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1
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Coelho MP, Pinho JO, Pinto SN, Gaspar MM. A step forward on the in vitro and in vivo validation of rifabutin-loaded liposomes for the management of highly virulent MRSA infections. J Control Release 2025; 380:348-361. [PMID: 39900224 DOI: 10.1016/j.jconrel.2025.01.083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/08/2025] [Accepted: 01/28/2025] [Indexed: 02/05/2025]
Abstract
Staphylococcus aureus (S. aureus) infections, especially methicillin resistant (MRSA), constitute an alarming public health issue due to its association with high mortality, morbidity, and hospitalization costs. The increasing antibiotic resistance and biofilm-associated infections of MRSA prompted the discovery of novel and more effective therapeutic strategies. Our team has been working on alternative therapies against S. aureus infections. For this, we have been repurposing an existing antibacterial drug, rifabutin (RFB), through its association to a nanotechnological platform, liposomes, aiming to promote a preferential targeting to infected sites and maximizing its potential antibacterial effect. The therapeutic potential of RFB formulations against a MRSA commercial strain (MRSA ATCC®-33592), either in planktonic or biofilm forms, was assessed. RFB displayed higher antibacterial effects towards biofilm than vancomycin (VCM), the gold standard treatment against MRSA infections, with MBIC50 values of 103 and > 800 μg/mL, respectively. Moreover, the antimicrobial effect of RFB-loaded liposomes demonstrated to be lipid composition-dependent based on MIC50 and MBIC50 values, which was also confirmed by confocal laser scanning microscopy. These studies supported that for positively charged RFB liposomes an electrostatic interaction at biofilm surface occurs without internalization. On the other hand, for RFB-loaded liposomes with neutral surface charge a high internalization within the biofilm was observed. Moreover, this RFB liposomal formulation has also demonstrated to be stable in human plasma, as more than 83 % of RFB was still associated to liposomes 24 h after incubation at 37 °C. The proof of concept of RFB formulations was assessed in MRSA systemic murine models of infection. Therapeutic effect and survival rates were evaluated for animals induced and treated with RFB in free and liposomal forms and compared with negative and positive controls. For the lower infection murine model, 100 % survival was achieved for all groups under study. However, in a higher infection model only for the group of animals treated with RFB incorporated in liposomes a 100 % survival was attained. In terms of bacterial burden, RFB formulations exhibited lower levels when compared to VCM, even using a lower therapeutic dose: 20 vs 40 mg/kg of body weight, respectively. Overall, RFB constitutes an alternative and effective therapeutic strategy towards MRSA infections, being this effect potentiated through its association to a lipid nanoplatform.
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Affiliation(s)
- Mariana P Coelho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
| | - Jacinta O Pinho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
| | - Sandra N Pinto
- iBB-Institute for Bioengineering and Biosciences and Associate Laboratory i4HB-Institute for Health and Bioeconomy at Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal.
| | - Maria Manuela Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; IBEB, Institute of Biophysics and Biomedical Engineering, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal.
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2
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Eggertsen TG, Travers JG, Hardy EJ, Wolf MJ, McKinsey TA, Saucerman JJ. Logic-based machine learning predicts how escitalopram attenuates cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A 2025; 122:e2420499122. [PMID: 40035765 PMCID: PMC11912418 DOI: 10.1073/pnas.2420499122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 01/14/2025] [Indexed: 03/06/2025] Open
Abstract
Cardiomyocyte hypertrophy is a key clinical predictor of heart failure. High-throughput and AI-driven screens have the potential to identify drugs and downstream pathways that modulate cardiomyocyte hypertrophy. Here, we developed LogiRx, a logic-based mechanistic machine learning method that predicts drug-induced pathways. We applied LogiRx to discover how drugs discovered in a previous compound screen attenuate cardiomyocyte hypertrophy. We experimentally validated LogiRx predictions in neonatal cardiomyocytes, adult mice, and two patient databases. Using LogiRx, we predicted antihypertrophic pathways for seven drugs currently used to treat noncardiac disease. We experimentally validated that escitalopram (Lexapro) and mifepristone inhibit hypertrophy of cultured cardiomyocytes in two contexts. The LogiRx model predicted that escitalopram prevents hypertrophy through an "off-target" serotonin receptor/PI3Kγ pathway, mechanistically validated using additional investigational drugs. Further, escitalopram reduced cardiomyocyte hypertrophy in a mouse model of hypertrophy and fibrosis. Finally, mining of both FDA and University of Virginia databases showed that patients with depression on escitalopram have a lower incidence of cardiac hypertrophy than those prescribed other serotonin reuptake inhibitors that do not target the serotonin receptor. Mechanistic machine learning by LogiRx discovers drug pathways that perturb cell states, which may enable repurposing of escitalopram and other drugs to limit cardiac remodeling through off-target pathways.
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Affiliation(s)
- Taylor G. Eggertsen
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA22908
| | - Joshua G. Travers
- Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO80045-2507
| | - Elizabeth J. Hardy
- Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO80045-2507
| | - Matthew J. Wolf
- Division of Cardiovascular Medicine, University of Virginia, Charlottesville, VA22908
| | - Timothy A. McKinsey
- Division of Cardiology and Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO80045-2507
| | - Jeffrey J. Saucerman
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA22908
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3
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Sarkar M, Sarkar J. Therapeutic drug monitoring in tuberculosis. Eur J Clin Pharmacol 2024; 80:1659-1684. [PMID: 39240337 DOI: 10.1007/s00228-024-03749-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024]
Abstract
PURPOSE Therapeutic drug monitoring (TDM) is a standard clinical procedure that uses the pharmacokinetic and pharmacodynamic parameters of the drug in the body to determine the optimal dose. The pharmacokinetic variability of the drug(s) is a significant contributor to poor treatment outcomes, including the development of acquired drug resistance. TDM aids in dose optimization and improves outcomes while lessening drug toxicity. TDM is used to manage patients with tuberculosis (TB) who exhibit a slow response to therapy, despite good compliance and drug-susceptible organisms. Additional indications include patients at risk of malabsorption or delayed absorption of TB drugs and patients with drug-drug interaction and drug toxicity, which confirm compliance with therapy. TDM usually requires two blood samples: the 2 h and the 6 h post-dose. This narrative review will discuss the pharmacokinetics and pharmacodynamics of TB drugs, determinants of poor response to therapy, indications of TDM, methods of performing TDM, and its interpretations. METHODS This is a narrative review. We searched PubMed, Embase, and the CINAHL from inception to April 2024. We used the following search terms: tuberculosis, therapeutic drug monitoring, anti-TB drugs, pharmacokinetics, pharmacodynamics, limited sample strategies, diabetes and TB, HIV and TB, and multidrug-resistant TB. All types of articles were selected. RESULTS TDM is beneficial in managing TB, especially in patients with slow responses, drug-resistance TB, recurrent TB, and comorbidities such as diabetes mellitus and human immunodeficiency virus infection. CONCLUSION TDM is beneficial for improving outcomes, reducing the risk of acquired drug resistance, and avoiding side effects.
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Affiliation(s)
- M Sarkar
- Department of Pulmonary Medicine, Indira Gandhi Medical College, Shimla, 171001, Himachal Pradesh, India.
| | - J Sarkar
- MRes Neuroscience, University of Leeds, Leeds, UK
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4
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Mallarino-Haeger C, Watson A, Mahgoub U, Francis L, Heydari M, Choudhary M, Garcia-Toca M, Patel M, Kempker RR, Fayfman M, Schechter MC. High Prescription Rate of Medications With Rifampin Drug-drug Interactions in Patients With Diabetic Foot Osteomyelitis: Should Rifabutin Be Included in Clinical Trials for Adjunctive Therapy? Open Forum Infect Dis 2024; 11:ofae582. [PMID: 39494450 PMCID: PMC11530956 DOI: 10.1093/ofid/ofae582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 10/09/2024] [Indexed: 11/05/2024] Open
Abstract
Rifampin may improve diabetic foot osteomyelitis outcomes, but its extensive drug-drug interactions could hamper its use. Here, through a review of the medications prescribed to a cohort of 190 persons with diabetic foot osteomyelitis, we show that rifabutin, a rifamycin with fewer drug-drug interactions, would be easier to implement in practice.
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Affiliation(s)
- Christina Mallarino-Haeger
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Allison Watson
- Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Umnia Mahgoub
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Lily Francis
- Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Maryam Heydari
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
| | - Muaaz Choudhary
- Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Manuel Garcia-Toca
- Division of Vascular Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
- Grady Health System, Atlanta, Georgia, USA
| | | | - Russell R Kempker
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Grady Health System, Atlanta, Georgia, USA
| | - Maya Fayfman
- Grady Health System, Atlanta, Georgia, USA
- Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Marcos C Schechter
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
- Grady Health System, Atlanta, Georgia, USA
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Ferreira M, Pinto M, Aires-da-Silva F, Bettencourt A, Gaspar MM, Aguiar SI. Rifabutin: a repurposed antibiotic with high potential against planktonic and biofilm staphylococcal clinical isolates. Front Microbiol 2024; 15:1475124. [PMID: 39450290 PMCID: PMC11499150 DOI: 10.3389/fmicb.2024.1475124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/05/2024] [Indexed: 10/26/2024] Open
Abstract
Staphylococcus aureus poses a significant threat as an opportunistic pathogen in humans, and animal medicine, particularly in the context of hospital-acquired infections (HAIs). Effective treatment is a significant challenge, contributing substantially to the global health burden. While antibiotic therapy remains the primary approach for staphylococcal infections, its efficacy is often compromised by the emergence of resistant strains and biofilm formation. The anticipated solution is the discovery and development of new antibacterial agents. However, this is a time consuming and expensive process with limited success rates. One potential alternative for addressing this challenge is the repurposing of existing antibiotics. This study investigated the potential of rifabutin (RFB) as a repurposed antibiotic for treating S. aureus infections. The minimum inhibitory concentration (MIC) of rifabutin was assessed by the broth microdilution method, in parallel to vancomycin, against 114 clinical isolates in planktonic form. The minimum biofilm inhibitory concentration (MBIC50) was determined by an adaptation of the broth microdilution method, followed by MTT assay, against a subset of selected 40 clinical isolates organized in biofilms. The study demonstrated that RFB MIC ranged from 0.002 to 6.250 μg/mL with a MIC50 of 0.013 μg/mL. RFB also demonstrated high anti-biofilm activity in the subset of 40 clinical isolates, with confirmed biofilm formation, with no significant MBIC50 differences observed between the MSSA and MRSA strains, in contrast to that observed for the VAN. These results highlight the promising efficacy of RFB against staphylococcal clinical isolates with different resistance patterns, whether in planktonic and biofilm forms.
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Affiliation(s)
- Magda Ferreira
- Center for Interdisciplinary Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal
| | - Margarida Pinto
- Laboratório de Microbiologia do Serviço de Patologia Clínica do Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal
| | - Frederico Aires-da-Silva
- Center for Interdisciplinary Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal
| | - Ana Bettencourt
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal
| | - Maria Manuela Gaspar
- Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, Lisbon, Portugal
- Faculty of Sciences, Institute of Biophysics and Biomedical Engineering (IBEB), Universidade de Lisboa, Lisbon, Portugal
| | - Sandra Isabel Aguiar
- Center for Interdisciplinary Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, Lisbon, Portugal
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6
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Semere Gebreyesus M, Wasmann RE, McIlleron H, Oladokun R, Okonkwo P, Wiesner L, Denti P, Rawizza HE. Population pharmacokinetics of rifabutin among HIV/TB co-infected children on lopinavir/ritonavir-based antiretroviral therapy. Antimicrob Agents Chemother 2024; 68:e0035424. [PMID: 39037240 PMCID: PMC11304744 DOI: 10.1128/aac.00354-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 07/01/2024] [Indexed: 07/23/2024] Open
Abstract
In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67-15.0) years, a median weight of 11 (range 4.5-45) kg, and a median weight-for-age z score of -3.33 (range -5.15 to -1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%-246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%-78.3%). Severely underweight children showed 26% (17.9%-33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6-20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median Cmax of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.
