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Mdlenyani L, Mohamed Z, Stadler JA, Mtwa N, Meintjes G, Warren R, Kuhlin J, Wasserman S. Treatment outcomes of bedaquiline-resistant tuberculosis: a retrospective and matched cohort study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.01.21.25320876. [PMID: 39974042 PMCID: PMC11838984 DOI: 10.1101/2025.01.21.25320876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Background Rising prevalence of bedaquiline resistance undermines benefits from this life-saving drug for rifampicin-resistant tuberculosis (RR-TB). Despite increasing awareness, patient-level outcomes for bedaquiline-resistant TB have not been well-characterised and case management poorly defined. Methods We conducted a retrospective cohort study with matched controls at a TB referral hospital in South Africa. Cases included patients ≥13 years with a phenotypic bedaquiline-resistant Mycobacterium tuberculosis isolate identified between January 2018 and June 2023. Matched controls (1:1) with bedaquiline-susceptible RR-TB were selected from a prospective observational study conducted at the same facility. Primary outcomes included time to sputum culture conversion (SCC), a modified WHO-defined unfavourable outcome, and TB-free survival (alive, with SCC, and in care or treatment completed) through 18 months. Adjusted analyses used Cox proportional hazards models. Findings Eighty-two patients with bedaquiline-resistant TB were included; 57 (70%) were HIV-positive and 17 (21%) had no prior exposure to bedaquiline or clofazimine. Bedaquiline was prescribed for 72 (88%) and meropenem (plus amoxicillin-clavulanate) for 32 (39%) after submission of the sputum sample with the first bedaquiline-resistant Mycobacterium tuberculosis isolate. At 18 months, 43 (52%) patients achieved TB-free survival; 17 (20%) failed to achieve sustained SCC, there were 19 (23%) deaths, and 50 (80%) survivors (n=63) were still on treatment. WHO treatment outcomes following treatment initiation were unfavourable in 54 (67%) patients, driven by treatment failure in 35 (43%). Median time to SCC after treatment initiation was 175 (IQR 100-254) days in the bedaquiline resistant cohort and 32 days (IQR 30-42 days) in the matched bedaquiline susceptible cohort. Baseline smear microscopy grade (HR 0·41, 95% CI 0·23-0·73, p=0·003) and bedaquiline resistance (HR 0·06, 95% CI 0·02-0·23, p<0·001) were associated with reduced SCC. Interpretation Current treatment options for bedaquiline-resistant TB result in prolonged therapy, delayed microbiological responses, and poor clinical outcomes. Funding This work was partially supported by the South African Medical Research Council (grant number MRC-RFA-SHIP 02-2018). JK was funded by Swedish Heart & Lung Foundation (20220859 and 20240774) Swedish Society of Medicine (SLS-985976). SW was supported by the National Institutes of Health (U01AI170426) and the Bill & Melinda Gates Foundation. GM was supported by the Wellcome Trust (214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787).
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Affiliation(s)
| | - Zahraa Mohamed
- Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa
- Department of Medicine, University of Cape Town, South Africa
| | - Jacob Am Stadler
- Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa
- Department of Medicine, University of Cape Town, South Africa
| | - Nomfuneko Mtwa
- Department of Health, Eastern Cape Province, South Africa
| | - Graeme Meintjes
- Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa
- Department of Medicine, University of Cape Town, South Africa
- Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - Robin Warren
- Division of Molecular Biology and Human Genetics, SAMRC Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Johanna Kuhlin
- Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Sean Wasserman
- Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa
- Institute for Infection and Immunity, City St George's, University of London, London, United Kingdom
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Kalawadia D, Gandhi D, Dirkhipa TY, Jaiswal A, Shah D, Salve J, Parmar M, Sachdeva KS, Bodhanwala M, Shah I. Effect of delamanid on interim outcomes of bacteriological conversion amongst pediatric drug resistant tuberculosis cases in India. Lung India 2024; 41:35-39. [PMID: 38160457 PMCID: PMC10883457 DOI: 10.4103/lungindia.lungindia_72_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/30/2023] [Accepted: 06/13/2023] [Indexed: 01/03/2024] Open
Abstract
AIM To determine the bacteriological conversion rate after 6 months of Delamanid (DLM) based treatment in children with drug-resistant tuberculosis (DR-TB) and determine factors associated with bacteriological conversion. METHODS This is a descriptive retrospective study done in children between the age of 6-17 years with DR-TB who received DLM-based therapy from October 2018 to May 2021. The drug resistance pattern of TB was detected using Xpert RIF/MTB and phenotypic drug sensitivity testing (DST) on TB-MGIT culture reports. Follow-up sputum TB MGIT culture was carried out monthly after DLM initiation for 6 months. Factors associated with sputum bacteriological conversion such as age, gender, pulmonary TB (PTB) versus disseminated TB, unilateral or bilateral lung involvement, type of DR-TB, prior treatment failure, and type of DR-TB regimen were analyzed. RESULTS Sixty patients received DLM of which two had extrapulmonary TB (EPTB) and sputum conversion could not be assessed. The mean age at presentation was 12.69 ± 3.03 years. Five patients (8.3%) died while on DLM treatment. On follow-up, 8 (13.7%) out of 58 patients had no sputum bacteriological conversion after 6 months of DLM initiation of which three patients were on salvage therapy; 46 (79.3%) had sputum bacteriological conversion within 6 months of DLM initiation. CONCLUSION Sputum bacteriological conversion rate was almost 80% at the end of 6 months of DLM-based treatment.
