opc-67683 and bedaquiline

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

Tuberculosis (TB) is a major public health problem, with nearly 10 million new cases and millions of deaths each year. Around 10% of these cases are in children, but only a fraction receive proper diagnosis and treatment. The spread of drug-resistant (DR) strain of TB has made it difficult to control, with only 60% of patients responding to treatment. Multi-drug resistant TB (MDR-TB) is often undiagnosed in children due to lack of awareness or under-diagnosis, and the target for children's DR-TB treatment has only been met in 15% of goals. New medications such as bedaquiline and delamanid have been approved for treating DR-TB. However, due to age and weight differences, adults and children require different dosages. The availability of child-friendly formulations is limited by a lack of clinical data in children. This paper reviews the development history of these drugs, their mechanism of action, efficacy, safety potential problems and current use in treating DR-TB in children.

Topics: Adult; Diarylquinolines; Humans; Nitroimidazoles; 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

Improved genetic understanding of Mycobacterium tuberculosis (MTB) resistance to novel and repurposed anti-tubercular agents can aid the development of rapid molecular diagnostics.. Adhering to PRISMA guidelines, in March 2018, we performed a systematic review of studies implicating mutations in resistance through sequencing and phenotyping before and/or after spontaneous resistance evolution, as well as allelic exchange experiments. We focused on the novel drugs bedaquiline, delamanid, pretomanid and the repurposed drugs clofazimine and linezolid. A database of 1373 diverse control MTB whole genomes, isolated from patients not exposed to these drugs, was used to further assess genotype-phenotype associations.. Of 2112 papers, 54 met the inclusion criteria. These studies characterized 277 mutations in the genes atpE, mmpR, pepQ, Rv1979c, fgd1, fbiABC and ddn and their association with resistance to one or more of the five drugs. The most frequent mutations for bedaquiline, clofazimine, linezolid, delamanid and pretomanid resistance were atpE A63P, mmpR frameshifts at nucleotides 192-198, rplC C154R, ddn W88* and ddn S11*, respectively. Frameshifts in the mmpR homopolymer region nucleotides 192-198 were identified in 52/1373 (4%) of the control isolates without prior exposure to bedaquiline or clofazimine. Of isolates resistant to one or more of the five drugs, 59/519 (11%) lacked a mutation explaining phenotypic resistance.. This systematic review supports the use of molecular methods for linezolid resistance detection. Resistance mechanisms involving non-essential genes show a diversity of mutations that will challenge molecular diagnosis of bedaquiline and nitroimidazole resistance. Combined phenotypic and genotypic surveillance is needed for these drugs in the short term.

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Humans; Linezolid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pharmaceutical Preparations; Tuberculosis, Multidrug-Resistant

Drug-resistant tuberculosis (TB) represents a substantial threat to the global efforts to control this disease. After decades of stagnation, the treatment of drug-resistant TB is undergoing major changes: two drugs with a new mechanism of action, bedaquiline and delamanid, have been approved by stringent regulatory authorities and are recommended by the WHO. This narrative review summarizes the evidence, originating from both observational studies and clinical trials, which is available to support the use of these drugs, with a focus on special populations. Areas of uncertainty, including the use of the two drugs together or for prolonged duration, are discussed. Ongoing clinical trials are aiming to optimize the use of bedaquiline and delamanid to shorten the treatment of drug-resistant TB.

Topics: Antitubercular Agents; Child; Clinical Trials as Topic; Diarylquinolines; Drug Therapy, Combination; Female; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pregnancy; Tuberculosis, Multidrug-Resistant

TB is a global disease and the leading cause of death among infectious diseases worldwide. TB was considered incurable till the mid 19th century. The major landmark in the treatment was the discovery of Rifampicin which has led to shorter courses of therapy as compared to the previous regimens which also consisted of injectables. Although, treatment for TB is evolving expeditiously today but a lot needs to be done as far as drug resistant TB (DRTB) is concerned. Non-standard regimens in private sector, lack of access to drug susceptibility testing, delay in the treatment, poor follow up and default in the treatment has led to emergence DRTB. Addition of newer drugs like bedaquiline and delamanid has made oral regimen possible in DRTB as well. Encouraging results of BPaL regimen for extensively drug resistant TB (XDR-TB) may prove to be a game changer. The target of TB elimination by 2025 is onerous considering the huge population, rising DRTB patients and private sector non engagement in the programme despite implementation of second largest national programme of the world.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Nitroimidazoles; Oxazoles; Tuberculosis, Pulmonary

The Lancet Respiratory Medicine Commission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9-11 month injectable-based 'Bangladesh' regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Linezolid; Nitroimidazoles; Oxazoles; Periodicals as Topic; Pulmonary Medicine; Societies, Medical; Tuberculosis; Tuberculosis, Multidrug-Resistant

Considering the extensive evolutionary history of Mycobacterium tuberculosis, anti-Tuberculosis (TB) drug therapy exerts a recent selective pressure. However, in a microorganism devoid of horizontal gene transfer and with a strictly clonal populational structure such as M. tuberculosis the usual, but not sole, path to overcome drug susceptibility is through de novo mutations on a relatively strict set of genes. The possible allelic diversity that can be associated with drug resistance through several mechanisms such as target alteration or target overexpression, will dictate how these genes can become associated with drug resistance. The success demonstrated by this pathogenic microbe in this latter process and its ability to spread is currently one of the major obstacles to an effective TB elimination. This article reviews the action mechanism of the more important anti-TB drugs, including bedaquiline and delamanid, along with new findings on specific resistance mechanisms. With the development, validation and endorsement of new in vitro molecular tests for drug resistance, knowledge on these resistance mechanisms and microevolutionary dynamics leading to the emergence and fixation of drug resistance mutations within the host is highly important. Additionally, the fitness toll imposed by resistance development is also herein discussed together with known compensatory mechanisms. By elucidating the possible mechanisms that enable one strain to reacquire the original fitness levels, it will be theoretically possible to make more informed decisions and develop novel strategies that can force M. tuberculosis microevolutionary trajectory down through a path of decreasing fitness levels.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Epistasis, Genetic; Humans; Mutation; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Phylogeny; Tuberculosis, Multidrug-Resistant

Improving treatment outcomes in multidrug-resistant tuberculosis (MDR-TB) is partly hampered by inadequate effective antitubercular agents. Development of bedaquiline and delamanid has potentially changed the treatment landscape for MDR-TB. This review provides an update on the progress of these novel antitubercular agents. We review published studies aimed at evaluating clinical efficacy and effectiveness of bedaquiline and delamanid. Five prospective clinical studies and seven retrospective studies on bedaquiline showed that patients treated with a bedaquiline-containing regimen had a high culture conversion rate ranging from 65 to 100% and a satisfactory treatment outcome. The combined use with linezolid might add to the effectiveness of bedaquiline. Controversies about bedaquiline resistance are discussed. Three clinical trials have reported outcomes on delamanid and showed that introducing delamanid to a background regimen improved culture conversion rate at 2 months from 29.6% to more than 40%. A higher favorable treatment rate was also observed among patients who received delamanid for more than 6 months, but about a quarter of patients defaulted in the control group. Seven retrospective studies were summarized and found a treatment benefit as well. More reliable evidence from randomized clinical trials reporting on the treatment outcomes is needed urgently to support a strong recommendation for the use of delamanid. Advances in the combined use of bedaquiline and delamanid are also reviewed, and the combination may be well tolerated but requires electrocardiograph monitoring.

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Electrocardiography; Humans; Nitroimidazoles; Oxazoles; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

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

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

Multidrug-resistant tuberculosis (MDR-TB) is a serious life threatening condition affecting children as well as adults worldwide. Timely diagnosis and effective treatment, both of which are complex in children, are the prerogatives for a favorable outcome. Areas covered: This review covers epidemiology, treatment regimen and duration, newer drugs and adverse events in children with MDR-TB. Special note has been made of epidemiology and principles of treatment followed in Indian children. Expert opinion: High index of suspicion is essential for diagnosing childhood MDR-TB. If there is high probability, a child can be diagnosed as presumptive MDR-TB and started on empiric treatment in consultation with experts. However, every effort should be made to confirm the diagnosis. Backbone of an effective MDR-TB regimen consists of four 2nd line anti-TB drugs plus pyrazinamide; duration being 18-24 months. The newer drugs delamanid and bedaquiline can be used in younger children if no other alternatives are available after consultation with experts. Wider availability of these drugs should be ensured for benefit to all concerned. More research is required for development of new and repurposed drugs to combat MDR-TB. Children need to be included in clinical trials for such life-saving drugs, so that nobody is denied the benefits.

Topics: Antitubercular Agents; Child; Diarylquinolines; Drug Administration Schedule; Humans; India; Microbial Sensitivity Tests; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis, Multidrug-Resistant

For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

Topics: Antitubercular Agents; Diarylquinolines; Health Services Accessibility; Human Rights; Humans; Injections; Nitroimidazoles; Oxazoles; Patient-Centered Care; Tuberculosis, Multidrug-Resistant

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

Non-tuberculous mycobacteria (NTM) infections are increasingly being reported worldwide. They are a major concern for healthcare professionals for multiple reasons, ranging from the intrinsic resistance of NTM to most conventionally utilized antimicrobials to inharmonious diagnostic criteria utilized for evaluation of NTM-infected patients, leading to high morbidity. In this review, we highlight the paucity of drugs having potent anti-NTM activity amongst the new antimicrobials currently under various stages of development for anti-tubercular activity and issue a call for the establishment of a concerted dedicated drug discovery pipeline targeting NTM.

