scholarly journals Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Jian Xu ◽  
Si-Yang Li ◽  
Deepak V. Almeida ◽  
Rokeya Tasneen ◽  
Kala Barnes-Boyle ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mouse Models ◽  
Treatment Duration ◽  
Resistant Mutant ◽  
Murine Models ◽  
First Line ◽  
Independent Contribution ◽  
Resistant Mutants ◽  
Treatment Of Infection ◽  
Selection Of

ABSTRACT Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined, and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in a 1-log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to that for BMZ treatment alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 versus 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to the level for BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.

scholarly journals Contribution of pretomanid to novel regimens containing bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis

2019 ◽  
Author(s):  
Jian Xu ◽  
Si-Yang Li ◽  
Deepak V. Almeida ◽  
Rokeya Tasneen ◽  
Kala Barnes-Boyle ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mouse Models ◽  
Treatment Duration ◽  
Resistant Mutant ◽  
Murine Models ◽  
First Line ◽  
Independent Contribution ◽  
Resistant Mutants ◽  
Treatment Of Infection ◽  
Selection Of

AbstractNovel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure TB in BALB/c mice compared to the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to BMZ resulted in a 1 log10 greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to BMZ alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 vs. 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.

scholarly journals Treatment-shortening effect of a novel regimen combining high-dose rifapentine and clofazimine in pathologically distinct mouse models of tuberculosis

2019 ◽  
Author(s):  
Vikram Saini ◽  
Nicole C. Ammerman ◽  
Yong Seok Chang ◽  
Rokeya Tasneen ◽  
Richard E. Chaisson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mouse Model ◽  
Mouse Models ◽  
Treatment Duration ◽  
High Dose ◽  
First Line ◽  
Duration Of Treatment ◽  
Treatment Regimens ◽  
Tb Treatment

ABSTRACTHigh-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.

scholarly journals Treatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of Tuberculosis

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Vikram Saini ◽  
Nicole C. Ammerman ◽  
Yong Seok Chang ◽  
Rokeya Tasneen ◽  
Richard E. Chaisson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mouse Model ◽  
Mouse Models ◽  
Treatment Duration ◽  
High Dose ◽  
First Line ◽  
Duration Of Treatment ◽  
Treatment Regimens ◽  
Tb Treatment

ABSTRACT 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.

scholarly journals Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB/FeJ Mice Is Best Explained by Neutral pH of Caseum

2015 ◽  
Vol 60 (2) ◽  
pp. 735-743 ◽  
Author(s):  
Jean-Philippe Lanoix ◽  
Thomas Ioerger ◽  
Aimee Ormond ◽  
Firat Kaya ◽  
James Sacchettini ◽  
...  
Keyword(s):  
Total Population ◽  
First Line ◽  
Epithelial Lining Fluid ◽  
Lung Lesions ◽  
Ph Values ◽  
Neutral Ph ◽  
Similar Dose ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACTPyrazinamide (PZA) is one of only two sterilizing drugs in the first-line antituberculosis regimen. Its activity is strongly pH dependent; the MIC changes by several orders of magnitude over a range of pH values that may be encountered in variousin vivocompartments. We recently reported selective inactivity of PZA in a subset of C3HeB/FeJ mice with large caseous lung lesions. In the present study, we evaluated whether such inactivity was explained by poor penetration of PZA into such lesions or selection of drug-resistant mutants. Despite demonstrating similar dose-proportional PZA exposures in plasma, epithelial lining fluid, and lung lesions, no dose response was observed in a subset of C3HeB/FeJ mice with the highest CFU burden. Although PZA-resistant mutants eventually replaced the susceptible bacilli in BALB/c mice and in C3HeB/FeJ mice with low total CFU burdens, they never exceeded 1% of the total population in nonresponding C3HeB/FeJ mice. The selective inactivity of PZA in large caseous lesions of C3HeB/FeJ mice is best explained by the neutral pH of liquefying caseum.

scholarly journals Fluoroquinolone Action against Mycobacteria: Effects of C-8 Substituents on Growth, Survival, and Resistance

1998 ◽  
Vol 42 (11) ◽  
pp. 2978-2984 ◽  
Author(s):  
Yuzhi Dong ◽  
Chen Xu ◽  
Xilin Zhao ◽  
John Domagala ◽  
Karl Drlica
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Species ◽  
Resistant Mutant ◽  
Methoxyl Group ◽  
Bacteriostatic Activity ◽  
Dna Breaks ◽  
Lethal Action ◽  
Resistant Strains ◽  
Resistant Mutants ◽  
Selection Of

