scholarly journals Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis

2020 ◽  
Author(s):  
Jian Xu ◽  
Paul J. Converse ◽  
Anna M. Upton ◽  
Khisimuzi Mdluli ◽  
Nader Fotouhi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Safety Margin ◽  
Drug Resistant ◽  
The Novel ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Short Course ◽  
Potential Safety ◽  
Emergence Of Resistance

AbstractSince its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8× MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.

scholarly journals Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistant Rv0678 mutant in a mouse model of tuberculosis

2021 ◽  
Author(s):  
Jian Xu ◽  
Paul J. Converse ◽  
Anna M. Upton ◽  
Khisimuzi Mdluli ◽  
Nader Fotouhi ◽  
...  
Keyword(s):  
Mouse Model ◽  
Safety Margin ◽  
Drug Resistant ◽  
The Novel ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Short Course ◽  
Potential Safety ◽  
Emergence Of Resistance

Since its conditional approval in 2012, bedaquiline (BDQ) has been a valuable tool for treatment of drug-resistant tuberculosis. More recently, a novel short-course regimen combining BDQ with pretomanid and linezolid won approval to treat highly drug-resistant tuberculosis. Clinical reports of emerging BDQ resistance have identified mutations in Rv0678 that de-repress the expression of the MmpL5/MmpS5 efflux transporter as the most common cause. Because the effect of these mutations on bacterial susceptibility to BDQ is relatively small (e.g., 2-8x MIC shift), increasing the BDQ dose would increase antibacterial activity but also pose potential safety concerns, including QTc prolongation. Substitution of BDQ with another diarylquinoline with superior potency and/or safety has the potential to overcome these limitations. TBAJ-587 has greater in vitro potency than BDQ, including against Rv0678 mutants, and may offer a larger safety margin. Using a mouse model of tuberculosis and different doses of BDQ and TBAJ-587, we found that against wild-type M. tuberculosis H37Rv and an isogenic Rv0678 mutant, TBAJ-587 has greater efficacy against both strains than BDQ, whether alone or in combination with pretomanid and either linezolid or moxifloxacin and pyrazinamide. TBAJ-587 also reduced the emergence of resistance to diarylquinolines and pretomanid.

Is short-course therapy enough at drug-resistant tuberculosis?

2018 ◽  
Vol 66 (4) ◽  
pp. 280-287
Author(s):  
Hamza OGUN ◽  
İpek ÖZMEN ◽  
Elif ÖZARI YILDIRIM ◽  
Tülay TÖRÜN ◽  
Haluk Celalettin ÇALIŞIR
Keyword(s):  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Short Course

scholarly journals Pharmacokinetics and target attainment of SQ109 in plasma and human-like tuberculosis lesions in rabbits

2021 ◽  
Author(s):  
Oluwaseun Egbelowo ◽  
Jansy P. Sarathy ◽  
Kamunkhwala Gausi ◽  
Matthew D. Zimmerman ◽  
Han Wang ◽  
...  
Keyword(s):  
Rabbit Model ◽  
Multidrug Resistant ◽  
Clinical Development ◽  
Drug Candidate ◽  
Parameter Estimates ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Bacterial Populations ◽  
Resistant Tuberculosis

