scholarly journals Sterilizing Activities of Novel Combinations Lacking First- and Second-Line Drugs in a Murine Model of Tuberculosis

2012 ◽  
Vol 56 (6) ◽  
pp. 3114-3120 ◽  
Author(s):  
Kathy Williams ◽  
Austin Minkowski ◽  
Opokua Amoabeng ◽  
Charles A. Peloquin ◽  
Dinesh Taylor ◽  
...  
Keyword(s):  
Murine Model ◽  
Rank Order ◽  
Building Blocks ◽  
Drug Combinations ◽  
New Drugs ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Duration Of Treatment ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis

ABSTRACTNovel oral regimens composed of new drugs with potent activity againstMycobacterium tuberculosisand no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

scholarly journals Sterilizing Activity of Novel TMC207- and PA-824-Containing Regimens in a Murine Model of Tuberculosis

2011 ◽  
Vol 55 (12) ◽  
pp. 5485-5492 ◽  
Author(s):  
Rokeya Tasneen ◽  
Si-Yang Li ◽  
Charles A. Peloquin ◽  
Dinesh Taylor ◽  
Kathy N. Williams ◽  
...  
Keyword(s):  
Murine Model ◽  
Building Blocks ◽  
Drug Combinations ◽  
New Drugs ◽  
Drug Resistant ◽  
First Line ◽  
Duration Of Treatment ◽  
Resistant Tuberculosis ◽  
Novel Drug

ABSTRACTTo truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.

Acquisition of cross-resistance to Bedaquiline and Clofazimine following treatment for Tuberculosis in Pakistan

2019 ◽  
Author(s):  
Arash Ghodousi ◽  
Alamdar Hussain Rizvi ◽  
Aurangzaib Quadir Baloch ◽  
Abdul Ghafoor ◽  
Faisal Masood Khanzada ◽  
...  
Keyword(s):  
Minimum Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Acquired Resistance ◽  
New Drugs ◽  
Cross Resistance ◽  
Whole Genome ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Tuberculosis Patients ◽  
Resistant Tuberculosis

AbstractWe report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential culture isolates from 30 drug-resistant tuberculosis patients on bedaquiline-containing regimen were tested for minimum inhibitory concentration (MIC) and whole genome sequencing. An increase in MICs associated with cross-resistance to clofazimine and appearance of specific mutations was documented in six cases. The study underlines that appropriate monitoring is mandatory for the introduction of new drugs.

scholarly journals Acquisition of Cross-Resistance to Bedaquiline and Clofazimine following Treatment for Tuberculosis in Pakistan

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Arash Ghodousi ◽  
Alamdar Hussain Rizvi ◽  
Aurangzaib Quadir Baloch ◽  
Abdul Ghafoor ◽  
Faisal Masood Khanzada ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
New Drugs ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Tuberculosis Patients ◽  
Resistant Tuberculosis ◽  
Surveillance Programs ◽  
Detection Of Mutations

ABSTRACT We report on the first six cases of acquired resistance to bedaquiline in Pakistan. Seventy sequential isolates from 30 drug-resistant-tuberculosis patients on bedaquiline-containing regimens were retrospectively tested for bedaquiline resistance by MIC testing and by the detection of mutations in relevant genes. We documented cases failing therapy that developed specific mutations in Rv0678 and had increased MICs associated with cross-resistance to clofazimine during treatment. This study underlines the relevance of surveillance programs following the introduction of new drugs.

scholarly journals New and repurposed drugs to treat multidrug- and extensively drug-resistant tuberculosis

2018 ◽  
Vol 44 (2) ◽  
pp. 153-160 ◽  
Author(s):  
Denise Rossato Silva ◽  
Margareth Dalcolmo ◽  
Simon Tiberi ◽  
Marcos Abdo Arbex ◽  
Marcela Munoz-Torrico ◽  
...  
Keyword(s):  
New Drugs ◽  
Special Focus ◽  
Drug Resistant ◽  
Success Rates ◽  
Duration Of Treatment ◽  
Drug Resistant Tuberculosis ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant ◽  
Repurposed Drugs

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the “white plague”, and promising results are being reported.

