The Experts below are selected from a list of 2538 Experts worldwide ranked by ideXlab platform
Eric L. Nuermberger - One of the best experts on this subject based on the ideXlab platform.
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treatment shortening effect of a novel regimen combining Clofazimine and high dose rifapentine in pathologically distinct mouse models of tuberculosis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Vikram Saini, Nicole C Ammerman, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Yong Seok Chang, Jacques H GrossetAbstract:Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of Clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and Clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding Clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and Clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and Clofazimine in clinical trials.
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treatment shortening effect of a novel regimen combining high dose rifapentine and Clofazimine in pathologically distinct mouse models of tuberculosis
bioRxiv, 2019Co-Authors: Nicole C Ammerman, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Vikram Saini, Yong Seok Chang, Jacques H GrossetAbstract:ABSTRACT High-dose rifapentine and Clofazimine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of Clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and Clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding Clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and Clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and Clofazimine in clinical trials.
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verapamil increases the bioavailability and efficacy of bedaquiline but not Clofazimine in a murine model of tuberculosis
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Rokeya Tasneen, Deepak V Almeida, Charles A Peloquin, Kala Barnesboyle, Eric L. NuermbergerAbstract:Drug efflux pumps play important roles in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, Clofazimine, and other drugs against Mycobacterium tuberculosis, has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances in vivo efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the in vitro activity of bedaquiline and Clofazimine against M. tuberculosis clinical isolates, including those harboring rv0678 mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on the oral bioavailability or efficacy of Clofazimine in mice. The addition of verapamil increased the sterilizing activity of a regimen composed of bedaquiline, Clofazimine, and pyrazinamide. These results confirm that verapamil has adjunctive activity in vivo, but they also demonstrate that the adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters, rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil versus increasing the doses of companion drugs.
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primary Clofazimine and bedaquiline resistance among isolates from patients with multidrug resistant tuberculosis
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Bin Wang, Eric L. Nuermberger, Fengmin Huo, Shaochen Guo, Wei JingAbstract:Clofazimine has been repurposed for the treatment of tuberculosis, especially for multidrug-resistant tuberculosis (MDR-TB). To test the susceptibility to Clofazimine of Mycobacterium tuberculosis clinical isolates, MICs of Clofazimine were determined using the microplate alamarBlue assay (MABA) method for 80 drug-resistant isolates and 10 drug-susceptible isolates for comparison. For five Clofazimine-resistant strains isolated from previously treated pre-extensively drug-resistant TB (pre-XDR-TB) and XDR-TB patients without prior exposure to Clofazimine or bedaquiline, Clofazimine MICs were ≥1.2 μg/ml. Four isolates with cross-resistance to bedaquiline had Rv0678 mutations. The other isolate with no resistance to bedaquiline had an Rv1979c mutation. This study adds to a recent study showing that 6.3% of MDR-TB patients without prior Clofazimine or bedaquiline exposure harbored isolates with Rv0678 mutations, which raises concern that preexisting resistance to these drugs may be associated with prior TB treatment. Furthermore, we propose a tentative breakpoint of 1.2 μg/ml for Clofazimine resistance using the MABA method. More-widespread surveillance and individualized testing for Clofazimine and bedaquiline resistance, together with assessment of their clinical usage, especially among previously treated and MDR-TB patients, are warranted.
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mutations in pepq confer low level resistance to bedaquiline and Clofazimine in mycobacterium tuberculosis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Deepak V Almeida, Jacques H Grosset, Sandeep Tyagi, Eric L. Nuermberger, Koen Andries, Thomas R Ioerger, Khisimuzi Mdluli, James C SacchettiniAbstract:The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level Clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and Clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without Clofazimine, and were shown to have bedaquiline and Clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and Clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.
Nicole C Ammerman - One of the best experts on this subject based on the ideXlab platform.
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treatment shortening effect of a novel regimen combining Clofazimine and high dose rifapentine in pathologically distinct mouse models of tuberculosis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Vikram Saini, Nicole C Ammerman, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Yong Seok Chang, Jacques H GrossetAbstract:Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of Clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and Clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding Clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and Clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and Clofazimine in clinical trials.
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treatment shortening effect of a novel regimen combining high dose rifapentine and Clofazimine in pathologically distinct mouse models of tuberculosis
bioRxiv, 2019Co-Authors: Nicole C Ammerman, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Vikram Saini, Yong Seok Chang, Jacques H GrossetAbstract:ABSTRACT High-dose rifapentine and Clofazimine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of Clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and Clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding Clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and Clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and Clofazimine in clinical trials.
