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18:341. Wkly. 38:563. doi: 10.1016/S0140-6736(06)69573-1. 15, 949954. Lab. Risk Manag. doi: 10.1016/j.rmed.2015.01.017, Dooley, K. E., Rosenkranz, S. L., Conradie, F., Moran, L., Hafner, R., von Groote-Bidlingmaier, F., et al. Preclinical results have signified that DLM is effective against growing or dormant bacilli, both in vitro and in vivo. 34, 12391243. Delamanid (DLM) is a prodrug that confers mycobactericidal activity by inhibiting the synthesis of methoxy and keto MA through the mycobacteria F420 system and generating nitrous oxide (Singh et al., 2008; Vilchze, 2020). 12 Mechanism of action For 24 patients (aged 019 years) with fluoroquinolone (FQ)-resistant TB, a treatment regimen, including DLM and BDQ in combination and separately, was utilized between September 2014 and June 2018. (2021). Crit. Top. PA-824 kills nonreplicating mycobacterium tuberculosis by intracellular NO release. Whole-genome sequencing-based analyses of drug-resistant Mycobacterium tuberculosis from Taiwan. J. Infect. A., Zignol, M., Nahid, P., et al. 9:677. doi: 10.2147/dddt.s60923, Tadolini, M., Garcia-Prats, A. J., DAmbrosio, L., Hewison, C., Centis, R., Schaaf, H. S., et al. Advances in clinical trial design: weaving tomorrows TB treatments. This finding emphasizes DLM as a treatment option for MDR-TB (Gler et al., 2012). 2023 Mar 9;19(3):e11099. Chemother. In this review, we address the antimycobacterial properties of DLM, report the global prevalence of DLM resistance, discuss the synergism of DLM with other anti-TB drugs, and evaluate the documented clinical trials to provide new insights into the clinical use of this antibiotic. Res. Disclaimer. Patterson, S., Wyllie, S., Norval, S., Stojanovski, L., Simeons, F. R., Auer, J. L., et al. The prompt development of resistance to DLM highlights the necessity for the optimal employment of new drugs, stringent stewardship for drug resistance surveillance, and thorough awareness of drug resistance mechanisms. M. bovis is a member of MTBC cultured under aerobic and anaerobic conditions to evaluate its killing capability in growing and dormant phenotypes. Unauthorized use of these marks is strictly prohibited. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. Chen, X., Hashizume, H., Tomishige, T., Nakamura, I., Matsuba, M., Fujiwara, M., et al. doi: 10.1016/j.jgar.2019.06.013, Chang, K. C., and Sotgiu, G. (2017). In patients with QTcF > 500 ms, DLM treatment either should not be initiated or should be interrupted. time elapsed since the thrombic crisis began these drugs are most effective within 6 hours of onset of symptoms. Delamanid is accumulated in the cell and has pharmacological potential activity against the replicating, dormant, and intra- and extracellular bacilli (Chen et al., 2017). Curr. Thus, any mutations in this pathway result in the reduction of Mycobacterium bacilli to metabolize prodrug and low- to high-level DLM resistance. Unable to load your collection due to an error, Unable to load your delegates due to an error. Because of QTc-prolonging effects on several second-line MDR-TB drugs, including FQs, co-administration of clofazimine and BDQ with DLM increases the concerns about cardiac arrhythmias (Matsumoto et al., 2006). Whole genome sequencing results associated with minimum inhibitory concentrations of 14 anti-tuberculosis drugs among rifampicin-resistant isolates of mycobacterium tuberculosis from Iran. Epidemiology of delamanid resistance. Respir. Based on the fractional inhibitory concentration index (FICI), the aforesaid drugs are classified as synergistic or partially synergistic for tested strains (Matsumoto et al., 2006). 