opc-67683 and Extensively-Drug-Resistant-Tuberculosis

The introduction of two novel drugs, bedaquiline and delamanid, has given hope for better and shorter treatments of drug-resistant tuberculosis. A systematic review was conducted to evaluate the efficacy and safety of concomitant bedaquiline and delamanid administration. Pooled estimates of World Health Organization-defined favorable treatment outcome and significant QTc-interval prolongation (QTc ≥500 ms or ≥60 ms increase from baseline) were calculated using a random-effects model. Thirteen studies including a total of 1031 individuals with multidrug-resistant/rifampicin-resistant tuberculosis who received bedaquiline and delamanid were included. The pooled estimate of favorable treatment outcome was 73.1% (95% confidence interval [CI]: 64.3-81.8%). Sputum culture conversion at 6 months ranged from 61% to 95%. Overall, the pooled proportion of QTc-prolongation was 7.8% (95% CI: 4.1-11.6%) and few cardiac events were reported (0.8%; n = 6/798). Rates of sputum culture conversion and favorable treatment outcome were high in patients treated concomitantly with bedaquiline and delamanid, and the treatment seemed tolerable with low rates of clinically significant cardiac toxicity.

Topics: Antitubercular Agents; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis, Multidrug-Resistant

The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Ethambutol; Extensively Drug-Resistant Tuberculosis; Humans; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifampin

Treatment of drug-sensitive tuberculosis (TB) is effective, whereas that of multidrug-resistant and extensively drug-resistant TB as well as nontuberculous mycobacterial (NTM) disease are less so. Therapy in general requires good adherence to potentially toxic drug regimens over prolonged periods. Poor adherence is associated with resistance development and poor outcome. This review will present promising new treatments, both new drugs and regimens, for difficult mycobacterial pulmonary infections.. A number of new and repurposed drugs including bedaquiline, delamanid, pretomanid, linezolid and clofazimine, and drug regimens, such as the The Evaluation of a Standard Treatment Regimen of Anti-tuberculosis Drugs for Patients With MDR-TB (STREAM) trial regimens, are currently progressing from basic research through clinical trials.

Topics: Amikacin; Anti-Bacterial Agents; Clofazimine; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Linezolid; Liposomes; Lung Diseases; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Nitroimidazoles; Oxazoles

Tuberculosis (TB) is now the biggest infectious disease killer worldwide. Although the estimated incidence of TB has marginally declined over several years, it is out of control in some regions including in Africa. The advent of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) threatens to further destabilize control in several regions of the world. Drug-resistant TB constitutes a significant threat because it underpins almost 25% of global TB mortality, is associated with high morbidity, is a threat to healthcare workers and is unsustainably costly to treat. The advent of highly resistant TB with emerging bacillary resistance to newer drugs has raised further concern. Encouragingly, in addition to preventative strategies, several interventions have recently been introduced to curb the drug-resistant TB epidemic, including newer molecular diagnostic tools, new (bedaquiline and delamanid) and repurposed (linezolid and clofazimine) drugs and shorter and individualized treatment regimens. However, there are several controversies that surround the use of new drugs and regimens, including whether, how and to what extent they should be used, and who specifically should be treated so that outcomes are optimally improved without amplifying the burden of drug resistance, and other potential drawbacks, thus sustaining effectiveness of the new drugs. The equipoise surrounding these controversies is discussed and some recommendations are provided.

Topics: Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; World Health Organization

Tuberculosis (TB) is a devastating threat to human health whose treatment without the emergence of drug resistant Mycobacterium tuberculosis (M. tuberculosis) is the million-dollar question at present. The pathogenesis of M. tuberculosis has been extensively studied which represents unique defence strategies by infecting macrophages. Several anti-tubercular drugs with varied mode of action and administration from diversified sources have been used for the treatment of TB that later contributed to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). However, few of potent anti-tubercular drugs are scheduled for clinical trials status in 2017-2018. Peptides of varied origins such as human immune cells and non-immune cells, bacteria, fungi, and venoms have been widely investigated as anti-tubercular agents for the replacement of existing anti-tubercular drugs in future. In the present review, we spotlighted not only on the mechanisms of action and mode of administration of currently available anti-tubercular drugs but also the recent comprehensive report of World Health Organization (WHO) on TB epidemic, diagnosis, prevention, and treatment. The major excerpt of the study also inspects the direct contribution of different computational tools during drug designing strategies against M. tuberculosis in order to grasp the interplay between anti-tubercular peptides and targeted bacterial protein. The potentiality of some of these anti-tubercular peptides as therapeutic agents unlocks a new portal for achieving the goal of end TB strategy.

