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Eric L Nuermberger - One of the best experts on this subject based on the ideXlab platform.
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differential in vitro activity of individual drugs and Bedaquiline rifabutin combinations against actively multiplying and nutrient starved mycobacterium abscessus
bioRxiv, 2020Co-Authors: Jin Lee, Nicole C Ammerman, Anusha Agarwal, Maram Naji, Eric L NuermbergerAbstract:Current treatment options for lung disease caused by Mycobacterium abscessus complex infections have limited effectiveness. To maximize the use of existing antibacterials and to help inform regimen design for treatment, we assessed the in vitro bactericidal activity of single drugs against actively multiplying and net non-replicating M. abscessus populations in nutrient-rich and nutrient starvation conditions, respectively. As single drugs, Bedaquiline and rifabutin exerted bactericidal activity only against nutrient-starved and actively growing M. abscessus, respectively. However, when combined, both Bedaquiline and rifabutin were able to specifically contribute bactericidal activity at relatively low, clinically relevant concentrations against both replicating and non-replicating bacterial populations. The addition of a third drug, amikacin, further enhanced the bactericidal activity of the Bedaquiline-rifabutin combination against nutrient-starved M. abscessus. Overall, these in vitro data suggest that Bedaquiline-rifabutin may be a potent backbone combination to support novel treatment regimens for M. abscessus infections. This rich dataset of differential time-and concentration-dependent activity of drugs, alone and together, against M. abscessus also highlights several issues affecting interpretation and translation of in vitro findings.
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activity of a long acting injectable Bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Amit Kaushik, Nicole C Ammerman, Eric L Nuermberger, Sandeep Tyagi, Vikram Saini, Iwan Vervoort, Sophie Lachaudurand, Koen AndriesAbstract:The potent antituberculosis activity and long half-life of Bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) Bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily Bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI Bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily Bedaquiline at 2.67 mg/kg (B2.67), 5.33 mg/kg (B5.33), or 8 mg/kg (B8) to deliver the same total amount of Bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of BLAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively, by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.
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activity of a long acting injectable Bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection
bioRxiv, 2019Co-Authors: Amit Kaushik, Nicole C Ammerman, Eric L Nuermberger, Sandeep Tyagi, Vikram Saini, Iwan Vervoort, Sophie Lachaudurand, Koen AndriesAbstract:The potent anti-tuberculosis activity and long half-life of Bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) Bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily Bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI Bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily Bedaquiline at 2.67 (B2.67), 5.33 (B5.33), or 8 (B8) mg/kg to deliver the same total Bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of BLA-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.
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contribution of pretomanid to novel regimens containing Bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis
Unknown Journal, 2019Co-Authors: Deepak V Almeida, Eric L Nuermberger, Khisimuzi Mdluli, Anna M Upton, Rokeya Tasneen, Kala Barnesboyle, Paul J Converse, Nader FotouhiAbstract: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.
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contribution of pretomanid to novel regimens containing Bedaquiline with either linezolid or moxifloxacin and pyrazinamide in murine models of tuberculosis
bioRxiv, 2019Co-Authors: Deepak V Almeida, Khisimuzi Mdluli, Anna M Upton, Rokeya Tasneen, Kala Barnesboyle, Paul J Converse, Nader Fotouhi, Eric L NuermbergerAbstract: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 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.
Koen Andries - One of the best experts on this subject based on the ideXlab platform.
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activity of a long acting injectable Bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Amit Kaushik, Nicole C Ammerman, Eric L Nuermberger, Sandeep Tyagi, Vikram Saini, Iwan Vervoort, Sophie Lachaudurand, Koen AndriesAbstract:The potent antituberculosis activity and long half-life of Bedaquiline make it an attractive candidate for use in long-acting/extended-release formulations for the treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) Bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: an untreated negative-control regimen; positive-control regimens of daily rifampin (10 mg/kg of body weight), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily Bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI Bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily Bedaquiline at 2.67 mg/kg (B2.67), 5.33 mg/kg (B5.33), or 8 mg/kg (B8) to deliver the same total amount of Bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative- and positive-control regimens performed as expected. One, two, and three doses of BLAI-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively, by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates that it shows promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.