Topics: Adamantane; Aminopyridines; Anti-Bacterial Agents; Azepines; Benzamides; Clinical Trials as Topic; Diarylquinolines; Drug Discovery; Ethylenediamines; Fluoroquinolones; Humans; Minocycline; Mycobacterium Infections, Nontuberculous; Nitroimidazoles; Nontuberculous Mycobacteria; Oxazoles; Piperazines; Spiro Compounds; Thiazines; Tigecycline; Uridine

Increasing numbers of children with drug-resistant tuberculosis are accessing second-line antituberculosis drugs; these are more toxic than first-line drugs. Little is known about the safety of new antituberculosis drugs in children. Knowledge of adverse effects, and how to assess and manage these, is important to ensure good adherence and treatment outcomes.. A Pubmed search was performed to identify articles addressing adverse effects of second-line antituberculosis drugs; a general search was done for the new drugs delamanid and bedaquiline. This review discusses adverse effects associated with oral second-line antituberculosis drugs. The spectrum of adverse effects caused by antituberculosis drugs is wide; the majority are mild or moderate, but these are important to manage as it could lead to non-adherence to treatment. Adverse effects may be more common in HIV-infected than in HIV-uninfected children.. Although children may experience fewer adverse effects from oral second-line antituberculosis drugs than adults, evidence from prospective studies of the incidence of adverse events in children is limited. Higher doses of second-line drugs, new antituberculosis drugs, and new drug regimens are being evaluated in children: these call for strict pharmacovigilance in children treated in the near future, as adverse effect profiles may change.

Topics: Age Factors; Antitubercular Agents; Child; Diarylquinolines; Dose-Response Relationship, Drug; HIV Infections; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo

Topics: Aged; Animals; Antitubercular Agents; Arrhythmias, Cardiac; Comorbidity; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diarylquinolines; Drug Interactions; Drug Monitoring; Humans; Hypoglycemic Agents; Middle Aged; Nitroimidazoles; Oxazoles; Polypharmacy; Risk Assessment; Risk Factors; Tuberculosis

Currently recommended regimens for multidrug-resistant tuberculosis (MDR-TB) contain painful daily injections and are unsuccessful in approximately half of patients. Removal of the injectable agent to fashion all-oral regimens could transform MDR-TB treatment and access to care.. To explore evidence for all-oral treatment regimens.. We review evidence on drugs that could be included in injection-free MDR-TB regimens. The oral drugs considered have an indication for or are recommended for off-label use for TB or MDR-TB, and have demonstrated bactericidal activity. Drugs with weak bactericidal activity should have limited prior population exposure and evidence of effectiveness in MDR-TB regimens.. Bedaquiline, delamanid, and linezolid all display strong bactericidal activity, while clofazimine has weak bactericidal activity. They all have limited prior population exposure and demonstrated effectiveness in MDR-TB regimens. Despite widespread exposure to pyrazinamide and late-generation fluoroquinolones in the population, all are bactericidal and have shown great value when included in treatment regimens for MDR-TB.. The evidence supports the use of all-oral regimens comprising new and existing drugs for MDR-TB treatment. Existing evidence of bactericidal activity and efficacy for these drugs provides a convincing argument for transitioning MDR-TB treatment towards all-oral regimens. These new regimens could mitigate the delivery, cost, and adherence challenges inherent to the current standard.

Topics: Administration, Oral; Antitubercular Agents; Clinical Trials, Phase III as Topic; Diarylquinolines; Evidence-Based Medicine; Humans; Linezolid; Needles; Nitroimidazoles; Oxazoles; Randomized Controlled Trials as Topic; Tuberculosis, Multidrug-Resistant

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

Tuberculosis is an airborne infectious disease treated with combination therapeutic regimens. Adherence to long-term antituberculosis therapy is crucial for maintaining adequate blood drug level. The emergence and spread of drug-resistant Mycobacterium tuberculosis strains are mainly favored by the inadequate medical management of the patients. The therapeutic approach for drug-resistant tuberculosis is cumbersome, because of the poor, expensive, less-effective, and toxic alternatives to the first-line drugs. New antituberculosis drugs (bedaquiline and delamanid) have been recently approved by the health authorities, but they cannot represent the definitive solution to the clinical management of drug-resistant tuberculosis forms, particularly in intermediate economy settings where the prevalence of drug resistance is high (China, India, and former Soviet Union countries). New research and development activities are urgently needed. Public health policies are required to preserve the new and old therapeutic options.

Topics: Antitubercular Agents; China; Diarylquinolines; Humans; India; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; USSR

Multidrug-resistant tuberculosis (MDR-TB) is on the rise, and is difficult to treat. The approval of two new drugs, bedaquiline and delamanid, and growing evidence for the use of linezolid, offer renewed hope for addressing MDR-TB. However, access to these medicines remains a significant challenge. These drugs have not been registered for TB in most settings; barriers to preapproval access persist; and high pricing and intellectual property restrictions limit access. Many unanswered research questions about optimal use of these drugs also limit access, particularly for vulnerable populations. This review outlines challenges in accessing drugs encountered from the perspective of clinicians, patients and affected communities, and offers potential solutions.

Topics: Antitubercular Agents; Compassionate Use Trials; Diarylquinolines; Health Services Accessibility; Humans; Linezolid; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Vulnerable Populations

In recent years, a pressing need to develop new, effective and safe drugs against tuberculosis (TB) has continued. Poor adherence to a long therapeutic regimen against TB, intermittent drug use, errors in medical prescriptions, low quality of old TB drugs and ineffective TB control have led to the emergence of resistant TB.. Two new drugs have gained importance and seem promising against resistant TB: bedaquiline and delamanid. This review summarizes the main characteristics of these two drugs and their role in TB management.. Bedaquiline and delamanid appear to be promising new anti-TB drugs. Due to a mechanism of action that is different from that of other available drugs, their efficacy has appeared optimal in cases of adults with resistant pulmonary TB. Although their pharmacokinetic and pharmacodynamic profiles seem optimal, potential cardiologic side effects such as QT-interval prolongation have been associated with their use. However, specific studies performed in the pediatric population are needed to confirm these results. This seems particularly important considering the long duration of TB treatment required for resistant TB as well as the potential interactions with other drugs included in anti-TB regimens or administered for an underlying comorbidity.

Topics: Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Interactions; Drug Resistance, Bacterial; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

Recent advances in the development of new drugs and regimens provide hope that well tolerated, effective, and shorter-duration treatments for tuberculosis (TB) will become available. This review covers the recent trials of new TB drugs and regimens.. Moxifloxacin and levofloxacin have equally good efficacy and safety in the early phase of treatment of multidrug-resistant TB (MDR-TB), and linezolid has the potential to cure refractory cases of MDR-TB. Bedaquiline and delamanid may be the best drug candidates for enhancing treatment options for MDR-TB. New chemicals, such as sutezolid, AZD5847, PA-824, SQ109, and BTZ043, show potent activity against Mycobacterium tuberculosis. Late-generation fluoroquinolones in combination with the first-line and second-line anti-TB drugs have been used to shorten the treatment duration in drug-susceptible and MDR-TB.. New drugs and new combination regimens in clinical trials are expected to increase therapeutic efficacy and shorten treatment duration in both drug-susceptible and drug-resistant TB.

Topics: Acetamides; Adamantane; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Administration Schedule; Drug Design; Ethylenediamines; Female; Fluoroquinolones; Humans; Levofloxacin; Linezolid; Male; Moxifloxacin; Nitroimidazoles; Oxazoles; Oxazolidinones; Spiro Compounds; Thiazines; Tuberculosis; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Aza Compounds; Cross-Sectional Studies; Diagnosis, Differential; Diarylquinolines; Fluoroquinolones; Germany; Humans; Moxifloxacin; Nitroimidazoles; Oxazoles; Prognosis; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

Tuberculosis (TB) is a serious public health issue, particularly in underdeveloped and developing countries. Furthermore the first-line anti-TB treatments were established over 40 years ago, multidrug-resistant Mycobacterium tuberculosis strains have been developed and the risk of coinfection with AIDS virus has highlighted this disease as a global emergency. The urgent need for more effective treatments against multidrug-resistant strains compatible with anti-AIDS drugs has prompted industries, governments and non-governmental agencies to pursue new drugs. In this study, we update the portfolio listed at Stop TB Partnership, present the biological activities as well as structure-activity relationship for these drugs and thoroughly discuss the synthetic methodologies used to produce these drugs.

Topics: Anti-HIV Agents; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Design; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

It is estimated that a third of the world's population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.

Topics: Adamantane; Animals; Antitubercular Agents; Diarylquinolines; Drug Design; Drug Resistance, Multiple, Bacterial; Ethylenediamines; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Quinolines; Structure-Activity Relationship; Tuberculosis, Pulmonary

Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.. Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.. DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.. DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Humans; Linezolid; Moxifloxacin; Oxazolidinones; Treatment Outcome; Tuberculosis, Pulmonary

Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens.

Topics: Diarylquinolines; Electrocardiography; Heart Rate; Humans; Nitroimidazoles; Oxazoles

Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.. ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.. Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.. Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.. Division of AIDS, National Institutes of Health.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Electrocardiography; Female; Humans; Male; Nitroimidazoles; Oxazoles; Peru; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Topics: Humans; Linezolid; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Humans; Mycobacterium avium; Mycobacterium tuberculosis; Salvage Therapy; Treatment Failure; Tuberculosis, Multidrug-Resistant

New classes of antitubercular drugs, diarylquinolines and nitroimidazoles, have been associated with improved outcomes in the treatment of drug-resistant tuberculosis, but that success is threatened by emerging drug resistance. We report a case of bedaquiline and delamanid resistance in a 55-year-old woman in South Africa with extensively drug-resistant tuberculosis and known HIV.