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Affiliation(s)
- Dhruv Kalawadia
- Pediatric TB Clinic, Pediatric Infectious Disease, B. J. Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Darshini Gandhi
- Department of Pediatric, Seth G. S. Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Tsering Y. Dirkhipa
- Department of Pediatric, Seth G. S. Medical College and KEM Hospital, Mumbai, Maharashtra, India
| | - Akanksha Jaiswal
- Pediatric TB Clinic, Pediatric Infectious Disease, B. J. Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Daksha Shah
- Joint Executive Health Officer, Municipal Corporation of Greater, Mumbai, Maharashtra, India
| | - Jyoti Salve
- World Health Organization—Country Office for India, New Delhi, India
| | - Malik Parmar
- Central TB Division, Ministry of Health and Family Welfare, Government of India, New Delhi, India
| | - Kuldeep S Sachdeva
- International Union Against Tuberculosis and Lung Disease, South East Asia
| | | | - Ira Shah
- Pediatric Infectious Diseases, Nodal Officer, Pediatric DR-TB Center and Pediatric HIV/ART Center at B.J. Wadia Hospital for Children, Mumbai, Maharashtra, India
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Shah I, Antony S, Jaiswal A, Bodhanwala M, Shah D, Tipre P, Salve J, Parmar M, Sachdeva KS. Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis. Pediatr Infect Dis J 2022; 41:401-404. [PMID: 35153288 DOI: 10.1097/inf.0000000000003486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
INTRODUCTION The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored. OBJECTIVES To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India. DESIGN AND METHODS Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described. RESULTS Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period. CONCLUSIONS Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.
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Affiliation(s)
- Ira Shah
- From the Pediatric TB Clinic, Department of Pediatric Infectious Diseases, B J Wadia Hospital for Children, Mumbai, India
| | - Sonu Antony
- From the Pediatric TB Clinic, Department of Pediatric Infectious Diseases, B J Wadia Hospital for Children, Mumbai, India
| | - Akanksha Jaiswal
- From the Pediatric TB Clinic, Department of Pediatric Infectious Diseases, B J Wadia Hospital for Children, Mumbai, India
| | | | - Daksha Shah
- Mumbai District Tuberculosis Control Society, Mumbai, India
| | - Pranita Tipre
- Mumbai District Tuberculosis Control Society, Mumbai, India
| | - Jyoti Salve
- World Health Organization-Country Office for India, New Delhi, India
| | - Malik Parmar
- World Health Organization-Country Office for India, New Delhi, India
- Central TB Division, Ministry of Health & Family Welfare, Government of India, New Delhi, India
| | - K S Sachdeva
- International Union Against Tuberculosis and Lung Disease, South East Asia
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Nahid P, Mase SR, Migliori GB, Sotgiu G, Bothamley GH, Brozek JL, Cattamanchi A, Cegielski JP, Chen L, Daley CL, Dalton TL, Duarte R, Fregonese F, Horsburgh CR, Ahmad Khan F, Kheir F, Lan Z, Lardizabal A, Lauzardo M, Mangan JM, Marks SM, McKenna L, Menzies D, Mitnick CD, Nilsen DM, Parvez F, Peloquin CA, Raftery A, Schaaf HS, Shah NS, Starke JR, Wilson JW, Wortham JM, Chorba T, Seaworth B. Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline. Am J Respir Crit Care Med 2019; 200:e93-e142. [PMID: 31729908 PMCID: PMC6857485 DOI: 10.1164/rccm.201909-1874st] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.
