Delamanid and Bedaquiline Resistance in <i>Mycobacterium tuberculosis</i> Ancestral Beijing Genotype Causing Extensively Drug-Resistant Tuberculosis in a Tibetan Refugee

Hoffmann, Harald; Kohl, Thomas A.; Hofmann-Thiel, Sabine; Merker, Matthias; Beckert, Patrick; Jaton, Katia; Nedialkova, Lubov; Sahalchyk, Evgeni; Rothe, Thomás; Keller, Peter M.; Niemann, Stefan

doi:10.1164/rccm.201502-0372le

Cited by 123 publications

(92 citation statements)

References 15 publications

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“…Over the last 40 years, no new antibiotics against tuberculosis have been developed and only recently several new drugs have been proposed: Bedaquiline (Mahajan, 2013), Delamanid (Gupta et al, 2015) and FS-1 (Ilin and Kulmanov, 2014; Kalykova et al, 2016). However, resistance to Bedaquiline and Delamanid has already been reported (Hoffmann et al, 2016). FS-1 is an iodine-containing nanomolecular complex showing an antimicrobial effect (Kalykova et al, 2016).…”

Section: Introductionmentioning

confidence: 97%

Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1

Il’in¹,

Kulmanov²,

Korotetskiy³

et al. 2017

Front. Cell. Infect. Microbiol.

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Drug induced reversion of antibiotic resistance is a promising way to combat multidrug resistant infections. However, lacking knowledge of mechanisms of drug resistance reversion impedes employing this approach in medicinal therapies. Induction of antibiotic resistance reversion by a new anti-tuberculosis drug FS-1 has been reported. FS-1 was used in this work in combination with standard anti-tuberculosis antibiotics in an experiment on laboratory guinea pigs infected with an extensively drug resistant (XDR) strain Mycobacterium tuberculosis SCAID 187.0. During the experimental trial, genetic changes in the population were analyzed by sequencing of M. tuberculosis isolates followed by variant calling. In total 11 isolates obtained from different groups of infected animals at different stages of disease development and treatment were sequenced. It was found that despite the selective pressure of antibiotics, FS-1 caused a counter-selection of drug resistant variants that speeded up the recovery of the infected animals from XDR tuberculosis. Drug resistance mutations reported in the genome of the initial strain remained intact in more sensitive isolates obtained in this experiment. Variant calling in the sequenced genomes revealed that the drug resistance reversion could be associated with a general increase in genetic heterogeneity of the population of M. tuberculosis. Accumulation of mutations in PpsA and PpsE subunits of phenolpthiocerol polyketide synthase was observed in the isolates treated with FS-1 that may indicate an increase of persisting variants in the population. It was hypothesized that FS-1 caused an active counter-selection of drug resistant variants from the population by aggravating the cumulated fitness cost of the drug resistance mutations. Action of FS-1 on drug resistant bacteria exemplified the theoretically predicted induced synergy mechanism of drug resistance reversion. An experimental model to study the drug resistance reversion phenomenon is hereby introduced.

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Section: Introductionmentioning

confidence: 97%

Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1

Il’in¹,

Kulmanov²,

Korotetskiy³

et al. 2017

Front. Cell. Infect. Microbiol.

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“…28 However, acquired resistance to delamanid and bedaquiline in therapy for tuberculosis is recently described. [29][30][31] The stepwise amplification of drug resistance of bedaquiline and delamanid in a patient with XDR-TB was observed. It serves as a warning for the future appearance of resistant TB against new antituberculosis drugs.…”

Section: Discussionmentioning

confidence: 95%

Preclinical study and clinical trial of a novel therapeutic vaccine against multi-drug resistant tuberculosis

Okada

Kita

Hashimoto

et al. 2016

Human Vaccines & Immunotherapeutics

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ABSTRACT[Purpose] Multi-drug resistant (MDR), Mycobacterium tuberculosis (TB) is a big problem in the world. We have developed novel TB therapeutic vaccine (HVJ-E/HSP65 DNA CIL-12 DNA).[Methods and Results] DNA vaccine expressing TB heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. This vaccine provided remarkable protective efficacy and strong therapeutic efficacy against MDR-TB and XDR-TB in murine models. Furthermore, this vaccine provided therapeutic efficacy of prolongation of survival time of TB infected monkeys and augmented the immune responses. Therefore, the preclinical tests were studied for clinical trial. The injection of 100 mg of the vaccine /mouse i.m. three times in two weeks induced significantly strong production of IFN-g and IL-2. 100 mg and 200 mg DNA vaccine/mouse i.m. augmented the production of these cytokines compared with 25 mg DNA vaccine/mouse i. m.. The ratio of 100 mg pDNA to 1AU HVJ-E enhanced the production of IFN-g and IL-2. The decrease in the number of M. tuberculosis in liver of mice was observed by the vaccination of 100mg pDNA. By using these conditions, safety pharmacology study and toxicology test is being studied in monkeys administered by GMP level DNA vaccines. By the toxicology test using monkeys, high dose GMP level vaccine/ monkey is administrated. Safety pharmacological study of repeated administration is also being investigated in GLP level. Furthermore, we have planned to do clinical phase I trial. Targets are human patients with MDR-TB. The safety and tolerability of the vaccine will be evaluated.[Conclusion and recommendations] These data indicate that our novel vaccine might be useful against tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical applications.