4. doi: 10.7759/cureus.35154. doi: 10.1016/j.tube.2018.04.008. Pieterman, E. D., Keutzer, L., van der Meijden, A., van den Berg, S., Wang, H., Zimmerman, M. D., et al. In vitro drug susceptibility of bedaquiline, delamanid, linezolid, clofazimine, moxifloxacin, and gatifloxacin against extensively drug-resistant tuberculosis in Beijing, China. It was inserted into the anti-TB regime in the 50's which remains to Combination therapy with DLM and other active anti-TB agents is suggested for the prevention of acquired resistance (Diel et al., 2015). Respir. After temporary discontinuation of treatment and the management of electrolyte imbalance and vomiting, the therapy was re-established (Tadolini et al., 2016). This study is focused on the action of a mycobacterial efflux pump as a mechanism of drug resistance. Tuberculosis 108, 186194. Although tuberculosis (TB) is preventable and curable, the lengthy treatment (generally 6 months), poor patient adherence, high inter-individual variability in pharmacokinetics (PK), emergence of drug resistance, presence of comorbidities, and adverse drug reactions complicate TB therapy and drive the need for new drugs and/or regimens. However, the metabolic pathway of DLM appeals for further investigation to fully be elucidated (Oye et al., 2013; Lewis and Sloan, 2015). The new anti-TB drug, DLM, is used to treat MDR- and XDR-TB. doi: 10.1016/j.yrtph.2016.12.002, Hartkoorn, R. C., Ryabova, O. Int. (2020). In a multicenter study conducted from 2010 to 2019 in Korea, 633 patients with MDR-TB were analyzed. 7, 499507. Multidrug and Extensively Drug-resistant TB (M/XDR-TB) WHO/HTM/TB/2010.3; Geneva, Switzerland: 2010. 366, 21512160. J. Respir. Mortal. 80, 98105. Thirty (58.8%) patients developed side effects, the most common of which were gastrointestinal and hematological disorders and QTc prolongation. The mechanism of activation has not yet been clearly understood as the binding interaction has not been appropriately established . doi: 10.1183/13993003.01420-2016. Khoshnood, S., Goudarzi, M., Taki, E., Darbandi, A., Kouhsari, E., Heidary, M., et al. This was an observational study to define the mechanism of adverse drug reactions in combination anti-tuberculosis therapy defined by the Revised National Tuberculosis Control Program. Infect. 63:e00665. Mok, J., Kang, H., Hwang, S. H., Park, J. S., Kang, B., Lee, T., et al. The results showed that the coadministration of DLM with other anti-TB antibiotics has no clinically significant interactions (Mallikaarjun et al., 2016). 24, 12651271. Final treatment outcomes of delamanid-containing regimens in patients with MDR-/XDR-TB in South Korea. (2019). Lineage-specific proteomic signatures in the mycobacterium tuberculosis complex reveal differential abundance of proteins involved in virulence, DNA repair, CRISPR-Cas, bioenergetics and lipid metabolism. (2017). It was recommended that before the beginning and throughout the period of treatment with DLM, frequent monitoring of electrocardiograms is essential. This result is the first evidence showing that DLM is a potential agent for the treatment of diseases caused by M. avium and M. intracellulare (Krieger et al., 2016). disclosed that mutations in each of these five genes led to the low metabolizing potency of M. bovis BCG Tokyo and MTB H37Rv mutants in vitro. The results of electrocardiograms showed that the median QTc change from baseline was 8.6 ms (DLM), 12.3 ms (BDQ), and 20.7 ms (DLM + BDQ). 63:e00031. Sasahara, K., Shimokawa, Y., Hirao, Y., Koyama, N., Kitano, K., Shibata, M., et al. J. World Health Organization. Migliori, G. B., Pontali, E., Sotgiu, G., Centis, R., DAmbrosio, L., Tiberi, S., et al. 25, 4859. Das, M., Dalal, A., Laxmeshwar, C., Ravi, S., Mamnoon, F., Meneguim, A. C., et al. Microorganisms. 21, 975983. 71, 15321539. (2019). DLM is able to substantially inhibit the biosynthesis of cell wall during the disruption of the MA biosynthesis pathway, eventually giving rise to the elimination of MTB (Rustomjee and Zumla, 2015). In a study conducted by Pieterman et al. In vitro evidence revealed that clinically relevant interactions of DLM with drugs, particularly those whose disposition is dependent on ATP-binding cassette (ABC) and solute carrier transporters, breast cancer-resistant proteins (BCRP/ABCG2), organic anion-transporting polypeptides, or organic cation transporter 1, are impossible (Hu et al., 2016). An important quality for an antimicrobial drug is selective toxicity, meaning that it selectively kills or inhibits the growth of microbial targets while causing . Int. Int. Overall, the outcomes of that investigation recognized DLM as a promising treatment options for MDR-TB (Gler et al., 2012). doi: 10.1371/journal.pmed.1002873. 6:ofz118. 