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Bastos ML, Lan Z, Menzies D. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis. Eur Respir J 2017; 49:49/3/1600803. [PMID: 28331031 DOI: 10.1183/13993003.00803-2016] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 01/10/2017] [Indexed: 11/05/2022]
Abstract
This systematic review aimed to update the current evidence for multidrug-resistant tuberculosis (MDR-TB) treatment.We searched for studies that reported treatment information and clinical characteristics for at least 25 patients with microbiologically confirmed pulmonary MDR-TB and either end of treatment outcomes, 6-month culture conversion or severe adverse events (SAEs). We assessed the association of these outcomes with patients' characteristics or treatment parameters. We identified 74 studies, including 17 494 participants.The pooled treatment success was 26% in extensively drug-resistant TB (XDR-TB) patients and 60% in MDR-TB patients. Treatment parameters such as number or duration and individual drugs were not associated with improved 6-month sputum culture conversion or end of treatment outcomes. However, MDR-TB patients that received individualised regimens had higher success than patients who received standardised regimens (64% versus 52%; p<0.0.01). When reports from 20 cohorts were pooled, proportions of SAE ranged from 0.5% attributed to ethambutol to 12.2% attributed to para-aminosalicylic acid. The lack of significant associations of treatment outcomes with specific drugs or regimens may reflect the limitations of pooling the data rather than a true lack of differences in efficacy of regimens or individual drugs.This analysis highlights the need for stronger evidence for treatment of MDR-TB from better-designed and reported studies.
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Affiliation(s)
- Mayara Lisboa Bastos
- Internal Medicine Graduate Program, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Zhiyi Lan
- Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, Montreal, QC, Canada
| | - Dick Menzies
- Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University, Montreal, QC, Canada
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Role of gyrB Mutations in Pre-extensively and Extensively Drug-Resistant Tuberculosis in Thai Clinical Isolates. Antimicrob Agents Chemother 2016; 60:5189-97. [PMID: 27297489 DOI: 10.1128/aac.00539-16] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 06/08/2016] [Indexed: 02/05/2023] Open
Abstract
DNA gyrase mutations are a major cause of quinolone resistance in Mycobacterium tuberculosis We therefore conducted the first comprehensive study to determine the diversity of gyrase mutations in pre-extensively drug-resistant (pre-XDR) (n = 71) and extensively drug-resistant (XDR) (n = 30) Thai clinical tuberculosis (TB) isolates. All pre-XDR-TB and XDR-TB isolates carried at least one mutation within the quinolone resistance-determining region of GyrA (G88A [1.1%], A90V [17.4%], S91P [1.1%], or D94A/G/H/N/V/Y [72.7%]) or GyrB (D533A [1.1%], N538D [1.1%], or E540D [2.2%]). MIC and DNA gyrase supercoiling inhibition assays were performed to determine the role of gyrase mutations in quinolone resistance. Compared to the MICs against M. tuberculosis H37Rv, the levels of resistance to all quinolones tested in the isolates that carried GyrA-D94G or GyrB-N538D (8- to 32-fold increase) were significantly higher than those in isolates bearing GyrA-D94A or GyrA-A90V (2- to 8-fold increase) (P < 0.01). Intriguingly, GyrB-E540D led to a dramatic resistance to later-generation quinolones, including moxifloxacin, gatifloxacin, and sparfloxacin (8- to 16-fold increases in MICs and 8.3- to 11.2-fold increases in 50% inhibitory concentrations [IC50s]). However, GyrB-E540D caused low-level resistance to early-generation quinolones, including ofloxacin, levofloxacin, and ciprofloxacin (2- to 4-fold increases in MICs and 1.5- to 2.0-fold increases in IC50s). In the present study, DC-159a was the most active antituberculosis agent and was little affected by the gyrase mutations described above. Our findings suggest that although they are rare, gyrB mutations have a notable role in quinolone resistance, which may provide clues to the molecular basis of estimating quinolone resistance levels for drug and dose selection.
