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Crowther A, LuTheryn G, Garcia-Maset R, Parhizkar M, Sutton JM, Hind C, Carugo D. Efficacy of nitric oxide donors and EDTA against Pseudomonas aeruginosa biofilms: Implications for antimicrobial therapy in chronic wounds. Biofilm 2025; 9:100280. [PMID: 40336941 PMCID: PMC12056783 DOI: 10.1016/j.bioflm.2025.100280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Revised: 04/09/2025] [Accepted: 04/14/2025] [Indexed: 05/09/2025] Open
Abstract
Opportunistic pathogen Pseudomonas aeruginosa plays a crucial role in chronic wound biofilms, increasing infection's morbidity and mortality. In recent years, the signalling molecule nitric oxide (NO) and chelating agent tetrasodium EDTA (T-EDTA) have been applied therapeutically owing to their multifactorial effects including bacterial killing, biofilm dispersal, and wound healing. However, previous studies assessing NO's antibiofilm efficacy have not considered the variable pH and temperature of the wound environment. Here, pH-dependent NO donors N-diazeniumdiolates (NONOates), PAPA NONOate (PA-NO) and Spermine NONOate (SP-NO), and T-EDTA were applied in wound-relevant pH environments (pH 5.5-8.5) and temperatures (32 °C and 37 °C) to P. aeruginosa PAO1 biofilms grown for either 24 or 48 h. At 32 °C and pH 7.5, 250 μM PA-NO reduced 24-h biofilm biomass by 35 %. At 37 °C, 250 μM PA-NO and 4 % w/v T-EDTA caused 21 % and 57 % biomass reduction in 24-h biofilms, respectively. In 48-h biofilms, NONOates did not induce significant biomass reduction, while T-EDTA maintained its efficacy with a 64 % reduction. A subsequent experiment investigated the impact of NONOates and T-EDTA as pre-treatments before exposure to ciprofloxacin. Unexpectedly, NONOate pre-treatment decreased ciprofloxacin's effectiveness, resulting in approximately 1-log increase in viable planktonic and biofilm-residing cells compared to ciprofloxacin alone. It was hypothesized that this protective effect might stem from NO-induced decreased cellular respiration, which inhibits reactive oxygen species (ROS)-mediated bactericidal mechanisms. These findings highlight both the potential and complexities of developing effective antimicrobial strategies for chronic wound infections, emphasizing the need for further research to optimize treatment approaches.
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Affiliation(s)
- Aaron Crowther
- Department of Pharmaceutics, School of Pharmacy, University College London, London, UK
- Institute of Biomedical Engineering, University of Oxford, Oxford, UK
| | - Gareth LuTheryn
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Ramón Garcia-Maset
- Centre for Urological Biology, Division of Medicine, University College London, London, UK
| | - Maryam Parhizkar
- Department of Pharmaceutics, School of Pharmacy, University College London, London, UK
| | - J. Mark Sutton
- UK Health Security Agency, Vaccine Development and Evaluation Centre, Porton Down, Salisbury, UK
| | - Charlotte Hind
- UK Health Security Agency, Vaccine Development and Evaluation Centre, Porton Down, Salisbury, UK
| | - Dario Carugo
- Department of Pharmaceutics, School of Pharmacy, University College London, London, UK
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
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Robinson CH, Harvey E, Nemec R, Karkut K, Tecson L, McKay AM. Use of 4% tetrasodium EDTA (KiteLock™) to prevent central venous catheter-related bloodstream infections in pediatric hemodialysis patients. Pediatr Nephrol 2025; 40:1081-1091. [PMID: 39576326 DOI: 10.1007/s00467-024-06601-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/05/2024] [Accepted: 11/05/2024] [Indexed: 03/08/2025]
Abstract
BACKGROUND Central venous catheter (CVC)-related bloodstream infections (CRBSI) are common in children receiving hemodialysis and cause significant morbidity and healthcare costs. Unlike standard locking solutions, 4% tetrasodium EDTA (KiteLock™) has antimicrobial and antibiofilm properties. We aimed to study the safety and efficacy of 4% tetrasodium EDTA CVC locking in pediatric hemodialysis. METHODS Single-center, before-and-after quality improvement study. We included all chronic hemodialysis patients (6 months-18 years) from 2016-2022 (before) to 2022-2024 (after). The standard CVC locking solution was changed from heparin (1000 units/mL) to 4% tetrasodium EDTA. We compared unit-level incidence of CRBSI, CVC replacement procedures (exchange or removal and reinsertion), laboratory results, alteplase use, and adverse events before and after 4% tetrasodium EDTA implementation. RESULTS We included 22 pediatric chronic hemodialysis patients (median age 13.5 years, 50% female). CRBSI incidence was 0.89 infections per 1000 catheter-days (25,769 total catheter-days) before and 0.18 per 1000 catheter-days (5426 total catheter-days) after 4% tetrasodium EDTA (IRR 0.21, 95%CI 0.03-1.52). CVC replacement procedure incidence was 1.99 procedures per 1000 catheter-days (4027 total catheter-days) before and 1.29 per 1000 catheter-days (5426 total catheter-days) after 4% tetrasodium EDTA (IRR 0.65, 95%CI 0.24-1.79). There were no significant differences in hemodialysis treatment parameters, alteplase use (12% of treatments before vs. 18% after), or access complications (12% of treatments before vs. 15% after). CONCLUSIONS CVC locking with 4% tetrasodium EDTA was associated with sustained reductions in CRBSI and CVC replacement procedure incidence. Incorporation of 4% tetrasodium EDTA locking into standardized CVC care bundles may prolong vascular access survival.
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Affiliation(s)
- Cal H Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.
- Department of Paediatrics, The University of Toronto, Toronto, Ontario, Canada.
- Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
- Peter Gilgan Centre for Research and Learning, SickKids Research Institute, 686 Bay St, Toronto, Ontario, M5G 0A4, Canada.
| | - Elizabeth Harvey
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, The University of Toronto, Toronto, Ontario, Canada
| | - Rose Nemec
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Katherine Karkut
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lor Tecson
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Ashlene M McKay
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Paediatrics, The University of Toronto, Toronto, Ontario, Canada
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Visek J, Ryskova L, Cesakova P, Stanclova J, Vajrychova M, Blaha V. Comparison of taurolidine with 4% ethylenediaminetetraacetic acid on antimicrobial lock effectiveness: An experimental study. JPEN J Parenter Enteral Nutr 2025; 49:373-378. [PMID: 39865419 DOI: 10.1002/jpen.2725] [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: 09/17/2024] [Revised: 12/11/2024] [Accepted: 01/08/2025] [Indexed: 01/28/2025]
Abstract
BACKGROUND Antimicrobial lock therapy is recommended for preventing and treating catheter-related bloodstream infections, but different solutions have uncertain efficacy. METHODS Two locks, 1.35% taurolidine and 4% ethylenediaminetetraacetic acid (EDTA), were tested on Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, multidrug-resistant P. aeruginosa, vancomycin-resistant Enterococcus faecium, Klebsiella oxytoca (carbapenemase producing), K. pneumoniae (extended-spectrum β-lactamase producing), Candida albicans, and Candida glabrata. Broviac catheter segments were incubated with these organisms and then exposed to various lock solutions. Colony-forming units (CFUs) were counted after 2, 4, and 24 h of incubation. RESULTS Taurolidine showed a significant decrease in CFUs after 2 h in S. aureus, S. epidermidis, methicillin-resistant S. aureus, vancomycin-resistant E. faecium, P. aeruginosa (both sensitive and multidrug-resistant strains), K. oxytoca, C. albicans, and C. glabrata. After 4 h, significant reductions were noted in S. aureus, S. epidermidis, methicillin-resistant S. aureus, P. aeruginosa, multidrug-resistant P. aeruginosa, K. pneumoniae, K. oxytoca, and C. albicans. Taurolidine was also effective after 24 h, especially against methicillin-resistant S. aureus and multidrug-resistant P. aeruginosa. Four percent EDTA acid showed a significant reduction in CFUs after 2 h in S. aureus, vancomycin-resistant E. faecium, P. aeruginosa, K. oxytoca, C. albicans, and C. glabrata. After 4 h, reductions occurred in P. aeruginosa, multidrug-resistant P. aeruginosa, K. oxytoca, and C. albicans and after 24 h in methicillin-resistant S. aureus, P. aeruginosa, and K. oxytoca. CONCLUSION Taurolidine is more effective than 4% EDTA acid in eradicating Gram-positive and Gram-negative microorganisms and fungi.
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Affiliation(s)
- Jakub Visek
- 3rd Department of Internal Medicine-Metabolic Care and Gerontology, University Hospital and Medical Faculty in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Lenka Ryskova
- Department of Clinical Microbiology, University Hospital and Medical Faculty in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Petra Cesakova
- Department of Clinical Microbiology, University Hospital and Medical Faculty in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Jana Stanclova
- Department of Clinical Microbiology, University Hospital and Medical Faculty in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
| | - Marie Vajrychova
- Biomedical Research Centre, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
| | - Vladimir Blaha
- 3rd Department of Internal Medicine-Metabolic Care and Gerontology, University Hospital and Medical Faculty in Hradec Kralove, Charles University in Prague, Hradec Kralove, Czech Republic
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Almatroudi A. Biofilm Resilience: Molecular Mechanisms Driving Antibiotic Resistance in Clinical Contexts. BIOLOGY 2025; 14:165. [PMID: 40001933 PMCID: PMC11852148 DOI: 10.3390/biology14020165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/02/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025]
Abstract
Healthcare-associated infections pose a significant global health challenge, negatively impacting patient outcomes and burdening healthcare systems. A major contributing factor to healthcare-associated infections is the formation of biofilms, structured microbial communities encased in a self-produced extracellular polymeric substance matrix. Biofilms are critical in disease etiology and antibiotic resistance, complicating treatment and infection control efforts. Their inherent resistance mechanisms enable them to withstand antibiotic therapies, leading to recurrent infections and increased morbidity. This review explores the development of biofilms and their dual roles in health and disease. It highlights the structural and protective functions of the EPS matrix, which shields microbial populations from immune responses and antimicrobial agents. Key molecular mechanisms of biofilm resistance, including restricted antibiotic penetration, persister cell dormancy, and genetic adaptations, are identified as significant barriers to effective management. Biofilms are implicated in various clinical contexts, including chronic wounds, medical device-associated infections, oral health complications, and surgical site infections. Their prevalence in hospital environments exacerbates infection control challenges and underscores the urgent need for innovative preventive and therapeutic strategies. This review evaluates cutting-edge approaches such as DNase-mediated biofilm disruption, RNAIII-inhibiting peptides, DNABII proteins, bacteriophage therapies, antimicrobial peptides, nanoparticle-based solutions, antimicrobial coatings, and antimicrobial lock therapies. It also examines critical challenges associated with biofilm-related healthcare-associated infections, including diagnostic difficulties, disinfectant resistance, and economic implications. This review emphasizes the need for a multidisciplinary approach and underscores the importance of understanding biofilm dynamics, their role in disease pathogenesis, and the advancements in therapeutic strategies to combat biofilm-associated infections effectively in clinical settings. These insights aim to enhance treatment outcomes and reduce the burden of biofilm-related diseases.
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Affiliation(s)
- Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
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Sivaranjani M, Sanderson H, Nnajide CR, Martens-Koop A, Blondeau JM, Stryker R, White AP. Microbiological analysis of tunneled hemodialysis catheters isolated from patients receiving hemodialysis in Saskatchewan. Future Microbiol 2024; 19:1129-1144. [PMID: 39149853 PMCID: PMC11529201 DOI: 10.1080/17460913.2024.2359879] [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: 02/28/2024] [Accepted: 05/22/2024] [Indexed: 08/17/2024] Open
Abstract
Aim: To compare the microbial communities inside hemodialysis catheters from symptomatic and asymptomatic patients to determine their differences.Materials & methods: Catheters (n = 41) were removed from patients in the Saskatchewan Health Authority over an 18-month period. The catheter section inside the body was flushed and the contents were evaluated using culture-dependent and culture-independent analysis.Results: All catheters were colonized by bacteria, with considerable overlap between groups based on microbial communities and the individual species detected. More Gram-negative species were detected by sequencing, whereas predominantly Gram-positive strains were cultured. Antibiotic resistance and biofilm formation was widespread and not correlated with either catheter group.Conclusion: Common pathogens were detected in each set of catheters, therefore predicting infections based on the microbiology is difficult.
