Treatment of multidrug-resistant and extensively drug-resistant tuberculosis: current status and future prospects

Drug resistance in Mycobacterium tuberculosis arises from the man-made selection of mutants that result from spontaneous chromosomal alterations. Preventing the development of drug-resistant TB through a good control program based on directly observed treatment, short-course, is of paramount importance. Established multidrug-resistant (MDR)-TB requires alternative specific chemotherapy, comprising drugs with higher cost and greater toxicity delivered on a programmatic basis. The development of new anti-TB drugs would help to prevent and treat MDR-TB. Notably, moxifloxacin and gatifloxacin are being tested for shortening treatment in Phase III trials, while three novel compounds, TMC-207, OPC-67683 and PA-824 are in Phase II studies for both drug-susceptible and drug-resistant disease. The roles of surgery and immunotherapy in the management of MDR-TB require further evaluation. The recent emergence of extensively drug-resistant TB poses a serious challenge to the global control of TB. In order to combat extensively drug-resistant TB, strengthening of directly observed treatment, short-course and drug-resistance programs, alongside other strategies, including the development of newer diagnostics and drugs, is mandatory.     

抗结核药物最新进展

结核病是病死率仅次于艾滋病的全球第二大感染性疾病。当前结核病的控制面临一系列挑战。世界卫生组织推荐的结核治疗方案疗程长,对敏感菌和耐药菌感染分别需6个月、20个月的持续治疗。现有抗结核一线化疗药仍为四十多年前所开发,品种有限,选择余地小。此外,多耐药结核病(MDR-TB)及广泛耐药结核病(XDR-TB)的流行,严重阻碍了结核病控制的进展。严峻的结核病防治形势急需抗结核新药的出现。近十年来,抗结核化疗新药研发在沉寂多年后取得了较明显进展。本文介绍了近年上市与处于临床及临床前研究阶段的抗结核新药。     

Synthetic investigational new drugs for the treatment of tuberculosis

Introduction: Tuberculosis (TB) is a major global health concern. And while there are treatments already on the market, there is a demand for new drugs that are effective and safe against Mycobacterium tuberculosis, which reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multidrug-resistant TB (MDR-TB).

Area covered: This review covers promising novel investigational TB drugs that are currently under development. Specifically, the authors review the efficacy of novel agents for the treatment of TB in preclinical, phase I and phase II clinical trials. The authors also review the safety and tolerability profiles of these drugs.

Expert opinion: Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB in combination with moxifloxacin and pyrazinamide. Linezolid shows marked efficacy in the treatment of MDR-TB and extensively drug-resistant TB (XDR-TB), but the drug is known to cause significant adverse drug reactions, including peripheral neuropathy, optic neuropathy and myelosuppression. These adverse reactions must be considered prior to prescribing long-term usage of this drug.     

Drug-resistant tuberculosis in Ethiopia: problem scenarios and recommendation

Tuberculosis (TB) is a major public health problem in Ethiopia. This review is prepared to indicate possible future challenges related to tuberculosis control and it includes previous reports of drug-resistant surveys in Ethiopia. Drug-resistant TB, both initial and acquired, was reported from different regions of the country. In studies from 1984 to 2001, the initial resistance to isoniazid ranges from 2% to 21% and initial resistance to streptomycin ranges from 2 to 20%. Multidrug-resistance (MDR) TB defined as resistance to at least isoniazid and rifampicin was also reported in about 1.2% of new cases and 12% of re-treatment cases. In all studies which included ethambutol susceptibility test, ethambutol resistance is either nil or very low (below 0.5%). All MDR isolates were susceptible to ethambutol. Treatment and re-treatment regimens recommended by the National TB/Leprosy Control Program could be effective on all cases other than those with MDR-TB. MDR-TB is difficult to cure. Therefore, special emphasis should be given to control the spread of MDR-TB. Lack of control efforts may lead to the increased resistance to both first- and second-line drugs. A well supported and controlled special treatment unit, which uses both first-line and second-line drugs is required for a proper management of these cases and for effective control of the spread of MDR-TB. A uniform susceptibility to ethambutol can be taken as an advantage to develop standard low-cost re-treatment regimen for MDR-TB patients.     