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activity of a long acting injectable Bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection
bioRxiv, 2019Co-Authors: Amit Kaushik, Nicole C Ammerman, Eric L Nuermberger, Sandeep Tyagi, Vikram Saini, Iwan Vervoort, Sophie Lachaudurand, Koen AndriesAbstract:The potent anti-tuberculosis activity and long half-life of Bedaquiline make it an attractive candidate for long-acting/extended release formulations for treatment of latent tuberculosis infection (LTBI). Our objective was to evaluate a long-acting injectable (LAI) Bedaquiline formulation in a validated paucibacillary mouse model of LTBI. Following immunization with Mycobacterium bovis rBCG30, BALB/c mice were challenged by aerosol infection with M. tuberculosis H37Rv. Treatment began 13 weeks after challenge infection with one of the following regimens: untreated negative control; positive controls of daily rifampin (10 mg/kg), once-weekly rifapentine (15 mg/kg) and isoniazid (50 mg/kg), or daily Bedaquiline (25 mg/kg); test regimens of one, two, or three monthly doses of LAI Bedaquiline at 160 mg/dose (BLAI-160); and test regimens of daily Bedaquiline at 2.67 (B2.67), 5.33 (B5.33), or 8 (B8) mg/kg to deliver the same total Bedaquiline as one, two, or three doses of BLAI-160, respectively. All drugs were administered orally, except for BLAI-160 (intramuscular injection). The primary outcome was the decline in M. tuberculosis lung CFU counts during 12 weeks of treatment. The negative and positive control regimens performed as expected. One, two, and three doses of BLA-160 resulted in decreases of 2.9, 3.2, and 3.5 log10 CFU/lung, respectively by week 12. Daily oral dosing with B2.67, B5.33, and B8 decreased lung CFU counts by 1.6, 2.8, and 4.1 log10, respectively. One dose of BLAI-160 exhibited activity for at least 12 weeks. The sustained activity of BLAI-160 indicates promise as a short-course LTBI treatment requiring few patient encounters to ensure treatment completion.
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unexpected high prevalence of resistance associated rv0678 variants in mdr tb patients without documented prior use of clofazimine or Bedaquiline
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: Cristina Villellas, Nele Coeck, Conor J Meehan, Nacer Lounis, Bouke C De Jong, Leen Rigouts, Koen AndriesAbstract:Objectives: Resistance-associated variants (RAVs) in Rv0678, a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of Bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in Bedaquiline treatment guidelines. Methods: Baseline isolates from two Bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding Bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort. Results: Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, Bedaquiline MICs for these isolates were high (> 0.24 mg/L, n = 8), normal (0.03−0.24 mg/L, n = 11) or low (< 0.03 mg/L, n = 4). A variant at position −11 in the intergenic region mmpS5–Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to Bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs. Conclusions: RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of Bedaquiline or clofazimine, and in the majority of cases do not lead to Bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess Bedaquiline susceptibility.
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mutations in pepq confer low level resistance to Bedaquiline and clofazimine in mycobacterium tuberculosis
Antimicrobial Agents and Chemotherapy, 2016Co-Authors: Deepak V Almeida, Koen Andries, Eric L Nuermberger, Sandeep Tyagi, Thomas R Ioerger, Khisimuzi Mdluli, Jacques H Grosset, James C SacchettiniAbstract: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 clofazimine, and were shown to have Bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered Bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer Bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene.
