Beige mice were inoculated intravenously with 10(7.90) CFU of Mycobacterium avium 101. Among the ... more Beige mice were inoculated intravenously with 10(7.90) CFU of Mycobacterium avium 101. Among the untreated control mice, when the mean CFU per spleen increased to a level greater than 10(8), small numbers of organisms resistant to clarithromycin (CLARI) were isolated from some of the spleens; the frequency of CLARI-resistant mutants was estimated to be between 10(-8) and 10(-9). In mice treated with 200 mg of CLARI per kg of body weight six times weekly, however, CLARI-resistant organisms were isolated from the spleens of all mice examined after treatment for 8 weeks; the mean CFU per spleen and the frequency of resistant mutants were significantly greater than those of control mice and increased further after treatment for 16 weeks. The MICs of CLARI against the resistant organisms isolated from both control and treated mice were > or = 512 micrograms/ml.
La tuberculose est une maladie infectieuse, contagieuse, connue depuis l’Antiquite, dont l’agent ... more La tuberculose est une maladie infectieuse, contagieuse, connue depuis l’Antiquite, dont l’agent responsable, Mycobacterium tuberculosis, a ete identifie en 1882 par Robert Koch. Bien que l’on dispose maintenant d’un traitement antibiotique efficace, la tuberculose est toujours d’actualite car elle reste en tete des maladies infectieuses en terme de mortalite, surtout dans les pays en developpement. Elle est en effet responsable du deces de 3 millions de personnes par an dans le monde [1]. Dans les pays industrialises, malgre un recul generalise de l’endemie tuberculeuse, il s’est produit un regain d’interet pour la tuberculose au debut des annees 90 en raison d’un arret brutal de la regression reguliere de l’incidence de la maladie aux Etats-Unis et de la montee de la resistance aux antibiotiques. Outre une remobilisation des autorites sanitaires et des acteurs de Sante publique, le regain d’interet pour la tuberculose a eu pour effet de donner un coup de fouet a la recherche sur l...
After 4 weeks of treatment, clarithromycin (CLAR) and amikacin showed similar antimicrobial activ... more After 4 weeks of treatment, clarithromycin (CLAR) and amikacin showed similar antimicrobial activities against the Mycobacterium avium complex in mice. There was a difference, however, in the effectiveness of the drugs in different types of mice: both drugs displayed bactericidal effects in beige mice but only bacteriostatic effects in nude mice. Because the effectiveness of CLAR is less in nude mice than in beige mice, the predictive value of the nude mouse model for the efficacy of chemotherapy is less than that of the beige mouse model.
Although the MICs of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin, or KRM... more Although the MICs of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin, or KRM-1648 (KRM), for Mycobacterium avium complex (MAC) were significantly lower than those of other drugs, its in vivo activity was very weak. Beginning 28 days after inoculation, beige mice that had been infected intravenously with 1.87 x 10(7) CFU of MAC 101 were administered KRM alone, clarithromycin (CLARI) alone, or CLARI plus KRM six times weekly for 16 weeks. In contrast to the mice treated with CLARI-containing regimens, the mortality and the mean spleen weights of mice treated with KRM alone (either 10 or 20 mg/kg of body weight per dose) did not differ significantly from those of untreated mice, their numbers of CFU were very much greater than pretreatment values, and multiplication of MAC was only slightly inhibited. Although monotherapy by KRM selected KRM-resistant mutants, the selection was very weak; the mean number of CFU and the frequency of KRM-resistant mutants increased b...
To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bacte... more To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bactericidal effect of a single-dose combination of ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), against Mycobacterium leprae was studied in the mouse footpad system and in previously untreated lepromatous leprosy patients. Bactericidal activity was measured by the proportional bactericidal method. In mouse experiments, the activity of a single dose of the combination OFLO-MINO was dosage related; the higher dosage of the combination displayed bactericidal activity which was significantly inferior to that of a single dose of RMP, whereas the lower dosage did not exhibit a bactericidal effect. In the clinical trial, 20 patients with previously untreated lepromatous leprosy were treated with a single dose consisting of either 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The OFLO-MINO combination exhibited definite bacter...
Buruli ulcer (BU), caused by Mycobacterium ulcerans , is a neglected tropical skin and soft tissu... more Buruli ulcer (BU), caused by Mycobacterium ulcerans , is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR).
Antimicrobial agents and chemotherapy, Jan 7, 2018
The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-cours... more The anti-leprosy 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 dose- and 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 impact 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) six months after stopping treatment, and the secondary outcome was bactericidal activity, , the decline in lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when co-administered with first-line ...
The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment... more 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 c...
Antimicrobial agents and chemotherapy, May 29, 2016
Experimental and clinical studies have indicated that the anti-leprosy drug clofazimine may contr... more Experimental and clinical studies have indicated that the anti-leprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in the tissues, has a long half-life, and remains in the body for months after stopping administration. We hypothesized that, in tuberculosis treatment, the 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 post-treatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation an...