Topics: Antitubercular Agents; Diarylquinolines; Female; Humans; Middle Aged; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Bedaquiline and delamanid were recently approved for multidrug resistant tuberculosis (MDR-TB). Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the risks of QT prolongation and hepatotoxicity for bedaquiline and delamanid.. We retrospectively analyzed data of MDR-TB patients retrieved from the South Korea national health insurance system database (2014-2020) to assess the risks of all-cause death, long QT-related cardiac event, and acute liver injury associated with bedaquiline or delamanid, compared with conventional regimen. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Stabilized inverse probability of treatment weighting based on propensity score was used to balance characteristics between the treatment groups.. Of 1998 patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively. Compared with conventional regimen, bedaquiline and delamanid did not increase risk of all-cause death at 24-month (HR 0.73 [95% CI, 0.42-1.27] and 0.89 [0.50-1.60], respectively). Bedaquiline-containing regimen increased risk of acute liver injury (1.76 [1.31-2.36]), while delamanid-containing regimen increased risk of long QT-related cardiac events (2.38 [1.05-3.57]) within 6 months of treatment.. This study adds to the emerging evidence refuting the higher mortality rate observed in the bedaquiline trial population. Association between bedaquiline and acute liver injury needs careful interpretation considering for other background hepatotoxic anti-TB drugs. Our finding on delamanid and long QT-related cardiac events suggest careful risk-benefit assessment in patients with pre-existing cardiovascular disease.

Topics: Antitubercular Agents; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.. Multicentre (16 countries), prospective, observational study reporting incidence and frequency of clinically relevant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.. Among 2296 patients, the most common clinically relevant AESIs were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients receiving injectables (N = 925) and linezolid (N = 1826) were most likely to experience events during exposure. Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95% CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis, and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure.. AEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations.. NCT02754765.

Topics: Antitubercular Agents; Diarylquinolines; Electrolytes; Humans; Linezolid; Nitroimidazoles; Oxazoles; Prospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.. We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.. Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure.. Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.

Topics: Antitubercular Agents; Clofazimine; Cohort Studies; Diarylquinolines; Electrolytes; Fluoroquinolones; Humans; Linezolid; Nitroimidazoles; Oxazoles; Prospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant

A recent landmark trial showed a 4-month regimen of rifapentine, pyrazinamide, moxifloxacin, and isoniazid (PZMH) to be noninferior to the 6-month standard of care. Here, two murine models of tuberculosis were used to test whether novel regimens replacing rifapentine and isoniazid with bedaquiline and another drug would maintain or increase the sterilizing activity of the regimen. In BALB/c mice, replacing rifapentine in the PZM backbone with bedaquiline (i.e., BZM) significantly reduced both lung CFU counts after 1 month and the proportion of mice relapsing within 3 months after completing 1.5 months of treatment. The addition of rifabutin to BZM (BZMRb) further increased the sterilizing activity. In the C3HeB/FeJ mouse model characterized by caseating lung lesions, treatment with BZMRb resulted in significantly fewer relapses than PZMH after 2 months of treatment. A regimen combining the new DprE1 inhibitor OPC-167832 and delamanid (BZOD) also had superior bactericidal and sterilizing activity compared to PZM in BALB/c mice and was similar in efficacy to PZMH in C3HeB/FeJ mice. Thus, BZM represents a promising backbone for treatment-shortening regimens. Given the prohibitive drug-drug interactions between bedaquiline and rifampin or rifapentine, the BZMRb regimen represents the best opportunity to combine, in one regimen, the treatment-shortening potential of the rifamycin class with that of BZM and deserves high priority for evaluation in clinical trials. Other 4-drug BZM-based regimens and BZOD represent promising opportunities for extending the spectrum of treatment-shortening regimens to rifamycin- and fluoroquinolone-resistant tuberculosis.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifabutin; Tuberculosis

Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered.. Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.. Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV).. This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

Topics: Adult; Albumins; Antitubercular Agents; Diarylquinolines; HIV Infections; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the deadliest infectious diseases worldwide. Multidrug and extensively drug-resistant strains are making disease control difficult, and exhausting treatment options. New anti-TB drugs bedaquiline (BDQ), delamanid (DLM) and pretomanid (PTM) have been approved for the treatment of multi-drug resistant TB, but there is increasing resistance to them. Nine genetic loci strongly linked to resistance have been identified (mmpR5, atpE, and pepQ for BDQ; ddn, fgd1, fbiA, fbiB, fbiC, and fbiD for DLM/PTM). Here we investigated the genetic diversity of these loci across >33,000 M. tuberculosis isolates. In addition, epistatic mutations in mmpL5-mmpS5 as well as variants in ndh, implicated for DLM/PTM resistance in M. smegmatis, were explored. Our analysis revealed 1,227 variants across the nine genes, with the majority (78%) present in isolates collected prior to the roll-out of BDQ and DLM/PTM. We identified phylogenetically-related mutations, which are unlikely to be resistance associated, but also high-impact variants such as frameshifts (e.g. in mmpR5, ddn) with likely functional effects, as well as non-synonymous mutations predominantly in MDR-/XDR-TB strains with predicted protein destabilising effects. Overall, our work provides a comprehensive mutational catalogue for BDQ and DLM/PTM associated genes, which will assist with establishing associations with phenotypic resistance; thereby, improving the understanding of the causative mechanisms of resistance for these drugs, leading to better treatment outcomes.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Humans; Mutation; Mycobacterium smegmatis; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

This study is the first to report a clinical case of simultaneously acquired resistance to bedaquiline (BDQ) and delamanid (DLM). Whole genome sequencing revealed 2 nucleotide insertions (Rv0678 and fbiC) in the Mycobacterium tuberculosis isolate. The minimum inhibitory concentrations for BDQ and DLM were 0.25 µg/mL and >2.0 µg/mL, respectively.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Diarylquinolines; Humans; Nitroimidazoles; Operations Research; Oxazoles; Prospective Studies; Tuberculosis, Multidrug-Resistant

The Médecins Sans Frontières Clinic in Mumbai, India, has been providing concomitant bedaquiline (BDQ) and delamanid (DLM) in treatment regimen for patients with drug-resistant tuberculosis (DR-TB) and limited therapeutic options, referred from other healthcare institutions, since 2016. The study documents the end-of-treatment outcomes, culture-conversion rates, and serious adverse events (SAEs) during treatment.. This was a retrospective cohort study based on routinely collected program data. In clinic, treatment regimens are designed based on culture drug sensitivity test patterns and previous drug exposures, and are provided for 20-22 months. BDQ and DLM are extended beyond 24 weeks as off-label use. Patients who initiated DR-TB treatment including BDQ and DLM (concomitantly for at least 4 weeks) during February 2016-February 2018 were included.. Of the 70 patients included, the median age was 25 (interquartile range [IQR], 22-32) years and 56% were females. All except 1 were fluoroquinolone resistant. The median duration of exposure to BDQ and DLM was 77 (IQR, 43-96) weeks. Thirty-nine episodes of SAEs were reported among 30 (43%) patients, including 5 instances of QTc prolongation, assessed as possibly related to BDQ and/or DLM. The majority (69%) had culture conversion before 24 weeks of treatment. In 61 (87%), use of BDQ and DLM was extended beyond 24 weeks. Successful end-of-treatment outcomes were reported in 49 (70%) patients.. The successful treatment outcomes of this cohort show that regimens including concomitant BDQ and DLM for longer than 24 weeks are effective and can be safely administered on an ambulatory basis. National TB programs globally should scale up access to life-saving DR-TB regimens with new drugs.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Female; Humans; India; Nitroimidazoles; Oxazoles; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

Topics: Antitubercular Agents; Cohort Studies; Diarylquinolines; Fluoroquinolones; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Republic of Korea; Tuberculosis, Multidrug-Resistant

Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.. To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.. A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.. Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.. We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Prospective Studies; Tuberculosis, Multidrug-Resistant

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

The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required.. We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens.. Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively.. The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Linezolid; Mice; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Recurrence; Tuberculosis

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

Rifampicin-resistant/multidrug-resistant (RR/MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis (TB) are serious public health problem in Kazakhstan. In 2012 and 2013, stringent regulatory authorities approved the first new TB drugs in fifty years, bedaquiline and delamanid, offering hope for more effective and less toxic MDR-TB treatment. The endTB Observational Study is a multi-country study that enrolled patients receiving a bedaquiline- or delamanid-containing regimen for RR/MDR-TB between 01 April 2015 and 30 September 2018. In Kazakhstan, 675 patients participated in the study; all had at least 6-months or longer of follow-up after the start of treatment. The present analysis focuses on endTB Observational Study patients living in Kazakhstan who had a positive baseline sputum culture (220 patients) and initiated a bedaquiline- or delamanid-containing regimen between February 1, 2016 and March 31, 2018. Of them, 195 (89%) of patients experienced culture conversion within six months.

Topics: Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Since 1 September 2016, bedaquiline and delamanid have been administered for the treatment of patients with multidrug-resistant/rifampicin-resistant tuberculosis after the official approval in South Korea. This study aimed to assess and compare the final treatment outcomes of patients who received bedaquiline with those of patients who received delamanid.. This is a nationwide cohort study of patients with multidrug-resistant/rifampicin-resistant tuberculosis in whom bedaquiline or delamanid was administered from 1 September 2016 to 28 February 2018, after receiving the official approval in South Korea. Patients were classified into the bedaquiline and delamanid group according to the first used drug. We evaluated and compared the final treatment outcomes between the groups.. During the study period, 284 patients with multidrug-resistant/rifampicin-resistant tuberculosis were approved to use bedaquiline or delamanid and 260 were included in the final analysis; 119 (45.8%) and 141 patients (54.2%) were classified into bedaquiline and delamanid groups, respectively. Among them, 30 patients (11.5%) exhibited additional resistance to second-line injectable drugs, 94 patients (36.2%) had additional resistance to fluoroquinolones, and 37 patients (14.2%) had resistance to both drugs. The overall treatment success rate was 79.2%. Initiation of bedaquiline rather than delamanid was not associated with treatment success (adjusted odds ratio, .671; 95% confidence interval, .350-1.285). Frequencies of adverse events were not significantly different between the 2 groups.. Initial choice of bedaquiline or delamanid did not make any significant difference in the final treatment outcome or the frequencies of adverse events among patients with multidrug-resistant/rifampicin-resistant tuberculosis.