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bactericidal mode of action of Bedaquiline
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: Kiel Hards, Koen Andries, Jennifer Robson, Michael Berney, Lisa Shaw, Dirk Bald, Anil Koul, Gregory M CookAbstract:Objectives: It is not fully understood why inhibiting ATP synthesis in Mycobacterium species leads to death in non-replicating cells. We investigated the bactericidal mode of action of the anti-tubercular F 1 F o -ATP synthase inhibitor Bedaquiline (Sirturo™) in order to further understand the lethality of ATP synthase inhibition. Methods: Mycobacterium smegmatis strains were used for all the experiments. Growth and survival during a Bedaquiline challenge were performed in multiple media types. A time-course microarray was performed during initial Bedaquiline challenge in minimal medium. Oxygen consumption and proton-motive force measurements were performed on whole cells and inverted membrane vesicles, respectively. Results: A killing of 3 log. 10 cfu/mL was achieved 4-fold more quickly in minimal medium (a glycerol carbon source) versus rich medium (LB with Tween 80) during Bedaquiline challenge. Assessing the accelerated killing condition, we identified a transcriptional remodelling of metabolism that was consistent with respiratory dysfunction but inconsistent with ATP depletion. In glycerol-energized cell suspensions, Bedaquiline caused an immediate 2.3-fold increase in oxygen consumption. Bedaquiline collapsed the transmembrane pH gradient, but not the membrane potential, in a dose-dependent manner. Both these effects were dependent on binding to the F. 1 F. o -ATP synthase. Conclusions: Challenge with Bedaquiline results in an electroneutral uncoupling of respiration-driven ATP synthesis. This may be a determinant of the bactericidal effects of Bedaquiline, while ATP depletion may be a determinant of its delayed onset of killing. We propose that Bedaquiline binds to and perturbs the a-c subunit interface of the F o , leading to futile proton cycling, which is known to be lethal to mycobacteria.
Keertan Dheda - One of the best experts on this subject based on the ideXlab platform.
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a regimen containing Bedaquiline and delamanid compared to Bedaquiline in patients with drug resistant tuberculosis
European Respiratory Journal, 2020Co-Authors: Olatunde Olayanju, Jason Limberis, Aliasgar Esmail, Keertan DhedaAbstract:There are limited data about combining delamanid and Bedaquiline in drug-resistant tuberculosis (DR-TB) regimens. Prospective long-term outcome data, including in HIV-infected persons, are unavailable. We prospectively followed up 122 South Africans (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We compared outcomes and safety in those who received a Bedaquiline-based regimen (n=82) to those who received a Bedaquiline-delamanid combination regimen (n=40). There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the Bedaquiline versus the Bedaquiline-delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant >5 drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment MDR-TB therapy failure; p 60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)], there were no symptomatic cases or drug withdrawal in either group. Results were similar in HIV-infected patients. A Bedaquiline-delamanid combination regimen showed comparable long-term safety, to a Bedaquiline-based regimen, in patients with DR-TB irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB endemic settings.
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outcomes of patients with drug resistant tuberculosis treated with Bedaquiline containing regimens and undergoing adjunctive surgery
Journal of Infection, 2019Co-Authors: S E Borisov, Keertan Dheda, Janwillem C Alffenaar, Lia Dambrosio, Rosella Centis, Simon Tiberi, Rohit Amale, Evgeny Belilowski, Judith Bruchfeld, Barbara CannetoAbstract:Summary Objectives No study evaluated the contribution of adjunctive surgery in Bedaquiline-treated patients. This study describes treatment outcomes and complications in a cohort of drug-resistant pulmonary tuberculosis (TB) cases treated with Bedaquiline-containing regimens undergoing surgery. Methods This retrospective observational study recruited patients treated for TB in 12 centres in 9 countries between January 2007 and March 2015. Patients who had surgical indications in a Bedaquiline-treated programme-based cohort were selected and surgery-related information was collected. Patient characteristics and surgical indications were described together with type of operation, surgical complications, bacteriological conversion rates, and treatment outcomes. Treatment outcomes were evaluated according to the time of surgery. Results 57 Bedaquiline-exposed cases resistant to a median of 7 drugs had indication for surgery (52 retreatments; 50 extensively drug-resistant (XDR) or pre XDR-TB). Sixty percent of cases initiated Bedaquiline treatment following surgery, while 36.4% underwent the Bedaquiline regimen before surgery and completed it after the operation. At treatment completion 90% culture-converted with 69.1% achieving treatment success; 21.8% had unfavourable outcomes (20.0% treatment failure, 1.8% lost to follow-up), and 9.1% were still undergoing treatment. Conclusions The study results suggest that Bedaquiline and surgery can be safely and effectively combined in selected cases with a specific indication.