Cross-Resistance in Anti-Tubercular Drugs - A Conundrum in the Management of Drug-Resistant Tuberculosis

2021 ◽  
Author(s):  
Amit Sharma
Keyword(s):  
Successful Outcome ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Duration Of Treatment ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Long Duration ◽  
Final Treatment ◽  
The World ◽  
Mdr Tb

The problem of DR-TB especially MDR-TB/RR-TB, Pre-XDR TB, and XDR TB is menacing the world in a fearsome manner. The treatment of patients with such complicated forms of TB is fraught with difficulties owing to the toxicity of second-line drugs and decreased efficacy, not to mention poor compliance by patients keeping in view the adverse effects and long duration of treatment. To add to all these strictures in the successful outcome of DR-TB outcomes, the phenomenon of Cross-Resistance amongst anti-tubercular drugs has also to be reckoned with. In this review, we have tried to address this particular aspect which plays one of the key roles in the final treatment outcome of patients with such complicated forms of TB.

Compassionate use of and expanded access to new drugs for drug-resistant tuberculosis [Review article]

2013 ◽  
Vol 17 (2) ◽  
pp. 146-152 ◽  
Author(s):  
C. R. Jr Horsburgh ◽  
M. Haxaire-Theeuwes ◽  
C. Lienhardt ◽  
C. Wingfield ◽  
D. McNeeley ◽  
...  
Keyword(s):  
Review Article ◽  
New Drugs ◽  
Drug Resistant ◽  
Compassionate Use ◽  
Drug Resistant Tuberculosis ◽  
Expanded Access ◽  
Resistant Tuberculosis

scholarly journals A Novel Inhibitor of Gyrase B Is a Potent Drug Candidate for Treatment of Tuberculosis and Nontuberculosis Mycobacterial Infections

2014 ◽  
Vol 59 (3) ◽  
pp. 1455-1465 ◽  
Author(s):  
Christopher P. Locher ◽  
Steven M. Jones ◽  
Brian L. Hanzelka ◽  
Emanuele Perola ◽  
Carolyn M. Shoen ◽  
...  
Keyword(s):  
Parent Compound ◽  
New Drugs ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Content Type ◽  
Mycobacterial Infections ◽  
Resistant Tuberculosis ◽  
Gyrase A

ABSTRACTNew drugs to treat drug-resistant tuberculosis are urgently needed. Extensively drug-resistant and probably the totally drug-resistant tuberculosis strains are resistant to fluoroquinolones like moxifloxacin, which target gyrase A, and most people infected with these strains die within a year. In this study, we found that a novel aminobenzimidazole, VXc-486, which targets gyrase B, potently inhibits multiple drug-sensitive isolates and drug-resistant isolates ofMycobacterium tuberculosisin vitro(MICs of 0.03 to 0.30 μg/ml and 0.08 to 5.48 μg/ml, respectively) and reduces mycobacterial burdens in lungs of infected micein vivo. VXc-486 is active against drug-resistant isolates, has bactericidal activity, and kills intracellular and dormantM. tuberculosisbacteria in a low-oxygen environment. Furthermore, we found that VXc-486 inhibits the growth of multiple strains ofMycobacterium abscessus,Mycobacterium aviumcomplex, andMycobacterium kansasii(MICs of 0.1 to 2.0 μg/ml), as well as that of several strains ofNocardiaspp. (MICs of 0.1 to 1.0 μg/ml). We made a direct comparison of the parent compound VXc-486 and a phosphate prodrug of VXc-486 and showed that the prodrug of VXc-486 had more potent killing ofM. tuberculosisthan did VXc-486in vivo. In combination with other antimycobacterial drugs, the prodrug of VXc-486 sterilizedM. tuberculosisinfection when combined with rifapentine-pyrazinamide and bedaquiline-pyrazinamide in a relapse infection study in mice. Furthermore, the prodrug of VXc-486 appeared to perform at least as well as the gyrase A inhibitor moxifloxacin. These findings warrant further development of the prodrug of VXc-486 for the treatment of tuberculosis and nontuberculosis mycobacterial infections.

scholarly journals Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment

2019 ◽  
Vol 69 (7) ◽  
pp. 1229-1231 ◽  
Author(s):  
Silke Polsfuss ◽  
Sabine Hofmann-Thiel ◽  
Matthias Merker ◽  
David Krieger ◽  
Stefan Niemann ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
New Drugs ◽  
Tuberculosis Treatment ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Low Level ◽  
Resistant Tuberculosis ◽  
Extensively Drug Resistant

Abstract Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.

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