Topics: Antitubercular Agents; Cohort Studies; Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

This brief report presents a series of 5 pregnant women treated for rifampicin-resistant tuberculosis with the novel drugs bedaquiline, delamanid, and linezolid as part of an optimized backbone regimen and reviews the outcomes of the children born to them. Although the case series is small, all children had excellent birth outcomes suggesting pregnant women should not be denied access to novel therapies for RR-TB.

Topics: Adult; Antitubercular Agents; Child Health; Child, Preschool; Diarylquinolines; Female; Humans; Infant; Infant Health; Linezolid; Nitroimidazoles; Oxazoles; Pregnancy; Pregnancy Outcome; Pregnant Women; South Africa; Tuberculosis, Multidrug-Resistant; Young Adult

The new antituberculous drugs delamanid and bedaquiline form the last line of defence against drug-resistant tuberculosis (TB). Understanding the background prevalence of resistance to new drugs can help predict the lifetime of these drugs' effectiveness and inform regimen design.. Mycobacterium tuberculosis without prior exposure to novel anti-TB drugs were analysed retrospectively. Drug susceptibility testing for bedaquiline, delamanid, linezolid, clofazimine and widely used first- and second-line anti-TB drugs was performed. All TB isolates with resistance to new or repurposed drugs were subjected to whole-genome sequencing to explore the molecular characteristics of resistance and to perform phylogenetic analysis.. Overall, resistance to delamanid, bedaquiline, linezolid and clofazimine was observed in 0.7% (11/1603), 0.4% (6/1603), 0.4% (7/1603) and 0.4% (6/1603) of TB isolates, respectively. Moreover, 1.0% (1/102), 2.9% (3/102), 3.9% (4/102) and 1.0% (1/102) of multidrug-resistant TB (MDR-TB) were resistant to bedaquiline, delamanid, linezolid and clofazimine, respectively. Whereas 22.2% (2/9) of extensively-drug resistant tuberculosis (XDR-TB) isolates were resistant to both delamanid and linezolid, and none was resistant to bedaquiline or clofazimine. Phylogenetic analysis showed that recent transmission occurred in two XDR-TB with additional resistance to delamanid and linezolid. None known gene mutation associated with delamanid resistance was detected. All four isolates with cross-resistance to bedaquiline and clofazimine had a detected gene mutation in Rv0678. Three of five strains with linezolid resistance had a detected gene mutation in rplC.. Detection of resistance to new anti-TB drugs emphasises the pressing need for intensive surveillance for such resistance before their wide usage.

Topics: China; Diarylquinolines; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Phylogeny; Prevalence; Retrospective Studies

There are limited data on combining delamanid and bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable.We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline-delamanid combination regimen (n=40).There was no significant difference in 6-month culture conversion (92.5%

Topics: Antitubercular Agents; Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Prospective Studies; Tuberculosis, Multidrug-Resistant

Bedaquiline and delamanid are newly available drugs for treating multidrug-resistant tuberculosis (MDR-TB); however, there are limited data guiding their use and no comparison studies.. We conducted a prospective, observational study among patients with MDR-TB in Georgia who were receiving a bedaquiline- or delamanid-based treatment regimen. Monthly sputum cultures, minimal inhibitory concentration testing, and adverse event monitoring were performed. Primary outcomes were culture conversion rates and clinical outcomes. Targeted maximum likelihood estimation and super learning were utilized to produce a covariate-adjusted proportion of outcomes for each regimen.. Among 156 patients with MDR-TB, 100 were enrolled and 95 were receiving a bedaquiline-based (n = 64) or delamanid-based (n = 31) regimen. Most were male (82%) and the median age was 38 years. Rates of previous treatment (56%) and cavitary disease (61%) were high. The most common companion drugs included linezolid, clofazimine, cycloserine, and a fluoroquinolone. The median numbers of effective drugs received among patients on bedaquiline-based (4; interquartile range [IQR], 4-4) and delamanid-based (4; IQR, 3.5-5) regimens were similar. Rates of acquired drug resistance were significantly higher among patients receiving delamanid versus bedaquiline (36% vs 10%, respectively; P < .01). Adjusted rates of sputum culture conversion at 2 months (67% vs 47%, respectively; P = .10) and 6 months (95% vs 74%, respectively; P < .01), as well as more favorable clinical outcomes (96% vs 72%, respectively; P < .01), were higher among patients receiving bedaquiline versus delamanid.. Among patients with MDR-TB, bedaquiline-based regimens were associated with higher rates of sputum culture conversion, more favorable outcomes, and a lower rate of acquired drug resistance versus delamanid-based regimens.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Female; Georgia; Humans; Male; Nitroimidazoles; Oxazoles; Prospective Studies; 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

The Korea Centers for Disease Control & Prevention has implemented a review process for the approval of new drugs used to treat patients with multidrug-resistant tuberculosis (MDR-TB) since September 2016. Therefore, this study aimed to evaluate the efficacy and safety of these new drugs bedaquiline (Bdq) and delamanid (Dlm).. A total of 318 patients with MDR-TB were reviewed by the committee from September 2016 to February 2018; 282 (88.7%) of them were treated with the new drugs (Bdq, 107 patients; Dlm, 108 patients; and both concurrently or sequentially, 67 patients) and retrospectively evaluated. Culture conversion rates, interim treatment outcomes at 12 months, and predictors of unfavorable outcomes were analyzed. Treatment efficacy was also compared between Bdq and Dlm.. The mean age of the patients was 49.3 years, and 197 (69.9%) were male. Three patients were HIV seropositive and 151 (53.5%) were quinolone resistant. The culture conversion rates at 2 and 6 months were 57.4% (81/141) and 89.4% (126/141), respectively. A favorable outcome at 12 months was achieved in 84.8% of patients (239/282). Differences in the culture conversion rate or interim treatment outcomes were not statistically significant among the drug susceptibility test patterns or new drugs used. Multivariable analysis showed that age >60 years and body mass index of <18.5 kg/m. The use of new drugs resulted in satisfactory interim treatment results, without significant differences between them.

Topics: Age Factors; Aged; Body Mass Index; Diarylquinolines; Drug Resistance, Bacterial; Drug Resistance, Multiple; Drug Therapy, Combination; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Nitroimidazoles; Oxazoles; Republic of Korea; Retrospective Studies; Risk Factors; Safety; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

The objective of this study was to evaluate the efficacy and safety of the sequential use of bedaquiline (Bdq) and delamanid (Dlm) in patients with multidrug-resistant tuberculosis (MDR-TB) and limited treatment options.. This study evaluated 74 MDR-TB patients treated between March 2016 and December 2018 with Bdq followed by Dlm (n = 22), or vice versa (n= 52), combined with optimized background regimens.. The mean age of the participants was 49.0 ± 15.8 years. Fifty-one (68.9%) of the participants were male. Fluoroquinolone resistance was identified in 54 (72.9%) patients, including 20 (27.0%) with extensively drug-resistant TB. Of the 47 (63.5%) patients with positive cultures at the commencement of the first new drug, culture conversion occurred in 44 (93.6%). The interim treatment outcome after 12 months was favourable in 68/74 patients (91.9%). Twenty-four weeks of treatment were completed in 137 of 148 episodes of new drug use (92.3%). Regarding the 11 early discontinuation events, six patients stopped using a new drug due to adverse drug reactions that were not life-threatening, including one (1.4%) who stopped Bdq due to QT-prolongation.. Sequential use of the two new drugs appears to be an effective and safe option for MDR-TB patients with few treatment options.

Topics: Adult; Aged; Antitubercular Agents; Diarylquinolines; Female; Humans; Male; Middle Aged; Nitroimidazoles; Oxazoles; Retrospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

The role of mutations in genes associated with phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in

Topics: Antitubercular Agents; Diarylquinolines; Genomics; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

At a time when programs were struggling to design effective regimens for the treatment of multidrug-resistant tuberculosis (MDR-TB), the marketing authorization of bedaquiline and delamanid was a critical development in the MDR-TB treatment landscape. However, despite their availability for routine programmatic use, the uptake of these drugs has remained slow; concerns included a lack of evidence on safety and efficacy and the need to protect the new drugs from the development of acquired resistance. As part of the endTB Project, we aimed to address these barriers by generating evidence on safety and efficacy of bedaquiline or delamanid based MDR-TB regimens.. This is a protocol for a multi-center prospective cohort study to enroll 2600 patients from April 2015 through September 2018 in 17 countries. The protocol describes inclusion of patients started on treatment with bedaquiline- or delamanid- containing regimens under routine care, who consented to participate in the endTB observational study. Patient follow-up was according to routine monitoring schedules recommended for patients receiving bedaquiline or delamanid as implemented at each endTB site. Therefore, no additional tests were performed as a part of the study. Data were to be collected in a customized, open-source electronic medical record (EMR) system developed as a part of the endTB Project across all 17 countries.. The endTB observational study will generate evidence on safety and efficacy of bedaquiline- and delamanid-containing regimens in a large, extremely heterogeneous group of MDR-TB patients, from 17 epidemiologically diverse countries. The systematic, prospective data collection of repeated effectiveness and safety measures, and analyses performed on these data, will improve the quality of evidence available to inform MDR-TB treatment and policy decisions. Further, the resources available to countries through implementation of the endTB project will have permitted countries to: gain experience with the use of these drugs in MDR-TB regimens, improve local capacity to record and report adverse events (pharmacovigilance), and enhance significantly the body of data available for safety evaluation of these drugs and other novel treatments.. This study was registered on 24 August 2017 at clincaltrials.gov (Registration number: NCT03259269).

