Sterilizing Activity of R207910 (TMC207)-containing Regimens in the Murine Model of Tuberculosis

Ibrahim, Michella; Truffot-Pernot, C.; Andries, Koen; Jarlier, Vincent; Véziris, Nicolas

doi:10.1164/rccm.200807-1152oc

Cited by 75 publications

(63 citation statements)

References 24 publications

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“…This reinforces that in murine studies, bactericidal activity of drug combinations is not predictive of sterilizing activity (39,40). However, here, the bactericidal activity was assessed only after 2 and 6 months.…”

Section: Discussionsupporting

confidence: 82%

Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis

Fillion

Aubry

Brossier

et al. 2013

Antimicrob Agents Chemother

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It has been shown previously that fluoroquinolone resistance (defined by resistance to at least 2 mg/liter ofloxacin) has a different impact on moxifloxacin monotherapy depending on the mutation in the sole fluoroquinolone target in Mycobacterium tuberculosis, i.e., DNA gyrase. Since tuberculosis treatment relies on multidrug therapy, we wished to determine the impact of fluoroquinolone resistance on the bactericidal and sterilizing activity of a second-line antituberculous regimen containing moxifloxacin. A total of 280 mice were inoculated with the wild-type Mycobacterium tuberculosis H37Rv strain or one of 3 isogenic fluoroquinolone-resistant mutant strains with increasing moxifloxacin resistance (the GyrB D500N, GyrA A90V, and GyrA D94G strains) and then treated for 6 months with a second-line regimen containing moxifloxacin, pyrazinamide, and ethionamide supplemented with amikacin during the first 2 months. Mice were sacrificed during treatment for measurement of bactericidal activity and 3 months after treatment completion for measurement of relapse rates (sterilizing activity). The CFU counts decreased faster in mice inoculated with the wild type than in mice inoculated with the mutant strains. The relapse rate after treatment completion was different among mice inoculated with mutant strains in relation to the drug resistance level: wild type, 0%; GyrB D500N strain, 33%; GyrA A90V strain, 50%; and GyrA D94G strain, 86%. The relapse rate observed with the GyrB D500N strain was the only one not statistically different from that observed with the wild-type strain. We demonstrated that the impact on sterilizing activity of the most active second-line drug regimen containing moxifloxacin depends on the MIC of moxifloxacin. We suggest that the precise level of moxifloxacin resistance be determined for all strains resistant to 2 mg/liter ofloxacin.

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Section: Discussionsupporting

confidence: 82%

Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis

Fillion

Aubry

Brossier

et al. 2013

Antimicrob Agents Chemother

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“…Bedaquiline targets both actively replicating and dormant bacilli [44][45][46], and therefore has the characteristics required of a core drug. The available evidence on efficacy and safety includes RCTs [17,18] and observational studies, including experience derived from compassionate use programmes [47][48][49].…”

Section: Linezolidmentioning

confidence: 99%

Classification of antituberculosis drugs: a new proposal based on the most recent evidence

Caminero

Scardigli

2015

Eur Respir J

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@ERSpublicationsThe classification of the anti-TB drugs should probably be modified to optimise the use old and new compounds http://ow.ly/QbDSP Multidrug-resistant (MDR) tuberculosis (TB) (resistance to at least isoniazid and rifampicin), with >480 000 cases in 2013, 10% of them being affected by extensively drug-resistant (XDR)-TB (MDR-TB with additional resistance to any fluoroquinolone, and to injectable second-line drugs (SLDs) (capreomycin, kanamycin or amikacin)), continues to represent a real threat to TB control [1][2][3][4]. In some high MDR-TB burden countries, the prevalence of MDR-TB among new cases exceeds 20% and among retreatment cases, reaches almost 50% [1,5].Prevention and quality diagnosis and treatment of MDR-and XDR-TB are part of the crucial interventions included in Pillar 1 of the new World Health Organization (WHO) End TB Strategy, which is focussed on the goal of TB elimination [6][7][8]. Unfortunately, the outcomes of these cases are suboptimal, with 60% success among MDR-TB cases [2], 40% among XDR-TB cases [3] and <20% among the cases with resistance patterns beyond XDR-TB [4]. This means not only high mortality but also significant human suffering and transmission of the Mycobacterium tuberculosis strains within the community [9]. Unfortunately, at present, the treatment of MDR/XDR-TB is still very long, toxic and expensive [10,11].The original WHO guidance on the management of MDR-TB was issued in 1996 [12] and since then, several updated guidelines have been published. The fundamentals on MDR/XDR-TB treatment were published in the 2006 and 2008 WHO guidelines [13,14], where the basic rationale to design therapeutic regimens for these cases was described. According to these recommendations, which are currently followed worldwide, the anti-TB drugs are classified into five main groups indirectly considering the evidence available, the safety and/or the effectiveness of the different drugs. These groups start from the most effective drugs (group 1), grouping the other drugs progressively according to decreasing order of efficacy [15].In the 2011 revision of the WHO MDR/XDR-TB guidelines [16], the composition of different groups of anti-TB drugs was not modified. Therefore, since 2006, the rationale of the classification of the anti-TB drugs has not been changed but several studies have examined the effectiveness, efficacy and safety of the group 5 drugs, and some of these drugs appear to be more effective and well tolerated than others that currently have "higher" ranking in the classification. Furthermore, promising new drugs active against M. tuberculosis have been discovered in the last couple of years [17][18][19][20] and have become progressively available in many parts of the world to treat MDR/XDR-TB.

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“…The route using an intravenous (i.v.) injection in the tail vein typically delivers a high-dose inoculum of M. tuberculosis (21,35,(48)(49)(50). Other mouse infection models for TB drug evaluations have used the intratracheal (46) or intranasal (7) route of infection, which are used less frequently.…”

mentioning

confidence: 99%

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

Groote

Gilliland

Wells

et al. 2011

Antimicrob Agents Chemother

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Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.For the first time in many years, there is a portfolio of promising new compounds at every level of tuberculosis (TB) drug discovery and development (4; www.tballiance.org). However, careful selection of new drug candidates is imperative, and efficient screening models for new drugs, including pertinent animal models, need to be further developed and studied. Preclinical testing in animals of newly discovered agents alone, and in combination with new and old agents, prior to being tested in humans is a crucial but lengthy process. These drug regimens include agents that provide bactericidal activities against rapidly growing bacilli, but they especially aim to include those that possess potent sterilizing activities and hence prevent relapse (8). The most commonly used animal species in TB drug development is the mouse, mainly because of economical and practical reasons, but also because of the limited requirement of compound (26).Various mouse Mycobacterium tuberculosis infection models are utilized by both industry and academia, and they differ in the route of infection with M. tuberculosis, inoculum and strain of M. tuberculosis, strain of mice, timing of the start of treatment after infection, the length of treatment, etc. A model where therapy is started immediately after in...

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Sterilizing Activity of R207910 (TMC207)-containing Regimens in the Murine Model of Tuberculosis

Cited by 75 publications

References 24 publications

Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis

Impact of Fluoroquinolone Resistance on Bactericidal and Sterilizing Activity of a Moxifloxacin-Containing Regimen in Murine Tuberculosis

Classification of antituberculosis drugs: a new proposal based on the most recent evidence

Comparative Studies Evaluating Mouse Models Used for Efficacy Testing of Experimental Drugs against Mycobacterium tuberculosis

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