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Affiliation(s)
| | - Haley Sanderson
- Biological Informatics Center of Excellence, Agriculture and Agri-Food Canada, Saskatoon, Saskatchewan, Canada
| | - Chinenye R Nnajide
- Vaccine & Infectious Disease Organization (VIDO), Saskatoon, Saskatchewan, Canada
- Department of Biochemistry, Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Anna Martens-Koop
- Vaccine & Infectious Disease Organization (VIDO), Saskatoon, Saskatchewan, Canada
- Department of Biochemistry, Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Joseph M Blondeau
- Department of Biochemistry, Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, Canada
- Division of Clinical Microbiology, Royal University Hospital & Saskatchewan Health Authority (SHA), Saskatoon, SK, Canada
- Department of Pathology & Ophthalmology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Rodrick Stryker
- Department of Medicine/Division of Nephrology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Aaron P White
- Vaccine & Infectious Disease Organization (VIDO), Saskatoon, Saskatchewan, Canada
- Department of Biochemistry, Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, Canada
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Khoury RD, de Carvalho LS, do Nascimento MFR, Alhussain F, Abu Hasna A. Endodontic irrigants from a comprehensive perspective. World J Clin Cases 2024; 12:4460-4468. [PMID: 39070803 PMCID: PMC11235474 DOI: 10.12998/wjcc.v12.i21.4460] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 05/06/2024] [Accepted: 06/03/2024] [Indexed: 06/30/2024] Open
Abstract
This review article explores the fundamental principles of modern endodontics with a focus on root canal cleaning and shaping. It reviews commonly used endodontic irrigant, namely sodium hypochlorite (NaOCl), herbal extracts, chlorhexidine (CHX), and chelating agents, highlighting their properties, applications, and potential drawbacks. NaOCl, a key antimicrobial agent, demonstrates effectiveness against various microorganisms but poses challenges such as high cytotoxicity. Herbal extracts, gaining recognition in endodontics, present an alternative with potential advantages in preserving dentin integrity. CHX, known for its broad-spectrum antimicrobial activity, is discussed in both liquid and gel formulations, emphasizing its role in reducing smear layer formation and preserving hybrid layer durability. Chelating agents, specifically ethylenediaminetetraacetic acid and citric acid, play a vital role in removing the smear layer, enhancing dentin permeability, and facilitating the penetration of antimicrobial agents. The review article underscores the importance of careful application and consideration of each irrigant's properties to ensure safe and effective endodontic procedures. It serves as a valuable guide for clinicians in selecting appropriate irrigants based on specific treatment requirements.
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Affiliation(s)
- Rayana Duarte Khoury
- Department of Restorative Dentistry, Endodontics Division, Institute of Science and Technology, São Paulo State University, São José dos Campos 12245000, SP, Brazil
| | - Lara Steffany de Carvalho
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University, São José dos Campos 12245000, SP, Brazil
| | - Mauro Felipe Rios do Nascimento
- School of Dentistry, The National Institute of Higher Education and Postgraduate Studies Padre Gervásio-INAPÓS, Pouso Alegre 37550-121, MG, Brazil
| | - Fadi Alhussain
- School of Dentistry, Syrian Private University, Al Kiswah 877C+P2, Damascus, Syria
| | - Amjad Abu Hasna
- Department of Restorative Dentistry, Endodontics Division, Institute of Science and Technology, São Paulo State University, São José dos Campos 12245000, SP, Brazil
- School of Dentistry, Universidad Espíritu Santo, Samborondón 092301, Ecuador
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Ullman A, Takashima M, Gibson V, Comber E, Borello E, Bradford N, Byrnes J, Cole R, Eisenstat D, Henson N, Howard P, Irwin A, Keogh S, Kleidon T, Martin M, McCleary K, McLean J, Moloney S, Monagle P, Moore A, Newall F, Noyes M, Rowan G, St John A, Wood A, Wolf J, Ware R. Preventing adverse events during paediatric cancer treatment: protocol for a multi-site hybrid randomised controlled trial of catheter lock solutions (the CLOCK trial). BMJ Open 2024; 14:e085637. [PMID: 38986559 PMCID: PMC11243282 DOI: 10.1136/bmjopen-2024-085637] [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: 02/22/2024] [Accepted: 06/24/2024] [Indexed: 07/12/2024] Open
Abstract
INTRODUCTION Central venous access devices (CVADs) are commonly used for the treatment of paediatric cancer patients. Catheter locking is a routine intervention that prevents CVAD-associated adverse events, such as infection, occlusion and thrombosis. While laboratory and clinical data are promising, tetra-EDTA (T-EDTA) has yet to be rigorously evaluated or introduced in cancer care as a catheter lock. METHODS AND ANALYSIS This is a protocol for a two-arm, superiority type 1 hybrid effectiveness-implementation randomised controlled trial conducted at seven hospitals across Australia and New Zealand. Randomisation will be in a 3:2 ratio between the saline (heparinised saline and normal saline) and T-EDTA groups, with randomly varied blocks of size 10 or 20 and stratification by (1) healthcare facility; (2) CVAD type and (3) duration of dwell since insertion. Within the saline group, there will be a random allocation between normal and heparin saline. Participants can be re-recruited and randomised on insertion of a new CVAD. Primary outcome for effectiveness will be a composite of CVAD-associated bloodstream infections (CABSI), CVAD-associated thrombosis or CVAD occlusion during CVAD dwell or at removal. Secondary outcomes will include CABSI, CVAD-associated-thrombosis, CVAD failure, incidental asymptomatic CVAD-associated-thrombosis, other adverse events, health-related quality of life, healthcare costs and mortality. To achieve 90% power (alpha=0.05) for the primary outcome, data from 720 recruitments are required. A mixed-methods approach will be employed to explore implementation contexts from the perspective of clinicians and healthcare purchasers. ETHICS AND DISSEMINATION Ethics approval has been provided by Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC) (HREC/22/QCHQ/81744) and the University of Queensland HREC (2022/HE000196) with subsequent governance approval at all sites. Informed consent is required from the substitute decision-maker or legal guardian prior to participation. In addition, consent may also be obtained from mature minors, depending on the legislative requirements of the study site. The primary trial and substudies will be written by the investigators and published in peer-reviewed journals. The findings will also be disseminated through local health and clinical trial networks by investigators and presented at conferences. TRIAL REGISTRATION NUMBER ACTRN12622000499785.