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Multicenter Studies as Topic; Nitroimidazoles; Observational Studies as Topic; Oxazoles; Prospective Studies; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Hong Kong is a high-income city of China with an intermediate tuberculosis (TB) burden, and 1% of TB cases are multidrug-resistant (MDR-TB). The aim of this study was to examine the potential cost-effectiveness of adding bedaquiline or delamanid to the background regimen (BR) for the treatment of MDR-TB in Hong Kong.. A decision-analytic model was designed to simulate outcomes over a 10-year time horizon for MDR-TB patients treated with bedaquiline plus BR (B-BR), delamanid plus BR (D-BR), or BR alone. Outcome measures included direct medical costs and quality-adjusted life-years (QALYs) gained.. In the base-case analysis, BR was the least costly regimen (USD 47396) with the lowest QALYs gained (6.347). Compared to BR, B-BR gained an additional 0.731 QALYs with incremental cost of USD 9. The incremental cost-effectiveness ratio (ICER) of B-BR was USD 12/QALY. D-BR was more costly than BR by USD 20 164 and gained an additional 0.012 QALYs. The ICER of D-BR was USD 1 680333/QALY. In the probabilistic sensitivity analysis with 10000 Monte Carlo simulations, B-BR and D-BR were cost-effective 99.98% and 5.13% of the time, respectively, using 1× gross domestic product per capita (USD 46 182) as the willingness-to-pay threshold.. Bedaquiline is more likely than delamanid to be cost-effective when added to BR for the treatment of MDR-TB in Hong Kong.

Topics: Adult; Cost-Benefit Analysis; Diarylquinolines; Follow-Up Studies; Hong Kong; Humans; Middle Aged; Monte Carlo Method; Nitroimidazoles; Oxazoles; Quality-Adjusted Life Years; Retrospective Studies; Socioeconomic Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Topics: Adolescent; Adult; Antitubercular Agents; Child; Compassionate Use Trials; Diarylquinolines; Drug Therapy, Combination; Female; HIV Infections; Humans; Internationality; Male; Middle Aged; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Young Adult

Despite being fundamental to all treatment decisions, the breakpoints that define susceptibility and resistance to conventional anti-tuberculosis (TB) drugs were traditionally defined based on expert opinion as opposed to modern microbiological principles. As a result, the breakpoints for several key drugs (i.e. amikacin, levofloxacin, and moxifloxacin) were too high, resulting in the systematic misclassification of a proportion of resistant strains as susceptible. Moreover, a recent systematic review of clinical outcome data prompted the World Health Organization (WHO) to make significant changes to its treatment guidelines. For example, capreomycin and kanamycin are no longer recommended for TB treatment because their use correlates with worse clinical outcomes. This history notwithstanding, robust breakpoints still do not exist for bedaquiline and delamanid six years after their approval. This was compounded by the fact that access to both agents for drug-susceptibility testing had initially been restricted. It is incumbent upon the European Medicines Agency, the United States Food and Drug Administration, and WHO to ensure that drug developers generate the necessary data to set breakpoints as a prerequisite for the approval of new agents.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles

NTP was pilot tested in Anantapur district of Andhra Pradesh during 1961 and thereafter the programme was launched throughout the country. In 1992, the Government of India together with the World Health Organization (WHO) and Swedish International Development Agency (SIDA) reviewed the National TB Programme and concluded that it suffered from managerial weakness, inadequate funding, over-reliance on x-ray, non-standard treatment regimens, low rates of treatment completion and lack of systematic information on treatment outcomes. Programme review showed that only 30% of patients were diagnosed and only 30% of those treated successfully. Based on the findings and recommendations of the review in 1992, the GOI evolved a revised strategy and launched the Revised National TB Control Programme (RNTCP).

Topics: Antitubercular Agents; Diarylquinolines; Directly Observed Therapy; Goals; History, 20th Century; History, 21st Century; Humans; India; National Health Programs; Nitroimidazoles; Oxazoles; Practice Guidelines as Topic; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Drug-Resistant Tuberculosis (DR-TB) patients for whom a WHO recommended regimen along with Bedaquiline (BDQ) cannot be prescribed, Delamanid (DLM) was added along with other drugs to provide a "Salvage Regimen". The experience of the Institute in respect of early efficacy and safety of both drugs given together is presented.. To ascertain the early efficacy, safety and tolerability of Bedaquline and Delamanid given together as a part of salvage regimen.. BDQ and DLM were used together to make regimens along with other drugs where four effective anti TB drugs could not be prescribed as per WHO recommendations. Patients were followed up for sputum smear and culture conversion and adverse events during the treatment.. In this cohort study, 53 DR-TB patients (Median age-24) were initiated on regimens containing both BDQ and DLM. Sputum smear conversion was seen in 35% and 94% patients at the end of 1st week and 3rd month respectively. 84% patients had culture conversion at the end of 4th month. 29 adverse events (AE) were reported among 17 patients and there were 11 deaths. QTc prolongation more than 500 MS was seen in only 1 patient.. BDQ and DLM given together in a salvage regimen is efficacious with low rate of adverse events. The combination provides hope to DR-TB patients with limited treatment options and should be provided as a life saving option.

Topics: Adult; Cardiotoxicity; Clofazimine; Diarylquinolines; Drug Therapy, Combination; Electrocardiography; Female; Humans; Imipenem; Male; Moxifloxacin; Nitroimidazoles; Oxazoles; Salvage Therapy; Sputum; Survival Rate; Tuberculosis, Multidrug-Resistant; Young Adult

Topics: Antitubercular Agents; Deafness; Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Randomized Controlled Trials as Topic; Research Design; Time Factors; Tuberculosis, Multidrug-Resistant

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

The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries. The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs. Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile. A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Feasibility Studies; Female; Humans; Male; Nitroimidazoles; Oxazoles; Pilot Projects; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

Topics: Antitubercular Agents; Cohort Studies; Diarylquinolines; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant

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

We evaluated the

Topics: Anti-Bacterial Agents; Antitubercular Agents; Diarylquinolines; Humans; Macrolides; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium Infections, Nontuberculous; Mycobacterium kansasii; Nitroimidazoles; Nontuberculous Mycobacteria; 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; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Administration Schedule; France; Humans; Latvia; Male; Nitroimidazoles; Oxazoles; Patient Safety; Treatment Outcome; Tuberculosis, Multidrug-Resistant

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

Topics: Armenia; Diarylquinolines; Humans; India; Nitroimidazoles; Oxazoles; Retrospective Studies; South Africa; Tuberculosis, Multidrug-Resistant

Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.. We retrospectively analysed a cohort of all patients who received 6-12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.. Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5-40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.. Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.. Médecins Sans Frontières (MSF).

Topics: Adult; Antitubercular Agents; Armenia; Arrhythmias, Cardiac; Cohort Studies; Diarylquinolines; Drug Therapy, Combination; HIV Infections; Humans; India; Nitroimidazoles; Oxazoles; Retrospective Studies; South Africa; Tuberculosis, Multidrug-Resistant

Relatively little is known about the efficacy and safety of the programmatic use of bedaquiline and delamanid in multidrug-resistant tuberculosis (MDR-TB) treatment.This study evaluated 61 patients with MDR-TB treated with bedaquiline (n=39), delamanid (n=11) or both, either sequentially (n=10) or in coadministration (n=1), for >1 month, combined with a World Health Organization-recommended regimen.Of these, 49 (80.3%) were male and 12 (19.7%) were female. The median (interquartile range (IQR)) age was 53 (38.5-61.0) years. 42 (68.9%) patients had fluoroquinolone-resistant MDR-TB and 16 (26.2%) had extensively drug-resistant TB. The median (IQR) duration of treatment with bedaquiline and/or delamanid was 168 (166.5-196.5) days, with 33 (54.1%) receiving linezolid for a median (IQR) of 673 (171-736) days. Of the 55 patients with positive sputum cultures at the start of bedaquiline and/or delamanid treatment, 39 (70.9%) achieved sputum culture conversion within a median of 119 days. Treatment was halted in four patients (6.6%) because of prolonged Fridericia's corrected QT interval.Bedaquiline and delamanid were effective and safe for treating MDR-TB, with initial evidence of sequential administration of these two drugs as a viable treatment strategy for patients when an adequate treatment regimen cannot be constructed.

Topics: Adult; Antitubercular Agents; Cohort Studies; Diarylquinolines; Drug Administration Schedule; Female; Geography; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Republic of Korea; Tuberculosis, Multidrug-Resistant; World Health Organization

Topics: Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

The World Health Organization recommended two new drugs, bedaquiline (BDQ) and delamanid (DLM), for the treatment of multidrug-resistant tuberculosis (MDR-TB) in 2013 and 2014, respectively. An estimated one third of patients with MDR-TB would benefit from the inclusion of these drugs in their treatment regimens.. A convenience sample of 36 countries voluntarily reported monthly data on cumulative programmatic use of new drugs to the Drug-Resistant TB Scale-Up Treatment Action Team between 1 July 2015 and 31 June 2017. Programmatic use was defined as treatment for MDR-TB with newer drugs outside of clinical trials or compassionate use.. A total of 10 164 persons were started on BDQ and 688 started on DLM during the reporting period. Only 15.7% of the 69 213 persons estimated to need newer drugs over the study period were reported to have received them.. While there has been significant progress in some countries, uptake of the newer drugs has not kept pace with a conservative estimate of need; fewer than 20% of persons likely to benefit from either BDQ or DLM have received them. Concerted efforts are needed to ensure that the newer drugs are made available more widely for persons with MDR-TB in need of these therapeutic options.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Internationality; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Communicable Disease Control; Databases, Factual; Diarylquinolines; Humans; Infectious Disease Medicine; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Patient Safety; Public Health; Rifampin; Tuberculosis, Multidrug-Resistant; World Health Organization

Topics: Antitubercular Agents; Diarylquinolines; Diffusion of Innovation; Drug and Narcotic Control; Drug Approval; Global Health; Health Services Accessibility; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Cardiotoxicity; Cross-Sectional Studies; Diarylquinolines; Electrocardiography; Europe; Humans; Internationality; Long QT Syndrome; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Humans; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Reproducibility of Results; Tuberculosis; Tuberculosis, Multidrug-Resistant

Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.. niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI).. PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval.. The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing.. We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.