Problems of multidrug- and extensively drug-resistant TB

Worldwide, it is thought that in 2010 around 9 million people developed tuberculosis (TB) and around 1.5 million people died from the disease. Standard therapy (6 months of rifampicin and isoniazid, plus pyrazinamide and ethambutol for the first 2 months) is recommended for newly diagnosed active respiratory TB and is effective if taken correctly. However, its effectiveness can be compromised by a number of factors including poor adherence (e.g. because of the long duration of treatment, occurrence of unwanted effects) or inadequate drug levels for other reasons (e.g. drug-drug interactions, poor quality medicines). These factors also contribute to the development of resistance to one or more of the drugs. Multidrug resistant TB (MDR-TB) is defined as TB with resistance to both rifampicin and isoniazid. Patients with MDR-TB are treated with a combination of first-line and second-line drugs based on the results of drug susceptibility testing. The treatment is longer, less effective, less tolerable, and more expensive than standard therapy, and involves the use of injectable drugs. Extensively drug-resistant TB (XDR-TB; defined as TB with resistance to rifampicin and isoniazid, and to at least one fluoroquinolone and one second-line injectable agent such as amikacin or capreomycin) is now emerging. Here we highlight patient groups at increased risk of MDR- and XDR-TB, and discuss how to investigate, manage and treat them.     

抗结核一线药物及结核分枝杆菌的耐药分子机制

近年来涌现出了耐多药结核病(Multidrug-resistanttuberculosis,MDR-TB)/广泛耐药结核病(Extensively drug-resistant tuberculosis,XDR-TB)。MDR-TB是指由耐异烟肼和利福平两种或以上抗结核药物的结核分枝杆菌引起的结核病。XDR-TB是指不...     

Stereochemistry at the forefront in the design and discovery of novel anti-tuberculosis agents

Today, 75% of new drugs introduced to the market are single enantiomers and new techniques in asymmetric synthesis and chiral separation expedites chiral drug discovery and development worldwide. The enantiomers of a chiral drug present unique chemical and pharmacological behaviors in a chiral environment, such as the human body, in which the stereochemistry of chiral drugs determines their pharmacokinetic, pharmacodynamic, and toxicological actions. Thus, it is imperative that only the pure and therapeutically active isomer be prepared and marketed. Tuberculosis (TB), a highly contagious and airborne disease that is caused by infection with Mycobacterium tuberculosis (Mtb), currently represents one of the most threatening health problems globally. The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), as well as HIV co-infection along with a lengthy treatment regimen, highlights an urgent need for the development of new anti-TB agents. Currently, new chiral anti-TB agents are being developed from some well-known anti-TB agents, high throughput screening (HTS) hits, and natural products. This review will focus on the reported chiral anti-TB agents together with the clinical importance of their chirality and stereochemistry.     

Drug-resistant tuberculosis: an insurmountable epidemic?

Drug-resistant tuberculosis has brought back the spectre of pre-antibiotic days. WHO surveillance data from 2007 showed multi-drug-resistant tuberculosis (MDR-TB)—tubercle bacillus resistant to both isoniazid and rifampicin accounting for 4.8% of all new and subsequent cases of tuberculosis. India and China—the two most populated countries of the world, house the maximum number of drug-resistant tuberculosis cases. In eastern European and central Asian countries, more than 6% of new TB cases are MDR-TB, whereas the number is <3% in the countries of the western world. Extensively drug-resistant tuberculosis (XDR-TB) has emerged with the prospect of tuberculosis becoming an incurable disease. A surveillance spreading over the six continents showed 10% of MDR-TB cases were also XDR-TB. The fact that tuberculosis is the most common opportunistic infection among HIV-infected patients in developing countries makes the challenge almost insurmountable. The mortality of HIV and MDR-TB co-infected patients is exceedingly high. The absence of guidelines for treatment of drug-resistant tuberculosis and of infrastructure for delivery of DOT program and rapid laboratory diagnostic facilities, including drug susceptibility testing for both first and second-line drugs, and lack of trained human resource in most of the developing world account for the emergence and perpetuation of this menacing problem. WHO along with partnership with Green Light Committee and individual national governments has started DOT plus program to control this global epidemic.     

