scholarly journals Combination Chemotherapy with the Nitroimidazopyran PA-824 and First-Line Drugs in a Murine Model of Tuberculosis

2006 ◽  
Vol 50 (8) ◽  
pp. 2621-2625 ◽  
Author(s):  
Eric Nuermberger ◽  
Ian Rosenthal ◽  
Sandeep Tyagi ◽  
Kathy N. Williams ◽  
Deepak Almeida ◽  
...  
Keyword(s):  
Murine Model ◽  
Multidrug Resistant ◽  
First Line ◽  
Duration Of Treatment ◽  
Standard Regimen ◽  
Drug Candidates ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Lower Lung ◽  
Tuberculosis Therapy

ABSTRACT The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.

scholarly journals Powerful Bactericidal and Sterilizing Activity of a Regimen Containing PA-824, Moxifloxacin, and Pyrazinamide in a Murine Model of Tuberculosis

2008 ◽  
Vol 52 (4) ◽  
pp. 1522-1524 ◽  
Author(s):  
Eric Nuermberger ◽  
Sandeep Tyagi ◽  
Rokeya Tasneen ◽  
Kathy N. Williams ◽  
Deepak Almeida ◽  
...  
Keyword(s):  
Murine Model ◽  
Multidrug Resistant ◽  
The Novel ◽  
Clinical Testing ◽  
First Line ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

ABSTRACT PA-824 is a nitroimidazo-oxazine in clinical testing for the treatment of tuberculosis. We report that the novel combination of PA-824, moxifloxacin, and pyrazinamide cured mice more rapidly than the first-line regimen of rifampin, isoniazid, and pyrazinamide. If applicable to humans, regimens containing this combination may radically shorten the treatment of multidrug-resistant tuberculosis.

scholarly journals Clofazimine shortens the duration of the first-line treatment regimen for experimental chemotherapy of tuberculosis

2015 ◽  
Vol 112 (3) ◽  
pp. 869-874 ◽  
Author(s):  
Sandeep Tyagi ◽  
Nicole C. Ammerman ◽  
Si-Yang Li ◽  
John Adamson ◽  
Paul J. Converse ◽  
...  
Keyword(s):  
Mouse Model ◽  
Controlled Trial ◽  
Multidrug Resistant ◽  
Duration Of Treatment ◽  
Standard Regimen ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Culture Positive ◽  
Culture Conversion

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.

scholarly journals Promising Antituberculosis Activity of the Oxazolidinone PNU-100480 Relative to That of Linezolid in a Murine Model

2008 ◽  
Vol 53 (4) ◽  
pp. 1314-1319 ◽  
Author(s):  
K. N. Williams ◽  
C. K. Stover ◽  
T. Zhu ◽  
R. Tasneen ◽  
S. Tyagi ◽  
...  
Keyword(s):  
Murine Model ◽  
Multidrug Resistant ◽  
First Line ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Lower Drug ◽  
Bactericidal Activities ◽  
Unit Reduction ◽  
Combination Regimens

ABSTRACT Oxazolidinone antibiotics have activity against Mycobacterium tuberculosis. Linezolid, the only marketed oxazolidinone, has been used off-label in combination regimens to treat multidrug-resistant tuberculosis, but its precise contribution to the efficacy of such combinations is unclear. Another oxazolidinone, PNU-100480, has been demonstrated to have more potent activity in vitro and in a murine model of tuberculosis. In this study, we compared the pharmacokinetics and the antituberculosis activities of these two oxazolidinones over a range of doses and found that linezolid has limited activity at clinically relevant doses in the murine model compared to that of PNU-100480, which has potent bactericidal activity, even at lower drug exposures. These findings were unexpected, given the similar in vitro activities of PNU-100480, its major metabolites, and linezolid. Moreover, the incorporation of PNU-100480 dramatically improved the bactericidal activities of regimens containing current first-line antituberculosis drugs and moxifloxacin. For example, the addition of PNU-100480 (100 mg/kg of body weight/day) to the standard daily regimen of rifampin (rifampicin), isoniazid, and pyrazinamide resulted in an additional 2.0-log10-unit reduction in lung CFU counts during the first 2 months of treatment. The combination of PNU-100480, moxifloxacin, and pyrazinamide, which does not contain either rifampin or isoniazid, was also more active than rifampin, isoniazid, and pyrazinamide. These results suggest that PNU-100480 may have the potential to significantly shorten the duration of therapy for drug-susceptible as well as multidrug-resistant tuberculosis.

scholarly journals Minimal inhibitory concentrations of first-line drugs of multidrug -resistant tuberculosis isolates

Lung India ◽  
2012 ◽  
Vol 29 (4) ◽  
pp. 309 ◽  
Author(s):  
Nicolas Schönfeld ◽  
Silvan Vesenbeckh ◽  
Holger Rüssmann ◽  
Thorsten Bergmann ◽  
Harald Mauch ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
First Line ◽  
Minimal Inhibitory Concentrations ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

scholarly journals Status of antituberculosis drug resistance in Saudi Arabia 1979-98

2021 ◽  
Vol 8 (4-5) ◽  
pp. 664-670
Author(s):  
K. K. Abu Amero
Keyword(s):  
Saudi Arabia ◽  
Drug Sensitivity ◽  
National Policy ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
First Line ◽  
Sensitivity Testing ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

All published material on the prevalence of drug-resistant tuberculosis within Saudi Arabia over the period 1979-98 was reviewed. The prevalence of single-drug-resistant tuberculosis ranged from 3.4% to 41% for isoniazid, 0% to 23.4% for rifampicin, 0.7% to 22.7% for streptomycin and 0% to 6.9% for ethambutol. The prevalence of multidrug-resistant tuberculosis [defined by WHO as resist1qance to two or more first-line antituberculosis drugs] ranged from 1.5% to 44% in different regions. No strong conclusions could be drawn owing to variations in the populations studied, geographical origins, site of Mycobacterium tuberculosis isolation [pulmonary or extrapulmonary] and drug sensitivity testing. However, the need to develop a standardized national policy for surveillance of drug-resistant tuberculosis in Saudi Arabia is clear

Tuberculosis Multidrug-resistant Tuberculosis – From Epidemiology to Treatment Design

2015 ◽  
Vol 01 (01) ◽  
pp. 20
Author(s):  
Jean-Pierre Zellweger ◽  
Keyword(s):  
Multidrug Resistant ◽  
Rapid Identification ◽  
Drug Management ◽  
Duration Of Treatment ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Selection Of

Multidrug-resistant tuberculosis (MDR-TB) and extensively resistant tuberculosis (XDR-TB) are present in most regions of the world and represent a serious threat to the control of tuberculosis. They usually result from errors somewhere along the chain of management of the disease that favoured the selection of resistant mutants, progressively replacing drug-sensitive strains and transmitted to further patients. The currently recommended strategies for the control of this serious situation is the rapid identification of drug-resistant strains, careful drug management of patients with second-line drugs and prevention of the transmission of mycobacteria to contacts. Optimal selection and number of drugs and duration of treatment are not clearly defined. Prevention of the creation of additional cases of MDR-TB is crucial.

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