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impact of Clofazimine dosing on treatment shortening of the first line regimen in a mouse model of tuberculosis
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Nicole C Ammerman, Rosemary V Swanson, Deepak V Almeida, Siyang Li, Elaine M Bautista, Vikram Saini, Till F Omansen, Yong Seok Chang, Asa TapleyAbstract:The antileprosy drug Clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, Clofazimine causes doseand duration-dependent skin discoloration in patients, and the optimal Clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of Clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that Clofazimine activity is most potent when coad-ministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that Clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform Clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.
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Clofazimine has delayed antimicrobial activity against mycobacterium tuberculosis both in vitro and in vivo
Journal of Antimicrobial Chemotherapy, 2017Co-Authors: Nicole C Ammerman, Rosemary V Swanson, Asa Tapley, Bongani Ngcobo, John W Adamson, Chivonne Moodley, Afton Dorasamy, Sashen Moodley, Zinhle Mgaga, Linda A BesterAbstract:Objectives The anti-leprosy drug Clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and has been associated with treatment-shortening activity in both clinical and preclinical studies of TB chemotherapy. However, a reported lack of early bactericidal activity (EBA) in TB patients has raised questions regarding the usefulness of Clofazimine as an anti-TB drug. Our objective was to systematically evaluate the EBA of Clofazimine in vitro and in vivo to provide insight into how and when this drug exerts its antimicrobial activity against M. tuberculosis. Methods We evaluated the 14 day EBA of Clofazimine (i) in vitro at concentrations ranging from 4 times below to 4 times above the MIC for M. tuberculosis and (ii) in vivo in infected BALB/c mice at doses ranging from 1.5 to 100 mg/kg/day, and serum Clofazimine levels were measured. In both experiments, isoniazid was used as the positive control. Results In vitro, Clofazimine, at any concentration tested, did not exhibit bactericidal activity during the first week of exposure; however, in the second week, it exhibited concentration-dependent antimicrobial activity. In vivo, Clofazimine, at any dose administered, did not exhibit bactericidal activity during the first week, and limited antimicrobial activity was observed during the second week of administration. While serum Clofazimine levels were clearly dose dependent, the antimicrobial activity was not significantly related to the dose administered. Conclusions Our data suggest that Clofazimine's delayed antimicrobial activity may be due more to its mechanism of action rather than to host-related factors.
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Clofazimine contributes sustained antimicrobial activity after treatment cessation in a mouse model of tuberculosis chemotherapy
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Rosemary V Swanson, Nicole C Ammerman, Bongani Ngcobo, John W Adamson, Chivonne Moodley, Afton Dorasamy, Sashen Moodley, Zinhle Mgaga, Linda A Bester, Sanil D SinghAbstract:Experimental and clinical studies have indicated that the antileprosy drug Clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in tuberculosis treatment, accumulated Clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the BALB/c mouse model of chronic tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either isoniazid alone, Clofazimine alone, the first-line regimen rifampin-isoniazid-pyrazinamide-ethambutol, or a first-line regimen where Clofazimine was administered in place of ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation and 2, 4, 6, and 8 weeks after treatment was stopped. Bacterial regrowth was delayed in all mice receiving Clofazimine, either alone or in combination, compared to the mice that did not receive Clofazimine. This effect was especially evident in mice receiving multidrug therapy. In mice not receiving Clofazimine, bacterial regrowth began almost immediately after treatment was stopped, while in mice receiving Clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum Clofazimine levels remained at or above the 0.25-μg/ml MIC for M. tuberculosis Thus, sustained activity of Clofazimine may be important in the treatment-shortening effect associated with this drug.
Jacques H Grosset - One of the best experts on this subject based on the ideXlab platform.
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treatment shortening effect of a novel regimen combining Clofazimine and high dose rifapentine in pathologically distinct mouse models of tuberculosis
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Vikram Saini, Nicole C Ammerman, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Yong Seok Chang, Jacques H GrossetAbstract:Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of Clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and Clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding Clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and Clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and Clofazimine in clinical trials.