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Affiliation(s)
- Manna Semere Gebreyesus
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Roeland E. Wasmann
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Helen McIlleron
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Regina Oladokun
- Department of Pediatrics, Faculty of Clinical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Lubbe Wiesner
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Paolo Denti
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Holly E. Rawizza
- Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
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7
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Pinho JO, Ferreira M, Coelho M, Pinto SN, Aguiar SI, Gaspar MM. Liposomal Rifabutin-A Promising Antibiotic Repurposing Strategy against Methicillin-Resistant Staphylococcus aureus Infections. Pharmaceuticals (Basel) 2024; 17:470. [PMID: 38675432 PMCID: PMC11053623 DOI: 10.3390/ph17040470] [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: 02/16/2024] [Revised: 03/23/2024] [Accepted: 04/04/2024] [Indexed: 04/28/2024] Open
Abstract
Methicillin-resistant Staphylococcus aureus (M RSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes aiming to promote the accumulation of RFB at infected sites and consequently enhance the therapeutic potency. Two clinical isolates of MRSA, MRSA-C1 and MRSA-C2, were used to test the developed formulations, as well as the positive control, vancomycin (VCM). RFB in free and liposomal forms displayed high antibacterial activity, with similar potency between tested formulations. In MRSA-C1, minimal inhibitory concentrations (MIC) for Free RFB and liposomal RFB were 0.009 and 0.013 μg/mL, respectively. Minimum biofilm inhibitory concentrations able to inhibit 50% biofilm growth (MBIC50) for Free RFB and liposomal RFB against MRSA-C1 were 0.012 and 0.008 μg/mL, respectively. Confocal microscopy studies demonstrated the rapid internalization of unloaded and RFB-loaded liposomes in the bacterial biofilm matrix. In murine models of systemic MRSA-C1 infection, Balb/c mice were treated with RFB formulations and VCM at 20 and 40 mg/kg of body weight, respectively. The in vivo results demonstrated a significant reduction in bacterial burden and growth index in major organs of mice treated with RFB formulations, as compared to Control and VCM (positive control) groups. Furthermore, the VCM therapeutic dose was two fold higher than the one used for RFB formulations, reinforcing the therapeutic potency of the proposed strategy. In addition, RFB formulations were the only formulations associated with 100% survival. Globally, this study emphasizes the potential of RFB nanoformulations as an effective and safe approach against MRSA infections.
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Affiliation(s)
- Jacinta O. Pinho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.O.P.); (M.F.); (M.C.)
| | - Magda Ferreira
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.O.P.); (M.F.); (M.C.)
- Center for Interdisciplinary Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, 1300-477 Lisboa, Portugal;
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Faculty of Veterinary Medicine, Universidade de Lisboa, 1300-477 Lisboa, Portugal
| | - Mariana Coelho
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.O.P.); (M.F.); (M.C.)
| | - Sandra N. Pinto
- iBB-Institute for Bioengineering and Biosciences and Associate Laboratory i4HB−Institute for Health and Bioeconomy at Department of Bioengineering, Instituto SuperiorTécnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal;
| | - Sandra I. Aguiar
- Center for Interdisciplinary Research in Animal Health (CIISA), Faculty of Veterinary Medicine, Universidade de Lisboa, 1300-477 Lisboa, Portugal;
| | - Maria Manuela Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.O.P.); (M.F.); (M.C.)
- IBEB, Institute of Biophysics and Biomedical Engineering, Faculty of Sciences, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
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8
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Nagashima A, Kobori T, Hattori M, Imura S, Okochi Y. A Case of Miliary Tuberculosis Complicated by Thyroid Involvement: Managing Rifampicin-Induced Thrombocytopenia With Rifabutin. Cureus 2024; 16:e57876. [PMID: 38725736 PMCID: PMC11081410 DOI: 10.7759/cureus.57876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2024] [Indexed: 05/12/2024] Open
Abstract
This case report presents an unusual occurrence of miliary tuberculosis with thyroid tuberculosis in a 75-year-old male patient, who successfully completed the treatment with rifabutin after rifampicin-induced thrombocytopenia. The patient has been suffering from diabetes mellitus and chronic heart failure, and had coronavirus disease of 2019 (COVID-19) just before being diagnosed with miliary tuberculosis. The patient had not been prescribed immunosuppressants and steroids. Chest computed tomography (CT) scans revealed multiple tiny nodules diffusely and equally distributed in bilateral lung fields. Subsequently, polymerase chain reaction (PCR) techniques on the urine samples and culture of sputum demonstrated positivity for Mycobacterium tuberculosis. Thus, we conclusively identified miliary tuberculosis and initiated treatment using anti-tuberculosis drugs. During treatment, the patient developed thyroid tuberculosis, resulting in an enlarged thyroid and hoarseness, but these symptoms improved with continued use of the anti-tuberculosis drugs. Moreover, regarding treatment, the rifabutin dosage was completed after changing drugs due to rifampicin-induced thrombocytopenia. Notably, miliary tuberculosis is rarely complicated by thyroid tuberculosis as a paradoxical reaction, and the substitution of rifabutin for rifampicin-induced thrombocytopenia is not fully studied. We present this case alongside relevant prior data for comprehensive clinical insight.
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Affiliation(s)
- Akimichi Nagashima
- Department of Respiratory Medicine, Japan Community Health Care Organization Tokyo Yamate Medical Center, Tokyo, JPN
| | - Tomoko Kobori
- Department of Respiratory Medicine, Japan Community Health Care Organization Tokyo Yamate Medical Center, Tokyo, JPN
| | - Mototaka Hattori
- Department of Respiratory Medicine, Japan Community Health Care Organization Tokyo Yamate Medical Center, Tokyo, JPN
| | - Shingo Imura
- Department of Respiratory Medicine, Japan Community Health Care Organization Tokyo Yamate Medical Center, Tokyo, JPN
| | - Yasumi Okochi
- Department of Respiratory Medicine, Japan Community Health Care Organization Tokyo Yamate Medical Center, Tokyo, JPN
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9
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Hasanuzzaman M, Bang CS, Gong EJ. Antibiotic Resistance of Helicobacter pylori: Mechanisms and Clinical Implications. J Korean Med Sci 2024; 39:e44. [PMID: 38288543 PMCID: PMC10825452 DOI: 10.3346/jkms.2024.39.e44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/29/2023] [Indexed: 02/01/2024] Open
Abstract
Helicobacter pylori is a pathogenic bacterium associated with various gastrointestinal diseases, including chronic gastritis, peptic ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. The increasing rates of H. pylori antibiotic resistance and the emergence of multidrug-resistant strains pose significant challenges to its treatment. This comprehensive review explores the mechanisms underlying the resistance of H. pylori to commonly used antibiotics and the clinical implications of antibiotic resistance. Additionally, potential strategies for overcoming antibiotic resistance are discussed. These approaches aim to improve the treatment outcomes of H. pylori infections while minimizing the development of antibiotic resistance. The continuous evolution of treatment perspectives and ongoing research in this field are crucial for effectively combating this challenging infection.
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Affiliation(s)
- Md Hasanuzzaman
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Eun Jeong Gong
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea.
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10
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Borody TJ, Ng J, Dolai S. Unlocking the path to efficient H. pylori eradication: Embracing potassium-competitive acid blockers (P-CABs). Saudi J Gastroenterol 2023; 29:323-325. [PMID: 37706422 PMCID: PMC10754378 DOI: 10.4103/sjg.sjg_297_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/15/2023] Open
Affiliation(s)
- Thomas J. Borody
- Department of Gastroenterology, The Centre for Digestive Diseases (CDD), Sydney, NSW, Australia
| | - John Ng
- Axent Medical Pty Ltd., Sydney, NSW, Australia
| | - Sibasish Dolai
- Department of Gastroenterology, The Centre for Digestive Diseases (CDD), Sydney, NSW, Australia
- Axent Medical Pty Ltd., Sydney, NSW, Australia
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11
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Chang YS, Li SY, Pertinez H, Betoudji F, Lee J, Rannard SP, Owen A, Nuermberger EL, Ammerman NC. Using Dynamic Oral Dosing of Rifapentine and Rifabutin to Simulate Exposure Profiles of Long-Acting Formulations in a Mouse Model of Tuberculosis Preventive Therapy. Antimicrob Agents Chemother 2023; 67:e0048123. [PMID: 37338374 PMCID: PMC10353356 DOI: 10.1128/aac.00481-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 05/18/2023] [Indexed: 06/21/2023] Open
Abstract
Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have antituberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We used a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that have utility beyond latent tuberculosis infection.
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Affiliation(s)
- Yong S. Chang
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Si-Yang Li
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Henry Pertinez
- Centre of Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Fabrice Betoudji
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jin Lee
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Steven P. Rannard
- Centre of Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Andrew Owen
- Centre of Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Eric L. Nuermberger
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nicole C. Ammerman
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medical Microbiology and Infectious Diseases, University Medical Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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12
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Osipova N, Budko A, Maksimenko O, Shipulo E, Vanchugova L, Chen W, Gelperina S, Wacker MG. Comparison of Compartmental and Non-Compartmental Analysis to Detect Biopharmaceutical Similarity of Intravenous Nanomaterial-Based Rifabutin Formulations. Pharmaceutics 2023; 15:pharmaceutics15041258. [PMID: 37111743 PMCID: PMC10145013 DOI: 10.3390/pharmaceutics15041258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Pharmacometric analysis is often used to quantify the differences and similarities between formulation prototypes. In the regulatory framework, it plays a significant role in the evaluation of bioequivalence. While non-compartmental analysis provides an unbiased data evaluation, mechanistic compartmental models such as the physiologically-based nanocarrier biopharmaceutics model promise improved sensitivity and resolution for the underlying causes of inequivalence. In the present investigation, both techniques were applied to two nanomaterial-based formulations for intravenous injection, namely, albumin-stabilized rifabutin nanoparticles and rifabutin-loaded PLGA nanoparticles. The antibiotic rifabutin holds great potential for the treatment of severe and acute infections of patients co-infected with human immunodeficiency virus and tuberculosis. The formulations differ significantly in their formulation and material attributes, resulting in an altered biodistribution pattern as confirmed in a biodistribution study in rats. The albumin-stabilized delivery system further undergoes a dose-dependent change in particle size which leads to a small yet significant change in the in vivo performance. A second analysis was conducted comparing the dose fraction-scaled pharmacokinetic profiles of three dose levels of albumin-stabilized rifabutin nanoparticles. The dose strength affects both the nanomaterial-related absorption and biodistribution of the carrier as well as the drug-related distribution and elimination parameters, increasing the background noise and difficulty of detecting inequivalence. Depending on the pharmacokinetic parameter (e.g., AUC, Cmax, Clobs), the relative (percentage) difference from the average observed using non-compartmental modeling ranged from 85% to 5.2%. A change in the formulation type (PLGA nanoparticles vs. albumin-stabilized rifabutin nanoparticles) resulted in a similar level of inequivalence as compared to a change in the dose strength. A mechanistic compartmental analysis using the physiologically-based nanocarrier biopharmaceutics model led to an average difference of 152.46% between the two formulation prototypes. Albumin-stabilized rifabutin nanoparticles tested at different dose levels led to a 128.30% difference, potentially due to changes in particle size. A comparison of different dose strengths of PLGA nanoparticles, on average, led to a 3.87% difference. This study impressively illustrates the superior sensitivity of mechanistic compartmental analysis when dealing with nanomedicines.
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Affiliation(s)
| | - Andrey Budko
- N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Science, Kashirskoye Shosse 24, 115478 Moscow, Russia
| | - Olga Maksimenko
- Nanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, Russia
| | - Elena Shipulo
- Nanosystem Ltd., Kolomenskiy Proezd 13A, 115446 Moscow, Russia
| | | | - Wenqian Chen
- Department of Pharmacy, Faculty of Science, 4 Science Drive 2, Singapore 117544, Singapore
| | | | - Matthias G Wacker
- Department of Pharmacy, Faculty of Science, 4 Science Drive 2, Singapore 117544, Singapore
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13
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Chang YS, Li SY, Pertinez H, Betoudji F, Lee J, Rannard SP, Owen A, Nuermberger EL, Ammerman NC. Using dynamic oral dosing of rifapentine and rifabutin to simulate exposure profiles of long-acting formulations in a mouse model of tuberculosis preventive therapy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.12.536604. [PMID: 37090528 PMCID: PMC10120629 DOI: 10.1101/2023.04.12.536604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
Administration of tuberculosis preventive therapy (TPT) to individuals with latent tuberculosis infection is an important facet of global tuberculosis control. The use of long-acting injectable (LAI) drug formulations may simplify and shorten regimens for this indication. Rifapentine and rifabutin have anti-tuberculosis activity and physiochemical properties suitable for LAI formulation, but there are limited data available for determining the target exposure profiles required for efficacy in TPT regimens. The objective of this study was to determine exposure-activity profiles of rifapentine and rifabutin to inform development of LAI formulations for TPT. We utilized a validated paucibacillary mouse model of TPT in combination with dynamic oral dosing of both drugs to simulate and understand exposure-activity relationships to inform posology for future LAI formulations. This work identified several LAI-like exposure profiles of rifapentine and rifabutin that, if achieved by LAI formulations, could be efficacious as TPT regimens and thus can serve as experimentally-determined targets for novel LAI formulations of these drugs. We present novel methodology to understand the exposure-response relationship and inform the value proposition for investment in development of LAI formulations that has utility beyond latent tuberculosis infection.