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“…A regimen containing linezolid, bedaquiline and delamanid may be adequate for the most difficult‐to‐treat MDR‐TB, but sequential acquisition of drug resistance to bedaquiline and delamanid, and to linezolid and delamanid, has been reported. This may be anticipated, as delamanid is prone to bacillary drug resistance, and the 120‐week culture conversion rates in patients with pre‐XDR‐ and XDR‐TB given an optimized background regimen plus bedaquiline in a clinical trial setting were only 70.5% and 62.2%, respectively .…”

Section: Mdr‐tb: Repurposed and Novel Drugsmentioning

confidence: 99%

“…While this approach might be attractive, there remained substantial concerns over the adverse effect profile of some of these newly introduced drugs, especially if they are to be regularly used in the treatment of the huge number of patients with fully drug-susceptible TB. Furthermore, like all antibiotics, new TB drugs are not exempted from the emergence of drug resistance, 19,20 thereby posing a question mark on the longer term sustainability of such an approach.…”

Section: Directly Observed Treatment Short-coursementioning

confidence: 99%

“…A regimen containing linezolid, bedaquiline and delamanid may be adequate for the most difficult-totreat MDR-TB, but sequential acquisition of drug resistance to bedaquiline and delamanid, 19 and to linezolid and delamanid, 112 has been reported. This may be anticipated, as delamanid is prone to bacillary drug resistance, 117,118 and the 120-week culture conversion rates in patients with pre-XDR-and XDR-TB given an 108 Its open-label extension suggested that delamanid used for more than 6 months, in comparison with its use for less than 2 months, significantly increased favourable outcomes (cure or treatment completion) from 55% to 74.5%, and significantly reduced mortality from 8.3% to 1.0% 109 (4) Otsuka Trial 213, involving use of delamanid at 100 mg bd for the first 2 months and 200 mg once daily for the next 4 months, showed small benefit from adding delamanid to an optimized background regimen, although delamanid may help prevent amplification of drug resistance 110 (1) Although delamanid is associated with QT prolongation, the effect predictably maximizes within 8 weeks of treatment, without associated cardiac clinical manifestations, and is not materially affected by concomitant use of levofloxacin and clofazimine 111 (2) Case reports have demonstrated the safety of delamanid in the treatment of complicated MDR-TB, [112][113][114][115] including one showing prolonged use for 24 months in a child with XDR-TB 116 (3) Trial 213 found no significant difference regarding treatment-emergent adverse events, drug-drug interactions between delamanid and antiretroviral drugs, and prolongation of the corrected QT interval 110 (4) With a relatively high propensity to develop bacillary drug resistance, 117,118 delamanid may be better used with potent companion agents that are less prone to develop bacillary drug resistance, for example, linezolid or bedaquiline 8,112 Pretomanid (PA-824) (1) Being a nitroimidazole that shares the same mechanism of action with delamanid, pretomanid is bactericidal against actively replicating mycobacteria (inhibiting mycolic acid biosynthesis) and non-replicating mycobacteria (generating nitric oxide inside the tubercle bacilli) 117,119,120 (1) Owing to similar structure, pretomanid expectedly shares cross-resistance with delamanid as well as a relatively high propensity to acquiring bacillary drug resistance (2) Not yet approved for use in clinical practice optimized background regimen plus bedaquiline in a clinical trial setting were only 70.5% and 62.2%, respectively.…”

Section: Clofaziminementioning

confidence: 99%

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New drugs and regimens for tuberculosis

et al. 2018

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Since standardized rifampin-based first-line regimens and fluoroquinolone-based second-line regimens were used to treat tuberculosis (TB), unfortunately without timely modification according to the drug resistance profile, TB and drug-resistant disease are still important public health threats worldwide. Although the last decade has witnessed advances in rapid diagnostic tools and use of repurposed and novel drugs for better managing drug-resistant TB, we need an appropriate TB control strategy and a well-functioning health infrastructure to ensure optimal operational use of rapid tests, judicious use of effective treatment regimens that can be rapidly tailored according to the drug resistance profile and timely management of risk factors and co-morbidities that promote infection and its progression to disease. We searched the published literature to discuss (i) standardized versus individualized therapies, including the choice between a single one-size-fit-all regimen versus different options with different key drugs determined mainly by rapid drug susceptibility testing, (ii) alternative regimens for managing drug-susceptible TB, (iii) evidence for using the World Health Organization (WHO) longer and shorter regimens for multidrug-resistant TB and (iv) evidence for using repurposed and novel drugs. We hope an easily applicable combination of biomarkers that accurately predict individual treatment outcome will soon be available to ultimately guide individualized therapy.

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Delamanid and Bedaquiline Resistance in Mycobacterium tuberculosis Ancestral Beijing Genotype Causing Extensively Drug-Resistant Tuberculosis in a Tibetan Refugee

Cited by 123 publications

References 15 publications

Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1

Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1

Preclinical study and clinical trial of a novel therapeutic vaccine against multi-drug resistant tuberculosis

New drugs and regimens for tuberculosis

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