ABSTRACT Fluoroquinolones trap gyrase on DNA as bacteriostatic complexes from which lethal DNA breaks are released. Substituents at the C-8 position increase activities of N-1-cyclopropyl fluoroquinolones against several bacterial species. In the present study, a C-8-methoxyl group improved bacteriostatic action againstgyrA (gyrase-resistant) strains ofMycobacterium tuberculosis and M. bovis BCG. It also enhanced lethal action against gyrase mutants of M. bovis BCG. When cultures of M. smegmatis, M. bovis BCG, and M. tuberculosis were challenged with a C-8-methoxyl fluoroquinolone, no resistant mutant was recovered under conditions in which more than 1,000 mutants were obtained with a C-8-H control. A C-8-bromo substituent also increased bacteriostatic and lethal activities against a gyrA mutant of M. bovisBCG. When lethal activity was normalized to bacteriostatic activity, the C-8-methoxyl compound was more bactericidal than its C-8-H control, while the C-8-bromo fluoroquinolone was not. The C-8-methoxyl compound was also found to be more effective than the C-8-bromo fluoroquinolone at reducing selection of resistant mutants when each was compared to a C-8-H control over a broad concentration range. These data indicate that a C-8-methoxyl substituent, which facilitates attack of first-step gyrase mutants, may help make fluoroquinolones effective antituberculosis agents.

scholarly journals Mutant Prevention Concentration as a Measure of Fluoroquinolone Potency against Mycobacteria

2000 ◽  
Vol 44 (12) ◽  
pp. 3337-3343 ◽  
Author(s):  
Georg Sindelar ◽  
Xilin Zhao ◽  
Anthony Liew ◽  
Yuzhi Dong ◽  
Tao Lu ◽  
...  
Keyword(s):  
Small Group ◽  
Mycobacterium Smegmatis ◽  
Resistant Mutant ◽  
Wild Type ◽  
Alkyl Groups ◽  
Mutant Prevention Concentration ◽  
Gyrase A ◽  
Resistant Mutants ◽  
Selection Of ◽  
Selection Of Resistance

ABSTRACT Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated. To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations. Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring. When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells. For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs. Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not. With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.

scholarly journals Bactericidal and Sterilizing Activity of a Novel Regimen with Bedaquiline, Pretomanid, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Si-Yang Li ◽  
Rokeya Tasneen ◽  
Sandeep Tyagi ◽  
Heena Soni ◽  
Paul J. Converse ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Murine Model ◽  
Drug Combination ◽  
Treatment Duration ◽  
Additional Treatment ◽  
Drug Resistant ◽  
The Novel ◽  
First Line ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome.

scholarly journals Dose-Ranging Comparison of Rifampin and Rifapentine in Two Pathologically Distinct Murine Models of Tuberculosis

2012 ◽  
Vol 56 (8) ◽  
pp. 4331-4340 ◽  
Author(s):  
Ian M. Rosenthal ◽  
Rokeya Tasneen ◽  
Charles A. Peloquin ◽  
Ming Zhang ◽  
Deepak Almeida ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Body Weight ◽  
Mycobacterium Tuberculosis ◽  
Mouse Strains ◽  
Murine Models ◽  
First Line ◽  
Duration Of Treatment ◽  
Content Type ◽  
Daily Dose ◽  
Dose Ranging

ABSTRACTIn previous experiments, replacing the 10-mg/kg of body weight daily dose of rifampin with 7.5 to 10 mg/kg of rifapentine in combinations containing isoniazid and pyrazinamide reduced the duration of treatment needed to cure tuberculosis in BALB/c mice by approximately 50% due to rifapentine's more potent activity and greater drug exposures obtained. In the present study, we performed dose-ranging comparisons of the bactericidal and sterilizing activities of rifampin and rifapentine, alone and in combination with isoniazid and pyrazinamide with or without ethambutol, in BALB/c mice and in C3HeB/FeJ mice, which develop necrotic lung granulomas after infection withMycobacterium tuberculosis. Each rifamycin demonstrated a significant increase in sterilizing activity with increasing dose. Rifapentine was roughly 4 times more potent in both mouse strains. These results reinforce the rationale for ongoing clinical trials to ascertain the highest well-tolerated doses of rifampin and rifapentine. This study also provides an important benchmark for the efficacy of the first-line regimen in C3HeB/FeJ mice, a strain in which the lung lesions observed afterM. tuberculosisinfection may better represent the pathology of human tuberculosis.

PILONIDAL DISEASE: CHANGES IN UNDERSTANDING OF ETIOLOGY, PATHOGENESIS AND APPROACH TO TREATMENT

2019 ◽  
Vol 72 (8) ◽  
pp. 1559-1565
Author(s):  
Viktor Konoplitskyi ◽  
Ruslan Shavliuk ◽  
Dmytro Dmytriiev ◽  
Kostiantyn Dmytriiev ◽  
Oleksii Kyrychenko ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Pilonidal Sinus ◽  
Randomized Clinical Trials ◽  
Web Of Science ◽  
Surgical Intervention ◽  
Pilonidal Disease ◽  
Treatment Methods ◽  
Principles Of Treatment ◽  
Selection Of

Data from Web of Science, SCOPUS, Pub Med, Medline, E-library, and other sources was used in writing this article. The main focus was directed towards literature written in English. The selection of literature was based on such concepts as: etiopathogenesis, historical principles of treatment, methods of surgical and non-surgical intervention. Data from metanalysis publications and randomized clinical trials pertaining to the treatment of the pilonidal sinus at various stages of its formation was used, as well.

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