48, 18031804. However, evidence on the safety and efficacy of DLM treatment in children is limited. doi: 10.1093/jac/dkx373, Mok, J., Kang, H., Koh, W.-J., Jhun, B. W., Yim, J.-J., Kwak, N., et al. Cell. PLoS Med. Substrate specificity of the deazaflavindependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. Accessibility However, no clinical symptoms, such as arrhythmias or syncope, were observed in patients with the episodes of QT interval prolongation (Gler et al., 2012). Using fresh human hepatocytes and human liver microsomes, in vitro investigations studied the effect of DLM on human cytochrome p450 enzymes. doi: 10.15252/msb.202211099. J. Glob. Thus, there is an urgent need for identification and development of novel TB drugs and drug regimens with comprehensive and specific mechanisms of action. Apart from many beneficial impacts of DLM on MDR- and XDR-TB, the side effects of its use have been reported in some patients. Pulmonology 27, 403412. 12:717045. doi: 10.3389/fmicb.2021.717045. Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: results from a large global cohort. Gler and colleagues reported the results of the phase II trial (trial 204) on 481 patients infected with pulmonary MDR-TB. A regimen containing bedaquiline and delamanid compared to bedaquiline in patients with drug-resistant tuberculosis. A brief outline of the mechanism of action and adverse effects of anti tubercular drugs Only First line and second line drugs are dealt with.First line drugs may be useful for MBBS students and the rest is directed for postgraduate students. The use of validated and nonvalidated surrogate endpoints in two european medicines agency expedited approval pathways: a cross-sectional study of products authorised 20112018. Enoyl-acyl carrier protein reductase, InhA, is a specific factor for the function of INH, while DLM needs mycobacterial F420 system for its activation (Parikh et al., 2000; Deane and Porkess, 2018). In combination regimens, varied absorption profiles between drugs may make coadministration complicated. BMC Infect. Eur. doi: 10.1016/j.tube.2017.12.006. 65:e01948. Agents Chemother. Ann. J. Antimicrob. Their results confirmed that the combination regimen is more effective than the standard regimen. World Health Organization. This reductive behavior could be the main reason that the coadministration of DLM with the mentioned CYP enzyme inducers was contraindicated by the European Medicines Agency. Clinical benefit of delamanid (OPC-67683) in the treatment of multidrug-resistant tuberculosis patients in China. Chem. sharing sensitive information, make sure youre on a federal Blair, H. A., and Scott, L. J. Koirala, S., Borisov, S., Danila, E., Mariandyshev, A., Shrestha, B., Lukhele, N., et al. Among 19 enrolled patients, a 17-year-old patient with XDR-TB had experienced renal impairment, severe vomiting, and severe electrolyte disorders, and subsequently QTcF prolongation. Adverse events among people on delamanid for rifampicin-resistant tuberculosis in a high HIV prevalence setting. The F420-dependent nitroreductase coded by ddn gene activates F420. Resist. Schena, E., Nedialkova, L., Borroni, E., Battaglia, S., Cabibbe, A. M., Niemann, S., et al. evaluated DLM susceptibility testing of 194 MTB strains recovered from patients. 27:jiab043. Discovery of delamanid for the treatment of multidrug-resistant pulmonary tuberculosis. Zheng, H., He, W., Jiao, W., Xia, H., Sun, L., Wang, S., et al. 109, 632641. In this respect, in vitro synergy assays have suggested strong synergistic interaction between -lactams (cephradine and faropenem) and DLM (FICI of 0.5) for MDR- and XDR-TB, which might possibly be effectual in reducing treatment length. 9:465. doi: 10.3390/jcm9020465. Delamanid for multidrug-resistant pulmonary tuberculosis. seven products for tuberculosis (TB) and nine for C. difficile infections (seven antibiotics and two biologicals) (Fig. -. 