Topics: Antitubercular Agents; Computational Biology; Diarylquinolines; Drug Design; Extensively Drug-Resistant Tuberculosis; Humans; Models, Molecular; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Peptides; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

Multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR)-TB epidemics are key obstacles towards TB control and elimination.. Diagnosis of MDR/XDR-TB is difficult and requires several weeks. New diagnostic tools are being tested and proposed allowing for shorter time to diagnosis and reduced delays in starting an adequate treatment regimen. MDR/XDR-TB treatment strategies are currently on an evolving stage. New shortened treatments based on the recommended 'Bangladesh regimen' or on the newer anti-TB drugs, delamanid and bedaquiline may represent part of the future scenario. In addition, more information on safety and efficacy of delamanid and bedaquiline has been published, allowing to better position these drugs. Recent information on treatment regimens for the paediatric age, with or without delamanid or bedaquiline, has become available. This is of great help in designing safer and more efficacious regimens for the treatment of MDR/XDR-TB in children and adolescents.. The accessibility, sustainability and scale-up of new diagnostic technologies are lagging behind and more efforts are needed. In addition, we need high-quality information on safety and efficacy of various combinations of drugs to obtain the best possible regimens to treat the largest possible proportion of patients.

Topics: Adolescent; Antitubercular Agents; Child; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.

Topics: Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Repositioning; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles

Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure. Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of XDR-TB. Improved diagnostic procedures and rapid molecular tests help to select appropriate drugs and dosages. Drugs dosages can be further tailored to the specific conditions of the patient based on quantitative susceptibility testing of the M. tuberculosis isolate and use of therapeutic drug monitoring. Pharmacovigilance is important for preserving activity of the novel drugs bedaquiline and delamanid. Furthermore, biomarkers of treatment response must be developed and validated to guide therapeutic decisions. Expert commentary: Given the currently poor treatment outcomes and the association of XDR-TB with HIV in endemic regions, a more patient oriented approach regarding diagnostics, drug selection and tailoring and treatment evaluation will improve treatment outcome. The different areas of expertise should be covered by a multidisciplinary team and may involve the transition of patients from hospitalized to home or community-based treatment.

Topics: Antitubercular Agents; Biomarkers; Clinical Trials as Topic; Coinfection; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; HIV Infections; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Practice Guidelines as Topic; Precision Medicine

The new drugs delamanid and bedaquiline are increasingly being used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). The World Health Organization, based on lack of evidence, recommends their use under specific conditions and not in combination. No systematic review has yet evaluated the efficacy, safety, and tolerability of delamanid and bedaquiline used in combination. A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of delamanid and bedaquiline-containing regimens in individuals with pulmonary/extrapulmonary disease, which were bacteriologically confirmed as M/XDR-TB. We used PubMed to identify any relevant manuscripts in English up to the 23 December 2016, excluding editorials and reviews. Three out of 75 manuscripts retrieved satisfied the inclusion criteria, whilst 72 were excluded for dealing with only one drug (three studies), being recommendations (one study) or identifying need for their use (one study), focusing on drug resistance aspects (six studies) or being generic reviews/other studies (61 papers). The studies retrieved reported two XDR-TB cases observed for six months and achieving consistent sputum smear and culture conversion. Case 2 experienced a short break of bedaquiline, which was re-started after introducing verapamil. After a transient and symptom-free increase of the QT interval from week 5 to 17, it then decreased below the 500 ms threshold.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are emerging problems in several countries. These infections require long and expensive treatment regimens. Recently, 2 new drugs, bedaquiline and delamanid, have been approved in several countries for use in adults with severe, difficult-to-treat MDR-TB, and it has been suggested that they could also be administered to children with MDR-TB and limited treatment options. However, no study has been completed on their efficacy.. This report describes a 12-year-old child with XDR-TB who was cured after a 24-month therapy regimen, which included delamanid.. The patient showed progressive clinical deterioration after 5 months of treatment with the majority of anti-TB drugs available on the market.. After unsuccessfull treatment with several anti-TB drugs for 5 months, he was treated with a regimen including for 24 months.. Direct smear microscopy of the gastric aspirates and gastric aspirate cultures for Mycobacterium tuberculosis became negative after only 1 week and remained persistently negative. During the 24-month treatment, all blood test results remained within the normal range, no adverse events were reported, and corrected QT interval was always normal. A clinical and laboratory control was performed 3 months after discontinuation of delamanid, and the other drugs did not reveal any modification of both general conditions as well as laboratory and radiological findings. The patient was considered cured.. The positive outcome associated with the favorable safety and tolerability profile showed that long-term therapy with delamanid can significantly contribute to treating apparently hopeless XDR-TB cases in children.