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Kiran D, Podell BK, Chambers M, Basaraba RJ. Host-directed therapy targeting the Mycobacterium tuberculosis granuloma: a review. Semin Immunopathol 2015; 38:167-83. [PMID: 26510950 PMCID: PMC4779125 DOI: 10.1007/s00281-015-0537-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 10/13/2015] [Indexed: 12/16/2022]
Abstract
Infection by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb) is a major cause of morbidity and mortality worldwide. Slow progress has been made in lessening the impact of tuberculosis (TB) on human health, especially in parts of the world where Mtb is endemic. Due to the complexity of TB disease, there is still an urgent need to improve diagnosis, prevention, and treatment strategies to control global spread of disease. Active research targeting avenues to prevent infection or transmission through vaccination, to diagnose asymptomatic carriers of Mtb, and to improve antimicrobial drug treatment responses is ongoing. However, this research is hampered by a relatively poor understanding of the pathogenesis of early infection and the factors that contribute to host susceptibility, protection, and the development of active disease. There is increasing interest in the development of adjunctive therapy that will aid the host in responding to Mtb infection appropriately thereby improving the effectiveness of current and future drug treatments. In this review, we summarize what is known about the host response to Mtb infection in humans and animal models and highlight potential therapeutic targets involved in TB granuloma formation and resolution. Strategies designed to shift the balance of TB granuloma formation toward protective rather than destructive processes are discussed based on our current knowledge. These therapeutic strategies are based on the assumption that granuloma formation, although thought to prevent the spread of the tubercle bacillus within and between individuals contributes to manifestations of active TB disease in human patients when left unchecked. This effect of granuloma formation favors the spread of infection and impairs antimicrobial drug treatment. By gaining a better understanding of the mechanisms by which Mtb infection contributes to irreversible tissue damage, down regulates protective immune responses, and delays tissue healing, new treatment strategies can be rationally designed. Granuloma-targeted therapy is advantageous because it allows for the repurpose of existing drugs used to treat other communicable and non-communicable diseases as adjunctive therapies combined with existing and future anti-TB drugs. Thus, the development of adjunctive, granuloma-targeted therapy, like other host-directed therapies, may benefit from the availability of approved drugs to aid in treatment and prevention of TB. In this review, we have attempted to summarize the results of published studies in the context of new innovative approaches to host-directed therapy that need to be more thoroughly explored in pre-clinical animal studies and in human clinical trials.
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Affiliation(s)
- Dilara Kiran
- Department of Microbiology, Immunology and Pathology, Metabolism of Infectious Diseases Laboratory and Mycobacteria Research Laboratories, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 200 West Lake Street, 1619 Campus Delivery, Fort Collins, CO, 80523-1619, USA
| | - Brendan K Podell
- Department of Microbiology, Immunology and Pathology, Metabolism of Infectious Diseases Laboratory and Mycobacteria Research Laboratories, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 200 West Lake Street, 1619 Campus Delivery, Fort Collins, CO, 80523-1619, USA
| | - Mark Chambers
- Department of Bacteriology, Animal and Plant Health Agency (APHA), Woodham Lane, New Haw, Addlestone, Surrey, KT15 3NB, UK.,School of Veterinary Medicine Faculty of Health and Medical Sciences, University of Surrey, Vet School Main Building, Daphne Jackson Road, Guildford, GU2 7AL, UK
| | - Randall J Basaraba
- Department of Microbiology, Immunology and Pathology, Metabolism of Infectious Diseases Laboratory and Mycobacteria Research Laboratories, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, 200 West Lake Street, 1619 Campus Delivery, Fort Collins, CO, 80523-1619, USA.
