Sterilizing Activity of Second-Line Regimens Containing TMC207 in a Murine Model of Tuberculosis

Véziris, Nicolas; Ibrahim, Michella; Lounis, Nacer; Andries, Koen; Jarlier, Vincent

doi:10.1371/journal.pone.0017556

Cited by 62 publications

(48 citation statements)

References 30 publications

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“…This result is consistent with those of previous in vivo studies showing that withholding moxifloxacin from a second-line regimen against the wild-type H37Rv strain reduces both bactericidal and sterilizing activity (15,18,28) and with the numerous studies that have shown that fluoroquinolone resistance is a major prognostic factor for therapeutic failure in cases of multidrug-resistant tuberculosis (5,29,30). Second, our data suggested that the sterilizing activity of the moxifloxacin-containing regimen decreases gradually against strains displaying levels of resistance increasing from low to intermediate to high.…”

Section: Discussionsupporting

confidence: 92%

“…Amikacin, 150 mg/kg, was administered by subcutaneous injection 5 days per week for the first 2 months. Drug dosages used were similar to those in our previous experiments (15,18). The moxifloxacin dosage allowed for an area under the curve (AUC) value close to that found in humans taking the recommended oral dose (400 mg/day), without excessively increasing the peak serum concentration (C max ) (14,19,20).…”

Section: Methodsmentioning

confidence: 76%

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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: 92%

Section: Methodsmentioning

confidence: 76%

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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“…The lack of a significant improvement when MOX was substituted for isoniazid was a disappointment, but another evaluation is currently in progress (Table 2). There are also other new anti-TB drugs in clinical trials, and preliminary studies have suggested that if these were combined with MOX, it might be possible to further shorten first-line therapy or perhaps reduce the duration of treatment required to cure multiresistant strains (56,86,91).…”

Section: Summary: Cautious Optimism On the Future Of Quinolones As Fimentioning

confidence: 99%

Current Prospects for the Fluoroquinolones as First-Line Tuberculosis Therapy

Takiff

Guerrero

2011

Antimicrob Agents Chemother

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While fluoroquinolones (FQs) have been successful in helping cure multidrug-resistant tuberculosis (MDR TB), studies in mice have suggested that if used as first-line agents they might reduce the duration of therapy required to cure drug-sensitive TB. The results of phase II trials with FQs as first-line agents have been mixed, but in at least three studies where moxifloxacin substituted for ethambutol, there was an increase in the early percentage of sputa that converted to negative for bacilli. Phase III trials are in progress to test the effectiveness of 4-month FQ-containing regimens, but there is concern that the widespread use of FQs for other infections could engender a high prevalence of FQ-resistant TB. However, several studies suggest that despite wide FQ use, the prevalence of FQ-resistant TB is low, and the majority of the resistance is low-level. The principal risk for resistance may be when FQs are used to treat nonspecific respiratory symptoms that are in fact TB, so curtailing this use of FQs could reduce the development of resistance and also the delays in TB diagnosis and treatment that have been documented when an FQ is given in this setting. While the future of FQs as first-line therapy will likely depend upon the results of the ongoing phase III trials, if they are to be effectively employed in high-TB-burden regions their use for community-acquired pneumonias should be restricted, the prevalence of FQ-resistant TB should be monitored, and the cost of the treatment should be comparable to that of current standard drug regimens.There are two main problems with tuberculosis (TB) chemotherapy, and the fluoroquinolones (FQs) may be able to help with both. First, although the total duration of treatment has been reduced from 18 to 24 months to 6 months by the systematic use of rifampin (RIF) and pyrazinamide, such a 6-month duration is still very long for patients and burdensome for health services in numerous countries where TB is highly endemic and can lead to the second problem, the development of strains resistant to the drugs. The success of the fluoroquinolone antibiotics in treating strains that are resistant to the standard first-line drugs has led to the suggestion that if used as first-line therapy they may be able shorten the duration of treatment. However, excitement over this possibility is tempered by the fear that their widespread community use for other infections will engender a high prevalence of FQ-resistant TB strains in the population. FQs: HIGH HOPES BUT ALSO HIGH RATES OF RESISTANCEThe quinolones are synthetic molecules that got their start when nalidixic acid was discovered in 1962 (47) and then introduced into clinical use in 1967 for the treatment of Gramnegative urinary tract infections (26). The addition of a fluorine atom significantly increased their antibacterial activity, and by adding various side groups literally thousands of different fluoroquinolones were synthesized. Although the increased broad-spectrum activity of ciprofloxacin (CIP) created the expectation ...

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“…Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model. 25 conducted a study where the mice were inoculated with M. tuberculosis and then treated with second-line drug combinations with or without the bedaquiline, and then followed without treatment for 3 more months to determine relapse rates. After addition of bedaquiline to this MDR TB regimen, the treatment duration needed to reach the same relapse rate dropped to 6 months.…”

Section: Lounis Et Almentioning

confidence: 99%

Bedaquiline: a new weapon against MDR and XDR-TB

Singh

Natt

Garewal

et al. 2013

Int J Basic Clin Pharmacol

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Multidrug-resistant tuberculosis (MDR-TB) is a global public health problem. It requires treatment with combination therapy consisting of four to six drugs including combinations of bactericidal and bacteriostatic drugs, usually for a period of 2 years. There is alarming rise in MDR and XDR-TB all over the world and better treatment options are needed to control the global MDR-TB and XDR-TB epidemic. Drugs which can shorten the treatment duration and which are free from serious adverse effects are urgently needed. Bedaquiline (TMC-207) is a newly FDA approved anti-TB drug, having unique mechanism of action i.e. causes inhibition of the proton pump activity of the ATP synthase in M. tuberculosis and targets the energy metabolism. It is found to active within macrophages, and is a promising agent in shortening the duration of anti- TB treatment. It is metabolized by CYP3A4, so interactions with inducers and inhibitors of this enzyme are expected. It has shown promising results in preclinical and clinical studies and it seems to be a good option for MDR and XDR-TB. Adverse effects reported in various studies were of mild nature except nausea which was the most commonly associated. Few cases of prolongation of QT intervals were reported, so it demands careful monitoring and use of bedaquiline as a reserve drug for patients in whom conventional regimens are not effective. Currently it is approved as part of combination therapy in adults of ≥18 year with pulmonary MDR-TB. Long term studies are needed to explore its full safety profile. [Int J Basic Clin Pharmacol 2013; 2(2.000): 96-102

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Sterilizing Activity of Second-Line Regimens Containing TMC207 in a Murine Model of Tuberculosis

Cited by 62 publications

References 30 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

Current Prospects for the Fluoroquinolones as First-Line Tuberculosis Therapy

Bedaquiline: a new weapon against MDR and XDR-TB

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