Topics: Antitubercular Agents; Child; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Italy; Male; Nitroimidazoles; Oxazoles

The United Nations Millennium Development Goal of reversing the global spread of tuberculosis by 2015 has been offset by the rampant re-emergence of drug-resistant tuberculosis, in particular fluoroquinolone-resistant multidrug-resistant and extensively drug-resistant tuberculosis. After decades of quiescence in the development of antituberculosis medications, bedaquiline and delamanid have been conditionally approved for the treatment of drug-resistant tuberculosis, while several other novel compounds (AZD5847, PA-824, SQ109 and sutezolid) have been evaluated in phase II clinical trials. Before novel drugs can find their place in the battle against drug-resistant tuberculosis, linezolid has been compassionately used with success in the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis. This review largely discusses six novel drugs that have been evaluated in phase II and III clinical trials, with focus on the clinical evidence for efficacy and safety, potential drug interactions, and prospect for using multiple novel drugs in new regimens.

Topics: Adamantane; Antitubercular Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diarylquinolines; Drug Therapy, Combination; Ethylenediamines; Extensively Drug-Resistant Tuberculosis; Female; Follow-Up Studies; Humans; Male; Nitroimidazoles; Oxazoles; Oxazolidinones; Treatment Outcome; Tuberculosis, Multidrug-Resistant

The research and development of delamanid was carried out by Otsuka Pharmaceutical Development and Commercialization (Osaka, Tokyo, Japan). It belongs to the group of nitroimidazoles. It inhibits the synthesis of mycolic acids, crucial component of the cell wall of the Mycobacterium tuberculosis complex. It is insoluble in water and its activity was proven in several in vitro and in vivo studies. Its market approval was obtained in April 2014 in Europe. Its bactericidal activity was demonstrated in individuals with drug-susceptible and drug-resistant tuberculosis (MDR- and XDR-TB). The safety and tolerability profile was good; the notified increased QT interval was not clinically relevant. It was approved for adults but ongoing clinical trials and clinical experiences have been proving its efficacy in the pediatric population.

Topics: Adult; Antitubercular Agents; Europe; Extensively Drug-Resistant Tuberculosis; Humans; Japan; Mycobacterium tuberculosis; Mycolic Acids; Nitroimidazoles; Oxazoles; Randomized Controlled Trials as Topic; World Health Organization

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB) are major public health concerns worldwide. Their association with HIV/AIDS infection has contributed to the slowing down of TB incidence decline over the last two decades, therefore representing one of the most important barriers to reach TB elimination.. The aim of this manuscript is to critically review the recent scientific evidence on the management of drug-resistant TB (essentially MDR- and XDR-TB) in subjects coinfected with HIV, focusing on the two new recently-approved anti-TB drugs delamanid and bedaquiline. The medical search-engine PubMed was used, selecting the time-period January 2013 - February 2015, and using the following. drug-resistant TB, multidrug resistant TB (or MDR-TB), extensively drug-resistant TB (or XDR-TB), delamanid and bedaquiline.. The TB/HIV co-epidemic can be faced by implementing the 12 TB/HIV collaborative activities recommended by the World Health Organization. They are focused on the systematic screening of individuals to detect the Mycobacterium tuberculosis infection in HIV-positives, as well as HIV infection in TB patients in order to ensure a rapid initiation of the anti-retroviral therapy (ART). The clinical and public health management of HIV-positive individuals with MDR-TB is complex and expensive, given the cost of second line anti-TB drugs (including the new drugs, delamanid and bedaquiline) and ART. Political commitment and more investment to identify shorter, cheaper and effective anti-TB and HIV regimens as well as better diagnostics and, hopefully, a vaccine will contribute to boost the efforts to eliminate TB.