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Affiliation(s)
- Amanda Ullman
- The University of Queensland, Brisbane, Queensland, Australia
| | - Mari Takashima
- The University of Queensland, Brisbane, Queensland, Australia
| | - Victoria Gibson
- The University of Queensland, Brisbane, Queensland, Australia
- Children's Health Queensland Hospital and Health Service, South Brisbane, Queensland, Australia
| | - Elouise Comber
- The University of Queensland, Brisbane, Queensland, Australia
| | - Eloise Borello
- The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Natalie Bradford
- Cancer and Palliative Care Outcomes Centre, Queensland University of Technology, South Brisbane, Queensland, Australia
| | - Joshua Byrnes
- Centre for Applied Health Economics, Griffith University, Brisbane, Queensland, Australia
| | - Roni Cole
- Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia
| | - David Eisenstat
- The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Nicole Henson
- Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia
| | - Philippa Howard
- The University of Queensland, Brisbane, Queensland, Australia
| | - Adam Irwin
- University Of Queensland Centre for Clinical Research, Herston, Queensland, Australia
- Department of Paediatric Infectious Diseases, Great Ormond Street Hospital for Children, London, UK
| | - Samantha Keogh
- School of Nursing, Queensland University of Technology, Brisbane, Queensland, Australia
- Queensland University of Technology, Brisbane, Queensland, Australia
| | - Tricia Kleidon
- Queensland Children's Hospital, Queensland Health, South Brisbane, Queensland, Australia
- Alliance for Vascular Access Teaching and Research Group, Menzies Health Institute Queensland, Nathan, Queensland, Australia
| | - Michelle Martin
- Monash Children's Hospital, Clayton, New South Wales, Australia
| | - Karen McCleary
- Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia
| | - Jordana McLean
- Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia
| | - Susan Moloney
- Gold Coast University Hospital, Southport, Queensland, Australia
| | - Paul Monagle
- Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Andrew Moore
- Children's Health Queensland Hospital and Health Service, South Brisbane, Queensland, Australia
| | - Fiona Newall
- The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Michelle Noyes
- Gold Coast Hospital and Health Service, Southport, Queensland, Australia
| | - Gemma Rowan
- The Royal Children's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Amanda St John
- Monash Children's Hospital, Clayton, New South Wales, Australia
| | - Andrew Wood
- Starship Children's Health, Auckland, Auckland, New Zealand
| | - Joshua Wolf
- St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Robert Ware
- Menzies Health Institute Queensland, Griffith University, Nathan, Queensland, Australia
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Tremain L, Collerman A, Harsha P, Ntow K, Main C, Wohlgemut J, Brown M, Scott T, Dietrich T. Implementing a 4% EDTA Central Catheter Locking Solution as a Quality Improvement Project in a Large Canadian Hospital. JOURNAL OF INFUSION NURSING 2024; 47:255-265. [PMID: 38968588 DOI: 10.1097/nan.0000000000000553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/07/2024]
Abstract
Oncology and critical care patients often require central vascular access devices (CVADs), which can make them prone to central line-associated bloodstream infections (CLABSIs) and thrombotic occlusions. According to the literature, CLABSIs are rampant and increased by 63% during the COVID-19 pandemic, highlighting the need for innovative interventions. Four percent ethylenediaminetetraacetic acid (4% EDTA) is an antimicrobial locking solution that reduces CLABSIs, thrombotic occlusions, and biofilm. This retrospective pre-post quality improvement project determined if 4% EDTA could improve patient safety by decreasing CLABSIs and central catheter occlusions. This was implemented in all adult cancer and critical care units at a regional cancer hospital and center. Before implementing 4% EDTA, there were 36 CLABSI cases in 16 months (27 annualized). After implementation, there were 6 cases in 6 months (12 annualized), showing a statistically significant decrease of 59% in CLABSIs per 1000 catheter days. However, there was no significant difference in occlusions (alteplase use). Eighty-eight percent of patients had either a positive or neutral outlook, while most nurses reported needing 4% EDTA to be available in prefilled syringes. The pandemic and nursing shortages may have influenced the results; hence, randomized controlled trials are needed to establish a causal relationship between 4% EDTA and CLABSIs and occlusions.
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Affiliation(s)
- Leanne Tremain
- Author Affiliations: Hamilton Health Sciences, Hamilton, Ontario, Canada (Tremain, Collerman, Harsha, Ntow, Main, Wohlgemut, Brown, Scott, Dietrich); McMaster University, Hamilton, Ontario, Canada (Ntow, Main, Scott)
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Hirsch TI, Fligor SC, Tsikis ST, Mitchell PD, DeVietro A, Carbeau S, Wang SZ, McClelland J, Carey AN, Gura KM, Puder M. Administration of 4% tetrasodium EDTA lock solution and central venous catheter complications in high-risk pediatric patients with intestinal failure: A retrospective cohort study. JPEN J Parenter Enteral Nutr 2024; 48:624-632. [PMID: 38837803 PMCID: PMC11216891 DOI: 10.1002/jpen.2644] [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: 02/01/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Selection of central venous catheter (CVC) lock solution impacts catheter mechanical complications and central line-associated bloodstream infections (CLABSIs) in pediatric patients with intestinal failure. Disadvantages of the current clinical standards, heparin and ethanol lock therapy (ELT), led to the discovery of new lock solutions. High-risk pediatric patients with intestinal failure who lost access to ELT during a recent shortage were offered enrollment in a compassionate use trial with 4% tetrasodium EDTA (T-EDTA), a lock solution with antimicrobial, antibiofilm, and antithrombotic properties. METHODS We performed a descriptive cohort study including 14 high-risk pediatric patients with intestinal failure receiving 4% T-EDTA as a daily catheter lock solution. CVC complications were documented (repairs, occlusions, replacements, and CLABSIs). Complication rates on 4% T-EDTA were compared with baseline rates, during which patients were receiving either heparin or ELT (designated as heparin/ELT). RESULTS Patients initiated 4% T-EDTA at the time they were enrolled in the compassionate use protocol. Use of 4% T-EDTA resulted in a 50% reduction in CVC complications, compared with baseline rates on heparin/ELT (incidence rate ratio: 0.50; 95% CI, 0.25-1.004; P = 0.051). CONCLUSION In a compassionate use protocol for high-risk pediatric patients with intestinal failure, the use of 4% T-EDTA reduced composite catheter complications, including those leading to emergency department visits, hospital admissions, additional procedures, and mortality. This outcome suggests 4% T-EDTA has benefits over currently available lock solutions.
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Affiliation(s)
- Thomas I Hirsch
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Scott C Fligor
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Savas T Tsikis
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Paul D Mitchell
- Biostatistics and Research Design Center, Boston Children’s Hospital, Boston, MA, USA
| | - Angela DeVietro
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
| | - Sarah Carbeau
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
| | - Sarah Z Wang
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jennifer McClelland
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA, USA
| | - Alexandra N Carey
- Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA, USA
| | - Kathleen M Gura
- Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital, Boston, MA, USA
- Department of Pharmacy, Boston Children’s Hospital, Boston, MA, USA
| | - Mark Puder
- Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Pauline ML, Labonne E, Wizzard PR, Turner JM, Wales PW. Association between 4%-tetrasodium EDTA and sepsis in neonatal piglets: A retrospective cohort study. JPEN J Parenter Enteral Nutr 2024; 48:495-501. [PMID: 38400572 DOI: 10.1002/jpen.2609] [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: 06/15/2023] [Revised: 01/10/2024] [Accepted: 01/28/2024] [Indexed: 02/25/2024]
Abstract
BACKGROUND Central line-associated bloodstream infections are a major concern for children with intestinal failure and in animal research using parenteral nutrition (PN). In neonatal piglets receiving PN, we compared sepsis, line occlusions, line replacements, mortality, and costs with and without the use of a 4%-tetrasodium ethylenediaminetetraacetic acid (T-EDTA) locking solution. METHODS We performed a retrospective review of piglets with a central venous jugular catheter enrolled in 14-day exclusive PN (TPN) trials or in 7-day short bowel syndrome (SBS) trials, before and after initiation of T-EDTA. Lines were locked with a 1-ml solution for 2 h daily (T-EDTATPN, n = 17; T-EDTASBS, n = 48) and compared with our prior standard of care using 1.5-ml heparin flushes twice daily (CONTPN, n = 34; CONSBS, n = 48). Line patency and signs of sepsis were checked twice daily. Jugular catheters were replaced for occlusions whenever possible. Humane end points were used for sepsis not responding to antibiotic treatment or unresolved catheter occlusions. RESULTS Compared with CON, sepsis was reduced using T-EDTA, significantly for TPN (P = 0.006) and with a trend for SBS piglets (P = 0.059). Line occlusions necessitating line changes were reduced 15% in TPN studies (P = 0.16), and no line occlusions occurred for T-EDTA SBS piglets. CONCLUSION In our neonatal piglet research, use of T-EDTA locking solution decreased sepsis and, although not statistically significant, reduced occlusions requiring line replacements. Given the expense of animal research, adding a locking solution must be cost-effective, and we were able to show that T-EDTA significantly reduced total research costs and improved animal welfare.
