New treatment options for multidrug-resistant tuberculosis

Abstract

Despite the development of effective treatments, tuberculosis (TB) remains a major health problem. TB continues to infect new victims and kills nearly 2 million people annually. The problem is much greater in resource-limited countries but is present worldwide. Inadequate public health resources, cost, the obligatory long treatment period, and adverse drug effects contribute to treatment failures and relapses. Drug-resistant Mycobacterium tuberculosis (MTB) strains arise spontaneously and are propagated by inadequate treatment. According to World Health Organization global data, 17% of MTB strains in new, previously untreated cases are resistant to at least one drug. Approximately, 3.3% of new MTB cases are resistant to both isoniazid and rifampin, also called multidrug resistant (MDR), and rates of MDR-TB are greater than 60% in previously treated patients in some countries. Approximately 5% of cases of MDR-TB are also resistant to fluoroquinolones and to injectable drugs, and are called extensively drug resistant (XDR). Recently, XDR strains have been isolated that are also resistant to all standard second-line anti-TB medications. Successful drug treatment of TB with complex resistance profiles is virtually impossible with currently available drugs. There is a desperate need for new compounds that cure strains resistant to currently available drugs and for drugs that are better tolerated and will shorten treatment regimens. In the short term, new strategies for the management of drug-resistant TB with currently available drugs are being explored. These include the use of high-dose isoniazid, substitution of rifabutin in a small proportion of rifampin-resistant cases, linezolid, fluoroquinolones, and phenothiazines. A number of novel drugs are undergoing clinical testing and will hopefully be available in the near future. These include the newer oxazolidinones, diarylquinolines, nitroimidazopyrans, ethenylenediamines, pyrroles, and benzothiazinones.

Tuberculosis: From an Untreatable Disease in Antiquity to an Untreatable Disease in Modern Times?

“…Some of these newer compounds include oxazolidinones, nitroimidazopyrans, diarylquinolones, pyrrols, ethenylenediamines, ethylenediamides, and benzothiaziones. [88][89][90]. Linezolid, a broad spectrum antibiotic that inhibits protein synthesis by interfering with mRNA binding to the ribosome is currently in phase II trials for the treatment of MDR-TB [87,88].…”

“…[88][89][90]. Linezolid, a broad spectrum antibiotic that inhibits protein synthesis by interfering with mRNA binding to the ribosome is currently in phase II trials for the treatment of MDR-TB [87,88]. Although no large clinical trials have been conducted to date, several small studies indicated that treatment regimens that include Linezolid can be used to successfully treat infections due to MDR-TB [88].…”

“…Sutezolid (PNU100480) and AZD5847 are other, newer oxazolidinones that are also in phase II studies [87]. Some preliminary evidence suggests that these drugs may have a better bioavailability and may be better tolerated by patients [88]. In addition, the two fluoroquinolones moxifloxacin and gatifloxacin are currently in phase III clinical trials [87].…”

“…Limited but promising data are available for diarylquinolones. These drugs reduce adenosine triphosphate (ATP) levels by selectively inhibiting the mycobacterial ATP synthase [87][88][89]. However, they do have little to no effect on other bacteria or eukaryotes.…”

Examples of bedaquiline introduction for the management of multidrug-resistant tuberculosis in five countries

“…3 This is the first time in the modern history of TB control that new drugs have been developed and approved for the treatment of MDR-TB, and the first time that national and international TB stakeholders have tried to introduce new drugs in a programmatic way. 4 Uptake of these drugs as part of MDR-TB treatment, however, has not kept pace with the need for these drugs, even in settings where resistance or intolerance to second-line drugs is common or where treatment outcomes are poor. 5 Multiple early barriers to programmatic introduction of new drugs have been identified, including lack of technical expertise and guidance, confusion about pharmacovigilance requirements, challenges with registration and import, and difficulties in obtaining the other medications needed for successful treatment outcomes.…”