SQ109 is a novel well-tolerated drug candidate in clinical development for the treatment of drug resistant tuberculosis (TB). It is the only inhibitor of the MmpL3 mycolic acid transporter in clinical development. No SQ109 resistant mutant has been directly isolated thus far, in vitro, in mice or in patients, tentatively attributed to its multiple targets. It is considered as a potential replacement for poorly tolerated components of multidrug-resistant TB regimens. To prioritize SQ109-containing combinations with best potential for cure and treatment shortening, one must understand its contribution against different bacterial populations in pulmonary lesions. Here we have characterized the pharmacokinetics of SQ109 in the rabbit model of active TB and its penetration at the sites of disease: lung tissue, cellular and necrotic lesions, and caseum. A two-compartment model with first-order absorption and elimination described the plasma pharmacokinetics. At the human-equivalent dose, parameter estimates fell within the ranges published for preclinical species. Tissue concentrations were modelled using an "effect" compartment, showing high accumulation in lung and cellular lesion areas with penetration coefficients in excess of 1,000, and lower passive diffusion in caseum after 7 daily doses. These results, together with the hydrophobic nature and high non-specific caseum binding of SQ109, suggest that multi-week dosing would be required to reach steady state in caseum and poorly vascularized compartments, similar to bedaquiline. Linking lesion pharmacokinetics to SQ109 potency in assays against replicating, non-replicating, and intracellular M. tuberculosis showed SQ109 concentrations markedly above pharmacokinetic-pharmacodynamic targets in lung and cellular lesions throughout the dosing interval. IMPORTANCE Drug-resistant tuberculosis (TB) accounts for over 20% of all fatalities due to drug-resistant pathogens. With recently approved drugs and a promising drug candidate pipeline, the challenge faced by clinical developers is prioritization of drug combinations with the best potential to improve cure rates and shorten treatment duration. To this end, one must understand the contribution of each partner drug against different bacterial populations in pulmonary TB lesions. SQ109 is a safe drug candidate in clinical development for the treatment of multidrug resistant TB. It is active against replicating and non-replicating Mycobacterium tuberculosis persisters in vitro, in mouse models and in patients. SQ109 exhibits extremely low frequency of resistance, unprecedented among all TB drugs so far. Here we characterize the pharmacokinetics and activity of SQ109 at the site of TB disease to inform the selection of drug regimens that account for its lesion-centric pharmacokinetic-pharmacodynamic parameters and best leverage its contribution to efficient disease cure.

scholarly journals Standard Short-Course Chemotherapy for Drug-Resistant Tuberculosis

JAMA ◽  
2000 ◽  
Vol 283 (19) ◽  
pp. 2537 ◽  
Author(s):  
Marcos A. Espinal ◽  
Sang Jae Kim ◽  
Pedro G. Suarez ◽  
Kai Man Kam ◽  
Alexander G. Khomenko ◽  
...  
Keyword(s):  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Short Course ◽  
Short Course Chemotherapy

scholarly journals Beta-lactam antibiotics as reserve medications for the treatment of drug-resistant tuberculosis

2021 ◽  
Vol 66 (5-6) ◽  
pp. 78-85
Author(s):  
G. N. Mozhokina ◽  
A. G. Samoilova ◽  
I. A. Vasilyeva
Keyword(s):  
Drug Resistance ◽  
Review Article ◽  
Drug Resistant ◽  
Beta Lactam ◽  
Drug Resistant Tuberculosis ◽  
Beta Lactam Antibiotics ◽  
Resistant Tuberculosis ◽  
Extensive Drug Resistance ◽  
Tuberculosis Activity

The review article presents an analysis of literature data on the necessity to expand the range of medications possessing anti-tuberculosis activity for the treatment of the most severe forms of drug-resistant tuberculosis through the use of beta-lactam antibiotics in chemotherapy regimens. The mechanism of action of beta- lactam antibiotics on mycobacterium tuberculosis is shown, and the results of in vitro studies to assess their anti-tuberculosis activity are presented. Clinical studies on the use of carbapenems prove the feasibility of their use for the treatment of patients with tuberculosis with multiple and extensive drug resistance of the pathogen.

scholarly journals The study of adverse drug reactions in indoor patients of tuberculosis taking standardized antitubercular therapy (directly observed treatment short-course and programmatic management of drug resistant tuberculosis) in a tertiary care hospital at Surat

2021 ◽  
Vol 10 (5) ◽  
pp. 507
Author(s):  
Payal P. Naik ◽  
Arvindsingh Panwar ◽  
Swati Patel
Keyword(s):  
Tertiary Care Hospital ◽  
Tertiary Care ◽  
P Value ◽  
Care Hospital ◽  
Drug Resistant ◽  
Drug Reactions ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Short Course ◽  
Directly Observed Treatment