Topics: Antitubercular Agents; Coinfection; Diarylquinolines; Disease Management; Extensively Drug-Resistant Tuberculosis; HIV Infections; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; World Health Organization

The current 6-month tuberculosis (TB) therapy is suboptimal with significant side effects and a poor patient compliance problem that frequently selects drug-resistant organisms. The increasing drug-resistant TB problem highlights the need to develop new and more effective drugs. Significant progress has been made recently with several new drug candidates currently in clinical trials. Improved understanding of persister biology and development of persister drugs are likely to be important for developing a more effective therapy.

Topics: Adamantane; AIDS-Related Opportunistic Infections; Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Drugs, Investigational; Ethylenediamines; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifampin; Treatment Refusal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.. endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.. This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.. ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Topics: Antitubercular Agents; Clinical Trials, Phase III as Topic; Clofazimine; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Linezolid; Randomized Controlled Trials as Topic; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Sputum; Treatment Outcome

To evaluate the access to comprehensive diagnostics and novel antituberculosis medicines in European countries.. We investigated the access to genotypic and phenotypic Mycobacterium tuberculosis drug susceptibility testing and the availability of antituberculosis drugs and calculated the cost of drugs and treatment regimens at major tuberculosis treatment centres in countries of the WHO European region where rates of drug-resistant tuberculosis are the highest among all WHO regions. Results were stratified by middle-income and high-income countries.. Overall, 43 treatment centres from 43 countries participated in the study. For WHO group A drugs, the frequency of countries with the availability of phenotypic drug susceptibility testing was as follows: (a) 75% (30/40) for levofloxacin, (b) 82% (33/40) for moxifloxacin, (c) 48% (19/40) for bedaquiline, and (d) 72% (29/40) for linezolid. Overall, of the 43 countries, 36 (84%) and 24 (56%) countries had access to bedaquiline and delamanid, respectively, whereas only 6 (14%) countries had access to rifapentine. The treatment of patients with extensively drug-resistant tuberculosis with a regimen including a carbapenem was available only in 17 (40%) of the 43 countries. The median cost of regimens for drug-susceptible tuberculosis, multidrug-resistant/rifampicin-resistant tuberculosis (shorter regimen, including bedaquiline for 6 months), and extensively drug-resistant tuberculosis (including bedaquiline, delamanid, and a carbapenem) were €44 (minimum-maximum, €15-152), €764 (minimum-maximum, €542-15152), and €8709 (minimum-maximum, €7965-11759) in middle-income countries (n = 12) and €280 (minimum-maximum, €78-1084), €29765 (minimum-maximum, €11116-40584), and €217591 (minimum-maximum, €82827-320146) in high-income countries (n = 29), respectively.. In countries of the WHO European region, there is a widespread lack of drug susceptibility testing capacity to new and repurposed antituberculosis drugs, lack of access to essential medications in several countries, and a high cost for the treatment of drug-resistant tuberculosis.

Topics: Antitubercular Agents; Europe; Extensively Drug-Resistant Tuberculosis; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant

The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored.. To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India.. Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described.. Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period.. Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

Topics: Adolescent; Antitubercular Agents; Child; Extensively Drug-Resistant Tuberculosis; Feasibility Studies; Female; Humans; Male; Meropenem; Nitroimidazoles; Oxazoles; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Tuberculosis is an endemic infection and a serious public health problem in India. India constitutes one-fourth of the global TB population. The emerging drug resistance is a major threat to global tuberculosis care and control.. We present a case of newly diagnosed microbiologically confirmed, extremely drugresistant primary pulmonary tuberculosis which was treated with Delamanid and was found to be cured of tuberculosis.. Delamanid is a new anti-tubercular drug, which is thought to primarily inhibit the synthesis of methoxy-mycolic, and keto-mycolic acid, which are components of the mycobacterial cell wall. In our patient who was a newly diagnosed case of MDR-TB converted to XDR-TB in little course of time and we were successful in treating him with Delamanid therapy. His sputum culture conversion was achieved in 20 days. Even though the patient did not tolerate well because of the side effects of the drug, still he became microbiologically negative for tuberculosis.. Delamanid fulfills many target criteria for new TB drugs and may be particularly useful for the treatment of MDR-TB. It can be administered orally and its bactericidal properties make it suitable in regimens designed to shorten treatment duration. Clinical efficacy data, while limited, are reassuring.