Beige mice were inoculated intravenously with 10(7.90) CFU of Mycobacterium avium 101. Among the ... more Beige mice were inoculated intravenously with 10(7.90) CFU of Mycobacterium avium 101. Among the untreated control mice, when the mean CFU per spleen increased to a level greater than 10(8), small numbers of organisms resistant to clarithromycin (CLARI) were isolated from some of the spleens; the frequency of CLARI-resistant mutants was estimated to be between 10(-8) and 10(-9). In mice treated with 200 mg of CLARI per kg of body weight six times weekly, however, CLARI-resistant organisms were isolated from the spleens of all mice examined after treatment for 8 weeks; the mean CFU per spleen and the frequency of resistant mutants were significantly greater than those of control mice and increased further after treatment for 16 weeks. The MICs of CLARI against the resistant organisms isolated from both control and treated mice were > or = 512 micrograms/ml.
La tuberculose est une maladie infectieuse, contagieuse, connue depuis l’Antiquite, dont l’agent ... more La tuberculose est une maladie infectieuse, contagieuse, connue depuis l’Antiquite, dont l’agent responsable, Mycobacterium tuberculosis, a ete identifie en 1882 par Robert Koch. Bien que l’on dispose maintenant d’un traitement antibiotique efficace, la tuberculose est toujours d’actualite car elle reste en tete des maladies infectieuses en terme de mortalite, surtout dans les pays en developpement. Elle est en effet responsable du deces de 3 millions de personnes par an dans le monde [1]. Dans les pays industrialises, malgre un recul generalise de l’endemie tuberculeuse, il s’est produit un regain d’interet pour la tuberculose au debut des annees 90 en raison d’un arret brutal de la regression reguliere de l’incidence de la maladie aux Etats-Unis et de la montee de la resistance aux antibiotiques. Outre une remobilisation des autorites sanitaires et des acteurs de Sante publique, le regain d’interet pour la tuberculose a eu pour effet de donner un coup de fouet a la recherche sur l...
After 4 weeks of treatment, clarithromycin (CLAR) and amikacin showed similar antimicrobial activ... more After 4 weeks of treatment, clarithromycin (CLAR) and amikacin showed similar antimicrobial activities against the Mycobacterium avium complex in mice. There was a difference, however, in the effectiveness of the drugs in different types of mice: both drugs displayed bactericidal effects in beige mice but only bacteriostatic effects in nude mice. Because the effectiveness of CLAR is less in nude mice than in beige mice, the predictive value of the nude mouse model for the efficacy of chemotherapy is less than that of the beige mouse model.
Although the MICs of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin, or KRM... more Although the MICs of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin, or KRM-1648 (KRM), for Mycobacterium avium complex (MAC) were significantly lower than those of other drugs, its in vivo activity was very weak. Beginning 28 days after inoculation, beige mice that had been infected intravenously with 1.87 x 10(7) CFU of MAC 101 were administered KRM alone, clarithromycin (CLARI) alone, or CLARI plus KRM six times weekly for 16 weeks. In contrast to the mice treated with CLARI-containing regimens, the mortality and the mean spleen weights of mice treated with KRM alone (either 10 or 20 mg/kg of body weight per dose) did not differ significantly from those of untreated mice, their numbers of CFU were very much greater than pretreatment values, and multiplication of MAC was only slightly inhibited. Although monotherapy by KRM selected KRM-resistant mutants, the selection was very weak; the mean number of CFU and the frequency of KRM-resistant mutants increased b...
To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bacte... more To develop a fully supervisable, monthly administered regimen for treatment of leprosy, the bactericidal effect of a single-dose combination of ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP), against Mycobacterium leprae was studied in the mouse footpad system and in previously untreated lepromatous leprosy patients. Bactericidal activity was measured by the proportional bactericidal method. In mouse experiments, the activity of a single dose of the combination OFLO-MINO was dosage related; the higher dosage of the combination displayed bactericidal activity which was significantly inferior to that of a single dose of RMP, whereas the lower dosage did not exhibit a bactericidal effect. In the clinical trial, 20 patients with previously untreated lepromatous leprosy were treated with a single dose consisting of either 600 mg of RMP plus 400 mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The OFLO-MINO combination exhibited definite bacter...
Buruli ulcer (BU), caused by Mycobacterium ulcerans , is a neglected tropical skin and soft tissu... more Buruli ulcer (BU), caused by Mycobacterium ulcerans , is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an 8-week course of rifampin (RIF) at 10 mg/kg of body weight and 150 mg/kg streptomycin (STR).
Antimicrobial agents and chemotherapy, Jan 7, 2018
The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-cours... more The anti-leprosy 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 dose- and 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 impact 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) six months after stopping treatment, and the secondary outcome was bactericidal activity, , the decline in lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when co-administered with first-line ...
The novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment... more 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 c...
Antimicrobial agents and chemotherapy, May 29, 2016
Experimental and clinical studies have indicated that the anti-leprosy drug clofazimine may contr... more Experimental and clinical studies have indicated that the anti-leprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in the tissues, has a long half-life, and remains in the body for months after stopping administration. We hypothesized that, in tuberculosis treatment, the 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 post-treatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation an...
Uploads
Papers by Jacques Grosset