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Winters N, Butler-Laporte G, Menzies D. Efficacy and safety of World Health Organization group 5 drugs for multidrug-resistant tuberculosis treatment. Eur Respir J 2015; 46:1461-70. [DOI: 10.1183/13993003.00649-2015] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 06/22/2015] [Indexed: 11/05/2022]
Abstract
The efficacy and toxicity of several drugs now used to treat multidrug-resistant tuberculosis (MDR-TB) have not been fully evaluated.We searched three databases for studies assessing efficacy in MDR-TB or safety during prolonged treatment of any mycobacterial infections, of drugs classified by the World Health Organization as having uncertain efficacy for MDR-TB (group 5).We included 83 out of 4002 studies identified. Evidence was inadequate for meropenem, imipenem and terizidone. For MDR-TB treatment, clarithromycin had no efficacy in two studies (risk difference (RD) −0.13, 95% CI −0.40–0.14) and amoxicillin–clavulanate had no efficacy in two other studies (RD 0.07, 95% CI −0.21–0.35). The largest number of studies described prolonged use for treatment of non-tuberculous mycobacteria. Azithromycin was not associated with excess serious adverse events (SAEs). Clarithromycin was not associated with excess SAEs in eight controlled trials in HIV-infected patients (RD 0.00, 95% CI −0.02–0.02), nor in six uncontrolled studies in HIV-uninfected patients, whereas six uncontrolled studies in HIV-infected patients clarithromycin caused substantial SAEs (proportion 0.20, 95% CI 0.12–0.27).For most group 5 drugs we found inadequate evidence of safety for prolonged use or for efficacy for MDR-TB, although macrolides appeared to be safe in prolonged use.
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Bruhn DF, Scherman MS, Liu J, Scherbakov D, Meibohm B, Böttger EC, Lenaerts AJ, Lee RE. In vitro and in vivo Evaluation of Synergism between Anti-Tubercular Spectinamides and Non-Classical Tuberculosis Antibiotics. Sci Rep 2015; 5:13985. [PMID: 26365087 PMCID: PMC4568539 DOI: 10.1038/srep13985] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Accepted: 08/12/2015] [Indexed: 12/04/2022] Open
Abstract
Spectinamides are new semi-synthetic spectinomycin derivatives with potent anti-tubercular activity. The reported synergism of the precursor spectinomycin with other antibiotics prompted us to examine whether spectinamides sensitize M. tuberculosis to other antibiotics not traditionally used in the treatment of tuberculosis to potentially expand therapeutic options for MDR/XDR Tuberculosis. Whole cell synergy checkerboard screens were performed using the laboratory strain M. tuberculosis H37Rv, lead spectinamide 1599, and a broad panel of 27 antibiotics. In vitro, 1599 synergized with 11 drugs from 6 antibiotic classes. The observed synergy was tested against clinical isolates confirming synergy with Clarithromycin, Doxycycline and Clindamycin, combinations of which were taken forward for in vivo efficacy determination. Co-administration of 1599 and clarithromycin provided additional bacterial killing in a mouse model of acute tuberculosis infection, but not in a chronic infection model. Further studies indicated that mismatched drug exposure profiles likely permitted induction of phenotypic clarithromycin resistance and subsequent loss of synergism. These studies highlight the importance of validating in vitro synergism and the challenge of matching drug exposures to obtain a synergistic outcome in vivo. Results from this study indicate that a 1599 clarithromycin combination is potentially viable, providing the drug exposures can be carefully monitored.
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Affiliation(s)
- David F. Bruhn
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Michael S. Scherman
- Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA
| | - Jiuyu Liu
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Dimitri Scherbakov
- Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland
| | - Bernd Meibohm
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Erik C. Böttger
- Institut für Medizinische Mikrobiologie, Nationales Zentrum für Mykobakterien, Universität Zürich, Zürich, Switzerland
| | - Anne J. Lenaerts
- Mycobacterial Research Laboratories, Department of Microbiology, Colorado State University, Fort Collins, Colorado, USA
| | - Richard E. Lee
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
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Li Q, Xie L, Long Q, Mao J, Li H, Zhou M, Xie J. Proteasome Accessory Factor C (pafC) Is a novel gene Involved in Mycobacterium Intrinsic Resistance to broad-spectrum antibiotics--Fluoroquinolones. Sci Rep 2015; 5:11910. [PMID: 26139381 PMCID: PMC4490553 DOI: 10.1038/srep11910] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 06/09/2015] [Indexed: 12/17/2022] Open
Abstract
Antibiotics resistance poses catastrophic threat to global public health. Novel insights into the underlying mechanisms of action will inspire better measures to control drug resistance. Fluoroquinolones are potent and widely prescribed broad-spectrum antibiotics. Bacterial protein degradation pathways represent novel druggable target for the development of new classes of antibiotics. Mycobacteria proteasome accessory factor C (pafC), a component of bacterial proteasome, is involved in fluoroquinolones resistance. PafC deletion mutants are hypersensitive to fluoroquinolones, including moxifloxacin, norfloxacin, ofloxacin, ciprofloxacin, but not to other antibiotics such as isoniazid, rifampicin, spectinomycin, chloramphenicol, capreomycin. This phenotype can be restored by complementation. The pafC mutant is hypersensitive to H2O2 exposure. The iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) can abolish the difference. The finding that pafC is a novel intrinsic selective resistance gene provided new evidence for the bacterial protein degradation pathway as druggable target for the development of new class of antibiotics.
