 2035. Globally, there were an estimated 55,100 new XDR-TB cases in 2015 in 117 countries. However, only one in 30 XDR-TB cases had been reported so far. Drug susceptibility test (DST) is the mainstay for diagnosing XDR-TB, but the lack of laboratory facilities in the resource-limited endemic countries limit its uses. A few new drugs including bedaquiline and delamanid, have the potential to improve the efficiency of XDR-TB treatment, but the drugs have been included in 39 countries only. The costs of XDR-TB treatment are several folds higher than that of the MDR-TB. Despite the financing from the donors, there is an urgent need to fill the current funding gap of US$ 2 billion to ensure effective treatment and robust surveillance. In the review article we have addressed current update on XDR-TB, including surveillance, diagnosis and the interventions needed to treat and limit its spread, emphasis on extensive financial support for implementing of current recommendations to meet the goals of End TB Strategy.

Overview of drug-resistant tuberculosis worldwide.

Even in the 21st century, we are losing the battle against eradication of tuberculosis (TB). In 2015, 9.6 million people were estimated to have fallen ill with TB, of which 1.5 million people died. This is the real situation despite the well-structured treatment programs and availability of effective treatment options since the 1950s. The high mortality rate has been associated with other risk factors, such as the HIV epidemic, underlying diseases, and decline of socioeconomic standards. Furthermore, the problem of drug resistance that was recognized in the early days of the chemotherapeutic era raises serious concerns. Although resistance to a single agent is the most common type, resistance to multiple agents is less frequent but of greater concern. The World Health Organization estimated approximately 5% of all new TB cases involved multidrug-resistant (MDR)-TB. The estimation for MDR-TB is 3.3% for new cases, and 20.5% for previously treated cases. Failure to identify and appropriately treat MDR-TB patients has led to more dangerous forms of resistant TB. Based on World Health Organization reports, 5% of global TB cases are now considered to be extensively drug resistant (XDR), defined as MDR with additional resistance to both fluoroquinolones and at least one second-line injectable drug. XDR-TB had been reported by 105 countries by 2015. An estimated 9.7% of people with MDR-TB have XDR-TB. More recently, another dangerous form of TB bacillus was identified, which was named totally drug resistant (TDR-TB) or extremely drug resistant TB. These strains were resistant to all first- and second-line anti-TB drugs. Collectively, it is accepted that 2% of MDR-TB strains turn to be TDR-TB. This number, however, may not reflect the real situation, as many laboratories in endemic TB countries do not have proper facilities and updated protocols to detect the XDR or TDR-TB strains. Nevertheless, existing data emphasize the need for additional control measures, such as new diagnostic methods, better drugs, and more effective vaccines to prevent the spread of these strains around the world.

Factors associated with treatment success and death in cases with multidrug-resistant tuberculosis in Bulgaria, 2009-2010.

OBJECTIVE: To analyze determinants of success and death in multidrug-resistant tuberculosis patients (MDR-TB; resistance to, at least, isoniazid and rifampicin) placed on treatment in Bulgaria during the period September 2009 to March 2010 using logistic regression. RESULTS: Fifty MDR-TB patients started treatment. Male:Female ratio was 2.3:1; mean age 43 years (range: 18-77); 19 patients (38%) were new; median duration of disease before treatment was 5 years (range: 1-13). All patients tested negative for HIV. Eight cases had XDR-TB (MDR-TB plus resistance to any fluoroquinolone and any second-line injectable). Twenty-four months after starting treatment, 24 patients (48%) had a successful outcome, in 6 (12%) treatment failed, 19 (38%) died, and one (2%) interrupted treatment. XDR-TB cases experienced higher mortality than others (75% vs. 30.9%, respectively, P<0.05). Sputum smear positivity at start of treatment and weight loss or no weight gain were positively associated with death (adjusted Odds ratio: 5.16; 95% confidence interval: 1.16-22.84 and 5.61; 1.48-21.20, respectively) and negatively with success (0.13; 0.02-0.94 and 0.02; 0.00-0.19). No previous TB treatment increased likelihood of success (7.82; 1.09-56.15). DISCUSSION AND CONCLUSIONS: Most MDR-TB patients in this first treatment cohort using WHO-recommended norms had advanced disease explaining the high mortality and low success. Early, adequate treatment of MDR-TB patients can improve outcomes and avert transmission.

The medical and surgical treatment of drug-resistant tuberculosis.

Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migration and travel, healthcare workers, researchers, and policy makers in TB endemic and non-endemic countries should familiarise themselves with issues relevant to the management of these patients. Given the lack of novel TB drugs and limited access to existing drugs such as linezolid and bedaquiline in TB endemic countries, significant numbers of therapeutic failures are emerging from the ranks of those with XDR-TB. Given the lack of appropriate facilities in resource-limited settings, such patients are being discharged back into the community where there is likely ongoing disease spread. In the absence of effective drug regimens, in appropriate patients, surgery is a critical part of management. Here we review the diagnosis, medical and surgical management of MDR-TB and XDR-TB.

Multidrug and extensively drug-resistant tuberculosis management: Evidences and controversies.

Multi-drug and extensively drug resistant tuberculosis (M/XDR-TB) has been an area of growing concern among clinicians, epidemiologists, and public health workers worldwide. Lack of controlled trials in M/XDR-TB patients hinders the optimal management of such patients, and guidelines that have been developed based largely on expert opinion are controversial. Lack of new effective drugs, improper regimens prescribed by poorly trained doctors and unreliable drug susceptibility testing add to the magnitude of the problem. M/XDR-TB is mostly a man made problem and its emergence can be checked by prompt diagnosis and effective use of first-line drugs in every new patient. DOTS-Plus proposed by World Health Organization (WHO) has highlighted the comprehensive management strategy to control multi-drug resistant tuberculosis (MDR-TB). Laboratory services must be strengthened for adequate and timely diagnosis of M/extensively drug resistant tuberculosis (XDR-TB) and programmatic management of M/XDR-TB must be scaled up as per target set by global plan to stop TB 2011-2015. In MDR-TB patients with localized disease, surgery, as an adjunct to chemotherapy, can improve outcomes and should be considered when there is poor response to appropriate chemotherapy. Proper use of second-line drugs must be ensured to cure existing MDR-TB, to reduce its transmission and to prevent emergence of XDR-TB.

Perfusing chemotherapy by percutaneous lung puncture in the treatment of extensive drug resistant pulmonary tuberculosis.

Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) during the past decade threatens to undermine these advances. XDR-TB has been found to be associated with scarce therapeutic options and high mortality rates. We describe the first case of XDR-TB cured by percutaneous lung puncture and with post-hospital 4 years follow-up involving radiologic imaging and septum smear and TB culture. We also review the epidemiology, diagnosis and treatment of tuberculosis all the world.