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Affiliation(s)
- Mirielle L Pauline
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Evan Labonne
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Pamela R Wizzard
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Justine M Turner
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Paul W Wales
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
- Cincinnati Center of Excellence in Intestinal Rehabilitation (CinCEIR), Cincinnati, Ohio, USA
- Department of Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
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11
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Hale SJM, Cameron AJ, Lux CA, Biswas K, Kim R, O'Carroll M, Harris PWR, Douglas RG, Wagner Mackenzie B. Polymyxin B and ethylenediaminetetraacetic acid act synergistically against Pseudomonas aeruginosa and Staphylococcus aureus. Microbiol Spectr 2024; 12:e0170923. [PMID: 38168683 PMCID: PMC10845947 DOI: 10.1128/spectrum.01709-23] [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: 04/25/2023] [Accepted: 10/05/2023] [Indexed: 01/05/2024] Open
Abstract
Polymyxin B and ethylenediaminetetraacetic acid are antimicrobials possessing antibiofilm activity. They act by displacement and chelation, respectively, of divalent cations in bacterial membranes and may therefore act synergistically when applied in combination. If so, this combination of agents may be useful for the treatment of diseases like cystic fibrosis (CF), in which biofilms are present on the respiratory epithelium. We used checkerboard assays to investigate the synergy between these agents using reference strains Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 6538 in planktonic form. We then determined the efficacy of each agent against biofilms of both species grown on 96-pin lids and proceeded to combination testing against the P. aeruginosa reference strain and 10 clinical isolates from patients with CF. Synergism was observed for planktonic forms of both species and for biofilms of P. aeruginosa. The susceptibility of biofilms of P. aeruginosa clinical isolates to these agents was variable compared to the laboratory reference strain. This combination of agents may be useful in the management of biofilm-associated conditions, particularly those amenable to topical therapies. These results provide a basis upon which the antimicrobial and antibiofilm efficacy of preparations containing these agents may be enhanced.IMPORTANCEBacteria living in biofilms produce a protective matrix which makes them difficult to kill. Patients with severe respiratory disease often have biofilms. Polymyxin B is an antibiotic commonly used in topical medications, such as eye drops and nasal sprays. Ethylenediaminetetraacetic acid (EDTA) is used widely as a preservative in medication but also has antimicrobial properties. It has been hypothesized that Polymyxin B and EDTA could have a synergistic relationship: when used in combination their antimicrobial effect is enhanced. Here, we evaluated the levels at which Polymyxin B and EDTA work together to kill common pathogens Pseudomonas aeruginosa and Staphylococcus aureus. We found that Polymyxin B and EDTA were synergistic. This synergy may be useful in the management of planktonic infection with P. aeruginosa and S. aureus, or biofilm infection with P. aeruginosa. This synergy may be beneficial in the treatment of respiratory biofilms, in which P. aeruginosa biofilms are common.
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Affiliation(s)
- Samuel J M Hale
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand
| | - Alan J Cameron
- School of Chemical Sciences and School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
| | - Christian A Lux
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand
| | - Kristi Biswas
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand
| | - Raymond Kim
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand
| | - Mark O'Carroll
- Respiratory Services, Auckland City Hospital, Te Toka Tumai, Te Whatu Ora, Auckland, New Zealand
| | - Paul W R Harris
- School of Chemical Sciences and School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand
| | - Richard G Douglas
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand
| | - Brett Wagner Mackenzie
- Department of Surgery, Faculty of Medical and Health Sciences, The University of Auckland, Grafton, Auckland, New Zealand
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12
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Gattini D, Yan H, Belza C, Avitzur Y, Wales PW. Cost-utility analysis of 4% tetrasodium ethylenediaminetetraacetic acid, taurolidine, and heparin lock to prevent central line-associated bloodstream infections in children with intestinal failure. JPEN J Parenter Enteral Nutr 2024; 48:47-56. [PMID: 37465871 DOI: 10.1002/jpen.2551] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 07/17/2023] [Accepted: 07/17/2023] [Indexed: 07/20/2023]
Abstract
BACKGROUND Central line-associated bloodstream infections (CLABSI) are a serious complication in children with intestinal failure. This study assessed the incremental costs of 4% tetrasodium ethylenediaminetetraacetic acid (EDTA) compared with taurolidine lock and heparin lock per quality-adjusted life-year (QALY) gained in children with intestinal failure from the healthcare payer and societal perspective. METHODS A Markov cohort model of a 1-year-old child with intestinal failure was simulated until the age of 17 years (time horizon), with a cycle length of 1 month. The health outcome measure was QALYs, with results expressed in terms of incremental costs and QALYs. Model parameters were obtained from published literature and institutional data. Deterministic, probabilistic, and scenario sensitivity analyses were performed. RESULTS 4% Tetrasodium EDTA was dominant (more effective and less expensive) compared with taurolidine and heparin, yielding an additional 0.17 QALYs with savings of CAD$88,277 compared with heparin, and an additional 0.06 QALYs with savings of CAD$52,120 compared with taurolidine lock from the healthcare payer perspective. From the societal perspective, 4% tetrasodium EDTA resulted in savings of CAD$90,696 compared with heparin and savings of CAD$36,973 compared with taurolidine lock. CONCLUSIONS This model-based analysis indicates that 4% tetrasodium EDTA can be considered the optimal strategy compared with taurolidine and heparin in terms of cost-effectiveness. The decision uncertainty can be reduced by conducting further research on the model input parameters. An expected value of perfect information analysis can identify what model input parameters would be most valuable to focus on.