Topics: Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Humans; Male; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles

There is limited evidence describing the safety and effectiveness of bedaquiline and delamanid containing regimens in children and adolescents with Multidrug-Resistant Tuberculosis (MDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) globally. In this nationwide descriptive cohort study from Belarus, we examined adverse drug events, time to culture conversion, treatment outcomes including post-treatment recurrence among children and adolescents (<18 years of age) treated with bedaquiline and/or delamanid containing regimens from 2015 to 2019. Of the 40 participants included (55% females; age range 10-17 years), 20 (50%) had XDR-TB and 15 (38%) had resistance to either fluoroquinolone or second-line injectable. Half of the patients received delamanid and another half received bedaquiline with one patient receiving both drugs. AEs were reported in all the patients. A total of 224 AEs were reported, most of which (76%) were mild in nature. Only 10 (5%) AEs were graded severe and one AE was graded life-threatening. A total of 7 AEs (3%) were classified as 'serious' and only one patient required permanent discontinuation of the suspected drug (linezolid). Most of the AEs (94%) were resolved before the end of treatment. All patients culture-positive at baseline (n=34) became culture-negative within three months of treatment. Median time to culture conversion was 1.1 months (interquartile range: 0.9-1.6). Two patients were still receiving treatment at the time of analysis. The remaining 38 patients successfully completed treatment. Among those eligible and assessed at 6 (n=32) and 12 months (n=27) post-treatment, no recurrences were detected. In conclusion, treatment of children and adolescents with MDR-TB and XDR-TB using bedaquiline and/or delamanid containing regimens was effective and had favourable safety profile. Achieving such excellent outcomes under programmatic settings is encouraging for other national tuberculosis programmes, which are in the process of introducing or scaling-up the use of these new drugs in their countries.

Topics: Adolescent; Antitubercular Agents; Child; Cohort Studies; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Nitroimidazoles; Oxazoles; Republic of Belarus

To address the sub-optimal treatment outcomes among patients with multidrug-resistant (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the National TB Programme in Belarus started using new drugs such as bedaquiline and delamanid in 2015-16. In this study, we assessed cardiovascular safety and effectiveness (culture conversion, treatment outcomes and post-treatment recurrence) of delamanid-containing regimens among adults (>18 years) with MDR-TB or XDR-TB from June 2016 to February 2018. This was a nationwide cohort study involving analysis of routinely collected programme data from the national and six regional TB hospitals. Cardiovascular adverse events (AEs) were classified as serious or not, based on international guidelines. We conducted Cox proportional hazards regression and calculated adjusted hazards ratio(aHR) and 95% confidence intervals(CI) to evaluate factors associated with AEs and unsuccessful treatment outcomes (death, failure and lost-to-follow-up). Of 125 patients enrolled (35, 28% females; mean age 43 years), 85(68%) had XDR-TB. All the patients received delamanid and 20 patients received both delamanid and bedaquiline. Cardiovascular AEs (177 episodes in total), were observed in the majority (73%) of patients but were mild and managed easily. The most common cardiovascular AEs were QTcF prolongation (64/177, 36%) and other electrocardiography (ECG) abnormalities (40/177, 23%). There were two instances of serious AEs leading to death, both of which were not related to delamanid. In multivariable analysis, male sex (aHR 0.72; 95% CI 0.51-0.99), and baseline ECG abnormalities (aHR 1.68; 95% CI 1.19-2.36) were associated with cardiovascular AEs. Median time to culture conversion was 1.1 months (interquartile range: 1.0-2.1). Culture conversion was observed in 115 (92%) patients at six months of treatment and 110 (88%) completed the treatment successfully. Loss to follow-up, failure and death were observed in 6%, 4% and 2% patients respectively. Among those assessed at 12 months post-treatment (n=33), recurrence was seen in one patient. The only factor associated with unsuccessful treatment outcomes in multivariable analysis was baseline Hepatitis C co-infection (aHR 3.61; 95% CI 1.09-11.95). In conclusion, treatment using delamanid-containing regimens was effective and had a favourable safety profile. We hope our findings inform the development of national clinical guidelines and scale-up of new drugs in other countries.