49:1700387. Yu, X., Gao, X., Li, C., Luo, J., Wen, S., Zhang, T., et al. doi: 10.1007/s40265-014-0331-4, Bloemberg, G. V., Gagneux, S., and Bttger, E. C. (2015). In another phase 2 RCT, Zhang et al. retrospectively reviewed 49 patients who received DLM and had final treatment outcomes after 24 weeks. Respir. The spontaneous frequency of DLM resistance has been reported as 6.44 106 to 4.19 105, highlighting the importance of this drug in combination with other active anti-TB drugs during therapy (Szumowski and Lynch, 2015). doi: 10.1371/journal.pmed.0030466, Matsumoto, M., Hashizume, H., Tsubouchi, H., Sasaki, H., Itotani, M., Kuroda, H., et al. The aforementioned highlights the urgent need for . The results revealed that the combination group possessed high prolongation of the QTcF (> 60 ms from baseline or >450 ms during treatment), but the long-term safety was greater for the combination than for the single-drug regimen (Olayanju et al., 2020). Figure 1. The complete oral bioavailability of DLM has not yet been measured; however, it seems to be between 25 and 47%. doi: 10.1021/jm060957y. 2020 Jun;128(6):1547-1567. doi: 10.1111/jam.14478. Tuberculosis 109, 1727. doi: 10.1128/mmbr.00070-15, Gurumurthy, M., Mukherjee, T., Dowd, C. S., Singh, R., Niyomrattanakit, P., Tay, J. Among the patients treated with BDQ, but not DLM, 284 (74.2%) achieved treatment success. 84, 18. Mallikaarjun et al. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR-and XDR-TB: a multicentre study. The https:// ensures that you are connecting to the There is an abundant room for future progress in determining the particular characteristics of pharmacokinetics and drug safety of new regimen, including DLM, for vulnerable populations such as pregnant women, children, and patients with HIV (Lienhardt et al., 2020). QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial. The .gov means its official. Antimicrob. This system is the analog of flavin mononucleotide complex and composed of two enzymes, deazaflavin-dependent nitroreductase (Ddn, Rv3547) and F420-dependent glucose-6-phosphate dehydrogenase (G6PD; FGD1, Rv0407), as well as four coenzymes, FbiA (Rv3361), FbiB (Rv3261), FbiC (Rv1173), and Rv0132c (Bashiri et al., 2010; Hartkoorn et al., 2014). The finding of an in vitro drug susceptibility assessment of 90 clinical XDR MTB isolates in China indicated that four (4.4%) isolates increased MIC for DLM, and codon 318 mutation of fbiC gene was recognized as a novel mutation contributed to DLM resistance. Although the full metabolic profile of DLM is unknown, this drug is seemingly converted to its primary metabolite, DM-6705, following the reaction of amino groups in serum albumin to this agent. The patients received DLM at a dose of 100 mg twice daily for 6 months and BDQ at a dose of 400 mg daily for 2 weeks, followed by 200 mg three times weekly for 5.5 months. J. Tuberc. In another evaluation of the in vitro activity of DLM accomplished by Jing et al. 8:114. doi: 10.3389/fcimb.2018.00114, Hanaki, E., Hayashi, M., and Matsumoto, M. (2017). doi: 10.1007/s10096-019-03551-w, Kadura, S., King, N., Nakhoul, M., Zhu, H., Theron, G., Kser, C. U., et al. Epub 2023 Jan 27. Int. have confirmed the highly variable antimicrobial activity of DLM against NTM and reported that DLM has a high MIC against slowly growing Mycobacterium species of NTM, i.e., M. avium and M. kansasii (Yu et al., 2019). Sci. J. 10:2278. doi: 10.3390/app10072278. FbiC encodes a F420-0 synthase that catalyzes the formation of the F420 precursor F420-0 (Fujiwara et al., 2018; Rifat et al., 2020). Curr. Modification of existing anti-TB drugs is an economical and simple route to the development of new anti-TB drugs. doi: 10.5588/ijtld.17.0706. 2023 Feb 18;15(2):e35154. Dis. Molecular targets related drug resistance mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis strains. In healthy volunteers, an interaction was observed between DLM and the strong CYP3A4 enzyme inducer, RIF, which diminished exposure to DLM by 47%. 11:550760. doi: 10.3389/fmicb.2020.550760. B. Moreover, the synergism of DLM in combination with BDQ can ameliorate the effectiveness of this agent against pan-drug-resistant MTB isolates. Gandhi N.R., Moll A., Sturm A.W., Pawinski R., Govender T., Lalloo U., Zeller K., Andrews J., Friedland G. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Schuster Bruce, C., Brhlikova, P., Heath, J., and McGettigan, P. (2019). Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 73, 503508. conducted a study focusing on the in vitro synergistic effect of DLM on moxifloxacin against drug-resistant clinical MTB isolates (INH- and RIF-monoresistant, MDR, Pre-XDR, and XDR-MTB. Tsubouchi, H., Sasaki, H., Ishikawa, H., and Matsumoto, M. (2016). Physiology, biochemistry, and applications of F420-and Fo-dependent redox reactions. DLM, a high percentage (> 99%) protein bound, has an exceptional apparent volume of distribution (Oye et al., 2013; Chang and Sotgiu, 2017). Science 322, 13921395. 49, 78547860. Biophys. It is important to note that the addition of DLM to the therapeutic regimen of MDR- and XDR-TB patients should be based on individual evaluation, including drug susceptibility information, safety and tolerability of drug, and assessment of riskbenefit ratio. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. doi: 10.5588/ijtld.10.0616, Diel, R., Hittel, N., and Schaberg, T. (2015). Recent high-throughput phenotypic screening strategies for anti-M. In 2018, Yang et al. Additional drug resistance in patients with multidrug-resistant tuberculosis in korea: a multicenter study from 2010 to 2019. Drug efflux and the activity of efflux transporters likely play important roles in the development of drug-tolerant and drug-resistant mycobacterial phenotypes. Isoniazid (isonicotinic acid hydrazide, INH) has been the most commonly used anti-tuberculosis since recognition of its clinical activity in 1952 (Robitzek and Selikoff 1952). 12 Patients should be counselled regarding the risk of optic neuritis and hepatic toxicity. This site needs JavaScript to work properly. Plasma samples were then analyzed for DLM and its metabolites by liquid chromatography-tandem mass spectrometry assay. HHS Vulnerability Disclosure, Help The two mutations in fbiA (D49Y and R175H) coincided with the development of phenotypic resistance to this new drug (Hoffmann et al., 2016). In 2016, the WHO issued an interim guideline for administrating DLM in 6- to 17-year-old children. (2014). Keywords: drug resistance; molecular mechanisms; Mycobacterium tuberculosis 1. Antimicrob. Compassionate and optimum use of new tuberculosis drugs. National Library of Medicine Is delamanid a potential agent in the treatment of diseases caused by Mycobacterium avium-intracellulare? Moreover, the serum electrolytes are required to be assessed at baseline, and in patients with electrolyte disturbances, especially hypokalemia and hypocalcemia, DLM should not be administrated (Deltyba Epar Product Information, 2014). Centers for Disease Control and Prevention Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugsworldwide, 20002004. This review sheds light on the current understanding of the pathogenesis of TB disease, molecular mechanisms of drug-resistance, progress on the development of novel or repurposed anti-TB drugs and regimens, host-directed therapies, with particular emphasis on underlying knowledge gaps and prospective for futuristic TB control programs. Fig. It seems that mutations in fbiC gene have a considerable role in DLM resistance, though further resistance mechanisms could not be neglected (Pang et al., 2017). Lewis, J. M., and Sloan, D. J. In a multinational phase II trial, 204 patients received an OBR combined with DLM or placebo for 2 months. Although the lipidomics of MAs is very different among MTBC strains, the biosynthesis pathway of these fatty acids is equal (Portevin et al., 2014; Yimer et al., 2020). In a guinea pig model of TB, the effective administration dose of DLM daily was 100 mg/kg to kill MTB within hypoxic lesions of the lungs (Chen et al., 2017). J. Med. One of the largest cohorts of children and adolescents treated with new anti-TB regimens was carried out in India. Figure 3. By using resazurin microtiter assay (REMA), they identified four resistant isolates with MIC values of >32.0 mg/L. In that study, 192/421 patients received DLM in combination with an OBR for 6 months, compared with 229/421 cases that received DLM for 2 months. (2020). Opin. J. Clin. Taken together, their evaluation demonstrated that DLM was effective and well tolerated for MDR-TB treatment (Zhang et al., 2013). A systematic review of mutations related to anti-TB drug resistance has stated 12 distinct mutations in the genes fbiA, fbiC, ddn, and fgd1 associated with DLM resistance. (2019). (2019). Another recently cloned gene involved in the biosynthetic pathway for the cofactor F420 is fbiD (Rv2983), which synthesizes the phosphoenolpyruvate moiety for subsequent steps done by fbiA (Bashiri et al., 2019). 