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Long-term Bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa
The European respiratory journal, 2018Co-Authors: Olatunde Olayanju, Jason Limberis, Aliasgar Esmail, Suzette Oelofse, Phindile Gina, Elize Pietersen, Mohammed Fadul, Rob Warren, Keertan DhedaAbstract:Bedaquiline remarkably improved treatment-related outcomes in patients with extensively drug resistant tuberculosis.
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effectiveness and safety of Bedaquiline containing regimens in the treatment of mdr and xdr tb a multicentre study
European Respiratory Journal, 2017Co-Authors: S E Borisov, Martin Enwerem, Keertan Dheda, Lia Dambrosio, Rosella Centis, Simon Tiberi, Rodolfo Romero Leyet, Giovanni Sotgiu, Janwillem C AlffenaarAbstract:Large studies on Bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of Bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to Bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-Bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.
Jennifer Hughes - One of the best experts on this subject based on the ideXlab platform.
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injectable free regimens containing Bedaquiline delamanid or both for adolescents with rifampicin resistant tuberculosis in khayelitsha south africa
EClinicalMedicine, 2020Co-Authors: Erika Mohrholland, Jennifer Furin, Vanessa Mudaly, Anja Reuter, Anthony J Garciaprats, Virginia De Azevedo, Yulene Kock, Laura Trivinoduran, Petros Isaakidis, Jennifer HughesAbstract:Abstract Background Limited data exist on the use of Bedaquiline and delamanid in adolescents with rifampicin-resistant tuberculosis (RR-TB). We describe RR-TB treatment of adolescents (10–19 years) with injectable-free regimens containing these drugs in Khayelitsha, South Africa. Methods This retrospective study included adolescents initiating injectable-free RR-TB treatment regimens containing Bedaquiline and/or delamanid from February 2015 to June 2018. We report adverse events (AEs) of interest, sputum culture conversion (SCC), and final end-of-treatment outcomes. Findings Twenty-two patients were included; median age at treatment initiation was 17 years (interquartile range [IQR] 15-18), and six (27%) were HIV-positive (median CD4 count 191 cells/mm3 [IQR 157-204]). Eight (36%) patients had RR-TB with fluoroquinolone resistance; ten (45%), eight (36%), and four (18%) patients received regimens containing Bedaquiline, delamanid, or the combination of Bedaquiline and delamanid, respectively. The median durations of exposure to Bedaquiline and delamanid were 5·6 (IQR 5·5-8·4) and 9·4 (IQR 5·9-14·4) months, respectively. There were 49 AEs of interest which occurred in 17 (77%) patients. Fourteen (64%) patients had pulmonary TB with positive sputum cultures at Bedaquiline and/or delamanid initiation; among these SCC at month 6 was 79%. Final end-of-treatment outcomes for the 22 adolescent were: 17 (77%) successfully treated, two (9%) lost-to-follow-up, two (9%) treatment failed, and one (5%) died. Interpretation This study found that injectable-free regimens containing Bedaquiline and/or delamanid in a programmatic setting were effective and well tolerated in adolescents and should be routinely provided for RR-TB treatment in this age group as recommended by the World Health Organisation.