Topics: Adult; Antitubercular Agents; Cohort Studies; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Nitroimidazoles; Oxazoles; Republic of Belarus; Treatment Outcome

Childhood and adolescent drug-resistant TB (DR-TB) is one of the neglected infectious diseases. Limited evidence exists around programmatic outcomes of children and adolescents receiving DR-TB treatment. The study aimed to determine the final treatment outcomes, culture conversion rates and factors associated with unsuccessful treatment outcome in children and adolescents with DR-TB.. This is a descriptive study including children (0-9 years) and adolescents (10-19 years) with DR-TB were who were initiated on ambulatory based treatment between January 2017-June 2018 in Shatabdi hospital, Mumbai, India where National TB elimination programme(NTEP) Mumbai collaborates with chest physicians and Médecins Sans Frontières(MSF) in providing comprehensive care to DR-TB patients. The patients with available end-of-treatment outcomes were included. The data was censored on February 2020.. A total of 268 patients were included; 16 (6%) of them were children (0-9 years). The median(min-max) age was 17(4-19) years and 192 (72%) were females. Majority (199, 74%) had pulmonary TB. Most (58%) had MDR-TB while 42% had fluoroquinolone-resistant TB. The median(IQR) duration of treatment (n = 239) was 24(10-25) months. Median(IQR) time for culture-conversion (n = 128) was 3(3-4) months. Of 268 patients, 166(62%) had successful end-of-treatment outcomes (cured-112; completed treatment-54). Children below 10 years had higher proportion of successful treatment outcomes (94% versus 60%) compared to adolescents. Patients with undernutrition [adjusted odds-ratio, aOR (95% Confidence Interval, 95%CI): 2.5 (1.3-4.8) or those with XDR-TB [aOR (95% CI): 4.3 (1.3-13.8)] had higher likelihood of having unsuccessful DR-TB treatment outcome.. High proportion of successful treatment outcome was reported, better than global reports. Further, the nutritional support and routine treatment follow up should be strengthened. All oral short and long regimens including systematic use of new TB drugs (Bedaquiline and Delamanid) should be rapidly scaled up in routine TB programme, especially for the paediatric and adolescent population.

Topics: Adolescent; Ambulatory Care Facilities; Antitubercular Agents; Child; Child, Preschool; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Female; Humans; India; Infant; Infant, Newborn; Male; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Bedaquiline and delamanid used to treat extensively drug-resistant tuberculosis are known to cause prolonged QTc. Two children with extensively drug-resistant tuberculosis were put on bedaquiline and delamanid and had prolonged QTc on the Bazett formula but normal QTc by the Fridericia formula. Both had no adverse effects. Correct formula for monitoring QTc should be used thereby preventing unnecessary withholding of medicines.

Topics: Adolescent; Antitubercular Agents; Child; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Nitroimidazoles; Oxazoles; Sputum; Tomography, X-Ray Computed

Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Treatment Outcome

Topics: Diarylquinolines; Drug Resistance; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles

The emergence of drug-resistant tuberculosis (TB) poses a serious challenge to existing anti-TB therapies. Hence, there is a direct need for identification of new drugs and effective combination regimens.. In this study, minimum inhibitory concentrations (MICs) of the anti-TB drugs bedaquiline (BDQ), delamanid (DEL) and moxifloxacin (MFX) were evaluated using a resazurin microtiter assay (REMA) against five drug-resistant clinicalMycobacterium tuberculosis (MTB) isolates as well as the drug-susceptible reference strain H37Rv. In addition, their fractional inhibitory concentration indices (FICIs) were evaluated using a REMA-based calorimetric chequerboard assay to assess their interaction profiles against the MTB isolates.. The FICI indicated that BDQ acted synergistically with DEL against isoniazid (INH)-monoresistant, rifampicin (RIF)-monoresistant and extensively drug-resistant (XDR) clinical MTB isolates. In addition, the combination of DEL acted synergistically with MFX against INH-monoresistant, RIF-monoresistant and XDR clinical MTB isolates. Moreover, the combination of BDQ and MFX showed a synergistic effect against RIF-monoresistant and pre-XDR clinical MTB isolates. DEL at 0.125×MIC (i.e. 0.015μg/mL) used in combination with BDQ at 0.25×MIC (i.e. 0.015μg/mL) had a stronger bactericidal effect against the XDR-TB clinical isolate than DEL alone at 1×MIC (i.e. 0.125μg/mL).. Synergistic and additive effects between these two-drug combinations offer an attractive chemotherapeutic regimen against drug-resistant clinical MTB isolates.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Drug Synergism; Extensively Drug-Resistant Tuberculosis; Humans; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazines; Oxazoles; Tuberculosis, Multidrug-Resistant; Xanthenes