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Affiliation(s)
- Yong S. Chang
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Touro College of Osteopathic Medicine-Middletown, Middletown, New York, USA (current address)
| | - Si-Yang Li
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Henry Pertinez
- Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Fabrice Betoudji
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Veterinary Medicine Division, USAMRIID, Fort Detrick, Frederick, Maryland, USA (current address)
| | - Jin Lee
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Steven P. Rannard
- Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Andrew Owen
- Centre of Excellence in Long-acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
| | - Eric L. Nuermberger
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Nicole C. Ammerman
- Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Medical Microbiology and Infectious Diseases, University Medical Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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14
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Santos AM, Carvalho Santana Júnior C, Nascimento Júnior JAC, Andrade TDA, Shanmugam S, Thangaraj P, Frank LA, Serafini MR. Antibacterial drugs and cyclodextrin inclusion complexes: a patent review. Expert Opin Drug Deliv 2023; 20:349-366. [PMID: 36722254 DOI: 10.1080/17425247.2023.2175815] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Bacterial antibiotic resistance occurs when bacteria mutate and escape the effect of antibiotics, which makes the antibiotics no longer effective in treating infections. New solutions for bacterial infections are a persistent need including the identification of drugs with better pharmacological profiles, more potent, and safer. Cyclodextrins inclusion complexes have been able to improve the physicochemical and pharmacological properties of the formulation molecules, resulting in new alternatives with better efficacy. AREAS COVERED The patents analyzed in the review used treatments based on antibiotics already on the market, natural products, and synthesized molecules composed of the formulation with cyclodextrins. The combination between cyclodextrin and nanostructures also were presented in the patents review process. Moreover, inclusion complexes have been an alternative in developing treatment mainly in China by the pharmaceutical industries in several countries such as Germany, Hungary, the United States of America, Japan and China. EXPERT OPINION This review is broad and complete since it considers the first patent involving cyclodextrins and antibacterial drugs. Therefore, the various inclusion complexes and antibacterial drugs alternatives presented in this review offer therapeutic options to fight bacterial infections. If shown to be effective, these drugs may be extremely important in the current clinical practice.
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Affiliation(s)
| | | | | | | | - Saravanan Shanmugam
- Department of Pharmacy, Federal University of Sergipe, São Cristóvão, Brazil
| | | | - Luiza Abrahão Frank
- Postgraduate Program in Pharmaceutical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - Mairim Russo Serafini
- Postgraduate Program in Health Sciences, Federal University of Sergipe, Aracaju, Brazil.,Department of Pharmacy, Federal University of Sergipe, São Cristóvão, Brazil.,Postgraduate Program in Pharmaceutical Sciences, Federal University of Sergipe, São Cristóvão, Brazil
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15
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Johnson TM, Byrd TF, Drummond WK, Childs-Kean LM, Mahoney MV, Pearson JC, Rivera CG. Contemporary Pharmacotherapies for Nontuberculosis Mycobacterial Infections: A Narrative Review. Infect Dis Ther 2023; 12:343-365. [PMID: 36609820 PMCID: PMC9925655 DOI: 10.1007/s40121-022-00750-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/19/2022] [Indexed: 01/08/2023] Open
Abstract
Nontuberculous mycobacteria (NTM) are a group of atypical bacteria that may cause a spectrum of clinical manifestations, including pulmonary, musculoskeletal, skin and soft tissue, and cardiac infections. Antimycobacterial medication regimens for NTM infections require multiple agents with prolonged treatment courses and are often associated with poor tolerance in patients and suboptimal clinical outcomes. This review summarizes NTM pharmacotherapy, including treatment concepts, preferred medication regimens according to NTM species and site of infection, and emerging treatment methods for difficult-to-treat species.
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Affiliation(s)
| | - Thomas F Byrd
- Division of Infectious Diseases, University of New Mexico, Albuquerque, NM, USA
| | - Wendi K Drummond
- Division of Infectious Diseases, Providence Portland Medical Center, Portland, OR, USA
| | | | - Monica V Mahoney
- Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Jeffrey C Pearson
- Department of Pharmacy Services, Brigham and Women's Hospital, Boston, MA, USA
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16
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Meesters K, Alemayehu T, Benou S, Buonsenso D, Decloedt EH, Pillay-Fuentes Lorente V, Downes KJ, Allegaert K. Pharmacokinetics of Antimicrobials in Children with Emphasis on Challenges Faced by Low and Middle Income Countries, a Clinical Review. Antibiotics (Basel) 2022; 12:17. [PMID: 36671218 PMCID: PMC9854442 DOI: 10.3390/antibiotics12010017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/16/2022] [Accepted: 12/18/2022] [Indexed: 12/25/2022] Open
Abstract
Effective antimicrobial exposure is essential to treat infections and prevent antimicrobial resistance, both being major public health problems in low and middle income countries (LMIC). Delivery of drug concentrations to the target site is governed by dose and pharmacokinetic processes (absorption, distribution, metabolism and excretion). However, specific data on the pharmacokinetics of antimicrobials in children living in LMIC settings are scarce. Additionally, there are significant logistical constraints to therapeutic drug monitoring that further emphasize the importance of understanding pharmacokinetics and dosing in LMIC. Both malnutrition and diarrheal disease reduce the extent of enteral absorption. Multiple antiretrovirals and antimycobacterial agents, commonly used by children in low resource settings, have potential interactions with other antimicrobials. Hypoalbuminemia, which may be the result of malnutrition, nephrotic syndrome or liver failure, increases the unbound concentrations of protein bound drugs that may therefore be eliminated faster. Kidney function develops rapidly during the first years of life and different inflammatory processes commonly augment renal clearance in febrile children, potentially resulting in subtherapeutic drug concentrations if doses are not adapted. Using a narrative review approach, we outline the effects of growth, maturation and comorbidities on maturational and disease specific effects on pharmacokinetics in children in LMIC.
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Affiliation(s)
- Kevin Meesters
- Department of Pediatrics, BC Children’s Hospital and The University of British Columbia, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada
| | - Tinsae Alemayehu
- Division of Pediatric Infectious Diseases, Department of Pediatrics and Child Health, St. Paul’s Hospital Millennium Medical College, Addis Ababa P.O. Box 1271, Ethiopia
- Division of Infectious Diseases and Travel Medicine, American Medical Center, Addis Ababa P.O. Box 62706, Ethiopia
| | - Sofia Benou
- Department of Pediatrics, General University Hospital of Patras, Medical School, University of Patras, 26504 Rion, Greece
| | - Danilo Buonsenso
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo A. Gemelli 8, 00168 Rome, Italy
- Centro di Salute Globale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Eric H. Decloedt
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7500, South Africa
| | - Veshni Pillay-Fuentes Lorente
- Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7500, South Africa
| | - Kevin J. Downes
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA
- Division of Infectious Diseases, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA
| | - Karel Allegaert
- Department of Development and Regeneration, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium
- Department of Clinical Pharmacy, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
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17
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Lan T, Ganapathy US, Sharma S, Ahn Y, Zimmerman M, Molodtsov V, Hegde P, Gengenbacher M, Ebright RH, Dartois V, Freundlich JS, Dick T, Aldrich CC. Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance. Angew Chem Int Ed Engl 2022; 61:e202211498. [PMID: 36222275 PMCID: PMC9633546 DOI: 10.1002/anie.202211498] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Indexed: 11/11/2022]
Abstract
Rifamycin antibiotics are a valuable class of antimicrobials for treating infections by mycobacteria and other persistent bacteria owing to their potent bactericidal activity against replicating and non-replicating pathogens. However, the clinical utility of rifamycins against Mycobacterium abscessus is seriously compromised by a novel resistance mechanism, namely, rifamycin inactivation by ADP-ribosylation. Using a structure-based approach, we rationally redesign rifamycins through strategic modification of the ansa-chain to block ADP-ribosylation while preserving on-target activity. Validated by a combination of biochemical, structural, and microbiological studies, the most potent analogs overcome ADP-ribosylation, restored their intrinsic low nanomolar activity and demonstrated significant in vivo antibacterial efficacy. Further optimization by tuning drug disposition properties afforded a preclinical candidate with remarkable potency and an outstanding pharmacokinetic profile.
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Affiliation(s)
- Tian Lan
- Department of Medicinal ChemistryCollege of PharmacyUniversity of Minnesota308 SE Harvard St SEMinneapolisMN 55455USA
| | - Uday S. Ganapathy
- Center for Discovery and InnovationHackensack Meridian Health & Department of Medical SciencesHackensack Meridian School of Medicine123 Metro BoulevardNutleyNJ 07110USA
| | - Sachin Sharma
- Department of Medicinal ChemistryCollege of PharmacyUniversity of Minnesota308 SE Harvard St SEMinneapolisMN 55455USA
| | - Yong‐Mo Ahn
- Department of Pharmacology and PhysiologyDepartment of MedicineCenter for Emerging and Reemerging PathogensRutgers University185 South Orange AvenueNewarkNJ 07103USA
- National Center for Advancing Translational SciencesNational Institutes of HealthRockvilleMD 20850USA
| | - Matthew Zimmerman
- Center for Discovery and InnovationHackensack Meridian Health & Department of Medical SciencesHackensack Meridian School of Medicine123 Metro BoulevardNutleyNJ 07110USA
| | - Vadim Molodtsov
- Waksman InstituteRutgers University190 Frelinghuysen RoadPiscatawayNJ 08854USA
| | - Pooja Hegde
- Department of Medicinal ChemistryCollege of PharmacyUniversity of Minnesota308 SE Harvard St SEMinneapolisMN 55455USA
| | - Martin Gengenbacher
- Center for Discovery and InnovationHackensack Meridian Health & Department of Medical SciencesHackensack Meridian School of Medicine123 Metro BoulevardNutleyNJ 07110USA
| | - Richard H. Ebright
- Waksman InstituteRutgers University190 Frelinghuysen RoadPiscatawayNJ 08854USA
| | - Véronique Dartois
- Center for Discovery and InnovationHackensack Meridian Health & Department of Medical SciencesHackensack Meridian School of Medicine123 Metro BoulevardNutleyNJ 07110USA
| | - Joel S. Freundlich
- Department of Pharmacology and PhysiologyDepartment of MedicineCenter for Emerging and Reemerging PathogensRutgers University185 South Orange AvenueNewarkNJ 07103USA
| | - Thomas Dick
- Center for Discovery and InnovationHackensack Meridian Health & Department of Medical SciencesHackensack Meridian School of Medicine123 Metro BoulevardNutleyNJ 07110USA
- Department of Microbiology and ImmunologyGeorgetown University3900 Reservoir Road NWWashingtonDC 20007USA
| | - Courtney C. Aldrich
- Department of Medicinal ChemistryCollege of PharmacyUniversity of Minnesota308 SE Harvard St SEMinneapolisMN 55455USA
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18
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Lan T, Ganapathy US, Sharma S, Ahn Y, Zimmerman M, Molodtsov V, Hegde P, Gengenbacher M, Ebright RH, Dartois V, Freundlich JS, Dick T, Aldrich CC. Redesign of Rifamycin Antibiotics to Overcome ADP‐Ribosylation‐Mediated Resistance. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202211498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Tian Lan
- Department of Medicinal Chemistry College of Pharmacy University of Minnesota 308 SE Harvard St SE Minneapolis MN 55455 USA
| | - Uday S. Ganapathy
- Center for Discovery and Innovation Hackensack Meridian Health & Department of Medical Sciences Hackensack Meridian School of Medicine 123 Metro Boulevard Nutley NJ 07110 USA
| | - Sachin Sharma
- Department of Medicinal Chemistry College of Pharmacy University of Minnesota 308 SE Harvard St SE Minneapolis MN 55455 USA
| | - Yong‐Mo Ahn
- Department of Pharmacology and Physiology Department of Medicine Center for Emerging and Reemerging Pathogens Rutgers University 185 South Orange Avenue Newark NJ 07103 USA
- National Center for Advancing Translational Sciences National Institutes of Health Rockville MD 20850 USA
| | - Matthew Zimmerman
- Center for Discovery and Innovation Hackensack Meridian Health & Department of Medical Sciences Hackensack Meridian School of Medicine 123 Metro Boulevard Nutley NJ 07110 USA
| | - Vadim Molodtsov
- Waksman Institute Rutgers University 190 Frelinghuysen Road Piscataway NJ 08854 USA
| | - Pooja Hegde
- Department of Medicinal Chemistry College of Pharmacy University of Minnesota 308 SE Harvard St SE Minneapolis MN 55455 USA
| | - Martin Gengenbacher
- Center for Discovery and Innovation Hackensack Meridian Health & Department of Medical Sciences Hackensack Meridian School of Medicine 123 Metro Boulevard Nutley NJ 07110 USA
| | - Richard H. Ebright
- Waksman Institute Rutgers University 190 Frelinghuysen Road Piscataway NJ 08854 USA
| | - Véronique Dartois
- Center for Discovery and Innovation Hackensack Meridian Health & Department of Medical Sciences Hackensack Meridian School of Medicine 123 Metro Boulevard Nutley NJ 07110 USA
| | - Joel S. Freundlich
- Department of Pharmacology and Physiology Department of Medicine Center for Emerging and Reemerging Pathogens Rutgers University 185 South Orange Avenue Newark NJ 07103 USA
| | - Thomas Dick
- Center for Discovery and Innovation Hackensack Meridian Health & Department of Medical Sciences Hackensack Meridian School of Medicine 123 Metro Boulevard Nutley NJ 07110 USA
- Department of Microbiology and Immunology Georgetown University 3900 Reservoir Road NW Washington DC 20007 USA
| | - Courtney C. Aldrich
- Department of Medicinal Chemistry College of Pharmacy University of Minnesota 308 SE Harvard St SE Minneapolis MN 55455 USA
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19
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Paulowski L, Beckham KSH, Johansen MD, Berneking L, Van N, Degefu Y, Staack S, Sotomayor FV, Asar L, Rohde H, Aldridge BB, Aepfelbacher M, Parret A, Wilmanns M, Kremer L, Combrink K, Maurer FP. C25-modified rifamycin derivatives with improved activity against Mycobacterium abscessus. PNAS NEXUS 2022; 1:pgac130. [PMID: 36714853 PMCID: PMC9802118 DOI: 10.1093/pnasnexus/pgac130] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 08/05/2022] [Indexed: 02/01/2023]
Abstract
Infections caused by Mycobacterium abscessus are difficult to treat due to its intrinsic resistance to most antibiotics. Formation of biofilms and the capacity of M. abscessus to survive inside host phagocytes further complicate eradication. Herein, we explored whether addition of a carbamate-linked group at the C25 position of rifamycin SV blocks enzymatic inactivation by ArrMab, an ADP-ribosyltransferase conferring resistance to rifampicin (RMP). Unlike RMP, 5j, a benzyl piperidine rifamycin derivative with a morpholino substituted C3 position and a naphthoquinone core, is not modified by purified ArrMab. Additionally, we show that the ArrMab D82 residue is essential for catalytic activity. Thermal profiling of ArrMab in the presence of 5j, RMP, or rifabutin shows that 5j does not bind to ArrMab. We found that the activity of 5j is comparable to amikacin against M. abscessus planktonic cultures and pellicles. Critically, 5j also exerts potent antimicrobial activity against M. abscessus in human macrophages and shows synergistic activity with amikacin and azithromycin.
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Affiliation(s)
| | | | | | | | - Nhi Van
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Boston, MA 02111, USA
| | - Yonatan Degefu
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Boston, MA 02111, USA
| | - Sonja Staack
- European Molecular Biology Laboratory, 22607 Hamburg, Germany
| | - Flor Vasquez Sotomayor
- National and WHO Supranational Reference Center for Mycobacteria, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany,Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Lucia Asar
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Holger Rohde
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Bree B Aldridge
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine and Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Boston, MA 02111, USA
| | - Martin Aepfelbacher
- Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Annabel Parret
- European Molecular Biology Laboratory, 22607 Hamburg, Germany,Charles River Laboratories, 2340 Beerse, Belgium
| | - Matthias Wilmanns
- European Molecular Biology Laboratory, 22607 Hamburg, Germany,University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Laurent Kremer
- Centre National de la Recherche Scientifique UMR 9004, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, 34293 Montpellier, France,INSERM, Institut de Recherche en Infectiologie de Montpellier, 34293 Montpellier, France
| | - Keith Combrink
- Department of Chemistry and Biochemistry, Texas A&M International University, Laredo, TX 77843, USA,Department of Chemistry, Blinn College, Bryan Campus, Brenham, TX 77833, USA
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20
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Kim M, Johnson CE, Schmalstig AA, Annis A, Wessel SE, Van Horn B, Schauer A, Exner AA, Stout JE, Wahl A, Braunstein M, Victor Garcia J, Kovarova M. A long-acting formulation of rifabutin is effective for prevention and treatment of Mycobacterium tuberculosis. Nat Commun 2022; 13:4455. [PMID: 35941109 PMCID: PMC9360445 DOI: 10.1038/s41467-022-32043-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 07/14/2022] [Indexed: 11/08/2022] Open
Abstract
Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb) and is a major cause of morbidity and mortality. Successful treatment requires strict adherence to drug regimens for prolonged periods of time. Long-acting (LA) delivery systems have the potential to improve adherence. Here, we show the development of LA injectable drug formulations of the anti-TB drug rifabutin made of biodegradable polymers and biocompatible solvents that solidifies after subcutaneous injection. Addition of amphiphilic compounds increases drug solubility, allowing to significantly increase formulation drug load. Solidified implants have organized microstructures that change with formulation composition. Higher drug load results in smaller pore size that alters implant erosion and allows sustained drug release. The translational relevance of these observations in BALB/c mice is demonstrated by (1) delivering high plasma drug concentrations for 16 weeks, (2) preventing acquisition of Mtb infection, and (3) clearing acute Mtb infection from the lung and other tissues.
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Affiliation(s)
- Manse Kim
- International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Claire E Johnson
- International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alan A Schmalstig
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ayano Annis
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sarah E Wessel
- International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Brian Van Horn
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Amanda Schauer
- UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Agata A Exner
- Department of Radiology, Case Western Reserve University, Cleveland, OH, USA
| | - Jason E Stout
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Angela Wahl
- International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Miriam Braunstein
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - J Victor Garcia
- International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Martina Kovarova
- International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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21
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Kim OH, Shim TS, Jo KW. Drug-level change and optimal dose adjustment of tacrolimus with the use of rifabutin for treating mycobacterial disease in solid organ transplant recipients. Transpl Infect Dis 2022; 24:e13893. [PMID: 35822673 DOI: 10.1111/tid.13893] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/24/2022] [Accepted: 06/14/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Little is known about the change in drug level and the need for dose adjustment of calcineurin inhibitor when it is used with rifabutin in solid organ transplant (SOT) recipients. We aimed to analyze whether the drug level of tacrolimus significantly reduced after the use of rifabutin and to assess optimal adjustment of tacrolimus dose in SOT recipients. METHODS Of the SOT recipients in a tertiary referral center in South Korea in 2000-2019, 50 patients who maintained an unchanged dose of tacrolimus after the use of rifabutin for treating mycobacterial disease were enrolled. Their medical records were reviewed retrospectively. RESULTS The mean age of the patients was 53.9 ± 11.5 years. The most commonly transplanted organ was the liver (66.0%). The most common indication of rifabutin use was for treating active tuberculosis (78.0%). After rifabutin initiation, the trough level of tacrolimus decreased significantly to the subtherapeutic range in 38 (76.0%) patients. The drug levels of these 38 patients dropped from 7.2 to 3.8 ng/mL (p < 0.001) after rifabutin treatment. In these patients, the median 1.5-fold increase in the tacrolimus dose was required to restore the drug level to the within-therapeutic range. CONCLUSIONS These findings indicate that careful tacrolimus drug-level monitoring and dose adjustment are necessary for most SOT recipients when rifabutin is administered for the treatment of mycobacterial disease. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Ock-Hwa Kim
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Chungnam National University Sejong Hospital, Sejong, Republic of Korea
| | - Tae Sun Shim
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung-Wook Jo
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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22
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MacDougall C, Canonica T, Keh C, P. Phan BA, Louie J. Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management. Pharmacotherapy 2022; 42:343-361. [DOI: 10.1002/phar.2672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 02/01/2023]
Affiliation(s)
- Conan MacDougall
- Department of Clinical Pharmacy University of California San Francisco School of Pharmacy San Francisco California USA
| | - Theora Canonica
- Department of Clinical Pharmacy San Francisco Veterans' Affairs Medical Center San Francisco California USA
| | - Chris Keh
- Division of Infectious Disease University of California, San Francisco San Francisco California USA
| | - Binh An P. Phan
- Division of Cardiology San Francisco General Hospital University of California, San Francisco San Francisco California USA
| | - Janice Louie
- Division of Infectious Diseases San Francisco Department of Public Health Tuberculosis Clinic University of California, San Francisco San Francisco California USA
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23
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Thill P, Robineau O, Roosen G, Patoz P, Gachet B, Lafon-Desmurs B, Tetart M, Nadji S, Senneville E, Blondiaux N. Rifabutin versus rifampicin bactericidal and antibiofilm activities against clinical strains of Staphylococcus spp. isolated from bone and joint infections. J Antimicrob Chemother 2022; 77:1036-1040. [PMID: 35028671 DOI: 10.1093/jac/dkab486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 12/08/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Staphylococci account for approximately 60% of periprosthetic joint infections (PJIs). Rifampicin (RMP) combination therapy is generally considered to be the treatment of choice for staphylococcal PJIs but carries an important risk of adverse events and drug-drug interactions. Rifabutin (RFB) shares many of the properties of rifampicin but causes fewer adverse events. OBJECTIVES To compare the minimal inhibitory concentration (MIC), the minimum bactericidal concentrations (MBC), and the minimum biofilm eradication concentrations (MBEC) of rifabutin and rifampicin for staphylococcal clinical strains isolated from PJIs. METHODS 132 clinical strains of rifampicin-susceptible staphylococci [51 Staphylococcus aureus (SA), 48 Staphylococcus epidermidis (SE) and 33 other coagulase-negative staphylococci (CoNS)] were studied. The MBC and the MBEC were determined using the MBEC® Assay for rifabutin and rifampicin and were compared. RESULTS When compared with the rifampicin MIC median value, the rifabutin MIC median value was significantly higher for SA (P < 0.05), but there was no statistically significant difference for SE (P = 0.25) and CoNS (P = 0.29). The rifabutin MBC median value was significantly higher than that of rifampicin for SA (P = 0.003) and was lower for SE (P = 0.003) and CoNS (P = 0.03). Rifabutin MBEC median value was statistically lower than that of rifampicin for all strains tested. CONCLUSIONS Using the determination of MBEC values, our study suggests that rifabutin is more effective than rifampicin against clinical strains of Staphylococcus spp. obtained from PJIs. Using MBECs instead of MICs seems to be of interest when considering biofilms. In vivo higher efficacy of rifabutin when compared with rifampicin needs to be confirmed.
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Affiliation(s)
- Pauline Thill
- Department of Infectious Diseases, Hospital of Tourcoing, Tourcoing, France
| | - Olivier Robineau
- Department of Infectious Diseases, Hospital of Tourcoing, Tourcoing, France.,EA2694, Univ Lille, Centre Hospitalier de Tourcoing, Tourcoing, France
| | - Gabrielle Roosen
- Department of Bacteriology, Hospital of Tourcoing, Tourcoing, France
| | - Pierre Patoz
- Department of Bacteriology, Hospital of Tourcoing, Tourcoing, France
| | - Benoit Gachet
- Department of Infectious Diseases, Hospital of Tourcoing, Tourcoing, France.,EA2694, Univ Lille, Centre Hospitalier de Tourcoing, Tourcoing, France
| | | | - Macha Tetart
- Department of Infectious Diseases, Hospital of Tourcoing, Tourcoing, France
| | - Safia Nadji
- Department of Bacteriology, Hospital of Tourcoing, Tourcoing, France
| | - Eric Senneville
- Department of Infectious Diseases, Hospital of Tourcoing, Tourcoing, France.,EA2694, Univ Lille, Centre Hospitalier de Tourcoing, Tourcoing, France
| | - Nicolas Blondiaux
- Department of Bacteriology, Hospital of Tourcoing, Tourcoing, France.,Univ. Lille, CNRS, Inserm, Institut Pasteur de Lille, U1019 - UMR9017 Center for Infection and Immunity of Lille, Lille, France
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24
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Arbiv OA, Kim JM, Yan M, Romanowski K, Campbell JR, Trajman A, Asadi L, Fregonese F, Winters N, Menzies D, Johnston JC. High-dose rifamycins in the treatment of TB: a systematic review and meta-analysis. Thorax 2022; 77:1210-1218. [PMID: 34996847 DOI: 10.1136/thoraxjnl-2020-216497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/02/2021] [Indexed: 11/04/2022]
Abstract
BACKGROUND There is growing interest in using high-dose rifamycin (HDR) regimens in TB treatment, but the safety and efficacy of HDR regimens remain uncertain. We performed a systematic review and meta-analysis comparing HDR to standard-dose rifamycin (SDR) regimens. METHODS We searched MEDLINE, Embase, CENTRAL, Cochrane Database of Systematic Reviews and clinicaltrials.gov for prospective studies comparing daily therapy with HDRs to SDRs. Rifamycins included rifampicin, rifapentine and rifabutin. Our primary outcome was the rate of severe adverse events (SAEs), with secondary outcomes of death, all adverse events, SAE by organ and efficacy outcomes of 2-month culture conversion and relapse. This study was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42020142519). RESULTS We identified 9057 articles and included 13 studies with 6168 participants contributing 7930 person-years (PY) of follow-up (HDR: 3535 participants, 4387 PY; SDR: 2633 participants, 3543 PY). We found no significant difference in the pooled incidence rate ratio (IRR) of SAE between HDR and SDR (IRR 1.00, 95% CI 0.82 to 1.23, I 2=41%). There was no significant difference when analysis was limited to SAE possibly, probably or likely medication-related (IRR 1.07, 95% CI 0.82 to 1.41, I 2=0%); studies with low risk of bias (IRR 0.98, 95% CI 0.79 to 1.20, I 2=44%); or studies using rifampicin (IRR 1.00, 95% CI 0. 0.75-1.32, I 2=38%). No significant differences were noted in pooled outcomes of death, 2-month culture conversion and relapse. CONCLUSIONS HDRs were not associated with a significant difference in SAEs, 2-month culture conversion or death. Further studies are required to identify specific groups who may benefit from HDR.
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Affiliation(s)
- Omri A Arbiv
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - JeongMin M Kim
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Marie Yan
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kamila Romanowski
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,TB Services, BC Centre for Disease Control, Vancouver, British Columbia, Canada
| | | | - Anete Trajman
- McGill International TB Centre, McGill University, Montreal, Québec, Canada.,Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Leyla Asadi
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Federica Fregonese
- McGill International TB Centre, McGill University, Montreal, Québec, Canada
| | - Nicholas Winters
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Québec, Canada
| | - Dick Menzies
- McGill International TB Centre, McGill University, Montreal, Québec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Québec, Canada.,Montreal Chest Institute, McGill University Health Centre, Montreal, Québec, Canada
| | - James C Johnston
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada .,TB Services, BC Centre for Disease Control, Vancouver, British Columbia, Canada.,McGill International TB Centre, McGill University, Montreal, Québec, Canada
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25
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Gonzalez-Bocco IH, Aleissa MM, Zhou E, Manne-Goehler J, Koo S, Cheng MP, Marty FM. Clarithromycin-Rifampin-Based Treatment for Nontuberculous Mycobacteria Infections in Immunocompromised Patients who Require Concomitant CYP-Metabolized Medications. Open Forum Infect Dis 2022; 9:ofab582. [PMID: 34988253 PMCID: PMC8709895 DOI: 10.1093/ofid/ofab582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 11/19/2021] [Indexed: 11/23/2022] Open
Abstract
Clarithromycin (CYP inhibitor) can be used instead of azithromycin for nontuberculous mycobacteria therapy in patients requiring CYP substrates to mitigate rifampin's CYP induction. We found no differences in adverse events (10/13 vs 14/17; P = .73), drug intolerability (1/5 vs 4/11; P = 1), or 90-day mortality (0/13 vs 1/17; P = 1) in patients receiving clarithromycin vs azithromycin.
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Affiliation(s)
- Isabel H Gonzalez-Bocco
- Division of Infectious Disease, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Muneerah M Aleissa
- Division of Infectious Disease, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Department of Pharmacy, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Eric Zhou
- Division of Infectious Disease, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Jennifer Manne-Goehler
- Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
- Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sophia Koo
- Division of Infectious Disease, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Matthew P Cheng
- Division of Infectious Diseases, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- Division of Medical Microbiology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
- McGill Interdisciplinary Initiative in Infection and Immunity, Montreal, Quebec, Canada
| | - Francisco M Marty
- Division of Infectious Disease, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Division of Infectious Disease, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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26
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Affiliation(s)
- David Y. Graham
- Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, RM 3C-190 (111D), 2002 Holcombe Boulevard, Houston, TX 77030, USA
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27
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Hajikhani B, Nasiri MJ, Adkinson BC, Azimi T, Khalili F, Goudarzi M, Dadashi M, Murthi M, Mirsaeidi M. Comparison of Rifabutin-Based Versus Rifampin-Based Regimens for the Treatment of Mycobacterium avium Complex: A meta-Analysis Study. Front Pharmacol 2021; 12:693369. [PMID: 34557091 PMCID: PMC8452959 DOI: 10.3389/fphar.2021.693369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 08/24/2021] [Indexed: 12/02/2022] Open
Abstract
Background: The incidence of Mycobacterium avium complex (MAC) increases as immunosuppressed conditions become more common. MAC's standard treatment regimen includes a macrolide, ethambutol, and a rifamycin, among which rifampin and rifabutin are the most commonly used. Although current guidelines recommend initial therapy for MAC with rifampin, it has been theorized to be less efficacious than rifabutin. Methods: We reviewed the relevant scientific literature published up to February 18, 2020. Statistical analyses were performed with Comprehensive Meta-Analysis Software Version 2.0 (Biostat, Englewood, NJ). The pooled frequency with 95% confidence intervals (CI) was assessed using a random-effect model. We considered P <0.05 as statistically significant for publication bias. Results: After reviewing 3665 records, we identified 24 studies that satisfied the inclusion criteria. Among these studies, 8 had rifabutin in their regimens (rifabutin group) and 16 had rifampin in their regimens (rifampin group). The estimated pooled treatment success rate was found to be 54.7% (95% CI 41.0-67.0%) in rifabutin groups and 67.5% (95% CI 55.7-77.4%) in rifampin groups. There was no evidence of publication bias among the included studies (Egger’s test p-value was 0.7). Conclusion: In this study, it was shown that in comparison to Rifabutin, rifampin has similar treatment success rates in treating MAC. In order to determine the exact preference of each of these drugs, double-blind clinical trial studies are recommended.
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Affiliation(s)
- Bahareh Hajikhani
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Brian C Adkinson
- Department of Pulmonary and Critical Care University of Miami Miller School of Medicine Miami, Miami, FL, United States
| | - Taher Azimi
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farima Khalili
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Goudarzi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Dadashi
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.,Non-Communicable Diseases Research Center, Alborz University of Medical Sciences,Karaj, Iran
| | - Mukunthan Murthi
- Department of Pulmonary and Critical Care University of Miami Miller School of Medicine Miami, Miami, FL, United States
| | - Mehdi Mirsaeidi
- Department of Pulmonary and Critical Care University of Miami Miller School of Medicine Miami, Miami, FL, United States
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28
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Model-based comparative analysis of rifampicin and rifabutin drug-drug interaction profile. Antimicrob Agents Chemother 2021; 65:e0104321. [PMID: 34228545 DOI: 10.1128/aac.01043-21] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) is a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice more potent than those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.
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29
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Trebosc V, Schellhorn B, Schill J, Lucchini V, Bühler J, Bourotte M, Butcher JJ, Gitzinger M, Lociuro S, Kemmer C, Dale GE. In vitro activity of rifabutin against 293 contemporary carbapenem-resistant Acinetobacter baumannii clinical isolates and characterization of rifabutin mode of action and resistance mechanisms. J Antimicrob Chemother 2021; 75:3552-3562. [PMID: 32869081 PMCID: PMC7662187 DOI: 10.1093/jac/dkaa370] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 08/03/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE. OBJECTIVES To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates. METHODS Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017-19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin's mode of action and resistance mechanisms. RESULTS Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore-drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10-9 at rifabutin concentrations at or above 2 mg/L. CONCLUSIONS This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver.
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Affiliation(s)
| | | | | | - Valentina Lucchini
- BioVersys AG, Basel, Switzerland.,Biozentrum, University of Basel, Basel, Switzerland
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30
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Kamada K, Yoshida A, Iguchi S, Arai Y, Uzawa Y, Konno S, Shimojima M, Kikuchi K. Nationwide surveillance of antimicrobial susceptibility of 509 rapidly growing mycobacteria strains isolated from clinical specimens in Japan. Sci Rep 2021; 11:12208. [PMID: 34108590 PMCID: PMC8190260 DOI: 10.1038/s41598-021-91757-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/31/2021] [Indexed: 12/25/2022] Open
Abstract
This study aimed to identify effective treatments against rapidly growing mycobacteria (RGM) infections by investigating the minimum inhibitory concentrations (MIC) of 24 antimicrobial agents and their molecular mechanisms of resistance. In total, 509 clinical RGM isolates were identified by analyzing the sequences of three housekeeping genes (hsp65, rpoB, and sodA), and their susceptibilities to 24 antimicrobial agents were tested. We also performed sequencing analysis of antimicrobial resistance genes (rrl, rrs, gyrA, and gyrB). To identify Mycobacteroides abscessus group subspecies, we performed PCR-based typing and determined the sequevar of erm(41). We identified 15 RGM species, most of which were susceptible to amikacin and linezolid. Among these species, arbekacin and sitafloxacin had the lowest MIC among the same class of antimicrobials. The MIC of rifabutin for M. abscessus subsp. abscessus (MAB) was lower than that for M. abscessus subsp. massiliense (MMA). The proportion of MAB isolates with MIC ≤ 2 mg/L for rifabutin was significantly higher than that of MMA [MAB: 50/178 (28.1%) vs. MMA: 23/130 (17.7%); p = 0.041]. In summary, our study revealed the antimicrobial susceptibility profile of 15 RGM species isolated in Japan and indicated that arbekacin, sitafloxacin, and rifabutin may be possible therapeutic options for RGM infections.
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Affiliation(s)
- Keisuke Kamada
- Department of Infectious Diseases, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan.,Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14-jo Nishi 5-chome, Kita-ku, Sapporo-shi, Hokkaido, 001-0014, Japan.,Department of Mycobacterium Reference and Research, The Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association, Tokyo, 204-0022, Japan
| | - Atsushi Yoshida
- Department of Infectious Diseases, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Shigekazu Iguchi
- Department of Infectious Diseases, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Yuko Arai
- Department of Infectious Diseases, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Yutaka Uzawa
- Department of Infectious Diseases, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Satoshi Konno
- Department of Respiratory Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 14-jo Nishi 5-chome, Kita-ku, Sapporo-shi, Hokkaido, 001-0014, Japan
| | | | - Ken Kikuchi
- Department of Infectious Diseases, Tokyo Women's Medical University, 8-1 Kawada-Cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
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31
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Gingold-Belfer R, Niv Y, Levi Z, Boltin D. Rifabutin triple therapy for first-line and rescue treatment of Helicobacter pylori infection: A systematic review and meta-analysis. J Gastroenterol Hepatol 2021; 36:1392-1402. [PMID: 33037845 DOI: 10.1111/jgh.15294] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 08/18/2020] [Accepted: 10/06/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND AIM Due to the increasing resistance of Helicobacter pylori, there is a need for novel antibiotic treatment protocols. We aimed to perform a systematic review and meta-analysis in order to determine the effectiveness and safety of rifabutin triple therapy for H. pylori infection. METHODS We performed a systematic review of prospective clinical trials with a treatment arm consisting of proton pump inhibitor, amoxicillin, and rifabutin and a meta-analysis of randomized controlled trials (RCTs). RESULTS Thirty-three prospective studies including 44 datasets were identified. Meta-analysis of four RCTs for rescue treatment found no difference between treatment groups (odds ratio [OR] 0.88, 95% confidence interval [CI] 0.437-1.791, I2 = 68.1%, P = 0.733). Only one RCT compared rifabutin therapy with control for first-line treatment of H. pylori infection (OR 3.78, 95% CI 2.44-5.87, P < 0.0001). Treatment was more likely to be successful in Asian versus non-Asian populations (81.0% vs 72.4%, P = 0.001) and when daily amoxicillin dose was ≥ 3000 mg or proton pump inhibitor dose was ≥ 80 mg or treatment duration was 14 days (80.6% vs 66.0%, P = 0.0001). The overall event rate for adverse effects was 24.8% (729/2937) (95% CI 0.23-0.26), and the pooled OR for adverse effects in the treatment versus control group was 0.93 (95% CI 0.50-1.75) (I2 = 79.76, P = 0.82). CONCLUSION Evidence for the effectiveness of rifabutin for the first-line treatment of H. pylori infection in adults is limited, and studies comparing rifabutin with conventional first-line treatments are lacking.
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Affiliation(s)
- Rachel Gingold-Belfer
- Division of Gastroenterology, Rabin Medical Center, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yaron Niv
- Division of Patient Safety and Quality Improvement, Ministry of Health, Jerusalem, Israel
| | - Zohar Levi
- Division of Gastroenterology, Rabin Medical Center, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Doron Boltin
- Division of Gastroenterology, Rabin Medical Center, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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32
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Serota DP, Chueng TA, Schechter MC. Applying the Infectious Diseases Literature to People who Inject Drugs. Infect Dis Clin North Am 2021; 34:539-558. [PMID: 32782101 DOI: 10.1016/j.idc.2020.06.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
People who inject drugs (PWID) presenting with injection drug use-associated infections are an understudied population excluded from most prospective infectious disease (ID) clinical trials. Careful application of the existing ID literature to PWID must consider their unique medical, psychological, and social challenges. Identification and treatment of the underlying substance use disorder are key underpinnings to any successful ID intervention.
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Affiliation(s)
- David P Serota
- Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, 1120 Northwest 14 Street, Suite 851, Miami, FL 33136, USA.
| | - Teresa A Chueng
- Division of Infectious Diseases, Department of Medicine, University of Miami Miller School of Medicine, 1120 Northwest 14 Street, Suite 851, Miami, FL 33136, USA; Jackson Memorial Hospital, Jackson Health System, Miami, FL, USA. https://twitter.com/teresachueng
| | - Marcos C Schechter
- Division of Infectious Diseases, Department of Medicine, Emory University, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303, USA. https://twitter.com/limbsandlungs
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Differential In Vitro Activities of Individual Drugs and Bedaquiline-Rifabutin Combinations against Actively Multiplying and Nutrient-Starved Mycobacterium abscessus. Antimicrob Agents Chemother 2021; 65:AAC.02179-20. [PMID: 33168614 DOI: 10.1128/aac.02179-20] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 10/30/2020] [Indexed: 12/20/2022] Open
Abstract
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 nonreplicating 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 nonreplicating 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 data set 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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Collyer R, Clancy A, Agrawal G, Borody TJ. Crohn’s strictures open with anti-mycobacterial antibiotic therapy: A retrospective review. World J Gastrointest Endosc 2020; 12:542-554. [PMID: 33362907 PMCID: PMC7739142 DOI: 10.4253/wjge.v12.i12.542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 11/02/2020] [Accepted: 11/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Medical therapy for strictures is limited and first-line treatment consists of endoscopic balloon dilatation, strictureplasty or surgical resection. Mycobacterium tuberculosis, Helicobacter pylori and Streptococcus can all cause stenosis, for which antibiotic treatment achieves stricture resolution. Mycobacterium avium ssp. paratuberculosis is a suspected causative agent in Crohn’s disease (CD). Thus, specialized antimicrobial treatment, in particular, anti-mycobacterial antibiotic therapy (AMAT) has been proposed as a potential treatment option. To our knowledge, the opening of CD strictures has not been recorded using any form of antibiotic therapy. We hypothesized that AMAT would resolve strictures in patients with CD.
AIM To investigate the effect and outcomes of AMAT in a cohort of CD patients with an ileal stricture.
METHODS A single center, retrospective, medical record case review was conducted on an observational cohort of patients with CD who had an ileal stricture on colonoscopy and were treated with AMAT. Forty patients meeting the inclusion criteria were identified from the internal medical database. Thirty (75%) patients had follow-up colonoscopy and clinical data available. The AMAT regimen was prescribed after the initial colonoscopy for a duration of at least six months until follow-up colonoscopy with the attending gastroenterologist. Patient demographics, symptoms, colonoscopy reports, inflammatory serum markers and concurrent medications were recorded at pre-treatment and follow-up between January 1995 and June 2018.
RESULTS Of the patients that returned for follow-up after > 24 mo of AMAT, twenty (67%) had complete resolution (CR) of their ileal strictures, three (10%) had partial resolution and seven (23%) had no resolution. Irrespective of stricture outcome, 21 patients (70%) demonstrated clinical response to AMAT and there was a statistically significant reduction in inflammatory serum markers C-reactive protein (P < 0.0001) and erythrocyte sedimentation rate (P = 0.04) from pre-treatment to follow-up. It was observed that 11 (37%) patients experienced side effects, but no serious adverse effects were attributable to AMAT. At follow-up there were 26 (87%) patients on concomitant medication for CD and a statistically significant association between CR and AMAT with a concomitant immunomodulator (P = 0.02).
CONCLUSION This study demonstrated a high rate of stricture resolution (67%) similar to that seen in tuberculosis strictures (70%), suggesting a shared mycobacterial origin of strictures, and perhaps disease.
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Affiliation(s)
- Rhys Collyer
- Centre for Digestive Diseases, Five Dock 2046, NSW, Australia
| | - Annabel Clancy
- Centre for Digestive Diseases, Five Dock 2046, NSW, Australia
| | - Gaurav Agrawal
- Centre for Digestive Diseases, Five Dock 2046, NSW, Australia
| | - Thomas J Borody
- Centre for Digestive Diseases, Five Dock 2046, NSW, Australia
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Phillips MC, Wald-Dickler N, Loomis K, Luna BM, Spellberg B. Pharmacology, Dosing, and Side Effects of Rifabutin as a Possible Therapy for Antibiotic-Resistant Acinetobacter Infections. Open Forum Infect Dis 2020; 7:ofaa460. [PMID: 33204754 PMCID: PMC7651144 DOI: 10.1093/ofid/ofaa460] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 09/23/2020] [Indexed: 12/15/2022] Open
Abstract
Acinetobacter baumannii has among the highest rates of antibiotic resistance encountered in hospitals. New therapies are critically needed. We found that rifabutin has previously unrecognized hyperactivity against most strains of A. baumannii. Here we review the pharmacology and adverse effects of rifabutin to inform potential oral dosing strategies in patients with A. baumannii infections. Rifabutin demonstrates dose-dependent increases in blood levels up to 900 mg per day, but plateaus thereafter. Furthermore, rifabutin induces its own metabolism after prolonged dosing, lowering its blood levels. Pending future development of an intravenous formulation, a rifabutin oral dose of 900-1200 mg per day for 1 week is a rational choice for adjunctive therapy of A. baumannii infections. This dosage maximizes AUC24 to drive efficacy while simultaneously minimizing toxicity. Randomized controlled trials will be needed to definitively establish the safety and efficacy of rifabutin to treat A. baumannii infections.
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Affiliation(s)
- Matthew C Phillips
- Los Angeles County + University of Southern California Medical Center, Los Angeles, California, USA
| | - Noah Wald-Dickler
- Los Angeles County + University of Southern California Medical Center, Los Angeles, California, USA.,Division of Infectious Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Katherine Loomis
- Los Angeles County + University of Southern California Medical Center, Los Angeles, California, USA
| | - Brian M Luna
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Brad Spellberg
- Los Angeles County + University of Southern California Medical Center, Los Angeles, California, USA
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Gomila-Grange A, Pérez-Recio S, Camprubí-Ferrer D, Lladó L, Fava A, García-Romero E, Grijota-Camino MD, Sabé N, Santin M. Rifabutin for treating tuberculosis in solid organ transplant recipients: A retrospective observational study and literature review. Transpl Infect Dis 2020; 23:e13471. [PMID: 32959494 DOI: 10.1111/tid.13471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/17/2020] [Accepted: 09/06/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND The treatment of tuberculosis (TB) in solid organ transplant (SOT) recipients is challenging owing to interactions between rifampin and immunosuppressive drugs. Rifabutin, a rifamycin with excellent activity against Mycobacterium tuberculosis and that induces cytochrome p450 less, may facilitate treatment. We report our experience with rifabutin for treating TB in SOT recipients and review the available literature. METHODS A retrospective observational study of all SOT recipients with TB between January 2000 and December 2019. The clinical characteristics and outcomes of patients treated with and without rifabutin-containing regimens were compared and a literature review was conducted. RESULTS We included 31 SOT recipients with TB, among whom 22 (71%) were men and the median age was 62 years (interquartile range 50-20). There were no significant differences between patients treated with rifabutin (n = 12), rifampin (n = 14), and non-rifamycins (n = 5) in clinical cure rates (83.3%, 64.3%, and 100%, respectively; P = .21), side effects (25%, 37.5%, and 20%, respectively; P = .74), or mortality (16.7%, 35.7%, and 0%, respectively; P = .21). Only one patient, treated with rifampin, suffered graft rejection. The literature review identified 59 SOT recipients with TB treated with rifabutin-containing regimens from 8 publications. Overall, the clinical cure, graft rejection, and mortality rates were 93.2%, 5.1%, and 6.8%, respectively. CONCLUSIONS Rifabutin-containing regimens offer a reliable alternative to rifampin when treating TB in SOT recipients.
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Affiliation(s)
- A Gomila-Grange
- Department of Infectious Diseases and Tuberculosis Unit, Bellvitge University Hospital-Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain
| | - S Pérez-Recio
- Department of Infectious Diseases and Tuberculosis Unit, Bellvitge University Hospital-Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain
| | - D Camprubí-Ferrer
- Department of Infectious Diseases and Tuberculosis Unit, Bellvitge University Hospital-Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain
| | - L Lladó
- Liver Transplantation Unit, Bellvitge University Hospital, Barcelona, Spain
| | - A Fava
- Kidney Transplantation Unit, Bellvitge University Hospital, Barcelona, Spain
| | - E García-Romero
- Cardiac Transplantation Unit, Bellvitge University Hospital, Barcelona, Spain
| | - M D Grijota-Camino
- Department of Infectious Diseases and Tuberculosis Unit, Bellvitge University Hospital-Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain
| | - N Sabé
- Department of Infectious Diseases and Tuberculosis Unit, Bellvitge University Hospital-Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain.,Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
| | - M Santin
- Department of Infectious Diseases and Tuberculosis Unit, Bellvitge University Hospital-Bellvitge Institute of Biomedical Research (IDIBELL), Barcelona, Spain.,Department of Clinical Sciences, University of Barcelona, Barcelona, Spain
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Hirata Y, Yamada A, Niikura R, Shichijo S, Hayakawa Y, Koike K. Efficacy and safety of a new rifabutin-based triple therapy with vonoprazan for refractory Helicobacter pylori infection: A prospective single-arm study. Helicobacter 2020; 25:e12719. [PMID: 32602161 DOI: 10.1111/hel.12719] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/27/2020] [Accepted: 05/29/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND A small proportion of Helicobacter pylori-infected individuals in Japan suffer failure of eradication therapy with third-line regimens containing the potent acid suppressor, vonoprazan, and a quinolone. OBJECTIVES This prospective study evaluated the efficacy and safety of rifabutin-based triple therapy with vonoprazan for refractory H pylori infection. METHODS Patients who failed H pylori eradication by clarithromycin-based first-line, metronidazole-based second-line, and sitafloxacin-based third-line therapies were recruited. After obtaining informed consent, patients received eradication therapy with vonoprazan (20 mg), amoxicillin (750 mg), and rifabutin (150 mg) twice daily for 10 days. Eradication was confirmed by a negative H pylori stool antigen or urea breath test at least 8 weeks after the end of therapy. RESULTS Nineteen patients were included in the study. All of the patients completed the course of medication. Eradication of H pylori was confirmed in all of the patients (19/19; 100%, 95% confidence interval; 83-100%). The most common adverse event was soft stool/diarrhea (4/19, 21%). No severe adverse event was observed. CONCLUSIONS Ten-day rifabutin with amoxicillin and vonoprazan triple therapy appears to be effective and safe for refractory H pylori infections. However, considering the recent publications showing high eradication rates with vonoprazan amoxicillin dual therapy, confirmation will require future studies comparing our new therapy with vonoprazan-amoxicillin dual with similar doses and duration and with vonoprazan-rifabutin dual therapy.
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Affiliation(s)
- Yoshihiro Hirata
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
- Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Atsuo Yamada
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Ryota Niikura
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Satoki Shichijo
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
- Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
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Wang YC, Salvador NG, Lin CC, Wu CC, Lin TL, Lee WF, Chan YC, Chen CL, Co JS, Encarnacion DD. Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis. Biomed J 2020; 44:S162-S170. [PMID: 35300949 PMCID: PMC9068555 DOI: 10.1016/j.bj.2020.08.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 08/20/2020] [Accepted: 08/24/2020] [Indexed: 12/25/2022] Open
Abstract
Background The Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB. Methods A retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants. Results Twenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups. Conclusion The use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.
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Affiliation(s)
- Yu-Chen Wang
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Noruel Gerard Salvador
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Che Lin
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
| | - Chao-Chien Wu
- Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ting-Lung Lin
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wei-Feng Lee
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi-Chia Chan
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Long Chen
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jeffrey Samuel Co
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Domelle Dave Encarnacion
- Liver Transplantation Center and Department of Surgery, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Boyanova L, Markovska R, Hadzhiyski P, Kandilarov N, Mitov I. Rifamycin use for treatment of Helicobacter pylori infection: a review of recent data. Future Microbiol 2020; 15:1185-1196. [PMID: 32954842 DOI: 10.2217/fmb-2020-0084] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Helicobacter pylori eradication has become increasingly challenging. We focused on recent data about rifamycin resistance and rifamycin-containing regimens. Rifampin (rifampicin) resistance rates were <1-18.8% (often ≤7%), while those to rifabutin were 0-<4%. To detect rifabutin resistance by rifampin, 4 mg/l breakpoint was suggested. Eradication success by rifaximin-based regimens was disappointing (<62%), while that of rifabutin-containing regimens was 54.5->96%, reaching >81% in four studies. Some newer rifamycin analogs like TNP-2092 need further investigation. Briefly, although rifabutin-based regimens carry a risk of adverse effects or increasing mycobacterial resistance, they may be a rational choice for some multidrug-resistant H. pylori strains and as a third-line eradication therapy. Bismuth addition to rifabutin-based therapy and combined rifabutin-containing capsules (Talicia) are promising treatment options.
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Affiliation(s)
- Lyudmila Boyanova
- Department of Medical Microbiology, Medical University of Sofia, Sofia, Bulgaria
| | - Rumyana Markovska
- Department of Medical Microbiology, Medical University of Sofia, Sofia, Bulgaria
| | - Petyo Hadzhiyski
- Specialized Hospital for Active Pediatric Treatment, Medical University of Sofia, Sofia, Bulgaria
| | - Nayden Kandilarov
- Department of General & Hepatobiliary Pancreatic Surgery, Department of Surgery, Medical University of Sofia, Sofia, Bulgaria
| | - Ivan Mitov
- Department of Medical Microbiology, Medical University of Sofia, Sofia, Bulgaria
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Anti-Mycobacterial Antibiotic Therapy Induces Remission in Active Paediatric Crohn's Disease. Microorganisms 2020; 8:microorganisms8081112. [PMID: 32722117 PMCID: PMC7464505 DOI: 10.3390/microorganisms8081112] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/21/2020] [Indexed: 12/23/2022] Open
Abstract
Crohn’s disease is increasing in incidence and prevalence in younger people and is of a particularly aggressive nature. One emerging treatment targets Mycobacterium avium paratuberculosis (MAP), an organism implicated in the causation of Crohn’s disease. This study reviewed a cohort of paediatric patients with active Crohn’s disease treated with Anti-Mycobacterial Antibiotic Therapy (AMAT). Sixteen paediatric patients, the majority of whom had failed conventional immunosuppressive therapy, were treated with AMAT. Endoscopic remission was scored using the Simple Endoscopic Score for Crohn’s Disease and clinical remission was assessed using the Weighted Paediatric Crohn’s Disease Activity Index (wPCDAI). Inflammatory blood markers were also routinely recorded. Patients were followed up clinically and endoscopically during treatment after an average of two months (range 1–6) and 17 months (range 2–49), respectively. A significant reduction in both scores assessing clinical improvement (p < 0.001) and mucosal healing (p < 0.0078) was observed at these timepoints; 47% of patients had achieved clinical remission and 63% endoscopic remission. Haemoglobin and serum inflammatory markers normalised for more than 50% of the cohort by six months of treatment. No adverse effects were reported throughout treatment. This is the first report of Anti-Mycobacterial Antibiotic Therapy offering a safe and efficacious therapy for paediatric patients with Crohn’s disease. Further larger randomised studies are required in order to validate these findings.
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Abad L, Josse J, Tasse J, Lustig S, Ferry T, Diot A, Laurent F, Valour F. Antibiofilm and intraosteoblastic activities of rifamycins against Staphylococcus aureus: promising in vitro profile of rifabutin. J Antimicrob Chemother 2020; 75:1466-1473. [DOI: 10.1093/jac/dkaa061] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/28/2020] [Accepted: 01/30/2020] [Indexed: 12/14/2022] Open
Abstract
Abstract
Background
Targeting biofilm-embedded and intraosteoblastic Staphylococcus aureus, rifampicin gained a pivotal role in bone and joint infection (BJI) treatment. Two other rifamycins, rifabutin and rifapentine, may represent better-tolerated alternatives, but their activity against bacterial reservoirs associated with BJI chronicity has never been evaluated.
Objectives
To evaluate the activities of rifampicin, rifabutin and rifapentine in osteoblast infection models.
Methods
Using three S. aureus isolates, rifamycins were compared regarding: (i) their intracellular activity in ‘acute’ (24 h) and ‘chronic’ (7 days) osteoblast infection models at 0.1× MIC, 1× MIC, 10× MIC and 100× MIC, while impacting infection-induced cytotoxicity (MTT assay), intracellular phenol-soluble modulin (PSM) secretion (RT–PCR), resistance selection and small colony variant (SCV) emergence; and (ii) their minimal biofilm eradication concentration (MBEC) and their MIC to prevent biofilm formation (bMIC).
Results
At 0.1× MIC, only rifabutin significantly reduced intracellular inoculum and PSM secretion. All rifamycins allowed a 50% reduction of intraosteoblastic inoculum at higher concentrations, with no difference between acute and chronic infection models, while reducing infection-induced cytotoxicity and PSM secretion. Dose-dependent emergence of intracellular SCVs was observed for all molecules. No intracellular emergence of resistance was detected. bMICs were equivalent for all molecules, but MBEC90s of rifapentine and rifabutin were 10- to 100-fold lower than those of rifampicin, respectively.
Conclusions
All rifamycins are efficient in reducing the S. aureus intraosteoblastic reservoir while limiting infection-induced cytotoxicity, with a higher activity of rifabutin at low concentrations. All molecules prevent biofilm formation, but only rifapentine and rifabutin consistently reduce formed biofilm-embedded bacteria for all isolates. The activity of rifabutin at lower doses highlights its therapeutic potential.
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Affiliation(s)
- Lélia Abad
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
- Université Claude Bernard Lyon 1, Lyon, France
- Laboratoire de bactériologie, Institut des Agents Infectieux, French National Reference Center for Staphylococci, Hospices Civils de Lyon, Lyon, France
| | - Jérôme Josse
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
| | - Jason Tasse
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
| | - Sébastien Lustig
- Université Claude Bernard Lyon 1, Lyon, France
- Centres de Référence pour la prise en charge des Infections ostéoarticulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France
- Department de chirurgie orthopédique, Hospices Civils de Lyon, Lyon, France
| | - Tristan Ferry
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
- Université Claude Bernard Lyon 1, Lyon, France
- Centres de Référence pour la prise en charge des Infections ostéoarticulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France
- Département maladies infectieuses et tropicales, Hospices Civils de Lyon, Lyon, France
| | - Alan Diot
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
| | - Frédéric Laurent
- Laboratoire de bactériologie, Institut des Agents Infectieux, French National Reference Center for Staphylococci, Hospices Civils de Lyon, Lyon, France
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
- Université Claude Bernard Lyon 1, Lyon, France
- Laboratoire de bactériologie, Institut des Agents Infectieux, French National Reference Center for Staphylococci, Hospices Civils de Lyon, Lyon, France
- Centres de Référence pour la prise en charge des Infections ostéoarticulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France
| | - Florent Valour
- CIRI – Centre International de Recherche en Infectiologie, Inserm, U1111, Université´ Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ Lyon, F-69007 Lyon, France
- Université Claude Bernard Lyon 1, Lyon, France
- Centres de Référence pour la prise en charge des Infections ostéoarticulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France
- Département maladies infectieuses et tropicales, Hospices Civils de Lyon, Lyon, France
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Dick T. Rifabutin: A Repurposing Candidate for Mycobacterium abscessus Lung Disease. Front Microbiol 2020; 11:371. [PMID: 32174907 PMCID: PMC7056868 DOI: 10.3389/fmicb.2020.00371] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 02/19/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Thomas Dick
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, United States.,Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, NJ, United States
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Sarkar T, Riccardi N, Wagh H, Udwadia Z. Safety of Rifabutin in patients with rifampicin-induced thrombocytopenia. Lung India 2020; 37:455-456. [PMID: 32883912 PMCID: PMC7857375 DOI: 10.4103/lungindia.lungindia_401_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Rockwood N, Cerrone M, Barber M, Hill AM, Pozniak AL. Global access of rifabutin for the treatment of tuberculosis - why should we prioritize this? J Int AIDS Soc 2019; 22:e25333. [PMID: 31318176 PMCID: PMC6637439 DOI: 10.1002/jia2.25333] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 06/05/2019] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION Rifabutin, a rifamycin of equivalent potency to rifampicin, has several advantages in its pharmacokinetic and toxicity profile, particularly in HIV co-infected patients on combined antiretroviral therapy (cART). In this commentary, we evaluate evidence supporting increased global use of rifabutin and highlight key recommendations for action. DISCUSSION Although extrapolation of data from HIV uninfected patients would suggest non-inferiority, there has been no randomized controlled study comparing rifabutin versus rifampicin in the outcomes of relapse-free cure, in drug susceptible tuberculosis (TB), in HIV co-infected patients on currently utilized cART regimens or in paediatric populations. An important advantage of rifabutin is that compared to the dose adjustments required with rifampicin, it can be co-administered with the integrase strand transfer inhibitors raltegravir or dolutegravir without the need for dose adjustments. This strategy would be easier to implement in a programmatic setting and would save costs. We have assessed cost incentives to utilize rifabutin and have estimated generic costs for a range of rifabutin dosage scenarios. Where facilities are present for drug re-challenge and monitoring for drug toxicity and cross-reactivity, rifabutin offers a switch alternative for adverse drug reactions (ADR)s attributed to rifampicin. This would negate the need to prolong treatment in the absence of a rifamycin as part of short-course multidrug therapy. There is evidence of incomplete cross-resistance to rifampicin and rifabutin. Rifabutin may be useful in rifampicin-resistant TB, in an estimated 20% of cases, based on phenotypic or genotypic rifabutin susceptibility testing. CONCLUSIONS Rifabutin should be available globally as a first-line rifamycin in HIV co-infected individuals and as a switch option in cases of rifampicin associated ADRs. Further studies are needed to ascertain the utility of rifabutin in rifampicin-resistant rifabutin-susceptible TB.
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Affiliation(s)
- Neesha Rockwood
- Department of MedicineImperial College LondonLondonUK
- Department of HIV MedicineChelsea and Westminster HospitalLondonUK
| | - Maddalena Cerrone
- Department of MedicineImperial College LondonLondonUK
- Department of HIV MedicineChelsea and Westminster HospitalLondonUK
| | - Melissa Barber
- Department of Global Health and PopulationHarvard TH Chan School of Public HealthBostonMAUSA
| | - Andrew M Hill
- Department of Pharmacology and TherapeuticsLiverpool UniversityLiverpoolUK
| | - Anton L Pozniak
- Department of HIV MedicineChelsea and Westminster HospitalLondonUK
- Department of Clinical ResearchLondon School of Tropical Medicine and HygieneLondonUK
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Sparkes T, Lemonovich TL. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13510. [PMID: 30817021 DOI: 10.1111/ctr.13510] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 02/12/2019] [Indexed: 01/14/2023]
Abstract
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation provide an update on potential drug-drug interactions between anti-infectives and immunosuppressants, which are most notable with calcineurin and mTOR inhibitors. Drug-drug interactions may occur through pharmacokinetic mechanisms leading to altered drug concentrations of either the anti-infective or immunosuppressive drug, or by pharmacodynamic interactions increasing or decreasing the efficacy or toxicity of the medications. Many of the significant pharmacokinetic interactions occur through inhibition or induction of the cytochrome 3A4 system by anti-infective agents leading to increased or decreased immunosuppressive agent levels, respectively. The membrane transporter P-glycoprotein is also often involved in drug interactions. Since the last iteration of these guidelines, multiple new hepatitis C virus direct-acting antivirals have become available for use in SOT recipients. Of these agents, some are substrates of cytochrome and drug transporter systems, while others inhibit these systems and may affect immunosuppressive agents. Due to the high risk for drug-drug interactions in the solid organ transplant population, practitioners must be aware of potential interactions and be vigilant in monitoring and adjusting drug dosing when appropriate.
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Affiliation(s)
- Tracy Sparkes
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, Maryland
| | - Tracy L Lemonovich
- Division of Infectious Diseases and HIV Medicine, Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio
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Savarino E, Bertani L, Ceccarelli L, Bodini G, Zingone F, Buda A, Facchin S, Lorenzon G, Marchi S, Marabotto E, De Bortoli N, Savarino V, Costa F, Blandizzi C. Antimicrobial treatment with the fixed-dose antibiotic combination RHB-104 for Mycobacterium avium subspecies paratuberculosis in Crohn's disease: pharmacological and clinical implications. Expert Opin Biol Ther 2019; 19:79-88. [PMID: 30574820 DOI: 10.1080/14712598.2019.1561852] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Crohn's disease (CD) is an inflammatory bowel disease of unknown etiology. However, increasing evidence suggests Mycobacterium avium subspecies paratuberculosis (MAP) as a putative causative agent: 1) MAP is the etiological agent of Johne's disease, a granulomatous enteritis affecting ruminants, which shares clinical and pathological features with CD; 2) MAP has been detected in tissues and blood samples from CD patients; 3) case reports have documented a favorable therapeutic response to anti-MAP antibiotics. Area covered: This review provides an appraisal of current information on MAP characteristics, diagnostic methodologies and emerging drug treatments. The authors focus on RHB-104, a novel oral formulation containing a fixed-dose combination of clarithromycin, clofazimine and rifabutin, endowed with synergistic inhibitory activity on MAP strains isolated from CD patients. Expert opinion: Based on encouraging in vitro data, RHB-104 has entered recently the clinical phase of its development, and is being investigated in a randomized, placebo-controlled phase III trial aimed at evaluating its efficacy and safety in CD. Provided that the overall clinical development will support the suitability of RHB-104 for inducing disease remission in CD patients with documented MAP infection, this novel antibiotic combination will likely take a relevant position in the therapeutic armamentarium for CD management.
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Affiliation(s)
- Edoardo Savarino
- a Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Lorenzo Bertani
- b Gastrointestinal Unit, Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa , Italy
| | - Linda Ceccarelli
- b Gastrointestinal Unit, Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa , Italy
| | - Giorgia Bodini
- c Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties , University of Genoa , Genoa , Italy
| | - Fabiana Zingone
- a Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Andrea Buda
- a Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Sonia Facchin
- a Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Greta Lorenzon
- a Gastrointestinal Unit, Department of Surgery, Oncology and Gastroenterology , University of Padua , Padua , Italy
| | - Santino Marchi
- b Gastrointestinal Unit, Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa , Italy
| | - Elisa Marabotto
- c Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties , University of Genoa , Genoa , Italy
| | - Nicola De Bortoli
- b Gastrointestinal Unit, Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa , Italy
| | - Vincenzo Savarino
- c Gastrointestinal Unit, Department of Internal Medicine and Medical Specialties , University of Genoa , Genoa , Italy
| | - Francesco Costa
- b Gastrointestinal Unit, Division of Gastroenterology, Department of Translational Research and New Technologies in Medicine and Surgery , University of Pisa , Pisa , Italy
| | - Corrado Blandizzi
- d Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
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El-Arabey AA, Abdalla M. Rifabutin induced multinucleated hepatocytes in rats: an overview with future prospects. Eur J Clin Microbiol Infect Dis 2019; 38:1-2. [PMID: 30368739 DOI: 10.1007/s10096-018-3411-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/22/2018] [Indexed: 11/30/2022]
Affiliation(s)
- Amr Ahmed El-Arabey
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
| | - Mohnad Abdalla
- Qingdao Institute of Bioenergy and Bioprocess Technology, Qingdao Shi, 266000, Shandong Sheng, People's Republic of China.
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Bosch A, Valour F, Dumitrescu O, Dumortier J, Radenne S, Pages-Ecochard M, Chidiac C, Ferry T, Perpoint T, Miailhes P, Conrad A, Goutelle S, Ader F. A practical approach to tuberculosis diagnosis and treatment in liver transplant recipients in a low-prevalence area. Med Mal Infect 2018; 49:231-240. [PMID: 30591271 DOI: 10.1016/j.medmal.2018.11.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/11/2018] [Accepted: 11/26/2018] [Indexed: 01/30/2023]
Abstract
Solid organ transplant candidates/recipients are at risk of mycobacterial infections. Although guidelines on the management of latent tuberculosis infection and active tuberculosis are available for solid organ transplant recipients, limited guidance focuses on end-stage liver disease or liver transplant recipients who require management in a referral center. Therapeutic challenges arise from direct antituberculosis drug-related hepatotoxicity, and substantial metabolic interactions between immunosuppressive and antituberculosis drugs. Another issue is the optimal timing of therapy with regards to the time of transplantation. This review focuses on the importance of tuberculosis screening with immunological tests, challenges in the diagnosis, management, and treatment of latent tuberculosis infection and active tuberculosis, as well as risk assessment for active tuberculosis in the critical peri-liver transplantation period. We detail therapeutic adjustments required for the management of antituberculosis drugs in latent tuberculosis infection and active tuberculosis, particularly when concomitantly using rifampicin and immunosuppressive drugs.
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Affiliation(s)
- A Bosch
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France
| | - F Valour
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France; Centre international de recherche en infectiologie (CIRI), Inserm, U1111, université Claude-Bernard Lyon 1, CNRS, UMR5308, École normale supérieure de Lyon, université Lyon, 69007 Lyon, France; Université Claude-Bernard Lyon 1, 69007 Lyon, France.
| | - O Dumitrescu
- Centre international de recherche en infectiologie (CIRI), Inserm, U1111, université Claude-Bernard Lyon 1, CNRS, UMR5308, École normale supérieure de Lyon, université Lyon, 69007 Lyon, France; Université Claude-Bernard Lyon 1, 69007 Lyon, France; Institut des agents infectieux, hospices civils de Lyon, 69004 Lyon, France
| | - J Dumortier
- Université Claude-Bernard Lyon 1, 69007 Lyon, France; Service d'hépato-gastro-entérologie et de transplantation hépatique, hôpital Édouard-Herriot, hospices civils de Lyon, 69007 Lyon, France
| | - S Radenne
- Service d'hépato-gastro-entérologie et de transplantation hépatique, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France
| | - M Pages-Ecochard
- Service d'hépato-gastro-entérologie et de transplantation hépatique, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France
| | - C Chidiac
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France; Centre international de recherche en infectiologie (CIRI), Inserm, U1111, université Claude-Bernard Lyon 1, CNRS, UMR5308, École normale supérieure de Lyon, université Lyon, 69007 Lyon, France; Université Claude-Bernard Lyon 1, 69007 Lyon, France
| | - T Ferry
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France; Centre international de recherche en infectiologie (CIRI), Inserm, U1111, université Claude-Bernard Lyon 1, CNRS, UMR5308, École normale supérieure de Lyon, université Lyon, 69007 Lyon, France; Université Claude-Bernard Lyon 1, 69007 Lyon, France
| | - T Perpoint
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France
| | - P Miailhes
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France
| | - A Conrad
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France; Centre international de recherche en infectiologie (CIRI), Inserm, U1111, université Claude-Bernard Lyon 1, CNRS, UMR5308, École normale supérieure de Lyon, université Lyon, 69007 Lyon, France; Université Claude-Bernard Lyon 1, 69007 Lyon, France
| | - S Goutelle
- Service de pharmaceutique, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France; UMR, CNRS 5558, laboratoire de biométrie et biologie évolutive, ISPB, faculté de pharmacie, université Claude-Bernard Lyon 1, 69007 Lyon, France
| | - F Ader
- Service des maladies infectieuses et tropicales, hôpital de la Croix-Rousse, hospices civils de Lyon, 69004 Lyon, France; Centre international de recherche en infectiologie (CIRI), Inserm, U1111, université Claude-Bernard Lyon 1, CNRS, UMR5308, École normale supérieure de Lyon, université Lyon, 69007 Lyon, France; Université Claude-Bernard Lyon 1, 69007 Lyon, France
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Evidence for Inhibition of Topoisomerase 1A by Gold(III) Macrocycles and Chelates Targeting Mycobacterium tuberculosis and Mycobacterium abscessus. Antimicrob Agents Chemother 2018; 62:AAC.01696-17. [PMID: 29483110 DOI: 10.1128/aac.01696-17] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 02/08/2018] [Indexed: 01/15/2023] Open
Abstract
Mycobacterium tuberculosis and the fast-growing species Mycobacterium abscessus are two important human pathogens causing persistent pulmonary infections that are difficult to cure and require long treatment times. The emergence of drug-resistant M. tuberculosis strains and the high level of intrinsic resistance of M. abscessus call for novel drug scaffolds that effectively target both pathogens. In this study, we evaluated the activity of bis(pyrrolide-imine) gold(III) macrocycles and chelates, originally designed as DNA intercalators capable of targeting human topoisomerase types I and II (Topo1 and Topo2), against M. abscessus and M. tuberculosis We identified a total of 5 noncytotoxic compounds active against both mycobacterial pathogens under replicating in vitro conditions. We chose one of these hits, compound 14, for detailed analysis due to its potent bactericidal mode of inhibition and scalable synthesis. The clinical relevance of this compound was demonstrated by its ability to inhibit a panel of diverse M. tuberculosis and M. abscessus clinical isolates. Prompted by previous data suggesting that compound 14 may target topoisomerase/gyrase enzymes, we demonstrated that it lacked cross-resistance with fluoroquinolones, which target the M. tuberculosis gyrase. In vitro enzyme assays confirmed the potent activity of compound 14 against bacterial topoisomerase 1A (Topo1) enzymes but not gyrase. Novel scaffolds like compound 14 with potent, selective bactericidal activity against M. tuberculosis and M. abscessus that act on validated but underexploited targets like Topo1 represent a promising starting point for the development of novel therapeutics for infections by pathogenic mycobacteria.
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