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treatment shortening effect of a novel regimen combining high dose rifapentine and Clofazimine in pathologically distinct mouse models of tuberculosis
bioRxiv, 2019Co-Authors: Nicole C Ammerman, Eric L. Nuermberger, Rokeya Tasneen, Sanjay K. Jain, Vikram Saini, Yong Seok Chang, Jacques H GrossetAbstract:ABSTRACT High-dose rifapentine and Clofazimine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of Clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and Clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding Clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and Clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and Clofazimine in clinical trials.
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mutations in pepq confer low level resistance to bedaquiline and Clofazimine in mycobacterium tuberculosis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Deepak V Almeida, Jacques H Grosset, Sandeep Tyagi, Eric L. Nuermberger, Koen Andries, Thomas R Ioerger, Khisimuzi Mdluli, James C SacchettiniAbstract:The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level Clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and Clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without Clofazimine, and were shown to have bedaquiline and Clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and Clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.
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Clofazimine shortens the duration of the first line treatment regimen for experimental chemotherapy of tuberculosis
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Sandeep Tyagi, John Adamson, Rosemary V Swanson, Paul J Converse, Deepak V Almeida, Nicole C Ammerman, Siyang Li, Jacques H GrossetAbstract:A key drug for the treatment of leprosy, Clofazimine has recently been associated with highly effective and significantly shortened regimens for the treatment of multidrug-resistant tuberculosis (TB). Consequently, we hypothesized that Clofazimine may also shorten the duration of treatment for drug-susceptible TB. We conducted a controlled trial in the mouse model of TB chemotherapy comparing the activity of the 6-mo standard regimen for TB treatment, i.e., 2 mo of daily rifampin, isoniazid, pyrazinamide, and ethambutol followed by 4 mo of rifampin and isoniazid, with a 4-mo Clofazimine-containing regimen: 2 mo of daily rifampin, isoniazid, pyrazinamide, and Clofazimine followed by 2 mo of rifampin, isoniazid, and Clofazimine. Treatment efficacy was assessed on the basis of Mycobacterium tuberculosis colony counts in the lungs and spleens during treatment and on the proportion of mice with culture-positive relapse 6 mo after treatment cessation. No additive effect of Clofazimine was observed after the first week of treatment, but, by the second week of treatment, the colony counts were significantly lower in the Clofazimine-treated mice than in the mice receiving the standard regimen. Lung culture conversion was obtained after 3 and 5 mo in mice treated with the Clofazimine-containing and standard regimens, respectively, and relapse-free cure was obtained after 3 and 6 mo of treatment with the Clofazimine-containing and standard regimens, respectively. Thus, Clofazimine is a promising anti-TB drug with the potential to shorten the duration of TB chemotherapy by at least half (3 mo vs. 6 mo) in the mouse model of TB.
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assessment of Clofazimine activity in a second line regimen for tuberculosis in mice
American Journal of Respiratory and Critical Care Medicine, 2013Co-Authors: Jacques H Grosset, Paul J Converse, Deepak V Almeida, Nicole C Ammerman, Sandeep Tyagi, William R Bishai, D A Enarson, A TrebucqAbstract:Rationale: Although observational studies suggest that Clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of Clofazimine for the treatment of this disease has never been systematically evaluated. Objectives: Our goal was to directly compare the activity of a standard second-line drug regimen with or without the addition of Clofazimine in a mouse model of multidrug-resistant tuberculosis. Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation. Methods: Mice were aerosol-infected with an isoniazid-resistant (as a surrogate of multidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily Clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce Clofazimine carryover. Relapse was assessed 6 months after treatment cessation. Measurements and Main Results: After 2 months, the bacillary load in lungs was reduced from 9.74 log10 at baseline to 3.61 and 4.68 in mice treated with or without Clofazimine, respectively (P < 0.001). Mice treated with Clofazimine were culture-negative after 5 months, whereas all mice treated without Clofazimine remained heavily culture-positive for the entire 9 months of the study. The relapse rate was 7% among mice treated with Clofazimine for 8 to 9 months. Conclusions: The Clofazimine contribution was substantial in these experimental conditions.
Rosemary V Swanson - One of the best experts on this subject based on the ideXlab platform.
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impact of Clofazimine dosing on treatment shortening of the first line regimen in a mouse model of tuberculosis
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Nicole C Ammerman, Rosemary V Swanson, Deepak V Almeida, Siyang Li, Elaine M Bautista, Vikram Saini, Till F Omansen, Yong Seok Chang, Asa TapleyAbstract:The antileprosy drug Clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, Clofazimine causes doseand duration-dependent skin discoloration in patients, and the optimal Clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of Clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that Clofazimine activity is most potent when coad-ministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that Clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform Clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.