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Affiliation(s)
- Qiming Li
- Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Longxiang Xie
- Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Quanxin Long
- 1] Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China [2] The Second Affiliated Hospital and the Key Laboratory of Molecular Biology of Infectious Diseases of the Ministry of Education, Chongqing Medical University, 1 Medical Road, Yuzhong District, Chongqing, 400016, China
| | - Jinxiao Mao
- Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Hui Li
- Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Mingliang Zhou
- Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
| | - Jianping Xie
- Institute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Eco-Environment and Bio-Resource of the Three Gorges Area, Key Laboratory of Eco-environments in Three Gorges Reservoir Region, Ministry of Education, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China
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van der Paardt AF, Wilffert B, Akkerman OW, de Lange WC, van Soolingen D, Sinha B, van der Werf TS, Kosterink JG, Alffenaar JWC. Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis. Eur Respir J 2015; 46:444-55. [DOI: 10.1183/09031936.00147014] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 03/20/2015] [Indexed: 01/16/2023]
Abstract
Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs.Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis drug by the World Health Organization; however, its role or efficacy in the treatment of MDR-TB is unclear. A systematic review of the literature was conducted to summarise the evidence for the activity of macrolides against MDR-TB, by evaluating in vitro, in vivo and clinical studies. PubMed and Embase were searched for English language articles up to May 2014.Even though high minimum inhibitory concentration values are usually found, suggesting low activity against Mycobacterium tuberculosis, the potential benefits of macrolides are their accumulation in the relevant compartments and cells in the lungs, their immunomodulatory effects and their synergistic activity with other anti-TB drugs.A future perspective may be use of more potent macrolide analogues to enhance the activity of the treatment regimen.
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Involvement of Holliday junction resolvase in fluoroquinolone-mediated killing of Mycobacterium smegmatis. Antimicrob Agents Chemother 2014; 59:1782-5. [PMID: 25534729 DOI: 10.1128/aac.04434-14] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The absence of the Holliday-junction Ruv resolvase of Mycobacterium smegmatis increased the bacteriostatic and bactericidal activities of the fluoroquinolone moxifloxacin, an important antituberculosis agent. The treatment of ruvAB-deficient cells with thiourea and 2,2'-bipyridyl lowered moxifloxacin lethality to wild-type levels, indicating that the absence of ruvAB stimulates a lethal pathway involving reactive oxygen species. A hexapeptide that traps the Holliday junction substrate of RuvAB potentiated moxifloxacin-mediated lethality, supporting the development of small-molecule enhancers for moxifloxacin activity against mycobacteria.
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Kumar N, Kedarisetty CK, Kumar S, Khillan V, Sarin SK. Antitubercular therapy in patients with cirrhosis: Challenges and options. World J Gastroenterol 2014; 20:5760-5772. [PMID: 24914337 PMCID: PMC4024786 DOI: 10.3748/wjg.v20.i19.5760] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/31/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Tuberculosis (TB) has been a human disease for centuries. Its frequency is increased manyfold in patients with liver cirrhosis. The gold standard of TB management is a 6-mo course of isoniazid, rifampicin, pyrazinamide and ethambutol. Although good results are seen with this treatment in general, the management of patients with underlying cirrhosis is a challenge. The underlying depressed immune response results in alterations in many diagnostic tests. The tests used for latent TB have many flaws in this group of patients. Three of four first-line antitubercular drugs are hepatotoxic and baseline liver function is often disrupted in patients with underlying cirrhosis. Frequency of hepatotoxicity is increased in patients with liver cirrhosis, frequently leading to severe liver failure. There are no established guidelines for the treatment of TB in relation to the severity of liver disease. There is no consensus on the frequency of liver function tests required or the cut-off used to define hepatotoxicity. No specific treatment exists for prevention or treatment of hepatotoxicity, making monitoring even more important. A high risk of multidrug-resistant TB is another major worry due to prolonged and interrupted treatment.
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