Novel insights into the pharmacometabonomics of first-line tuberculosis drugs relating to metabolism,mechanism of action and drug-resistance

Abstract

The World Health Organization recommends the directly observed therapy short-course (DOTS) regimen, a combination of four first-line antibiotics (isoniazid, rifampicin, pyrazinamide and ethambutol), for the treatment of active pulmonary tuberculosis (TB). However, despite the fact that this treatment regimen is commonly used worldwide, the metabolism and anti-bacterial mechanisms of these drugs are not yet fully understood. This lack of information ultimately contributes to the poor patient compliance and the subsequent treatment failure and post treatment relapse seen in some TB patients. Pharmacometabonomics, the latest addition to the omics research domain, focuses on the identification of drug-induced metabolome variations. The observed metabolite changes can be used to better understand drug metabolism, drug action and drug-resistance mechanisms. In this review, we summarize the generally known biological mechanisms of the first-line TB drugs included in the DOTS program, and we additionally elaborate on the contribution that pharmacometabonomics has made to the expansion of this knowledge.     

Managing multiple and extensively drug-resistant tuberculosis and HIV

Global increases in multi-drug-resistant and extensively drug-resistant tuberculosis (TB), are threatening both TB and HIV treatment programs worldwide. Together, they raise concerns of a global epidemic of untreatable TB. In the developing world, the directly observed treatment, short course (DOTS) strategy is proving ineffective as available resources are being outstripped by the large number of patients needing treatment. Thus, TB treatment and outcomes are sub-optimal, and multi-drug resistant and extensively drug-resistant TB are on the rise.     

Managing multiple and extensively drug-resistant tuberculosis and HIV

Global increases in multi-drug-resistant and extensively drug-resistant tuberculosis (TB), are threatening both TB and HIV treatment programs worldwide. Together, they raise concerns of a global epidemic of untreatable TB. In the developing world, the directly observed treatment, short course (DOTS) strategy is proving ineffective as available resources are being outstripped by the large number of patients needing treatment. Thus, TB treatment and outcomes are sub-optimal, and multi-drug resistant and extensively drug-resistant TB are on the rise.     

Nanocarrier-based interventions for the management of MDR/XDR-TB

Emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB over the past decade presents an unprecedented public health challenge to which countries of concern are responding far too slowly. Global Tuberculosis Report 2014 marks the 20th anniversary of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance, indicating the highest global level of drug-resistance ever recorded detection of 97?000 patients with MDR-TB resulting in 170?000 deaths in 2013. Treatment of MDR-TB is expensive, complex, prolonged (18–24 months) and associated with a higher incidence of adverse events. In this context, nanocarrier delivery systems (NDSs) efficiently encapsulating considerable amounts of second-line anti tubercular drugs (^sATDs), eliciting controlled, sustained and more profound effect to trounce the need to administer ^sATDs at high and frequent doses, would assist in improving patient compliance and avoid hepatotoxicity and/or nephrotoxicity/ocular toxicity/ototoxicity associated with the prevalent ^sATDs. Besides, NDSs are also known to inhibit the P-glycoprotein efflux, reduce metabolism by gut cytochrome P-450 enzymes and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review first provides a holistic account on MDR-TB and discusses the molecular basis of Mycobacterium tuberculosis resistance to anti-tubercular drugs. It also provides an updated bird’s eye view on current treatment strategies and laboratory diagnostic test for MDR-TB. Furthermore, a relatively pithy view on patent studies on second-line chemotherapy using NDSs will be discussed.     

Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms

One-third of the world's population is infected with Mycobacterium (M.) tuberculosis. Tuberculosis continues to be the most common infectious cause of death and still has a serious impact, medically, socially and financially. Multidrug-resistant tuberculosis (MDR-TB), caused by tubercle bacilli that are resistant to at least isoniazid and rifampin, is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients for whom treatment has failed have a high risk of death. Drugs used to treat tuberculosis are classified into first-line and second-line agents. First-line essential anti-tuberculosis agents are the most effective, and are a necessary component of any short-course therapeutic regimen. The drugs in this category are isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit severe reactions much more frequently. These drugs include para-aminosalicylic acid (PAS), ethionamide, cycloserine, amikacin and capreomycin. New drugs, which are yet to be assigned to the above categories, include rifapentine, levofloxacin, gatifloxacin and moxifloxacin. Recently there has been much development in the molecular pharmacology of anti-tuberculosis drugs. This review summarizes information for isoniazid, rifampicin, ethambutol, pyrazinamide, and fluoroquinolones, and describes their resistance mechanisms.     

Fixed dose combinations for tuberculosis: Lessons learned from clinical, formulation and regulatory perspective

Worldwide, tuberculosis (TB) remains one of the most important communicable diseases in terms of morbidity and mortality. Its control requires multi-drug therapy for at least six months, which could lead to patient non-compliance, failure of therapy and ultimately resulting in the emergence of drug resistance. Fixed dose combinations (FDCs) in TB therapy reduce the number of tablets to be consumed and thereby increase patient compliance with recommended treatment regimens. Thus, FDCs play a significant role in preventing the emergence of drug resistance and successful treatment. However, the quality of FDCs with respect to variable bioavailability and their registration requirements are major hurdles to their implementation in national TB control programs. It is anticipated that a large global market for FDCs will encourage large-scale production and increased competition, which in turn will result in FDCs at affordable prices. The Global Drug Facility (GDF), established by the World Health Organization (WHO), aims to ensure universal uninterrupted access to quality TB drugs for implementation of directly observed treatment short-course (DOTS) in resource-poor countries. In this program, four FDCs were accepted as the drugs of first choice because of their obvious advantages in controlling TB. This demands the necessity of addressing quality and registration requirements of FDCs systematically. In light of this current knowledge on anti-TB FDCs, their dosage, combinations, available clinical studies and the experiences with TB therapy has been discussed in this article, which should serve as lessons for selection of appropriate FDCs for other diseases such as malaria and AIDS.     

Pediatric drug-resistant tuberculosis: a global perspective: a global perspective

This article was based on a presentation given at the 26th International Pediatric Association Conference of Pediatrics, Johannesburg, South Africa, 4-9 August 2010. In 2009, there were 9.4?million new cases of tuberculosis (TB) globally, and, of these, approximately 1?million were pediatric cases. Drug-resistant TB makes up a relatively small proportion of new TB cases, but is much more likely in previously treated cases. Pediatric TB remains difficult to diagnose microbiologically, with the result that detection of drug-resistant TB in children is an ongoing challenge. Since children diagnosed with TB predominantly represent recently acquired TB infection, they provide an important indication of drug-resistant TB prevalence and transmission within their communities. Drug-resistant TB is essentially a man-made problem, which consumes large amounts of healthcare resources. Recent technologic advances may pave the way to more rapid and accurate diagnosis of TB in children. Similarly, these advances are likely to result in improved detection of drug-resistant pediatric TB isolates. The treatment of pediatric drug-resistant TB requires prolonged courses of expensive and potentially toxic drugs, many of which are not available in child-friendly formulations. New anti-TB drugs are at various stages of pre-clinical development and will hopefully allow for shorter, more effective treatment regimens in the not too distant future. HIV-infected children are at extremely high risk for TB acquisition and subsequent progression to symptomatic disease; therefore, many cases of pediatric drug-resistant TB occur in HIV-infected children. This often results in complicated pharmacologic regimens (including anti-TB and antiretroviral drugs) that are difficult to comply with and may have unpredictable interactions. There are limited reports of long-term clinical outcomes of children diagnosed with drug-resistant TB, but improvements in the diagnosis and pharmacologic management of these cases have the potential to improve the quality of care offered to these children.     