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Clofazimine has delayed antimicrobial activity against mycobacterium tuberculosis both in vitro and in vivo
Journal of Antimicrobial Chemotherapy, 2017Co-Authors: Nicole C Ammerman, Rosemary V Swanson, Asa Tapley, Bongani Ngcobo, John W Adamson, Chivonne Moodley, Afton Dorasamy, Sashen Moodley, Zinhle Mgaga, Linda A BesterAbstract:Objectives The anti-leprosy drug Clofazimine has been shown to have antimicrobial activity against Mycobacterium tuberculosis and has been associated with treatment-shortening activity in both clinical and preclinical studies of TB chemotherapy. However, a reported lack of early bactericidal activity (EBA) in TB patients has raised questions regarding the usefulness of Clofazimine as an anti-TB drug. Our objective was to systematically evaluate the EBA of Clofazimine in vitro and in vivo to provide insight into how and when this drug exerts its antimicrobial activity against M. tuberculosis. Methods We evaluated the 14 day EBA of Clofazimine (i) in vitro at concentrations ranging from 4 times below to 4 times above the MIC for M. tuberculosis and (ii) in vivo in infected BALB/c mice at doses ranging from 1.5 to 100 mg/kg/day, and serum Clofazimine levels were measured. In both experiments, isoniazid was used as the positive control. Results In vitro, Clofazimine, at any concentration tested, did not exhibit bactericidal activity during the first week of exposure; however, in the second week, it exhibited concentration-dependent antimicrobial activity. In vivo, Clofazimine, at any dose administered, did not exhibit bactericidal activity during the first week, and limited antimicrobial activity was observed during the second week of administration. While serum Clofazimine levels were clearly dose dependent, the antimicrobial activity was not significantly related to the dose administered. Conclusions Our data suggest that Clofazimine's delayed antimicrobial activity may be due more to its mechanism of action rather than to host-related factors.
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Clofazimine contributes sustained antimicrobial activity after treatment cessation in a mouse model of tuberculosis chemotherapy
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Rosemary V Swanson, Nicole C Ammerman, Bongani Ngcobo, John W Adamson, Chivonne Moodley, Afton Dorasamy, Sashen Moodley, Zinhle Mgaga, Linda A Bester, Sanil D SinghAbstract:Experimental and clinical studies have indicated that the antileprosy drug Clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in tuberculosis treatment, accumulated Clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the BALB/c mouse model of chronic tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either isoniazid alone, Clofazimine alone, the first-line regimen rifampin-isoniazid-pyrazinamide-ethambutol, or a first-line regimen where Clofazimine was administered in place of ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation and 2, 4, 6, and 8 weeks after treatment was stopped. Bacterial regrowth was delayed in all mice receiving Clofazimine, either alone or in combination, compared to the mice that did not receive Clofazimine. This effect was especially evident in mice receiving multidrug therapy. In mice not receiving Clofazimine, bacterial regrowth began almost immediately after treatment was stopped, while in mice receiving Clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum Clofazimine levels remained at or above the 0.25-μg/ml MIC for M. tuberculosis Thus, sustained activity of Clofazimine may be important in the treatment-shortening effect associated with this drug.
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pharmacokinetics and pharmacodynamics of Clofazimine in a mouse model of tuberculosis
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Rosemary V Swanson, Nicole C Ammerman, Asa Tapley, Bongani Ngcobo, Chivonne Moodley, Afton Dorasamy, Sashen Moodley, Zinhle Mgaga, John H Adamson, Linda A BesterAbstract:The antileprosy drug Clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of the drug is not evidence based, and the optimal dosing is unknown. Our objective was to conduct a preclinical evaluation of the pharmacokinetics and pharmacodynamics of Clofazimine in the mouse model of tuberculosis, with the goal of providing useful information on dosing for future studies. Pharmacokinetic parameters were evaluated in infected and uninfected BALB/c mice. Pharmacodynamic parameters were evaluated in Mycobacterium tuberculosis-infected mice that were treated for 12 weeks with one of six different Clofazimine dosing regimens, i.e., doses of 6.25, 12.5, and 25 mg/kg of body weight/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, livers, and spleens of the mice, reaching levels of greater than 50 μg/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 μg/ml. Elimination of Clofazimine was extremely slow, and the half-life was dependent on the duration of drug administration. Clofazimine exhibited dose-dependent tissue and serum concentrations. At any dose, Clofazimine did not have bactericidal activity during the first 2 weeks of administration but subsequently demonstrated potent, dose-independent bactericidal activity. The antituberculosis activity of Clofazimine was dependent on neither the dose administered nor the drug concentrations in the tissues, suggesting that much lower doses could be effectively used for tuberculosis treatment.