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Affiliation(s)
- Daniela Gattini
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Division of Gastroenterology, Hepatology & Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Group for Improvement of Intestinal Function and Treatment, Transplant and Regenerative Medicine Centre, Toronto, Ontario, Canada
| | - Han Yan
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Christina Belza
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Group for Improvement of Intestinal Function and Treatment, Transplant and Regenerative Medicine Centre, Toronto, Ontario, Canada
| | - Yaron Avitzur
- Division of Gastroenterology, Hepatology & Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
- Group for Improvement of Intestinal Function and Treatment, Transplant and Regenerative Medicine Centre, Toronto, Ontario, Canada
| | - Paul W Wales
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
- Division of General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, University of Toronto, Cincinnati, Ohio, United States
- Cincinnati Center of Excellence for Intestinal Rehabilitation, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
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13
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Takashima M, Ezure Y, Furuya-Kanamori L, Wolf J, Dufficy M, Gibson V, Clark J, Ullman A. Pediatric Central Venous Access Device Lock Solutions: A Network Meta-analysis. Pediatrics 2024; 153:e2023063264. [PMID: 38287882 DOI: 10.1542/peds.2023-063264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2023] [Indexed: 01/31/2024] Open
Abstract
CONTEXT Central venous access device (CVAD) locks are routine interventions used to prevent and treat complications, such as infection, thrombosis, and catheter occlusion. OBJECTIVE To compare and rank lock-solutions for prevention or treatment of complications in pediatrics. Design Systematic review and network meta-analysis. DATA SOURCES Five databases and 2 clinical trial registries were searched. STUDY SELECTION Published and unpublished randomized controlled trials that enrolled pediatric patients with a CVAD and compared the effectiveness of lock-solutions. DATA EXTRACTION Data extraction was conducted by 2 reviewers. Odds ratio (OR) for prevention or treatment of CVAD-associated bloodstream infection (BSI), thrombosis, occlusion, CVAD-failure, and mortality were calculated, with point estimates ranking lock-solutions. RESULTS Twenty-nine studies were included. Chelating agents and antibiotic locks given as prevention were associated with lower odds (OR: 0.11; 95% confidence interval [CI]: 0.02-0.67; moderate-quality; OR: 0.19; 95% CI: 0.05-0.79, high-quality, respectively) of CVAD-associated BSI compared with heparinized saline (reference). Preventative thrombolytic agents had lower odds (OR: 0.64, 95% CI: 0.44-0.93; low-quality) of CVAD occlusion, whereas ethanol had higher odds (OR: 2.84, 95% CI: 1.31-6.16; high-quality) compared with heparinized saline (reference). No lock solution had effects on thrombosis prevention or treatment, CVAD-failure, CVAD-associated BSI treatment failure, or mortality. LIMITATIONS There was substantial uncertainty around the point estimates because of the limited number of studies for outcomes and study heterogeneity. More high-quality studies are needed to confirm the efficacy of lock solutions. CONCLUSIONS Chelating agents and antibiotic locks may be effective for CVAD-associated BSI prevention in pediatrics. Thrombolytic agents can be an option for CVAD occlusion prevention, whereas ethanol may not be recommended.
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Affiliation(s)
- Mari Takashima
- School of Nursing, Midwifery and Social Work, The University of Queensland, St Lucia, Queensland, Australia
- Children's Health Research Centre, The University of Queensland, St Lucia, Queensland, Australia
- Queensland Children's Hospital, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia
| | - Yukiko Ezure
- School of Public Health, The University of Queensland, Herston, Queensland, Australia
| | - Luis Furuya-Kanamori
- School of Public Health, The University of Queensland, Herston, Queensland, Australia
| | - Joshua Wolf
- Department of Infectious Diseases, St Jude Children's Research Hospital, Tennessee
- Department of Pediatrics, University of Tennessee Health Science Center, Tennessee
| | - Mitchell Dufficy
- School of Nursing, Midwifery and Social Work, The University of Queensland, St Lucia, Queensland, Australia
| | - Victoria Gibson
- School of Nursing, Midwifery and Social Work, The University of Queensland, St Lucia, Queensland, Australia
| | | | - Amanda Ullman
- School of Nursing, Midwifery and Social Work, The University of Queensland, St Lucia, Queensland, Australia
- Children's Health Research Centre, The University of Queensland, St Lucia, Queensland, Australia
- Queensland Children's Hospital, Children's Health Queensland Hospital and Health Service, Brisbane, Queensland, Australia
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Horowitz RI, Fallon J, Freeman PR. Comparison of the Efficacy of Longer versus Shorter Pulsed High Dose Dapsone Combination Therapy in the Treatment of Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome with Bartonellosis and Associated Coinfections. Microorganisms 2023; 11:2301. [PMID: 37764145 PMCID: PMC10537894 DOI: 10.3390/microorganisms11092301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 08/27/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Twenty-five patients with relapsing and remitting Borreliosis, Babesiosis, and bartonellosis despite extended anti-infective therapy were prescribed double-dose dapsone combination therapy (DDDCT), followed by one or several courses of High Dose Dapsone Combination Therapy (HDDCT). A retrospective chart review of these 25 patients undergoing DDDCT therapy and HDDCT demonstrated that 100% improved their tick-borne symptoms, and patients completing 6-7 day pulses of HDDCT had superior levels of improvement versus 4-day pulses if Bartonella was present. At the completion of treatment, 7/23 (30.5%) who completed 8 weeks of DDDCT followed by a 5-7 day pulse of HDDCT remained in remission for 3-9 months, and 3/23 patients (13%) who recently finished treatment were 1 ½ months in full remission. In conclusion, DDDCT followed by 6-7 day pulses of HDDCT could represent a novel, effective anti-infective strategy in chronic Lyme disease/Post Treatment Lyme Disease Syndrome (PTLDS) and associated co-infections, including Bartonella, especially in individuals who have failed standard antibiotic protocols.
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Affiliation(s)
- Richard I. Horowitz
- Lyme and Tick-Borne Diseases Working Group, New York State Department of Health, Albany, NY 12224, USA
- Hudson Valley Healing Arts Center, Hyde Park, NY 12538, USA; (J.F.); (P.R.F.)
| | - John Fallon
- Hudson Valley Healing Arts Center, Hyde Park, NY 12538, USA; (J.F.); (P.R.F.)
| | - Phyllis R. Freeman
- Hudson Valley Healing Arts Center, Hyde Park, NY 12538, USA; (J.F.); (P.R.F.)