Topics: Adolescent; Adult; Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Liberation; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Nitroimidazoles; Oxazoles; Proof of Concept Study; Rifampin; Treatment Outcome; Young Adult

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

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

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

Many drugs with potential QT prolongation effects (QT drugs) have already been used for decades in patients with multidrug-resistant TB (MDR-TB) or non-tuberculous mycobacterial (NTM) disease, but without a common consensus.. To investigate the effects of QT drugs on cardiac events in patients with MDR-TB or NTM disease.. We retrospectively reviewed 373 patients (mean age: 56.4 years) with MDR-TB or NTM disease treated for >1 month with clofazimine (CFZ), moxifloxacin (MFX), bedaquiline (BDQ), delamanid (DLM) or macrolides (clarithromycin or azithromycin). Adverse cardiac events, death and QTcF changes were evaluated.. Forty-four per cent had MDR-TB; 165 (44%), 315 (85%), 10 (3%), 229 (61%) and 1 patient received CFZ, MFX, BDQ, macrolides and DLM, respectively. Except for three patients (0.8%) lost to follow-up with unknown cause of death, 3 (0.8%, 95%CI 0.2-2.4) adverse cardiac events were documented: atrial fibrillation, cardiac tamponade due to TB pericarditis and cardiac arrest, which was determined to not have been caused by QT drugs. Clinically significant QTcF changes (QTcF > 500 msec or an increase > 60 msec) were observed in 10/60 patients (17%, 95%CI 8.0-30.7) without clinical events.. The use of QT drugs, alone or in combination, in the treatment of MDR-TB or NTM disease is relatively safe.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Azithromycin; Child; Clarithromycin; Clofazimine; Diarylquinolines; Female; Fluoroquinolones; Follow-Up Studies; Humans; Lost to Follow-Up; Macrolides; Male; Middle Aged; Moxifloxacin; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nitroimidazoles; Nontuberculous Mycobacteria; Oxazoles; Retrospective Studies; Tuberculosis, Multidrug-Resistant; Young Adult

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Rifampin; Tuberculosis, Multidrug-Resistant

Novel therapies for multidrug-resistant tuberculosis (MDR-TB) are likely to be expensive. The cost of novel drugs (e.g., bedaquiline, delamanid) may be so prohibitively high that a traditional cost-effectiveness analysis (CEA) would rate regimens containing these drugs as not cost-effective. Traditional CEA may not appropriately account for considerations of social justice, and may put the most disadvantaged populations at greater risk. Using the example of novel drug regimens for MDR-TB, we propose a novel methodology, 'justice-enhanced CEA', and demonstrate how such an approach can simultaneously assess social justice impacts alongside traditional cost-effectiveness ratios. Justice-enhanced CEA, as we envision it, is performed in three steps: 1) systematic data collection about patients' lived experiences, 2) use of empirical findings to inform social justice assessments, and 3) incorporation of data-informed social justice assessments into a decision analytic framework that includes traditional CEA. These components are organized around a core framework of social justice developed by Bailey et al. to compare impacts on disadvantage not otherwise captured by CEA. Formal social justice assessments can produce three composite levels: 'expected not to worsen…', 'may worsen…', and 'expected to worsen clustering of disadvantage'. Levels of social justice impact would be assessed for each major type of outcome under each policy scenario compared. Social justice assessments are then overlaid side-by-side with cost-effectiveness assessments corresponding to each branch pathway on the decision tree. In conclusion, we present a 'justice-enhanced' framework that enables the incorporation of social justice concerns into traditional CEA for the evaluation of new regimens for MDR-TB.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Decision Trees; Diarylquinolines; Humans; Models, Theoretical; Nitroimidazoles; Oxazoles; Social Justice; Social Stigma; South Africa; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The World Health Organization uses a Grading of Recommendations Assessment, Development, and Evaluation process to make recommendations for treating multidrug-resistant tuberculosis. Even with this standardized approach, there have been discrepancies between recommendations for newer drugs such as bedaquiline and delamanid and the shorter regimen. This may be because newer drugs are novel chemical entities and may merit closer scrutiny. Here, we explore the problematic nature of this supposition, arguing that although the newer drugs have been used in fewer individuals, they may have more robust efficacy and safety data than many of the second-line drugs used in the shorter regimen.

Topics: Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Humans; Nitroimidazoles; Oxazoles; Practice Guidelines as Topic; Tuberculosis, Multidrug-Resistant; World Health Organization

To evaluate the use of Bayesian adaptive randomization for clinical trials of new treatments for multidrug-resistant tuberculosis.. We built a response-adaptive randomization procedure, adapting on two preliminary outcomes for tuberculosis patients in a trial with five experimental regimens and a control arm. The primary study outcome is treatment success after 73 weeks from randomization; preliminary responses are culture conversion at 8 weeks and treatment success at 39 weeks. We compared the adaptive randomization design with balanced randomization using hypothetical scenarios.. When we compare the statistical power under adaptive randomization and non-adaptive designs, under several hypothetical scenarios we observe that adaptive randomization requires fewer patients than non-adaptive designs. Moreover, adaptive randomization consistently allocates more participants to effective arm(s). We also show that these advantages are limited to scenarios consistent with the assumptions used to develop the adaptive randomization algorithm.. Given the objective of evaluating several new therapeutic regimens in a timely fashion, Bayesian response-adaptive designs are attractive for tuberculosis trials. This approach tends to increase allocation to the effective regimens.

Topics: Adaptive Clinical Trials as Topic; Algorithms; Antitubercular Agents; Bayes Theorem; Computer Simulation; Diarylquinolines; Humans; Nitroimidazoles; Oxazoles; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome; Tuberculosis, Multidrug-Resistant

In spite of the recent introduction of two new drugs (delamanid and bedaquiline) and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB), clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as the 'Bangladesh regimen') proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide, and ethambutol. However, recent evidence from Europe and Latin America identified prevalences of resistance to the first-line drugs in this regimen (ethambutol and pyrazinamide) exceeding 60%, and of prothionamide exceeding 50%. Furthermore, the proportions of resistance to the two most important pillars of the regimen - quinolones and kanamycin - were higher than 40%. Overall, only 14 out of 348 adult patients (4.0%) were susceptible to all of the drugs composing the regimen, and were therefore potentially suitable for the 'shorter regimen'. A shorter, cheaper, and well-tolerated MDR-TB regimen is likely to impact the number of patients treated and improve adherence if prescribed to the right patients through the systematic use of rapid MTBDRsl testing.

Topics: Antitubercular Agents; Clinical Protocols; Diarylquinolines; Drug Therapy, Combination; Ethambutol; Fluoroquinolones; Humans; Isoniazid; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Tuberculosis, Multidrug-Resistant; World Health Organization

The estimated worldwide annual incidence of MDR-TB is 480 000, representing 5% of TB incidence, but 20% of mortality. Multiple drugs have recently been developed or repurposed for the treatment of MDR-TB. Currently, treatment for MDR-TB costs thousands of dollars per course.. To estimate generic prices for novel TB drugs that would be achievable given large-scale competitive manufacture.. Prices for linezolid, moxifloxacin and clofazimine were estimated based on per-kilogram prices of the active pharmaceutical ingredient (API). Other costs were added, including formulation, packaging and a profit margin. The projected costs for sutezolid were estimated to be equivalent to those for linezolid, based on chemical similarity. Generic prices for bedaquiline, delamanid and pretomanid were estimated by assessing routes of synthesis, costs/kg of chemical reagents, routes of synthesis and per-step yields. Costing algorithms reflected variable regulatory requirements and efficiency of scale based on demand, and were validated by testing predictive ability against widely available TB medicines.. Estimated generic prices were US$8-$17/month for bedaquiline, $5-$16/month for delamanid, $11-$34/month for pretomanid, $4-$9/month for linezolid, $4-$9/month for sutezolid, $4-$11/month for clofazimine and $4-$8/month for moxifloxacin. The estimated generic prices were 87%-94% lower than the current lowest available prices for bedaquiline, 95%-98% for delamanid and 94%-97% for linezolid. Estimated generic prices were $168-$395 per course for the STREAM trial modified Bangladesh regimens (current costs $734-$1799), $53-$276 for pretomanid-based three-drug regimens and $238-$507 for a delamanid-based four-drug regimen.. Competitive large-scale generic manufacture could allow supplies of treatment for 5-10 times more MDR-TB cases within current procurement budgets.

Topics: Algorithms; Antitubercular Agents; Commerce; Diarylquinolines; Drug Costs; Drugs, Generic; Fluoroquinolones; Humans; Moxifloxacin; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Diarylquinolines; Health Services Accessibility; Humans; India; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Treatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective.. A cohort-based Markov model was developed to simulate the incremental cost-effectiveness ratio of bedaquiline plus BR, delamanid plus BR, or linezolid plus BR versus BR alone in the treatment of MDR-TB, over a 10-year time horizon. Effectiveness of treatment was evaluated in Quality-Adjusted Life-Years (QALYs) and Life-Years Gained (LYG), using inputs from clinical trials for bedaquiline and delamanid and from a German observational study for linezolid. Cost data were obtained from German Drug Directory costs (€/2015), published literature, and expert opinion. A 3% yearly discount rate was applied. Probabilistic and deterministic sensitivity analyses were conducted.. The total discounted costs per-patient were €85,575 for bedaquiline plus BR, €81,079 for delamanid plus BR, and €80,460 for linezolid plus BR, compared with a cost of €60,962 for BR alone. The total discounted QALYs per-patient were 5.95 for bedaquiline plus BR, 5.36 for delamanid plus BR, and 3.91 for linezolid plus BR, compared with 3.68 for BR alone. All interventions were therefore associated with higher QALYs and higher costs than BR alone, with incremental costs per QALY gained of €22,238 for bedaquiline, €38,703 for delamanid, and €87,484 for linezolid, versus BR alone. In a fully incremental analysis, bedaquiline plus BR was the most cost-effective treatment option at thresholds greater than €22,000 per QALY gained. In probabilistic analyses, the probability that bedaquiline plus BR was the most cost-effective treatment strategy at a willingness-to-pay threshold of €30,000 was 54.5%, compared with 22.9% for BR alone, 18.2% for delamanid plus BR, and 4.4% for linezolid.. In Germany, the addition of bedaquiline, delamanid, or linezolid to a BR would result in QALY gains over BR alone. Based on this analysis, bedaquiline is likely to be the most cost-effective intervention for the treatment of MDR-TB, when added to a BR regimen at thresholds greater than €22,000 per QALY.