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injectable free regimens containing Bedaquiline delamanid or both for adolescents with rifampicin resistant tuberculosis in khayelitsha south africa
Social Science Research Network, 2019Co-Authors: Erika Mohrholland, Jennifer Furin, Vanessa Mudaly, Anja Reuter, Anthony J Garciaprats, Virginia De Azevedo, Yulene Kock, Laura Trivinoduran, Petros Isaakidis, Jennifer HughesAbstract:Background: Limited data exist on use of Bedaquiline and delamanid in adolescents with rifampicin-resistant tuberculosis (RR-TB). We describe RR-TB treatment of adolescents (10-19 years) with injectable-free regimens containing these drugs in Khayelitsha, South Africa. Methods: This retrospective study included adolescents initiating injectable-free RR-TB treatment regimens containing Bedaquiline and/or delamanid from February 2015 to June 2018. We report adverse events (AEs) of interest, sputum culture conversion (SCC), and final end-of-treatment outcomes. Findings: Twenty-two patients were included; median age at treatment initiation was 17 years (interquartile range [IQR] 15-18), and six (27%) were HIV-positive (median CD4 count 191 cells/mm3 [IQR 157-204]). Eight (36%) patients had RR-TB with fluoroquinolone resistance; ten (45%), eight (36%), and four (18%) patients received regimens containing Bedaquiline, delamanid, or the combination of Bedaquiline and delamanid, respectively. The median durations of exposure to Bedaquiline and delamanid were 5*6 (IQR 5*5-8*4) and 9*4 (IQR 5*9-14*4) months, respectively. There were 49 AEs of interest which occurred in 17 (77%) patients. Fourteen (64%) patients had pulmonary TB with positive sputum cultures at Bedaquiline and/or delamanid initiation; among these SCC at month 6 was 79%. Final end-of-treatment outcomes for the 22 adolescent were: 17 (77%) successfully treated, two (9%) lost-to-follow-up, two (9%) treatment failed, and one (5%) died. Interpretation: This study found that injectable-free regimens containing Bedaquiline and/or delamanid in a programmatic setting were effective and well tolerated in adolescents and should be routinely provided for RR-TB treatment in this age group. Funding Statement: Medecins Sans Frontieres (MSF). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: Ethical approval was obtained from the University of Cape Town Human Research Ethics Committee (HREC 499/2011) for this study. Additionally this research fulfilled the exemption criteria set by the MSF Ethics Review Board for a posteriori analyses of routinely collected clinical data.
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effect of Bedaquiline on mortality in south african patients with drug resistant tuberculosis a retrospective cohort study
The Lancet Respiratory Medicine, 2018Co-Authors: Kathryn Schnippel, Norbert Ndjeka, Gary Maartens, Iqbal Master, Graeme Meintjes, Nazir Ismail, Jennifer Hughes, Hannetjie Ferreira, Xavier Padanilam, Rodolfo RomeroAbstract:Summary Background Addition of Bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of Bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including Bedaquiline. Methods In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received Bedaquiline in treatment regimens and those who did not. Patients who did not receive Bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. Findings 24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A Bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received Bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28–0·46) and extensively drug-resistant tuberculosis (0·26, 0·18–0·38) compared with standard regimens. Interpretation Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that Bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen. Funding None.
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early safety and efficacy of the combination of Bedaquiline and delamanid for the treatment of patients with drug resistant tuberculosis in armenia india and south africa a retrospective cohort study
Lancet Infectious Diseases, 2018Co-Authors: Gabriella Ferlazzo, Jennifer Hughes, Erika Mohr, Chinmay Laxmeshwar, Catherine Hewison, Sylvie Jonckheere, Naira Khachatryan, Virginia De Avezedo, Lusine Egazaryan, Amir ShroufiAbstract:Summary Background Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Medecins Sans Frontieres has supported the use of combination Bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the Bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa. Methods We retrospectively analysed a cohort of all patients who received 6–12 months of oral Bedaquiline and delamanid in combination (400 mg Bedaquiline once per day for 2 weeks, then 200 mg Bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment. Findings Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5–40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment. Interpretation Use of the Bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to Bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials. Funding Medecins Sans Frontieres (MSF).