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15
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Wong DG, Shiang A, Ostergar A, Sands KG. Enhanced popcorning using polyanionic chelating solutions as irrigation. Urolithiasis 2023; 51:90. [PMID: 37351653 DOI: 10.1007/s00240-023-01464-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 06/12/2023] [Indexed: 06/24/2023]
Abstract
Poly-anionic compounds can chelate divalent cations and dissolve calcium oxalate stone. Our objective was to assess how much concurrent irrigation with poly-anionic chelating solutions during non-contact laser lithotripsy or popcorning could improve stone ablation rate. A popcorning model was created by lowering a ureteroscope with thulium fiber laser into a test tube calyx. Begostones of matching size and mass were placed in the test tube and treated with the laser while irrigating with different iso-osmolar poly-anionic solutions. We compared 0.9% sodium chloride (NaCl), sodium citrate, sodium hexa-metaphosphate, and sodium ethylenediaminetetraacetate (EDTA) solutions. After treatment, residual stones were passed through a 1 mm sieve, and remaining fragments greater than 1 mm were weighed as remaining stone mass. Average remaining stone mass after lithotripsy with NaCl irrigation was 27.8% (± 10.0%). The average remaining stone mass after lithotripsy with hexa-metaphosphate, sodium citrate, and EDTA irrigation was 28.9% (± 13.4%), 17.5% (± 10.5%), and 9.8% (± 5.7%) respectively. Compared with NaCl, there was a 37% reduction in remaining stone mass when using citrate (p = 0.008) and a 64.7% reduction when using EDTA irrigation during lithotripsy (p < 0.001). Concurrent irrigation with citrate or EDTA solutions synergistically enhances the efficacy laser lithotripsy in this in vitro popcorning model. This may lead to tangible improvements in endoscopic stone removal outcomes; however, the effectiveness on different stone types and safety during short duration lithotripsy should be further investigated.
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Affiliation(s)
- Daniel G Wong
- Division of Urological Surgery, Department of Surgery, Washington University in St Louis School of Medicine, 4960 Children's Place, Campus Box 8242, St. Louis, MO, 63110, USA.
| | - Alexander Shiang
- Division of Urological Surgery, Department of Surgery, Washington University in St Louis School of Medicine, 4960 Children's Place, Campus Box 8242, St. Louis, MO, 63110, USA
| | - Adam Ostergar
- Division of Urological Surgery, Department of Surgery, Washington University in St Louis School of Medicine, 4960 Children's Place, Campus Box 8242, St. Louis, MO, 63110, USA
| | - Kenneth G Sands
- Division of Urological Surgery, Department of Surgery, Washington University in St Louis School of Medicine, 4960 Children's Place, Campus Box 8242, St. Louis, MO, 63110, USA
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16
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Hindieh P, Yaghi J, Khoury AE, Chokr A, Atoui A, Louka N, Assaf JC. Lactobacillus rhamnosus and Staphylococcus epidermidis in gut microbiota: in vitro antimicrobial resistance. AMB Express 2022; 12:128. [PMID: 36190582 PMCID: PMC9530110 DOI: 10.1186/s13568-022-01468-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 09/21/2022] [Indexed: 11/10/2022] Open
Abstract
The gastrointestinal tract is one of the most complex microbiological niches containing beneficial and non-pathogenic bacterial strains of which some may evolve into virulent under specific conditions. Lactobacillus rhamnosus GG is of the most known beneficial species with an ability to protect the intestine as opposed to Staphylococcus epidermidis 444 which causes serious health risks due to its high antimicrobial resistance. This study investigates first the survival and coexistence ability of L. rhamnosus GG, and S. epidermidis 444 at different pH levels. Subsequently, lysozyme's antimicrobial and antibiofilm effect on these two strains was elucidated before adding different concentrations of oxytetracycline hydrochloride antibiotic. Results showed that 50% inhibition of L. rhamnosus GG, S. epidermidis 444, and a co-culture of these planktonic strains were obtained respectively at a lysozyme concentration of 30, 18, and 26 mg/mL after the addition of ethylenediamine tetra-acetic acid (EDTA). At a pH of 7.5, mixing lysozyme (at IC50) and EDTA with oxytetracycline hydrochloride (700 μg/mL) showed an additional bactericidal effect as compared to its known bacteriostatic effect. Similarly, the addition of lysozyme to the antibiotic further increased the biofilm eradication of S. epidermidis 444 and L. rhamnosus GG where a maximal eradication of 70% was reached. Therefore, the potential development of new drugs based on adding a lysozyme-EDTA mixture to different types of antibiotics may be highly promising.
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Affiliation(s)
- Pamela Hindieh
- Centre d'Analyses et de Recherche (CAR), Unité de Recherche TVA/Résistance aux Antibiotiques et Impact Industriel (RAII), Faculté des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon.,Laboratoire de Mycologie Et Sécurité Des Aliments (LMSA), Faculté Des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon.,Ecole Doctorale "Sciences Et Santé", Université Saint-Joseph de Beyrouth, Campus des Sciences Médicales et Infirmières, Riad El Solh, Beirut, Lebanon
| | - Joseph Yaghi
- Centre d'Analyses et de Recherche (CAR), Unité de Recherche TVA/Résistance aux Antibiotiques et Impact Industriel (RAII), Faculté des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon.,Laboratoire de Mycologie Et Sécurité Des Aliments (LMSA), Faculté Des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon
| | - André El Khoury
- Centre d'Analyses et de Recherche (CAR), Unité de Recherche TVA/Résistance aux Antibiotiques et Impact Industriel (RAII), Faculté des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon.,Laboratoire de Mycologie Et Sécurité Des Aliments (LMSA), Faculté Des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon
| | - Ali Chokr
- Research Laboratory of Microbiology (RLM), Department of Life and Earth Sciences, Faculty of Sciences I, Lebanese University, Hadat Campus, Beirut, Lebanon.,Platform of Research and Analysis in Environmental Sciences (PRASE), Doctoral School of Sciences and Technologies, Lebanese University, Hadat Campus, Beirut, Lebanon
| | - Ali Atoui
- Research Laboratory of Microbiology (RLM), Department of Life and Earth Sciences, Faculty of Sciences I, Lebanese University, Hadat Campus, Beirut, Lebanon
| | - Nicolas Louka
- Centre d'Analyses et de Recherche (CAR), Unité de Recherche TVA/Résistance aux Antibiotiques et Impact Industriel (RAII), Faculté des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon
| | - Jean Claude Assaf
- Centre d'Analyses et de Recherche (CAR), Unité de Recherche TVA/Résistance aux Antibiotiques et Impact Industriel (RAII), Faculté des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon. .,Laboratoire de Mycologie Et Sécurité Des Aliments (LMSA), Faculté Des Sciences, Université Saint-Joseph de Beyrouth, Campus des sciences et technologies, Mar Roukos, Matn, Lebanon.