Topics: Adult; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Middle Aged; Nitroimidazoles; Oxazoles; Republic of Korea; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

Topics: Adult; Antitubercular Agents; Colistin; Diarylquinolines; Drug Synergism; Extensively Drug-Resistant Tuberculosis; Humans; Isoniazid; Male; Medication Adherence; Mycobacterium tuberculosis; Netherlands; Nitroimidazoles; Oxazoles; Patient Isolation; Phenotype; Trimethoprim, Sulfamethoxazole Drug Combination; United Kingdom

Delamanid, bedaquiline, and linezolid have recently been approved for the treatment of multidrug- and extensively drug-resistant (MDR and XDR, respectively) tuberculosis (TB). To use these drugs effectively, drug susceptibility tests, including rapid molecular techniques, are required for accurate diagnosis and treatment. Furthermore, mutation analyses are needed to assess the potential for resistance. We evaluated the minimum inhibitory concentrations (MICs) of these three anti-TB drugs for Korean MDR and XDR clinical strains and mutations in genes related to resistance to these drugs.. MICs were determined for delamanid, bedaquiline, and linezolid using a microdilution method. The PCR products of drug resistance-related genes from 420 clinical Mycobacterium tuberculosis strains were sequenced and aligned to those of M. tuberculosis H37Rv.. The overall MICs for delamanid, bedaquiline, and linezolid ranged from ≤0.025 to >1.6 mg/L, ≤0.0312 to >4 mg/L, and ≤0.125 to 1 mg/L, respectively. Numerous mutations were found in drug-susceptible and -resistant strains. We did not detect specific mutations associated with resistance to bedaquiline and linezolid. However, the Gly81Ser and Gly81Asp mutations were associated with resistance to delamanid.. We determined the MICs of three anti-TB drugs for Korean MDR and XDR strains and identified various mutations in resistance-related genes. Further studies are needed to determine the genetic mechanisms underlying resistance to these drugs.

Topics: Antitubercular Agents; Diarylquinolines; DNA Mutational Analysis; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Humans; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Republic of Korea; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Compassionate Use Trials; Extensively Drug-Resistant Tuberculosis; Health Services Accessibility; Humans; Nitroimidazoles; Oxazoles; United States

Extensively drug-resistant tuberculosis (XDR-TB) is a deadly form of TB that can be incurable due to its extreme drug resistance. In this study, we aimed to explore the

Topics: Antitubercular Agents; Beijing; China; Clofazimine; Diarylquinolines; DNA Gyrase; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Gatifloxacin; Humans; Linezolid; Microbial Sensitivity Tests; Moxifloxacin; Mutation; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles

Topics: Adolescent; Adult; Antitubercular Agents; Child; Communicable Disease Control; Compassionate Use Trials; Extensively Drug-Resistant Tuberculosis; Female; Global Health; Humans; Male; Middle Aged; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis, Multidrug-Resistant; World Health Organization

We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.