Topics: Adult; Antitubercular Agents; Clinical Protocols; Clinical Trials as Topic; Cost-Benefit Analysis; Diarylquinolines; Drug Costs; Drug Therapy, Combination; Female; Germany; Humans; Linezolid; Male; Nitroimidazoles; Observational Studies as Topic; Oxazoles; Quality-Adjusted Life Years; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

The World Health Organization recommends adding bedaquiline or delamanid to multidrug-resistant tuberculosis (MDR-TB) regimens for which four effective drugs are not available, and delamanid for patients at high risk of poor outcome.. To identify patients at risk of unfavourable outcomes who may benefit from the new drugs.. Retrospective cohort study of treatment outcomes involving four to five effective drugs for 15-24 months in programmes in Uzbekistan, Georgia, Armenia, Swaziland and Kenya between 2001 and 2011.. Of 1433 patients, 48.5% had body mass index (BMI) <18.5 kg/m(2), 72.9% had a high bacillary load, 16.7% were resistant to two injectables, 2.9% were resistant to ofloxacin (OFX) and 3.0% had extensively drug-resistant TB (XDR-TB). Treatment success ranged from 59.7% (no second-line resistance) to 27.0% (XDR-TB). XDR-TB (aOR 8.16, 95%CI 3.22-20.64), resistance to two injectables (aOR 1.90, 95%CI 1.00-3.62) or OFX (aOR 5.56, 95%CI 2.15-14.37), past incarceration (aOR 1.88, 95%CI 1.11-3.2), history of second-line treatment (aOR 3.24, 95%CI 1.53-6.85), low BMI (aOR 2.22, 95%CI 1.56-3.12) and high bacillary load (aOR 2.32, 95%CI 1.15-4.67) were associated with unfavourable outcomes. Patients started on capreomycin rather than kanamycin were more likely to have an unfavourable outcome (aOR 1.54, 95%CI 1.04-2.28).. In our cohort, patients who may benefit from bedaquiline and delamanid represented up to two thirds of all MDR-TB patients.

Topics: Adult; Antitubercular Agents; Bacterial Load; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Eswatini; Female; Humans; Kenya; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Nitroimidazoles; Odds Ratio; Oxazoles; Patient Selection; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant; USSR; Young Adult

This paper explores the notion of reciprocity in the context of active pulmonary and laryngeal tuberculosis (TB) treatment and related control policies and practices. We seek to do three things: First, we sketch the background to contemporary global TB care and suggest that poverty is a key feature when considering the treatment of TB patients. We use two examples from TB care to explore the role of reciprocity: isolation and the use of novel TB drugs. Second, we explore alternative means of justifying the use of reciprocity through appeal to different moral and political theoretical traditions (i.e., virtue ethics, deontology, and consequentialism). We suggest that each theory can be used to provide reasons to take reciprocity seriously as an independent moral concept, despite any other differences. Third, we explore general meanings and uses of the concept of reciprocity, with the primary intention of demonstrating that it cannot be simply reduced to other more frequently invoked moral concepts such as beneficence or justice. We argue that reciprocity can function as a mid-level principle in public health, and generally, captures a core social obligation arising once an individual or group is burdened as a result of acting for the benefit of others (even if they derive a benefit themselves). We conclude that while more needs to be explored in relation to the theoretical justification and application of reciprocity, sufficient arguments can be made for it to be taken more seriously as a key principle within public health ethics and bioethics more generally.

Topics: Antitubercular Agents; Beneficence; Communicable Disease Control; Congresses as Topic; Diarylquinolines; Directly Observed Therapy; Ethical Analysis; Ethical Theory; Global Health; Humans; Moral Obligations; Nitroimidazoles; Oxazoles; Patient Isolation; Personal Autonomy; Pharmacovigilance; Poverty; Public Health; Social Justice; Social Responsibility; Tuberculosis, Laryngeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Virtues

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

Two new drugs-bedaquiline and delamanid-have recently been approved by stringent regulatory authorities to treat multidrug-resistant tuberculosis (TB) and recommended by the World Health Organization for use under defined programmatic conditions. Introducing the medications in TB programs worldwide has not kept pace with the need for these drugs. In response, the DR-TB STAT (Drug-Resistant TB Scale-up Treatment Action Team) task force was formed in April 2015 to monitor progress and help overcome challenges. Information was collected from multiple sources and assessed monthly. Some progress has been made in introducing bedaquiline: as of October 2015, a total of 1,258 persons were on the medication under programmatic conditions. For delamanid, >100 patients, but few under programmatic conditions, have received the medication. Coordinated global action might help assist making these medications accessible for persons who need them most.

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

New treatments for multidrug-resistant tuberculosis (MDR TB) are urgently needed. Two new drugs, bedaquiline and delamanid, have recently been released, and several new drugs and treatment regimens are in the pipeline. Misuse of TB drugs is a principal cause of drug resistance. As new drugs and regimens reach the market, the need to make them available to patients must be balanced with regulation of their use so that resistance to the new drugs can be prevented. To foster the rational use of new drugs, we propose 1) expanding/strengthening the capacity for drug susceptibility testing, beginning with countries with a high TB burden; 2) regulating prescribing practices by banning over-the-counter sale of TB drugs and enacting an accreditation system whereby providers must be certified to prescribe new drugs; and 3) decentralizing MDR TB care in rural communities by employing trained community health workers, using promising mobile technologies, and enlisting the aid of civil society organizations.

Topics: Antitubercular Agents; Diarylquinolines; Drug Prescriptions; Drug Resistance, Bacterial; Drug Utilization; Humans; Legislation, Drug; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

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

No clear evidence on the comparative effectiveness of delamanid (DLM) and bedaquiline (BDQ) has been published.. This study aims to estimate the incremental effectiveness of DLM versus BDQ in patients with multidrug-resistant tuberculosis (MDR-TB).. We developed a Markov model based on a cohort with MDR-TB, which consisted of success, failure, loss to follow-up, and death. The cohort simulation was conducted assuming each patient was 36 years old and, lived until age 82, and that the cycle length was 1 year. Patients with an inadequate response to DLM, the background regimen, or BDQ for 2 years were transitioned through the next treatment sequence. We evaluated the incremental effectiveness of the drugs using the quality-adjusted life-year (QALY) resulting from this Markov model over a lifetime.. The incremental effectiveness of DLM (13.96 QALYs) was greater by 2.44 QALYs per patient than the background regimen (11.52 QALY), while the incremental effectiveness of BDQ (10.40 QALY) was higher by 1.14 QALY per patient than the background regimen (9.26 QALY). Consequently, the incremental effectiveness of DLM was relatively more positive by 1.30 QALY than those of BDQ per patient over a lifetime.. This study is a simulation study. Therefore, the treatment sequence for patients may be different in the real world.. Our lifetime simulated data found that DLM was relatively more favorable than BDQ. A Markov model can be considered an alternative approach when there is an absence of head-to-head clinical data.

Topics: Aged; Diarylquinolines; Female; Humans; Male; Middle Aged; Nitroimidazoles; Oxazoles; Quality-Adjusted Life Years; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Global Health; Humans; Nitroimidazoles; Oxazoles; Tuberculosis

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

New regimens based on two or more novel agents are sought in order to shorten or simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. PA-824 is a nitroimidazo-oxazine now in phase II trials and has shown significant early bactericidal activity alone and in combination with the newly approved agent bedaquiline or with pyrazinamide with or without moxifloxacin. While the development of PA-824 continues, a potential next-generation derivative, TBA-354, has been discovered to have in vitro potency superior to that of PA-824 and greater metabolic stability than that of the other nitroimidazole derivative in clinical development, delamanid. In the present study, we compared the activities of PA-824 and TBA-354 as monotherapies in murine models of the initial intensive and continuation phases of treatment, as well as in combination with bedaquiline plus pyrazinamide, sutezolid, and/or clofazimine. The monotherapy studies demonstrated that TBA-354 is 5 to 10 times more potent than PA-824, but selected mutants are cross-resistant to PA-824 and delamanid. The combination studies revealed that TBA-354 is 2 to 4 times more potent than PA-824 when combined with bedaquiline, and when administered at a dose equivalent to that of PA-824, TBA-354 demonstrated superior sterilizing efficacy. Perhaps most importantly, the addition of either nitroimidazole significantly improved the sterilizing activities of bedaquiline and sutezolid, with or without pyrazinamide, confirming the value of each agent in this potentially universally active short-course regimen.

Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Fluoroquinolones; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Oxazines; Oxazoles; Pyrazinamide; Random Allocation; Tuberculosis

Topics: Antitubercular Agents; Diarylquinolines; Drug Approval; Humans; Mutation; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Bedaquiline (Sirturo) and delamanid (Deltyba) have recently been approved by the regulatory authorities for treatment of multidrug-resistant tuberculosis (MDR-TB). Antimicrobial susceptibility testing is not established for either substance. On the basis of the use of the MGIT 960 system equipped with EpiCenter/TB eXiST, we determined a mean bedaquiline MIC for wild-type strains of 0.65 mg/liter (median, 0.4 mg/liter) and an epidemiological cutoff (ECOFF) of 1.6 mg/liter; for delamanid, a mean wild-type drug MIC of 0.013 mg/liter (median, 0.01 mg/liter) and an ECOFF of 0.04 mg/liter were determined.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Reference Values; Tuberculosis; Tuberculosis, Multidrug-Resistant

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

Treatment of multidrug-resistant Mycobacterium tuberculosis is a challenge. This letter describes the emergence of resistance to new therapies, bedaquiline and delamanid.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Male; Mutation; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Developing Countries; Diarylquinolines; Health Services Accessibility; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Fewer than 20% of patients with multidrug-resistant (MDR) tuberculosis are receiving treatment and there is an urgent need to scale up treatment programmes. One of the biggest barriers to scale-up is the treatment regimen, which is lengthy, complex, ineffective, poorly tolerated and expensive. For the first time in over 50 years, new drugs have been developed specifically to treat tuberculosis, with bedaquiline and potentially delamanid expected to be available soon for treatment of MDR cases. However, if the new drugs are merely added to the current treatment regimen, the new regimen will be at least as lengthy, cumbersome and toxic as the existing one. There is an urgent need for strategy and evidence on how to maximize the potential of the new drugs to improve outcomes and shorten treatment. We devised eight key principles for designing future treatment regimens to ensure that, once they are proven safe in clinical trials, they will be clinically effective and programmatically practicable. Regimens should contain at least one new class of drug; be broadly applicable for use against MDR and extensively drug-resistant Mycobacterium tuberculosis complex strains; contain three to five effective drugs, each from a different drug class; be delivered orally; have a simple dosing schedule; have a good side-effect profile that allows limited monitoring; last a maximum of 6 months; and have minimal interaction with antiretrovirals. Following these principles will maximize the potential of new compounds and help to overcome the clinical and programmatic disadvantages and scale-up constraints that plague the current regimen.. Moins de 20% des patients atteints de tuberculose multirésistante (MDR) reçoivent actuellement un traitement et il est urgent de renforcer les programmes de traitement. Un des plus grands obstacles à ce renforcement est le schéma thérapeutique qui est long, complexe, inefficace, mal toléré et coûteux. Pour la première fois en plus de 50 ans, de nouveaux médicaments ont été développés spécifiquement pour traiter la tuberculose, dont la bedaquiline et potentiellement la delamanid qui devraient être bientôt disponibles pour traiter les cas de MDR. Cependant, si les nouveaux médicaments sont juste ajoutés au schéma thérapeutique actuel, le nouveau schéma thérapeutique sera au moins aussi long, lourd et toxique que celui qui existe déjà. Il est urgent d'élaborer une stratégie et d'obtenir des preuves concernant la façon de maximiser le potentiel des nouveaux médicaments pour améliorer les résultats et raccourcir la durée du traitement. Nous avons mis au point huit principes clés pour la conception des futurs schémas thérapeutiques afin de s'assurer que, une fois qu'ils aient été éprouvés comme sûrs dans des essais cliniques, ils soient cliniquement efficaces et utilisables dans le cadre d'un programme. Les schémas thérapeutiques doivent comprendre au moins une nouvelle classe de médicament; être généralement applicables pour une utilisation contre les MDR et plus largement contre les souches complexes de. Menos del 20 % de los pacientes con tuberculosis multirresistente (MDR) recibe tratamiento, al tiempo que existe una necesidad apremiante de ampliar los programas de tratamiento. Uno de los mayores obstáculos para la ampliación es el propio programa de tratamiento, el cual resulta largo, complejo, ineficaz, caro y no se tolera bien. Por primera vez en más de 50 años se han desarrollado fármacos nuevos específicos para tratar la tuberculosis y se espera que la bedaquilina y, potencialmente, la delamanida estén disponibles pronto para tratar los casos de tuberculosis multirresistente. Sin embargo, si se limitan a introducir los fármacos nuevos al programa de tratamiento actual, el programa nuevo será, como mínimo, tan largo, complicado y tóxico como el presente. Es, por tanto, muy urgente diseñar una estrategia y reunir pruebas sobre cómo maximizar el potencial de los fármacos nuevos para mejorar los resultados y acortar el tratamiento. Hemos establecido ocho principios esenciales para el diseño de los programas de tratamiento futuros a fin de garantizar que, una vez que se hayan probado en ensayos clínicos, sean eficaces desde el punto de vista clínico y viables mediante programación. Los programas deben contener, al menos, un tipo nuevo de fármaco, poder aplicarse de forma amplia para su uso contra la tuberculosis multirresistente y las cepas complejas de. يتلقى أقل من 20 % من مرضى السل المقاوم للأدوية المتعددة العلاج وتوجد حاجة ملحة لزيادة حجم برامج العلاج. وتتمثل إحدى العقبات الكبرى التي تحول دون زيادة حجم النظام العلاجي في أنه طويل ومعقد وغير فعال وباهظ الثمن وسيء التحمل. وللمرة الأولى فيما يزيد عن 50 سنة، تم تطوير أدوية جديدة لاسيما لعلاج السل، باستخدام البيداكيلين وربما الديلامانيد المتوقع إتاحتهما قريباً لعلاج حالات السل المقاوم للأدوية المتعددة. ومع ذلك، إذا لم يتم سوى إضافة الأدوية الجديدة إلى النظام العلاجي الراهن، فسوف يكون النظام الجديد على الأقل طويلاً ومزعجاً وساماً مثل النظام القائم. وتوجد حاجة ملحة لاستراتيجية وبيّنات بشأن كيفية مضاعفة احتمالات الأدوية الجديدة في تحسين الحصائل وتقصير مدة العلاج. وقمنا باستحداث ثمانية مبادئ رئيسية لتصميم النظم العلاجية المستقبلية لضمان فعاليتها من الناحية السريرية وقابليتها للتطبيق من الناحية البرمجية بمجرد إثبات سلامتها في التجارب السريرية. وينبغي أن تحتوي النظم على فئة دواء واحدة جديدة على الأقل؛ وأن يتم تطبيقها على نطاق واسع لاستخدامها ضد السل المقاوم للأدوية المتعددة والسلالات المعقدة من البكتريا المتفطرة السليّة الشديدة المقاومة للأدوية؛ وتحتوي على ثلاثة إلى خمسة أدوية ناجعة، ينتمي كل منها إلى فئة دوائية مختلفة؛ ويتم تناولها عن طريق الفم؛ وتكون ذات جدول جرعات بسيط؛ وذات مستوى آثار جانبية جيد يسمح بالرصد المحدود؛ وتستمر لمدة 6 أشهر على الأكثر؛ وتكون أقل تفاعلاً مع مضادات الفيروسات القهقرية. وسوف يضاعف اتباع هذه المبادئ احتمالية التوصل إلى مركبات جديدة ويساعد على التغلب على العيوب السريرية والبرمجية وعلى صعوبات زيادة الحجم التي تزعج النظام الراهن.. 在患有耐多药肺结核(MDR)的病人当中,正在接受治疗的人数不到20%,治疗计划迫切需要扩大。而扩大计划的最大障碍之一在于漫长、复杂、低效、不堪忍受且昂贵的治疗方案。50 多年来人们首次专门针对治疗肺结核研发新药,贝达喹啉和可能的Delamanid预计将很快可以用于治疗MDR病例。 然而,如果这些新药物仅仅是添加到当前的治疗方案中,新方案将至少和现有的方案一样漫长、繁琐并且有毒害作用。目前迫切需要有关如何最大化各个新药物潜能的战略和证据,以改善效果,缩短治疗周期。为确保实现这一目标,我们设想了设计未来治疗方案的八大原则,来确保只要这些方案经过临床试验证明安全,就将成为临床有效且程序上可行的方案。方案应包含至少一种新药物;广泛适用于对抗耐多药和广泛耐药结核分枝杆菌复合菌株;包含三到五种有效的药物,每种都分属不同的药物类别;口服;拥有简单的用药方案;有完善的不良反应量表,从而仅需要进行有限的监控;最多持续六个月;与抗逆转录病毒药物交互作用很小。遵循这些原则将最大程度挖掘新复方的潜能,有助于克服临床和程序上的缺点,解除对扩大的羁绊,使其不再困扰当前方案。. Лечение проходят лишь менее 20% пациентов, страдающих туберкулезом с множественной лекарственной устойчивостью (МЛУ), поэтому необходимо срочно расширить охват населения программами по лечению данного заболевания. Одним из основных препятствий по распространению таких программ является применяемая схема лечения, которая слишком продолжительна, сложна, неэффективна, плохо переносится и является дорогостоящей. Впервые за последние 50 лет был разработан новый лекарственный препарат, предназначенный исключительно для лечения туберкулеза. Препараты бедаквилин и, с высокой долей вероятности, деламанид должны скоро стать доступны для проведения лечения в случае заболевания туберкулезом с МЛУ. Тем не менее, если новые лекарственные препараты будут лишь добавлены к текущей схеме лечения, новая схема будет как минимум такой же продолжительной, громоздкой и токсичной, как и применяемая в настоящее время. Необходимо срочно разработать стратегию и практические методы, позволяющие в максимальной мере реализовать потенциал новых препаратов с целью улучшить результаты и сократить время лечения. Мы сформулировали восемь основных принципов для разработки перспективных схем приема лекарственных препаратов, которые, после подтверждения их безопасности с помощью клинических испытаний, будут эффективны как с клинической точки зрения, так и с точки зрения разработки программ лечения на их основе. Схема приема должна включать в себя как минимум один препарат нового класса; должна быть пригодна для широкомасштабного применения против сложных штаммов

Topics: Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Approval; Drug Design; Drug Resistance, Multiple, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Approval; Drug Discovery; Global Health; Humans; Nitroimidazoles; Oxazoles; Research Support as Topic; Tuberculosis

Topics: Acetamides; Antitubercular Agents; Diarylquinolines; Humans; Linezolid; Nitroimidazoles; Oxazoles; Oxazolidinones; Quinolines