2010 Global Report on Surveillance and Response. Safety assessments indicated that 98% of patients had at least one clinical manifestation, of which approximately 27% were serious. (2018). Bicyclic nitroimidazooxazole, an analog of azomycin known as 2-nitro-imidazole, is isolated from Streptomyces eurocidicus and has potent in vitro and in vivo anti-TB activity (Igarashi, 2017). Eur. Non-selective NSAIDs (nsNSAIDs) also bind to the COX-1 enzyme. Med. Drug Metab. (2017). Mutations in fbiD (Rv2983) as a novel determinant of resistance to pretomanid and delamanid in Mycobacterium tuberculosis. In another retrospective cohort study in South Korea, the safety and tolerability of DLM in 32 enrolled patients were assessed. (2016). J. Med. conducted a phase two RCT on the effects of DLM and/or BDQ on QT interval in patients with drug-resistant TB. (2015). (2019). (2021). In a randomized phase III trial carried out in seven countries, 341 patients with MDR-TB received DLM-containing regimens for 6 months (DLM group), and 170 participants received placebo plus an OBR (placebo group). Based on the 2017 WHO Global TB Report, using BDQ and DLM was initiated in 89 and 54 countries, respectively (Cox et al., 2018). Chandramohan, Y., Padmanaban, V., Bethunaickan, R., Tripathy, S., Swaminathan, S., and Ranganathan, U. D. (2019). Previous studies demonstrated up-regulation . Mechanisms of resistance to delamanid, a drug for Mycobacterium tuberculosis. [Frontier of mycobacterium research--host vs. mycobacterium]. In conclusion, while collateral drug resistance in M. tuberculosis is most . Li, Y., Sun, F., and Zhang, W. (2019). Dispos. Hydroxylation of the oxazole moiety of M1, the most crucial starting point, to form M2, and also consecutive oxidation to the ketone form (M3), are two main pathways in humans that are mostly performed by CYP3A4 (Figure 3) (Sasahara et al., 2015). Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit . doi: 10.1080/03007995.2017.1415057. eCollection 2023. Pharmacokinetics and metabolism of delamanid, a novel anti-tuberculosis drug, in animals and humans: importance of albumin metabolism in vivo. Infect. 23, 10171023. The results of that study indicated faster eradication (by at least 2 months) and shorter duration of clinical treatment of viable TB in the lungs of murine compared with the standard regimen, i.e., RIF (5 mg/kg), INH (10 mg/kg), ETB (100 mg/kg), and PYR (100 mg/kg) (Matsumoto et al., 2006). (2018). The most common side effects related to DLM consumption were vomiting, QTcB > 450 ms, and myalgia. New Engl. Antimicrob. Physical examination shows no muscle tenderness or other evidence of joint disease in both arms. However, limited treatment options make the management of multidrug-resistant tuberculosis (MDR-TB) and other chronic TB cases clinically challenging, as well as raise public health concerns. Chemother. Soni et al. J. Med. Singh, R., Manjunatha, U., Boshoff, H. I., Ha, Y. H., Niyomrattanakit, P., Ledwidge, R., et al. (2015). (2018). Emergence of new forms of totally drug-resistant tuberculosis bacilli: Super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. doi: 10.1111/j.1742-4658.2011.08404.x, Hameed, H., Islam, M. M., Chhotaray, C., Wang, C., Liu, Y., Tan, Y., et al. Early safety and efficacy of the combination of bedaquiline and delamanid for the treatment of patients with drug-resistant tuberculosis in Armenia, India, and South Africa: a retrospective cohort study. Microbiol. Stinson and associates reported a very low minimum inhibitory concentration (MIC; 0.0010.05 g/ml) of DLM against the clinical and reference strains of MTB (Stinson et al., 2016). J. Clin. In addition, DLM was more effective in intracellular MTB compared with RIF (at the concentrations of 3 and 0.1 g/ml, respectively). The 6-nitro-2,3-dihydroimidazo[2,1-b]oxazole is a racemic mixture so that right-handed, but not left-handed, enantiomers have activity against Mycobacterium tuberculosis complex (MTBC).
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