空洞型耐多药肺结核患者耐药性分析及治疗方案探索

目的探讨耐多药肺结核患者耐药性产生原因及治疗方法。方法对2012年10月～2013年10月间，本院收治的68例空洞型耐多药肺结核患者耐药性进行分析，并探讨治疗方法。结果本次调研发现，患者治疗依从性差，是导致多重耐药肺结核的因素，其次，治疗方法的不合理同样导致患者感染，因此针对患者采用个性化的治疗是治疗耐多药肺结核患者的重要手段，本次实验中，观察组患者使用个性化的耐药菌敏感药物进行治疗，治疗效果优于对照组（χ^2=4．239，P=0．036〈0．05）。结论导致患者耐多药感染的主要因素是由于治疗依从性差及治疗方案的不合理，因此对患者进行教育和心理疏导以及个体化全面治疗，有助于耐多药肺结核治疗。     

Selective drug deposition in lungs through pulmonary drug delivery system for effective management of drug-resistant TB

Introduction: The emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is a major health issue and continues to be a global health concern. Despite significant advancements in treatment modalities, ~1.6 million deaths worldwide occur due to TB infection. This is because of tuberculosis reservoirs in the alveoli making it a challenge for the formulation scientist to target this.

Area covered: This review recent investigations on the forefront of pulmonary drug delivery for managing MDR-TB and XDR-TB. Novel delivery systems like liposomes, niosomes, employing carbohydrate, and -coated molecules via conjugation to selectively deliver the drugs to the lung TB reservoir via pulmonary administration are discussed.

Expert opinion: Poor patient adherence to treatment due to side effects and extended therapeutic regimen leads to drug-resistant TB. Thus, it is essential to design novel strategies this issue by developing new chemical entities and/or new delivery systems for delivery to the lungs, consequently reducing the side effects, the frequency and the duration of treatment. Delivery of drugs to enhance the efficacy of new/existing anti-TB drugs to overcome the resistance and enhance patient compliance is underway.     

Resistant TB: Newer Drugs and Community Approach

Drug resistance in tuberculosis (TB) is a serious problem compromising both the treatment and control programs. Poor usage of the available anti TB drugs has led to progressive drug resistance-multi drug resistance (MDR), extensively drug-resistance (XDR) and even total drug resistance (TDR). While drug sensitive TB is completely curable, MDR-TB is difficult to treat, XDR and TDR are often fatal. Non availability of new drugs to treat drug resistant cases further complicates the problem. The Global Alliance for Tuberculosis Drug Developments, a non-profit organization with the World Health Organization (WHO) as a partner was formed in February 2000 for the development of new drugs. In the last decade this venture has resulted in several promising new antituberculosis drugs like TMC207 (diaryquinoline), PA-824 (nitroimidazo-oxazine), OPC-67683 (nitroimidazo-oxazole) and SQ 109 (diamine compound). Drug resistance in TB is a man made problem. Therefore, while global efforts towards new drug development must continue it is equally important to have a well defined community approach to prevent the emergence of drug resistance to the existing and newer drugs. The present review article discusses some recent drug patents for the treatment of tuberculosis and the appropriate community approach to prevent and treat drug resistant TB.     

Drug-resistant tuberculosis in the WHO European Region: An analysis of surveillance data

To review the latest information about levels of anti-tuberculosis (TB) drug resistance in the European Region of the World Health Organization (WHO) and time-trends in multidrug-resistant TB (resistance to isoniazid and rifampicin; MDR-TB) over the past fifteen years.We analysed data on drug resistance among new and previously treated TB cases reported from 1997 to 2012. Data are collected in surveys of representative samples of TB patients or from surveillance systems based on diagnostic drug susceptibility testing.A total of 15.7% (95% confidence limits (CI): 9.5–21.9) of new and 45.3% (95%CI: 39.2–51.5) of previously treated TB cases are estimated to have MDR-TB in the Region. Extensively drug-resistant TB (MDR-TB and resistance to fluoroquinolones and second-line injectables; XDR-TB) had been reported by 38 of the 53 countries of the region (72%). The proportion of MDR-TB cases with XDR-TB is 11.4% (95%CI: 8.6–14.2). Between 1997 and 2012, population rates of MDR-TB declined in Estonia, Latvia and Germany and increased in the United Kingdom, Sweden and Tomsk Oblasts of the Russian Federation.Surveillance of drug resistance has been strengthened in the WHO European Region, which has the highest proportions of MDR-TB and XDR-TB ever reported globally. More complete data are needed particularly from the Russian Federation.