Tuberculosis represents one of the biggest challenges in the medical field. According to World Health Organization (WHO) Global Tuberculosis Report, 2012, there were estimated 8.7 million new TB cases worldwide while 1.4 million people died of TB. Additionally, 90% of the cases of TB are reported in developing countries, with India having the largest number of incident cases. The current treatment method includes the administration of a cocktail of drugs which includes Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB) and Pyrazinamide (PZA) which are referred to as the first line of drugs. Isoniazid and Rifampicin are currently the two most powerful anti-TB medications.The occurrences of multi-drug and extensive-drug resistant strains (MDR-TB and XDR-TB, respectively) have become a global concern and pose a serious challenge for public health management. Treatment of these resistant cases involves the usage of the second line of anti-tuberculosis drugs which are less effective than the first line and are known to cause adverse reactions or toxic side-effects. Tuberculosis research should not only focus on treatment methods but also on management of the current cases of resistance and measures to prevent an outbreak of resistant TB infection. This review outlines the mechanism of action of isoniazid and rifampicin and how resistance to these drugs emerges. We also provide a brief insight into the prevalence of HIV in TB patients and the challenges associated with treatment regimens in this co-infection.

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. https://bit.ly/3i43wb6Cite this article as: Antimycobacterial Susceptibility Testing Group. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment. Eur

Background: Considering the potentials of gatifloxacin and moxifloxacin in the treatment of tuberculosis, the present study was aimed to define resistance to both these drugs. Methods: Fifty Mycobacterium tuberculosis isolates, consisting of 30 ofloxacin-susceptible and 20 ofloxacin-resistant strains, were tested for their susceptibility to gatifloxacin and moxifloxacin using different susceptibility testing methods, namely the absolute concentration method on Lowenstein-Jensen medium (LJ), the proportion susceptibility testing method (PST) on LJ and 7H11 agar media, and the BACTEC radiometric method. Result: The minimal inhibitory concentration (MIC) of gatifloxacin and moxifloxacin was 1 µg/ml by the absolute concentration method on LJ. In the PST method on LJ and 7H11, using a criterion of ≧1% growth as resistant, there was 100% agreement with the absolute concentration method at a concentration of 0.5 µg/ml for gatifloxacin, and 96% agreement with the BACTEC method at a concentration of 0.25 µg/ml. For moxifloxacin, results by the PST method showed 96% agreement with the absolute concentration method on LJ at a concentration of 1 µg/ml and 92% agreement at a concentration of 0.5 µg/ml for both the absolute concentration method on 7H11 and the BACTEC method. Conclusions: The MICs of gatifloxacin and moxifloxacin were much lower than the MICs of other quinolones like ofloxacin and ciprofloxacin. Additionally, these two drugs have shown a low mean MIC and low concentration as a definition of resistance, which might help in treating the patients with low levels of quinolone resistance.

No abstract

BackgroundThe resurgence of multi-drug resistant tuberculosis (MDR-TB) and HIV associated tuberculosis (TB) are of serious global concern. To contain this situation, new anti-tuberculosis drugs and reduced treatment regimens are imperative. Recently, a nitroimidazole, PA-824, has been shown to be active against both replicating and non-replicating bacteria. It is activated by the enzyme Deazaflavin-dependent nitroreductase (Ddn) present in Mycobacterium tuberculosis which catalyzes the reduction of PA-824, resulting in the release of lethal reactive nitrogen species (RNS) within the bacteria. In this context, PA-824 was analyzed for its activity against latent tuberculosis under anaerobic conditions and compared with rifampicin (RIF) and pyrazinamide (PZA). Recent mutagenesis studies have identified A76E mutation which affects the above mentioned catalysis and leads to PA-824 resistance. Hence, novel analogues which could cope up with their binding to mutant Ddn receptor were also identified through this study.ResultsPA-824 at an optimum concentration of 12.5 μg/ml showed enhanced bactericidal activity, resulting in 0 CFU/ml growth when compared to RIF and PZA at normal pH and anaerobic condition. Further docking studies revealed that a combinatorial structure of PA-824 conjugated with moxifloxacin (ligand 8) has the highest binding affinity with the wild type and mutant Ddn receptor.ConclusionsPA-824 has been demonstrated to have better activity under anaerobic condition at 12.5 μg/ml, indicating an optimized dose that is required for overcoming the detoxifying mechanisms of M. tuberculosis and inducing its death. Further, the development of resistance through A76E mutation could be overcome through the in silico evolved ligand 8.