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Clofazimine shortens the duration of the first line treatment regimen for experimental chemotherapy of tuberculosis
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Sandeep Tyagi, John Adamson, Rosemary V Swanson, Paul J Converse, Deepak V Almeida, Nicole C Ammerman, Siyang Li, Jacques H GrossetAbstract:A key drug for the treatment of leprosy, Clofazimine has recently been associated with highly effective and significantly shortened regimens for the treatment of multidrug-resistant tuberculosis (TB). Consequently, we hypothesized that Clofazimine may also shorten the duration of treatment for drug-susceptible TB. We conducted a controlled trial in the mouse model of TB chemotherapy comparing the activity of the 6-mo standard regimen for TB treatment, i.e., 2 mo of daily rifampin, isoniazid, pyrazinamide, and ethambutol followed by 4 mo of rifampin and isoniazid, with a 4-mo Clofazimine-containing regimen: 2 mo of daily rifampin, isoniazid, pyrazinamide, and Clofazimine followed by 2 mo of rifampin, isoniazid, and Clofazimine. Treatment efficacy was assessed on the basis of Mycobacterium tuberculosis colony counts in the lungs and spleens during treatment and on the proportion of mice with culture-positive relapse 6 mo after treatment cessation. No additive effect of Clofazimine was observed after the first week of treatment, but, by the second week of treatment, the colony counts were significantly lower in the Clofazimine-treated mice than in the mice receiving the standard regimen. Lung culture conversion was obtained after 3 and 5 mo in mice treated with the Clofazimine-containing and standard regimens, respectively, and relapse-free cure was obtained after 3 and 6 mo of treatment with the Clofazimine-containing and standard regimens, respectively. Thus, Clofazimine is a promising anti-TB drug with the potential to shorten the duration of TB chemotherapy by at least half (3 mo vs. 6 mo) in the mouse model of TB.
Deepak V Almeida - One of the best experts on this subject based on the ideXlab platform.
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impact of Clofazimine dosing on treatment shortening of the first line regimen in a mouse model of tuberculosis
Antimicrobial Agents and Chemotherapy, 2018Co-Authors: Nicole C Ammerman, Rosemary V Swanson, Deepak V Almeida, Siyang Li, Elaine M Bautista, Vikram Saini, Till F Omansen, Yong Seok Chang, Asa TapleyAbstract:The antileprosy drug Clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, Clofazimine causes doseand duration-dependent skin discoloration in patients, and the optimal Clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impacts of duration, dose, and companion drugs on the treatment-shortening activity of Clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) 6 months after stopping treatment, and the secondary outcome was bactericidal activity, i.e., the decline in the lung bacterial burden during treatment. Our findings indicate that Clofazimine activity is most potent when coad-ministered with first-line drugs continuously throughout treatment and that equivalent treatment-shortening results are obtained with half the dose commonly used in mice. However, our studies also suggest that Clofazimine at low exposures may have negative impacts on treatment outcomes, an effect that was evident only after the first 3 months of treatment. These data provide a sound evidence base to inform Clofazimine dosing strategies to optimize the antituberculosis effect while minimizing skin discoloration. The results also underscore the importance of conducting long-term studies to allow the full evaluation of drugs administered in combination over long durations.
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verapamil increases the bioavailability and efficacy of bedaquiline but not Clofazimine in a murine model of tuberculosis
Antimicrobial Agents and Chemotherapy, 2017Co-Authors: Rokeya Tasneen, Deepak V Almeida, Charles A Peloquin, Kala Barnesboyle, Eric L. NuermbergerAbstract:Drug efflux pumps play important roles in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, Clofazimine, and other drugs against Mycobacterium tuberculosis, has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances in vivo efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the in vitro activity of bedaquiline and Clofazimine against M. tuberculosis clinical isolates, including those harboring rv0678 mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on the oral bioavailability or efficacy of Clofazimine in mice. The addition of verapamil increased the sterilizing activity of a regimen composed of bedaquiline, Clofazimine, and pyrazinamide. These results confirm that verapamil has adjunctive activity in vivo, but they also demonstrate that the adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters, rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil versus increasing the doses of companion drugs.