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off label use of Bedaquiline in children and adolescents with multidrug resistant tuberculosis
Emerging Infectious Diseases, 2017Co-Authors: Jay Achar, Jennifer Hughes, Cathy Hewison, Ana P Cavalheiro, Alena Skrahina, Junia Cajazeiro, Parpieva Nargiza, Krzysztof Herboczek, Assliddin S Rajabov, Gabriella FerlazzoAbstract:We describe 27 children and adolescents <18 years of age who received Bedaquiline during treatment for multidrug-resistant tuberculosis. We report good treatment responses and no cessation attributable to adverse effects. Bedaquiline could be considered for use with this age group for multidrug-resistant tuberculosis when treatment options are limited.
Max R Odonnell - One of the best experts on this subject based on the ideXlab platform.
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antiretroviral switching and Bedaquiline treatment of drug resistant tuberculosis hiv co infection
The Lancet HIV, 2019Co-Authors: Max R Odonnell, Kelly E Dooley, Nesri Padayatchi, Amrita Daftary, Catherine Orrell, Rivet K Amico, Gerald FriedlandAbstract:Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and Bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with Bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without Bedaquiline drug interactions should be strongly considered.
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pilot evaluation of a second generation electronic pill box for adherence to Bedaquiline and antiretroviral therapy in drug resistant tb hiv co infected patients in kwazulu natal south africa
BMC Infectious Diseases, 2018Co-Authors: N Bionghi, Max R Odonnell, Nesri Padayatchi, Amrita Daftary, Catherine Orrell, Gerald Friedland, B Maharaj, Z Msibi, K R AmicoAbstract:The introduction of Bedaquiline, the first new antimycobacterial drug in over 40 years, has highlighted the critical importance of medication adherence in drug-resistant tuberculosis (DR-TB) treatment to prevent amplified drug-resistance and derive sustained benefit. Real-time electronic dose monitoring (EDM) accurately measures adherence and allows for titration of adherence support for anti-retroviral therapy (ART). The goal of this study was to evaluate the accuracy and acceptability of a next-generation electronic pillbox (Wisepill RT2000) for Bedaquiline-containing TB regimens. Eligible patients were DR-TB/HIV co-infected adults hospitalized for the initiation of Bedaquiline-containing treatment regimens in KwaZulu-Natal, South Africa. A one-way crossover design was used to evaluate levels of adherence and patient acceptance of EDM. Each patient was given a Wisepill device which was filled with ART, Levofloxacin or Bedaquiline over three consecutive weeks. Medication adherence was measured using Wisepill counts, patient-reported seven-day recall, and weekly pill count. An open-ended qualitative questionnaire at the end of the study evaluated participant acceptability of the Wisepill device. We enrolled 21 DR-TB/HIV co-infected inpatients admitted for the initiation of Bedaquiline from August through September 2016. In aggregate patients were similarly adherent to Bedaquiline (100%) compared to Levofloxacin (100%) and ART (98.9%) by pill count. Wisepill was more sensitive (100%) compared to seven-day recall (0%) in detecting non-adherence events (p = 0.02). Patients reported positive experiences with Wisepill and expressed willingness to use the device during a full course of DR-TB treatment. There were no concerns about stigma, confidentiality, or remote monitoring. In this pilot study patients were highly adherent to Bedaquiline by all adherence measures. However, there was lower adherence to ART by pill count and Wisepill suggesting a possible challenge for adherence with ART. The use of EDM identified significantly more missed doses than seven-day recall. Wisepill was highly acceptable to DR-TB/HIV patients in South Africa, and is a promising modality to support and monitor medication adherence in complex treatment regimens.