Background: Tuberculosis is a serious public health issue in India. The treatment regimen followed is Directly observed treatment short-course (DOTS) and Programmatic Management of Drug resistant Tuberculosis (PMDT) approach. In a long period of treatment adverse drug reactions (ADRs) can be an important programmatic issue. Thus, study was undertaken to assess the ADRs caused by antitubercular therapy in indoor patients in a tertiary care hospital at Surat.Methods: The Observational, prospective study was carried out for one year period. The causality was determined by WHO UMC scale and severity was determined by Modified Hartwig and Siegel scale. Chi square test was applied for statistical analysis.Results: Among 255 tuberculosis patients, 85 (33.3%) patients developed ADRs. Occurrence of ADRs was more among females (46.6%). The commonly involved systems are gastrointestinal (40.6%) followed by haematological (17.9%). The most common ADRs observed were nausea and vomiting (21.7%). High percentage of ADRs causing drugs were isoniazid (30.6%) followed by rifampicin (26.1%). Causality assessment showed 60.4% ADRs were possible, 37.7% ADRs were probable and 1.9% ADRs was certain. Severity assessment scale showed 81.1% of moderate, 12.3% of mild and 6.6% of severe grading. Occurrence of ADRs was more among PMDT (60%) in comparison to DOTS therapy (31.06%) [p value = 0.0084 (significant p value < 0.05)].Conclusions: Antitubercular treatment is safer but early detection, management and reporting of ADRs is required to prevent it at initial stage and helps to decrease default rate.

scholarly journals In-vitro Anti-Tuberculosis, Anti-Efflux Pumps and Anti-Biofilm Effects of Crinum Asiaticum Bulbs

2021 ◽  
Vol 14 (4) ◽  
pp. 1905-1915
Author(s):  
Michael Ofori ◽  
Cynthia Amaning Danquah ◽  
Selase Ativui ◽  
Peace Doe ◽  
Williams Adu Asamoah
Keyword(s):  
Biofilm Formation ◽  
Efflux Pumps ◽  
Chloroform Extract ◽  
World Health ◽  
Drug Resistant ◽  
Drug Resistant Tuberculosis ◽  
Resistant Tuberculosis ◽  
Tract Infections ◽  
Crinum Asiaticum

Drug resistant tuberculosis remains one of the major challenges associated with treatment and management of tuberculosis (TB) in the public health system and in clinical settings. In 2020, the World Health Organization (WHO) estimated that about 186,772 people died from drug-resistant tuberculosis out of the 500000 reported cases and this is alarming. There is a pressing need from every angle in drug discovery to develop novel compounds that could possess diverse mechanisms of action to tackle drug-resistant tuberculosis. The Crinum asiaticum bulbs extract are used ethno medicinally to treat upper respiratory tract infections and as well as wound healing agent. The aim of this work is to investigate the in-vitro anti-tuberculosis effect of Crinum asiaticum bulbs extracts and to assess the inhibitory properties against bacteria efflux pumps expression and biofilm formation. The results obtained showed that the Crinum asiaticum bulbs extracts (CAE) were effective in inhibiting Mycobacterium smegmatis (NCTC 8159) and Mycobacterium aurum (NCTC 10437) with minimum inhibitory concentration (MIC) of 125 μg/ml and 250 μg/ml against M. smegmatis and M. aurum respectively. The CAE markedly inhibited the efflux pumps of both M. smegmatis and M. aurum from expressing with the chloroform extract producing the greatest inhibition. The CAE (ethanol, methanol, chloroform and hexane) significantly (***ρ˂0.005) inhibited M. smegmatis’ and M. aurum’s biofilm formation in-vitro. Among the various extracts of Crinum asiaticum, the chloroform extract exhibited the greatest inhibition against M. smegmatis and M. aurum biofilm formation with significance levels of ***ρ˂0.005 and ***ρ˂0.005. In conclusion the CAE has anti-tuberculosis effect and could tackle drug resistant TB as exhibited through the anti-efflux and anti-biofilm forming properties of the extract against the selected Mycobacterium species.

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