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mutations in pepq confer low level resistance to bedaquiline and Clofazimine in mycobacterium tuberculosis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Deepak V Almeida, Jacques H Grosset, Sandeep Tyagi, Eric L. Nuermberger, Koen Andries, Thomas R Ioerger, Khisimuzi Mdluli, James C SacchettiniAbstract:The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, ≥4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level Clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and Clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without Clofazimine, and were shown to have bedaquiline and Clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and Clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.
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Clofazimine shortens the duration of the first line treatment regimen for experimental chemotherapy of tuberculosis
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Sandeep Tyagi, John Adamson, Rosemary V Swanson, Paul J Converse, Deepak V Almeida, Nicole C Ammerman, Siyang Li, Jacques H GrossetAbstract:A key drug for the treatment of leprosy, Clofazimine has recently been associated with highly effective and significantly shortened regimens for the treatment of multidrug-resistant tuberculosis (TB). Consequently, we hypothesized that Clofazimine may also shorten the duration of treatment for drug-susceptible TB. We conducted a controlled trial in the mouse model of TB chemotherapy comparing the activity of the 6-mo standard regimen for TB treatment, i.e., 2 mo of daily rifampin, isoniazid, pyrazinamide, and ethambutol followed by 4 mo of rifampin and isoniazid, with a 4-mo Clofazimine-containing regimen: 2 mo of daily rifampin, isoniazid, pyrazinamide, and Clofazimine followed by 2 mo of rifampin, isoniazid, and Clofazimine. Treatment efficacy was assessed on the basis of Mycobacterium tuberculosis colony counts in the lungs and spleens during treatment and on the proportion of mice with culture-positive relapse 6 mo after treatment cessation. No additive effect of Clofazimine was observed after the first week of treatment, but, by the second week of treatment, the colony counts were significantly lower in the Clofazimine-treated mice than in the mice receiving the standard regimen. Lung culture conversion was obtained after 3 and 5 mo in mice treated with the Clofazimine-containing and standard regimens, respectively, and relapse-free cure was obtained after 3 and 6 mo of treatment with the Clofazimine-containing and standard regimens, respectively. Thus, Clofazimine is a promising anti-TB drug with the potential to shorten the duration of TB chemotherapy by at least half (3 mo vs. 6 mo) in the mouse model of TB.
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assessment of Clofazimine activity in a second line regimen for tuberculosis in mice
American Journal of Respiratory and Critical Care Medicine, 2013Co-Authors: Jacques H Grosset, Paul J Converse, Deepak V Almeida, Nicole C Ammerman, Sandeep Tyagi, William R Bishai, D A Enarson, A TrebucqAbstract:Rationale: Although observational studies suggest that Clofazimine-containing regimens are highly active against drug-resistant tuberculosis, the contribution of Clofazimine for the treatment of this disease has never been systematically evaluated. Objectives: Our goal was to directly compare the activity of a standard second-line drug regimen with or without the addition of Clofazimine in a mouse model of multidrug-resistant tuberculosis. Our comparative outcomes included time to culture conversion in the mouse lungs and the percentage of relapses after treatment cessation. Methods: Mice were aerosol-infected with an isoniazid-resistant (as a surrogate of multidrug-resistant) strain of Mycobacterium tuberculosis. Treatment, which was administered for 5 to 9 months, was initiated 2 weeks after infection and comprised the following second-line regimen: daily (5 d/wk) moxifloxacin, ethambutol, and pyrazinamide, supplemented with amikacin during the first 2 months. One-half of the mice also received daily Clofazimine. The decline in lung bacterial load was assessed monthly using charcoal-containing agar to reduce Clofazimine carryover. Relapse was assessed 6 months after treatment cessation. Measurements and Main Results: After 2 months, the bacillary load in lungs was reduced from 9.74 log10 at baseline to 3.61 and 4.68 in mice treated with or without Clofazimine, respectively (P < 0.001). Mice treated with Clofazimine were culture-negative after 5 months, whereas all mice treated without Clofazimine remained heavily culture-positive for the entire 9 months of the study. The relapse rate was 7% among mice treated with Clofazimine for 8 to 9 months. Conclusions: The Clofazimine contribution was substantial in these experimental conditions.