Topics: Adolescent; Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Nitroimidazoles; Oxazoles; Tuberculosis, Pulmonary; Young Adult

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Extensively Drug-Resistant Tuberculosis; Female; Humans; Latvia; Male; Middle Aged; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

[Objective] We experienced use of new anti- tuberculous drug, Delamanid in multi- and extensively drug resistant tuberculosis (M (X) DR-TB) in our hospital. [Materials and Methods] Fifteen cases who were diagnosed M(X)DR-TB had been used Delamanid in our hospital from 2014 to 2015. [Results] The gender distribution consisted of eleven males and four females in M(X)DR-TB. The mean age was 53.3 years old in male and 28.3 years old in female. Japanese were eight cases, and Chinese were five cases, and other countries patients were two cases. Twelve cases were MDR-TB cases, and three cases were XDR-TB cases. Six cases of fifteen cases were sputum culture positive before using Delamanid. Two cases (13.3%) had been appearanced QTc extension in EKG by using Delamanid. But these cases had not seen symptom. Other typical side effects had not seen. Six cases (40.0%) of fifteen cases had done surgical resection. One case of fifteen cases had been died with intractable pneumothorax, and one case had been discontinued for leukopenia. All cases containing two discontinued cases had obtained negative conversion of sputum culture. [Conclusion] We experienced new anti-tuberculous drug, Delamanid. If we add Delamanid only for MDR-TB patients with only one or two sensitive anti-tuberculous drugs, it will be possible to make anew resistance. We used one more another new drug, for example Linezolid or high dose isoniazid or Meropenem and Ampicilin Clavulanate acid with Delamanid and sensitive anti-tuberculous drugs. We need to investigate risk and benefit when we use new anti-tuberculous drug. We need not to make more another MDR-TB cases.

Topics: Adult; Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Female; Humans; Isoniazid; Male; Middle Aged; Nitroimidazoles; Oxazoles

Topics: Antitubercular Agents; Awards and Prizes; Diarylquinolines; Drug Discovery; Extensively Drug-Resistant Tuberculosis; Humans; Motivation; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Adult; Antitubercular Agents; Beijing; Compassionate Use Trials; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Genotype; Humans; Male; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Refugees; Tibet

New drugs offer options for patients with drug-resistant tuberculosis (DR-TB). We describe four individuals with DR-TB in KwaZulu-Natal, South Africa, with prior exposure to clofazimine who would benefit from access to delamanid (DLM). Without DLM, individual options are limited, and there is a risk of resistance amplification and both community and nosocomial spread of DR-TB.

Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Health Services Accessibility; Humans; Male; Nitroimidazoles; Oxazoles; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

Topics: Adult; Antitubercular Agents; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Female; Humans; Nitroimidazoles; Oxazoles

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Compassionate Use Trials; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles

Topics: Antitubercular Agents; Carbapenems; Clavulanic Acid; Clofazimine; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Infectious Disease Medicine; Linezolid; Nitroimidazoles; Oxazoles; Practice Guidelines as Topic; Tuberculosis, Multidrug-Resistant; World Health Organization

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Health Services Accessibility; Humans; Male; Nitroimidazoles; Oxazoles; Pneumonectomy

Topics: Antitubercular Agents; Computer Simulation; Cost-Benefit Analysis; Diarylquinolines; Drug Costs; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Germany; Humans; Markov Chains; Models, Economic; Nitroimidazoles; Oxazoles; Pyrazinamide; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Child; Compassionate Use Trials; Disease Outbreaks; Europe; Extensively Drug-Resistant Tuberculosis; Humans; Italy; Male; Nitroimidazoles; Oxazoles; Program Development; Societies, Medical; Treatment Outcome; World Health Organization

Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are associated with worse treatment outcomes for patients, including higher mortality, than for drug-sensitive tuberculosis. Delamanid (OPC-67683) is a novel anti-TB medication with demonstrated activity against multidrug-resistant disease. Patients who participated in the previously reported randomised, placebo-controlled trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Treatment outcomes, as assessed by clinicians and defined by the World Health Organization, were categorised as favourable and unfavourable. Delamanid treatment groups were combined for analysis, based on their duration of treatment. In total, for 421 (87.5%) out of 481 patients from the original randomised controlled trial, consent was granted for follow-up assessments. Favourable outcomes were observed in 143 (74.5%) out of 192 patients who received delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among patients with extensively drug-resistant TB. This analysis suggests that treatment with delamanid for 6 months in combination with an optimised background regimen can improve outcomes and reduce mortality among patients with both multidrug-resistant and extensively drug-resistant TB.

Topics: Adolescent; Adult; Antitubercular Agents; Drug Administration Schedule; Extensively Drug-Resistant Tuberculosis; Female; Follow-Up Studies; Humans; Male; Middle Aged; Nitroimidazoles; Oxazoles; Randomized Controlled Trials as Topic; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult