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Masaki M, Matsuo T, Kobayashi D, Mori N. SEASON GAP score: A predictor of Clostridioides difficile infection among patients with tube feeding. J Infect Chemother 2022; 28:1131-1137. [DOI: 10.1016/j.jiac.2022.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 03/25/2022] [Accepted: 04/08/2022] [Indexed: 10/18/2022]
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Sartelli M, Di Bella S, McFarland LV, Khanna S, Furuya-Kanamori L, Abuzeid N, Abu-Zidan FM, Ansaloni L, Augustin G, Bala M, Ben-Ishay O, Biffl WL, Brecher SM, Camacho-Ortiz A, Caínzos MA, Chan S, Cherry-Bukowiec JR, Clanton J, Coccolini F, Cocuz ME, Coimbra R, Cortese F, Cui Y, Czepiel J, Demetrashvili Z, Di Carlo I, Di Saverio S, Dumitru IM, Eckmann C, Eiland EH, Forrester JD, Fraga GP, Frossard JL, Fry DE, Galeiras R, Ghnnam W, Gomes CA, Griffiths EA, Guirao X, Ahmed MH, Herzog T, Kim JI, Iqbal T, Isik A, Itani KMF, Labricciosa FM, Lee YY, Juang P, Karamarkovic A, Kim PK, Kluger Y, Leppaniemi A, Lohsiriwat V, Machain GM, Marwah S, Mazuski JE, Metan G, Moore EE, Moore FA, Ordoñez CA, Pagani L, Petrosillo N, Portela F, Rasa K, Rems M, Sakakushev BE, Segovia-Lohse H, Sganga G, Shelat VG, Spigaglia P, Tattevin P, Tranà C, Urbánek L, Ulrych J, Viale P, Baiocchi GL, Catena F. 2019 update of the WSES guidelines for management of Clostridioides ( Clostridium) difficile infection in surgical patients. World J Emerg Surg 2019; 14:8. [PMID: 30858872 PMCID: PMC6394026 DOI: 10.1186/s13017-019-0228-3] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 02/17/2019] [Indexed: 02/08/2023] Open
Abstract
In the last three decades, Clostridium difficile infection (CDI) has increased in incidence and severity in many countries worldwide. The increase in CDI incidence has been particularly apparent among surgical patients. Therefore, prevention of CDI and optimization of management in the surgical patient are paramount. An international multidisciplinary panel of experts from the World Society of Emergency Surgery (WSES) updated its guidelines for management of CDI in surgical patients according to the most recent available literature. The update includes recent changes introduced in the management of this infection.
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Affiliation(s)
- Massimo Sartelli
- Department of Surgery, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Stefano Di Bella
- Infectious Diseases Department, Trieste University Hospital, Trieste, Italy
| | - Lynne V. McFarland
- Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA USA
| | - Sahil Khanna
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN USA
| | - Luis Furuya-Kanamori
- Research School of Population Health, Australian National University, Acton, ACT Australia
| | - Nadir Abuzeid
- Department of Microbiology, Faculty of Medical Laboratory Sciences, Omdurman Islamic University, Khartoum, Sudan
| | - Fikri M. Abu-Zidan
- Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
| | - Luca Ansaloni
- Department of General Surgery, Bufalini Hospital, Cesena, Italy
| | - Goran Augustin
- Department of Surgery, University Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Miklosh Bala
- Trauma and Acute Care Surgery Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Offir Ben-Ishay
- Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
| | - Walter L. Biffl
- Trauma and Acute Care Surgery, Scripps Memorial Hospital La Jolla, La Jolla, CA USA
| | - Stephen M. Brecher
- Pathology and Laboratory Medicine, VA Boston Healthcare System, West Roxbury MA and BU School of Medicine, Boston, MA USA
| | - Adrián Camacho-Ortiz
- Department of Internal Medicine, University Hospital, Dr. José E. González, Monterrey, Mexico
| | - Miguel A. Caínzos
- Department of Surgery, University of Santiago de Compostela, A Coruña, Spain
| | - Shirley Chan
- Department of General Surgery, Medway Maritime Hospital, Gillingham, Kent UK
| | - Jill R. Cherry-Bukowiec
- Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI USA
| | - Jesse Clanton
- Department of Surgery, West Virginia University Charleston Division, Charleston, WV USA
| | | | - Maria E. Cocuz
- Faculty of Medicine, Transilvania University, Infectious Diseases Hospital, Brasov, Romania
| | - Raul Coimbra
- Riverside University Health System Medical Center and Loma Linda University School of Medicine, Moreno Valley, CA USA
| | | | - Yunfeng Cui
- Department of Surgery, Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, Tianjin, China
| | - Jacek Czepiel
- Department of Infectious Diseases, Jagiellonian University, Medical College, Kraków, Poland
| | - Zaza Demetrashvili
- Department of Surgery, Tbilisi State Medical University, Kipshidze Central University Hospital, Tbilisi, Georgia
| | - Isidoro Di Carlo
- Department of Surgical Sciences, Cannizzaro Hospital, University of Catania, Catania, Italy
| | - Salomone Di Saverio
- Department of Surgery, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Irina M. Dumitru
- Clinical Infectious Diseases Hospital, Ovidius University, Constanta, Romania
| | - Christian Eckmann
- Department of General, Visceral and Thoracic Surgery, Klinikum Peine, Hospital of Medical University Hannover, Peine, Germany
| | | | | | - Gustavo P. Fraga
- Division of Trauma Surgery, Hospital de Clinicas, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Jean L. Frossard
- Service of Gastroenterology and Hepatology, Geneva University Hospital, Genève, Switzerland
| | - Donald E. Fry
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL USA
- University of New Mexico School of Medicine, Albuquerque, NM USA
| | - Rita Galeiras
- Critical Care Unit, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, Spain
| | - Wagih Ghnnam
- Department of Surgery Mansoura, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Carlos A. Gomes
- Surgery Department, Hospital Universitario (HU) Terezinha de Jesus da Faculdade de Ciencias Medicas e da Saude de Juiz de Fora (SUPREMA), Hospital Universitario (HU) Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, Brazil
| | | | - Xavier Guirao
- Unit of Endocrine, Head, and Neck Surgery and Unit of Surgical Infections Support, Department of General Surgery, Parc Taulí, Hospital Universitari, Sabadell, Spain
| | - Mohamed H. Ahmed
- Department of Medicine, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, Buckinghamshire UK
| | - Torsten Herzog
- Department of Surgery, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Jae Il Kim
- Department of Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
| | - Tariq Iqbal
- Department of Gastroenterology, Queen Elizabeth Hospital, Birmingham, UK
| | - Arda Isik
- General Surgery Department, Magee Womens Hospital, UPMC, Pittsburgh, USA
| | - Kamal M. F. Itani
- Department of Surgery, VA Boston Health Care System, Boston University and Harvard Medical School, Boston, MA USA
| | | | - Yeong Y. Lee
- School of Medical Sciences, University Sains Malaysia, Kota Bharu, Kelantan Malaysia
| | - Paul Juang
- Department of Pharmacy Practice, St Louis College of Pharmacy, St Louis, MO USA
| | - Aleksandar Karamarkovic
- Faculty of Mediine University of Belgrade Clinic for Surgery “Nikola Spasic”, University Clinical Center “Zvezdara” Belgrade, Belgrade, Serbia
| | - Peter K. Kim
- Department of Surgery, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY USA
| | - Yoram Kluger
- Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
| | - Ari Leppaniemi
- Abdominal Center, Helsinki University Hospital Meilahti, Helsinki, Finland
| | - Varut Lohsiriwat
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Gustavo M. Machain
- Department of Surgery, Universidad Nacional de Asuncion, Asuncion, Paraguay
| | - Sanjay Marwah
- Department of Surgery, Post-Graduate Institute of Medical Sciences, Rohtak, India
| | - John E. Mazuski
- Department of Surgery, Washington University School of Medicine, Saint Louis, USA
| | - Gokhan Metan
- Department of Infectious Diseases and Clinical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ernest E. Moore
- Department of Surgery, University of Colorado, Denver Health Medical Center, Denver, CO USA
| | | | - Carlos A. Ordoñez
- Department of Surgery, Fundación Valle del Lili, Hospital Universitario del Valle, Universidad del Valle, Cali, Colombia
| | - Leonardo Pagani
- Infectious Diseases Unit, Bolzano Central Hospital, Bolzano, Italy
| | - Nicola Petrosillo
- National Institute for Infectious Diseases - INMI - Lazzaro Spallanzani IRCCS, Rome, Italy
| | - Francisco Portela
- Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Kemal Rasa
- Department of Surgery, Anadolu Medical Center, Kocaali, Turkey
| | - Miran Rems
- Department of Abdominal and General Surgery, General Hospital Jesenice, Jesenice, Slovenia
| | | | | | - Gabriele Sganga
- Division of Emergency Surgery, Department of Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Vishal G. Shelat
- Department of Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Patrizia Spigaglia
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Pierre Tattevin
- Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France
| | - Cristian Tranà
- Department of Surgery, Macerata Hospital, Via Santa Lucia 2, 62100 Macerata, Italy
| | - Libor Urbánek
- First Department of Surgery, Faculty of Medicine, Masaryk University Brno and University Hospital of St. Ann Brno, Brno, Czech Republic
| | - Jan Ulrych
- First Department of Surgery, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
| | - Pierluigi Viale
- Clinic of Infectious Diseases, St Orsola-Malpighi University Hospital, Bologna, Italy
| | - Gian L. Baiocchi
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Fausto Catena
- Emergency Surgery Department, Maggiore Parma Hospital, Parma, Italy
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Hyams JS, Dubinsky M, Rosh J, Ruemmele FM, Eichner SF, Maa JF, Lazar A, Alperovich G, Mostafa NM, Robinson AM. The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn's disease: a post hoc analysis. Aliment Pharmacol Ther 2019; 49:155-164. [PMID: 30506693 DOI: 10.1111/apt.15054] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 04/18/2018] [Accepted: 10/20/2018] [Indexed: 12/29/2022]
Abstract
BACKGROUND In the IMAgINE 1 study, adalimumab induced and maintained remission of moderate-to-severe Crohn's disease in children. AIM To assess the efficacy, pharmacokinetics, immunogenicity and safety of immunomodulator and adalimumab combination therapy vs adalimumab monotherapy in paediatric patients with Crohn's disease. METHODS Patients 6-17 years old with moderate-to-severe Crohn's disease (n = 192) received weight-based adalimumab induction at baseline and week 2. At week 4, 188 patients were randomised to high-dose or low-dose adalimumab. Patients receiving immunomodulators (investigator's decision) at baseline maintained a stable dose until week 26; patients could then discontinue immunomodulators. Adalimumab serum concentrations were measured at weeks 4, 26 and 52. Safety was evaluated at each study visit. Data were analysed using non-responder imputation (NRI; week 4) or modified NRI (weeks 26; 52). RESULTS At week 4, patients with (n = 117) and without (n = 71) baseline immunomodulator use had similar response (79%; 87%; P = 0.235) and remission (26%; 30%; P = 0.737) rates. At week 26, patients with and without baseline immunomodulators had no significant difference in response (68%; 55%; P = 0.086) or remission (41%; 30%; P = 0.122). At week 52, patients with (n = 82) and without (n = 106) immunomodulator use had no significant difference in response (56%; 46%; P = 0.189) or remission (38%; 33%; P = 0.539). Adalimumab serum trough concentrations and serious infection rates (7%; 6%) were not significantly different between groups. CONCLUSIONS Analyses found no statistically significant difference in response or remission between patients receiving adalimumab monotherapy vs immunomodulator and adalimumab combination therapy. Serious and infectious adverse event rates were similar between groups.
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Affiliation(s)
- Jeffrey S Hyams
- Connecticut Children's Medical Center, Hartford, Connecticut
| | - Marla Dubinsky
- Icahn School of Medicine at Mount Sinai, New York City, New York
| | - Joel Rosh
- Goryeb Children's Hospital/Atlantic Health, Morristown, New Jersey
| | - Frank M Ruemmele
- Universite Sorbonne Paris-Cite, Hospital Necker-Enfants Malades, Paris, France
| | | | | | - Andreas Lazar
- AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany
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Colman RJ, Lawton RC, Dubinsky MC, Rubin DT. Methotrexate for the Treatment of Pediatric Crohn's Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 2018; 24:2135-2141. [PMID: 29688409 PMCID: PMC6994018 DOI: 10.1093/ibd/izy078] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methotrexate (MTX) is an immunomodulator used for the treatment of pediatric inflammatory bowel disease (IBD). There are currently no RCTs that assess the treatment efficacy of methotrexate within the pediatric IBD patient population. This systematic review and meta-analysis assesses the efficacy of MTX therapy among the existing pediatric literature. METHODS A systematic literature search was performed using MEDLINE and the Cochrane library from inception until March 2016. Synonyms for 'pediatric', 'methotrexate' and 'IBD' were utilized as both free text and MESH search terms. The studies included contained clinical remission (CR) rates for MTX treatment of pediatric IBD patients 18 yrs old, as mono- or combination therapy. Case studies with <10 patients were excluded. Quality assessment was performed with the Newcastle-Ottawa Scale. Meta-analysis calculated pooled CR rates. A random-effects meta-analysis with forest plots was performed using R. RESULTS Fourteen (11 monotherapy, 1 combination therapy, 2 both; n = 886 patients) observational studies were eligible out of 202 studies. No interventional studies were identified. The pooled achieved CR rate for pediatric CD patients on monotherapy within 3-6 months was 57.7% (95% CI 48.2-66.6%), (P =0.22; I2 = 29.8%). The CR was 37.1% (95% CI 29.5-45.5%), (P = 0.20; I2 = 37.4%) for maintenance therapy at 12 months. Sub-analysis could not identify CR differences between MTX administration types, thiopurine exposure. CONCLUSIONS This meta-analysis demonstrated that, over 50% of pediatric Crohn's disease patients induced with methotrexate achieved clinical remission, while 12-month remission rate was only 37%. Prospective controlled interventional trials should assess treatment efficacy among patient subgroups. 10.1093/ibd/izy078_video1izy078.video15774883936001.
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Affiliation(s)
- Ruben J Colman
- Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois,Pediatrics, SBH Health System, Bronx, New York
| | | | | | - David T Rubin
- Inflammatory Bowel Disease Center, The University of Chicago Medicine, Chicago, Illinois,Address correspondence to: David T. Rubin, MD, 5841 S. Maryland Ave., MC 4076, Chicago, IL 60637 ()
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D’Aoust J, Battat R, Bessissow T. Management of inflammatory bowel disease with Clostridium difficile infection. World J Gastroenterol 2017; 23:4986-5003. [PMID: 28785153 PMCID: PMC5526769 DOI: 10.3748/wjg.v23.i27.4986] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/16/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To address the management of Clostridium difficile (C. difficile) infection (CDI) in the setting of suspected inflammatory bowel disease (IBD)-flare.
METHODS A systematic search of the Ovid MEDLINE and EMBASE databases by independent reviewers identified 70 articles including a total of 932141 IBD patients or IBD-related hospitalizations.
RESULTS In those with IBD, CDI is associated with increased morbidity, including subsequent escalation in IBD medical therapy, urgent colectomy and increased hospitalization, as well as excess mortality. Vancomycin-containing regimens are effective first-line therapies for CDI in IBD inpatients. No prospective data exists with regards to the safety or efficacy of initiating or maintaining corticosteroid, immunomodulator, or biologic therapy to treat IBD in the setting of CDI. Corticosteroid use is a risk factor for the development of CDI, while immunomodulators and biologics are not.
CONCLUSION Strong recommendations regarding when to initiate IBD specific therapy in those with CDI are precluded by a lack of evidence. However, based on expert opinion and observational data, initiation or resumption of immunosuppressive therapy after 48-72 h of targeted antibiotic treatment for CDI may be considered.
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Mahida JB, Asti L, Deans KJ, Minneci PC, Nwomeh BC. Laparoscopic bowel resection for pediatric inflammatory bowel disease. J Surg Res 2015; 199:130-6. [DOI: 10.1016/j.jss.2015.04.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Revised: 03/24/2015] [Accepted: 04/02/2015] [Indexed: 12/14/2022]
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Sartelli M, Malangoni MA, Abu-Zidan FM, Griffiths EA, Di Bella S, McFarland LV, Eltringham I, Shelat VG, Velmahos GC, Kelly CP, Khanna S, Abdelsattar ZM, Alrahmani L, Ansaloni L, Augustin G, Bala M, Barbut F, Ben-Ishay O, Bhangu A, Biffl WL, Brecher SM, Camacho-Ortiz A, Caínzos MA, Canterbury LA, Catena F, Chan S, Cherry-Bukowiec JR, Clanton J, Coccolini F, Cocuz ME, Coimbra R, Cook CH, Cui Y, Czepiel J, Das K, Demetrashvili Z, Di Carlo I, Di Saverio S, Dumitru IM, Eckert C, Eckmann C, Eiland EH, Enani MA, Faro M, Ferrada P, Forrester JD, Fraga GP, Frossard JL, Galeiras R, Ghnnam W, Gomes CA, Gorrepati V, Ahmed MH, Herzog T, Humphrey F, Kim JI, Isik A, Ivatury R, Lee YY, Juang P, Furuya-Kanamori L, Karamarkovic A, Kim PK, Kluger Y, Ko WC, LaBarbera FD, Lee JG, Leppaniemi A, Lohsiriwat V, Marwah S, Mazuski JE, Metan G, Moore EE, Moore FA, Nord CE, Ordoñez CA, Júnior GAP, Petrosillo N, Portela F, Puri BK, Ray A, Raza M, Rems M, Sakakushev BE, Sganga G, Spigaglia P, Stewart DB, Tattevin P, Timsit JF, To KB, Tranà C, Uhl W, Urbánek L, van Goor H, Vassallo A, Zahar JR, Caproli E, Viale P. WSES guidelines for management of Clostridium difficile infection in surgical patients. World J Emerg Surg 2015; 10:38. [PMID: 26300956 PMCID: PMC4545872 DOI: 10.1186/s13017-015-0033-6] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 08/12/2015] [Indexed: 02/08/2023] Open
Abstract
In the last two decades there have been dramatic changes in the epidemiology of Clostridium difficile infection (CDI), with increases in incidence and severity of disease in many countries worldwide. The incidence of CDI has also increased in surgical patients. Optimization of management of C difficile, has therefore become increasingly urgent. An international multidisciplinary panel of experts prepared evidenced-based World Society of Emergency Surgery (WSES) guidelines for management of CDI in surgical patients.
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Affiliation(s)
- Massimo Sartelli
- />Department of Surgery, Macerata Hospital, Via Santa Lucia 2, 62019 Macerata, Italy
| | | | - Fikri M. Abu-Zidan
- />Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
| | | | - Stefano Di Bella
- />2nd Infectious Diseases Division, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
| | - Lynne V. McFarland
- />Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Washington, USA
| | - Ian Eltringham
- />Department of Medical Microbiology, King’s College Hospital, London, UK
| | - Vishal G. Shelat
- />Department of Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - George C. Velmahos
- />Emergency Surgery, and Surgical Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA USA
| | - Ciarán P. Kelly
- />Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Sahil Khanna
- />Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN USA
| | | | - Layan Alrahmani
- />Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI USA
| | - Luca Ansaloni
- />General Surgery I, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Goran Augustin
- />Department of Surgery, University Hospital Center Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Miklosh Bala
- />Trauma and Acute Care Surgery Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Frédéric Barbut
- />UHLIN (Unité d’Hygiène et de Lutte contre les Infections Nosocomiales) National Reference Laboratory for Clostridium difficile Groupe Hospitalier de l’Est Parisien (HUEP), Paris, France
| | - Offir Ben-Ishay
- />Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
| | - Aneel Bhangu
- />Academic Department of Surgery, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
| | - Walter L. Biffl
- />Department of Surgery, University of Colorado, Denver Health Medical Center, Denver, USA
| | - Stephen M. Brecher
- />Pathology and Laboratory Medicine, VA Boston Healthcare System, West Roxbury MA and BU School of Medicine, Boston, MA USA
| | - Adrián Camacho-Ortiz
- />Department of Internal Medicine, University Hospital, Dr.José E. González, Monterrey, Mexico
| | - Miguel A. Caínzos
- />Department of Surgery, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Laura A. Canterbury
- />Department of Pathology, University of Alberta Edmonton, Edmonton, AB Canada
| | - Fausto Catena
- />Emergency Surgery Department, Maggiore Parma Hospital, Parma, Italy
| | - Shirley Chan
- />Department of General Surgery, Medway Maritime Hospital, Gillingham Kent, UK
| | - Jill R. Cherry-Bukowiec
- />Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI USA
| | - Jesse Clanton
- />Department of Surgery, Northeast Ohio Medical University, Summa Akron City Hospital, Akron, OH USA
| | | | - Maria Elena Cocuz
- />Faculty of Medicine, Transilvania University, Infectious Diseases Hospital, Brasov, Romania
| | - Raul Coimbra
- />Division of Trauma, Surgical Critical Care, Burns, and Acute Care Surgery, University of California San Diego Health Science, San Diego, USA
| | - Charles H. Cook
- />Division of Acute Care Surgery, Trauma and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA
| | - Yunfeng Cui
- />Department of Surgery,Tianjin Nankai Hospital, Nankai Clinical School of Medicine, Tianjin Medical University, Tianjin, China
| | - Jacek Czepiel
- />Department of Infectious Diseases, Jagiellonian University, Medical College, Kraków, Poland
| | - Koray Das
- />Department of General Surgery, Adana Numune Training and Research Hospital, Adana, Turkey
| | - Zaza Demetrashvili
- />Department of Surgery, Tbilisi State Medical University, Kipshidze Central University Hospital, Tbilisi, Georgia
| | | | | | | | - Catherine Eckert
- />National Reference Laboratory for Clostridium difficile, AP-HP, Saint-Antoine Hospital, Paris, France
| | - Christian Eckmann
- />Department of General, Visceral and Thoracic Surgery, Klinikum Peine, Hospital of Medical University Hannover, Peine, Germany
| | | | - Mushira Abdulaziz Enani
- />Department of Medicine, Section of Infectious Diseases, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mario Faro
- />Department of General Surgery, Trauma and Emergency Surgery Division, ABC Medical School, Santo André, SP Brazil
| | - Paula Ferrada
- />Division of Trauma, Critical Care and Emergency Surgery, Virginia Commonwealth University, Richmond, VA USA
| | | | - Gustavo P. Fraga
- />Division of Trauma Surgery, Hospital de Clinicas, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Jean Louis Frossard
- />Service of Gastroenterology and Hepatology, Geneva University Hospital, Genève, Switzerland
| | - Rita Galeiras
- />Critical Care Unit, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), A Coruña, Spain
| | - Wagih Ghnnam
- />Department of Surgery Mansoura, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Carlos Augusto Gomes
- />Surgery Department, Hospital Universitario (HU) Terezinha de Jesus da Faculdade de Ciencias Medicas e da Saude de Juiz de Fora (SUPREMA), Hospital Universitario (HU) Universidade Federal de Juiz de Fora (UFJF), Juiz de Fora, Brazil
| | - Venkata Gorrepati
- />Department of Internal Medicine, Pinnacle Health Hospital, Harrisburg, PA USA
| | - Mohamed Hassan Ahmed
- />Department of Medicine, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, Buckinghamshire UK
| | - Torsten Herzog
- />Department of Surgery, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Felicia Humphrey
- />Department of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA USA
| | - Jae Il Kim
- />Department of Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea
| | - Arda Isik
- />General Surgery Department, Erzincan University Mengücek Gazi Training and Research Hospital, Erzincan, Turkey
| | - Rao Ivatury
- />Division of Trauma, Critical Care and Emergency Surgery, Virginia Commonwealth University, Richmond, VA USA
| | - Yeong Yeh Lee
- />School of Medical Sciences, Universiti Sains Malaysia, Kota Bharu, Kelantan Malaysia
| | - Paul Juang
- />Department of Pharmacy Practice, St Louis College of Pharmacy, St Louis, MO USA
| | - Luis Furuya-Kanamori
- />Research School of Population Health, The Australian National University, Acton, ACT Australia
| | - Aleksandar Karamarkovic
- />Clinic For Emergency surgery, University Clinical Center of Serbia, Faculty of Medicine University of Belgrade, Belgrade, Serbia
| | - Peter K Kim
- />General and Trauma Surgery, Albert Einstein College of Medicine, North Bronx Healthcare Network, Bronx, NY USA
| | - Yoram Kluger
- />Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
| | - Wen Chien Ko
- />Division of Infectious Diseases, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
| | | | - Jae Gil Lee
- />Division of Critical Care & Trauma Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Ari Leppaniemi
- />Abdominal Center, Helsinki University Hospital Meilahti, Helsinki, Finland
| | - Varut Lohsiriwat
- />Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sanjay Marwah
- />Department of Surgery, Post-Graduate Institute of Medical Sciences, Rohtak, India
| | - John E. Mazuski
- />Department of Surgery, Washington University School of Medicine, Saint Louis, USA
| | - Gokhan Metan
- />Department of Infectious Diseases and Clinical Microbiology, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ernest E. Moore
- />Department of Surgery, University of Colorado, Denver Health Medical Center, Denver, USA
| | | | - Carl Erik Nord
- />Department of Laboratory Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Carlos A. Ordoñez
- />Department of Surgery, Fundación Valle del Lili, Hospital Universitario del Valle, Universidad del Valle, Cali, Colombia
| | | | - Nicola Petrosillo
- />2nd Infectious Diseases Division, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy
| | - Francisco Portela
- />Gastroenterology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Basant K. Puri
- />Department of Medicine, Hammersmith Hospital and Imperial College London, London, UK
| | - Arnab Ray
- />Department of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, LA USA
| | - Mansoor Raza
- />Infectious Diseases and Microbiology Unit, Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, Buckinghamshire UK
| | - Miran Rems
- />Department of Abdominal and General Surgery, General Hospital Jesenice, Jesenice, Slovenia
| | | | - Gabriele Sganga
- />Division of General Surgery and Organ Transplantation, Department of Surgery, Catholic University of the Sacred Heart, Rome, Italy
| | - Patrizia Spigaglia
- />Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - David B. Stewart
- />Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA USA
| | - Pierre Tattevin
- />Infectious Diseases and Intensive Care Unit, Pontchaillou University Hospital, Rennes, France
| | | | - Kathleen B. To
- />Department of Surgery, Division of Acute Care Surgery, University of Michigan, Ann Arbor, MI USA
| | - Cristian Tranà
- />Emergency Medicine and Surgery, Macerata hospital, Macerata, Italy
| | - Waldemar Uhl
- />Department of Surgery, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
| | - Libor Urbánek
- />1st Surgical Clinic, University Hospital of St. Ann Brno, Brno, Czech Republic
| | - Harry van Goor
- />Department of Surgery, Radboud University Medical Center, Nijmegen, Netherlands
| | - Angela Vassallo
- />Infection Prevention/Epidemiology, Providence Saint John’s Health Center, Santa Monica, CA USA
| | - Jean Ralph Zahar
- />Infection Control Unit, Angers University, CHU d’Angers, Angers, France
| | - Emanuele Caproli
- />Department of Surgery, Ancona University Hospital, Ancona, Italy
| | - Pierluigi Viale
- />Clinic of Infectious Diseases, St Orsola-Malpighi University Hospital, Bologna, Italy
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Wagner N. Neue Entwicklungen in der Therapie chronisch-entzündlicher Darmkrankheiten. Monatsschr Kinderheilkd 2015. [DOI: 10.1007/s00112-014-3280-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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9
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Dulai PS, Thompson KD, Blunt HB, Dubinsky MC, Siegel CA. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clin Gastroenterol Hepatol 2014; 12:1443-51; quiz e88-9. [PMID: 24462626 DOI: 10.1016/j.cgh.2014.01.021] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Revised: 12/27/2013] [Accepted: 01/08/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Many physicians hesitate to recommend anti-tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of concerns about risk of infection and cancer. We performed a systematic review to quantify the incidence of serious infection, lymphoma, and death among pediatric patients with IBD who received anti-TNF therapy. These values were compared with those expected from other treatments, from adults with IBD, and from the general pediatric population. METHODS We searched MEDLINE, EMBASE, the Cochrane Collaboration, and Web of Knowledge for studies of infliximab therapy for children with ulcerative colitis or Crohn's disease, or adalimumab therapy for children with Crohn's disease. Standardized incidence ratios (SIRs) were calculated, comparing rates of infection and cancer among pediatric patients exposed to anti-TNF agents vs expected rates from pediatric patients not exposed to anti-TNF therapies or adult patients exposed to anti-TNF agents. Our analysis included 5528 patients with 9516 patient-years of follow-up evaluation (PYF). RESULTS The rate of serious infections among pediatric patients treated with anti-TNF agents (352/10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR, 1.06; 95% confidence interval [CI], 0.83-1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR, 0.48; 95% CI, 0.40-0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR, 0.54; 95% CI, 0.43-0.67). Five treatment-related deaths occurred (4 from sepsis and 1 from arrhythmia). Two patients developed lymphoma (2.1/10,000 PYF). This value was similar to the expected rate of lymphoid neoplasia in the entire pediatric population (5.8/100,000 PYF; SIR, 3.5; 95% CI, 0.35-19.6), and lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03-6.44), and among adults treated with anti-TNF agents (6.1/10,000 PYF; SIR, 0.34; 95% CI, 0.04-1.51). CONCLUSIONS Based on a systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.
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Affiliation(s)
- Parambir S Dulai
- Inflammatory Bowel Disease Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Kimberly D Thompson
- Inflammatory Bowel Disease Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
| | - Heather B Blunt
- Biomedical Libraries, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Marla C Dubinsky
- Pediatric Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Corey A Siegel
- Inflammatory Bowel Disease Center, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire.
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Swaminath A, Taunk R, Lawlor G. Use of methotrexate in inflammatory bowel disease in 2014: A User’s Guide. World J Gastrointest Pharmacol Ther 2014; 5:113-121. [PMID: 25133040 PMCID: PMC4133437 DOI: 10.4292/wjgpt.v5.i3.113] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 04/10/2014] [Accepted: 06/20/2014] [Indexed: 02/06/2023] Open
Abstract
Methotrexate has been used an immunomodulator in many autoimmune diseases, including inflammatory bowel disease. However, many physicians are unfamiliar or uncomfortable with its use in the management of inflammatory bowel disease. We summarize the data for use of methotrexate in common clinical scenarios: (1) steroid dependant Crohn’s disease (CD); (2) maintenance of remission in steroid free CD; (3) azathioprine failures in CD; (4) in combination therapy with Anti-TNF agents in CD; (5) decreasing antibody formation to Anti-TNF therapy in CD; (6) management of fistulizing disease in CD; and (7) as well as induction and maintenance of remission in ulcerative colitis. An easy to use algorithm is provided for the busy clinician to access and safely prescribe methotrexate for their inflammatory bowel disease patients.
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11
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Lawrance IC. What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails? World J Gastroenterol 2014; 20:1248-1258. [PMID: 24574799 PMCID: PMC3921507 DOI: 10.3748/wjg.v20.i5.1248] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 11/05/2013] [Accepted: 12/13/2013] [Indexed: 02/06/2023] Open
Abstract
The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient’s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn’s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNFα) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNFα agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.
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12
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Valentino PL, Church PC, Shah PS, Beyene J, Griffiths AM, Feldman BM, Kamath BM. Hepatotoxicity caused by methotrexate therapy in children with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2014; 20:47-59. [PMID: 24280876 DOI: 10.1097/01.mib.0000436953.88522.3e] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD. METHODS We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model. RESULTS Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%-18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%-9.5%), whereas 4.5% (95% CI 2.8%-7.2%) of patients required discontinuation. CONCLUSIONS Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.
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Affiliation(s)
- Pamela L Valentino
- 1Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 2Neonatal Intensive Care Unit, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada; 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Toronto, ON, Canada; and 4Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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Nitzan O, Elias M, Chazan B, Raz R, Saliba W. Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment. World J Gastroenterol 2013; 19:7577-7585. [PMID: 24282348 PMCID: PMC3837256 DOI: 10.3748/wjg.v19.i43.7577] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2013] [Revised: 10/05/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023] Open
Abstract
Clostridium difficile (C. difficile) is the leading cause of antibiotic associated colitis and nosocomial diarrhea. Patients with inflammatory bowel disease (IBD) are at increased risk of developing C. difficile infection (CDI), have worse outcomes of CDI-including higher rates of colectomy and death, and experience higher rates of recurrence. However, it is still not clear whether C. difficile is a cause of IBD or a consequence of the inflammatory state in the intestinal environment. The burden of CDI has increased dramatically over the past decade, with severe outbreaks described in many countries, which have been attributed to a new and more virulent strain. A parallel rise in the incidence of CDI has been noted in patients with IBD. IBD patients with CDI tend be younger, have less prior antibiotic exposure, and most cases of CDI in these patients represent outpatient acquired infections. The clinical presentation of CDI in these patients can be unique-including diversion colitis, enteritis and pouchitis, and typical findings on colonoscopy are often absent. Due to the high prevalence of CDI in patients hospitalized with an IBD exacerbation, and the prognostic implications of CDI in these patients, it is recommended to test all IBD patients hospitalized with a disease flare for C. difficile. Treatment includes general measures such as supportive care and infection control measures. Antibiotic therapy with either oral metronidazole, vancomycin, or the novel antibiotic-fidaxomicin, should be initiated as soon as possible. Fecal macrobiota transplantation constitutes another optional treatment for severe/recurrent CDI. The aim of this paper is to review recent data on CDI in IBD: role in pathogenesis, diagnostic methods, optional treatments, and outcomes of these patients.
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Adjunctive treatment to antitumor necrosis factor in pediatric patients with refractory Crohn's disease. Curr Opin Pediatr 2013; 25:624-8. [PMID: 23995433 DOI: 10.1097/mop.0b013e328364df22] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW The use of antitumor necrosis factor (anti-TNF) agents to treat Crohn's disease in children has become quite common over the past decade. There are incomplete data to guide the clinician in choosing whether adjunctive therapy should be added to optimize response to these drugs. RECENT FINDINGS Addition of immunomodulators such as thiopurines or possibly methotrexate can increase anti-TNF drug levels, reduce the risk of antidrug antibodies, and improve response. This is tempered by the reports of younger patients developing hepato-splenic T-cell lymphoma while taking thiopurines with and without concomitant anti-TNF medications. The available data are reviewed including recent pediatric reports. SUMMARY The addition of immunomodulators to anti-TNF therapies can optimize their performance. Careful discussion of the risks and side-effects must be undertaken when considering this approach. Additional knowledge is required to stratify which children with inflammatory bowel disease need this approach, and/or who are at risk for significant complications.
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Antoniani D, Rossi E, Rinaldo S, Bocci P, Lolicato M, Paiardini A, Raffaelli N, Cutruzzolà F, Landini P. The immunosuppressive drug azathioprine inhibits biosynthesis of the bacterial signal molecule cyclic-di-GMP by interfering with intracellular nucleotide pool availability. Appl Microbiol Biotechnol 2013; 97:7325-36. [PMID: 23584245 DOI: 10.1007/s00253-013-4875-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 03/20/2013] [Accepted: 03/21/2013] [Indexed: 12/21/2022]
Abstract
In Gram-negative bacteria, production of the signal molecule c-di-GMP by diguanylate cyclases (DGCs) is a key trigger for biofilm formation, which, in turn, is often required for the development of chronic bacterial infections. Thus, DGCs represent interesting targets for new chemotherapeutic drugs with anti-biofilm activity. We searched for inhibitors of the WspR protein, a Pseudomonas aeruginosa DGC involved in biofilm formation and production of virulence factors, using a set of microbiological assays developed in an Escherichia coli strain expressing the wspR gene. We found that azathioprine, an immunosuppressive drug used in the treatment of Crohn's disease, was able to inhibit WspR-dependent c-di-GMP biosynthesis in bacterial cells. However, in vitro enzymatic assays ruled out direct inhibition of WspR DGC activity either by azathioprine or by its metabolic derivative 2-amino-6-mercapto-purine riboside. Azathioprine is an inhibitor of 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase, an enzyme involved in purine biosynthesis, which suggests that inhibition of c-di-GMP biosynthesis by azathioprine may be due to perturbation of intracellular nucleotide pools. Consistent with this hypothesis, WspR activity is abolished in an E. coli purH mutant strain, unable to produce AICAR transformylase. Despite its effect on WspR, azathioprine failed to prevent biofilm formation by P. aeruginosa; however, it affected production of extracellular structures in E. coli clinical isolates, suggesting efficient inhibition of c-di-GMP biosynthesis in this bacterium. Our results indicate that azathioprine can prevent biofilm formation in E. coli through inhibition of c-di-GMP biosynthesis and suggest that such inhibition might contribute to its anti-inflammatory activity in Crohn's disease.
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Affiliation(s)
- Davide Antoniani
- Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy
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