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17
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Duval V, Dunn M, Vachon C. Use of tetrasodium EDTA acid for the treatment of intraluminal obstruction of subcutaneous ureteral bypass devices. J Feline Med Surg 2022; 24:e330-e337. [PMID: 35762269 PMCID: PMC9511240 DOI: 10.1177/1098612x221107795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES The aim of this study was to evaluate the efficacy and tolerability of a 4% tetrasodium EDTA (tEDTA) infusion protocol in the subcutaneous ureteral bypass (SUB) devices of cats with intraluminal obstruction at a veterinary teaching hospital between July 2017 and April 2020. METHODS This was a retrospective controlled study. Cats with an obstructed SUB device underwent a 4% tEDTA infusion protocol. Obstruction of the device was diagnosed based on renal pelvic dilation, dilatation of the ureter, mineralized material within the device (cystostomy or nephrostomy catheters) seen on ultrasound, the absence of visible bubbles within the renal pelvis and/or urinary bladder following ultrasound-guided flushing of the device with saline. RESULTS A total of 16 tEDTA infusion protocols were performed in 14 cats. The infusion protocol was considered successful in 11/16 SUB devices (68.8%). Six devices (n = 6/11; 54.5%) had recurrence of obstruction with a median time of 87 days. One or more episodes of self-limiting pollakiuria and/or hematuria following infusion was seen in eight patients (n = 8/14; 57.1%). CONCLUSIONS AND RELEVANCE Infusions of 4% tEDTA successfully relieved intraluminal obstruction in patients with occluded SUB devices; however, the recurrence of obstruction was common. Additional studies evaluating case selection and optimal protocols are warranted.
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Affiliation(s)
- Valerie Duval
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montréal, Saint-Hyacinthe, QC, Canada
| | - Marilyn Dunn
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montréal, Saint-Hyacinthe, QC, Canada
| | - Catherine Vachon
- Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Montréal, Saint-Hyacinthe, QC, Canada
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18
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Ornowska M, Wong H, Ouyang Y, Mitra A, White A, Willems S, Wittmann J, Reynolds S. Control of Line Complications with KiteLock (CLiCK) in the critical care unit: study protocol for a multi-center, cluster-randomized, double-blinded, crossover trial investigating the effect of a novel locking fluid on central line complications in the critical care population. Trials 2022; 23:719. [PMID: 36042488 PMCID: PMC9425798 DOI: 10.1186/s13063-022-06671-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 08/18/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Insertion of a central venous access device (CVAD) allows clinicians to easily access the circulation of a patient to administer life-saving interventions. Due to their invasive nature, CVADs are prone to complications such as bacterial biofilm production and colonization, catheter-related bloodstream infection, occlusion, and catheter-related venous thrombosis. A CVAD is among the most common interventions for patients in the intensive care unit (ICU), exposing this vulnerable population to the risk of nosocomial infection and catheter occlusion. The current standard of care involves the use of normal saline as a catheter locking solution for central venous catheters (CVCs) and peripherally inserted central catheter (PICC) lines, and a citrate lock for hemodialysis catheters. Saline offers little prophylactic measures against catheter complications. Four percent of tetrasodium ethylenediaminetetraacetic acid (EDTA) fluid (marketed as KiteLock Sterile Locking Solution™) is non-antibiotic, possesses antimicrobial, anti-biofilm, and anti-coagulant properties, and is approved by Health Canada as a catheter locking solution. As such, it may be a superior CVAD locking solution than the present standard of care lock in the ICU patient population. METHODS Our team proposes to fill this knowledge gap by performing a multi-center, cluster-randomized, crossover trial evaluating the impact of 4% tetrasodium EDTA on a primary composite outcome of the incidence rate of central line-associated bloodstream infection (CLABSI), catheter occlusion leading to removal, and use of alteplase to resolve catheter occlusion compared to the standard of care. The study will be performed at five critical care units. DISCUSSION If successful, the results of this study can serve as evidence for a shift of standard of care practices to include EDTA locking fluid in routine CVAD locking procedures. Completion of this study has the potential to improve CVAD standard of care to become safer for patients, as well as provides an opportunity to decrease strain on healthcare budgets related to treating preventable CVAD complications. Success and subsequent implementation of this intervention in the ICU may also be extrapolated to other patient populations with heavy CVAD use including hemodialysis, oncology, parenteral nutrition, and pediatric patient populations. On a global scale, eradicating biofilm produced by antibiotic-resistant bacteria may serve to lessen the threat of "superbugs" and contribute to international initiatives supporting the termination of antibiotic overuse. TRIAL REGISTRATION ClinicalTrials.gov NCT04548713, registered on September 9th, 2020.
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Affiliation(s)
| | - Hubert Wong
- Center for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, Canada
| | - Yongdong Ouyang
- Center for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, Canada
| | - Anish Mitra
- University of British Columbia, Vancouver, Canada
- Fraser Health Authority, Surrey, Canada
| | - Aaron White
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada
| | | | | | - Steven Reynolds
- Simon Fraser University, Burnaby, Canada
- University of British Columbia, Vancouver, Canada
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Hale SJM, Wagner Mackenzie B, Lux CA, Biswas K, Kim R, Douglas RG. Topical Antibiofilm Agents With Potential Utility in the Treatment of Chronic Rhinosinusitis: A Narrative Review. Front Pharmacol 2022; 13:840323. [PMID: 35770097 PMCID: PMC9234399 DOI: 10.3389/fphar.2022.840323] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
The role of bacterial biofilms in chronic and recalcitrant diseases is widely appreciated, and the treatment of biofilm infection is an increasingly important area of research. Chronic rhinosinusitis (CRS) is a complex disease associated with sinonasal dysbiosis and the presence of bacterial biofilms. While most biofilm-related diseases are associated with highly persistent but relatively less severe inflammation, the presence of biofilms in CRS is associated with greater severity of inflammation and recalcitrance despite appropriate treatment. Oral antibiotics are commonly used to treat CRS but they are often ineffective, due to poor penetration of the sinonasal mucosa and the inherently antibiotic resistant nature of bacteria in biofilms. Topical non-antibiotic antibiofilm agents may prove more effective, but few such agents are available for sinonasal application. We review compounds with antibiofilm activity that may be useful for treating biofilm-associated CRS, including halogen-based compounds, quaternary ammonium compounds and derivatives, biguanides, antimicrobial peptides, chelating agents and natural products. These include preparations that are currently available and those still in development. For each compound, antibiofilm efficacy, mechanism of action, and toxicity as it relates to sinonasal application are summarised. We highlight the antibiofilm agents that we believe hold the greatest promise for the treatment of biofilm-associated CRS in order to inform future research on the management of this difficult condition.
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Affiliation(s)
- Samuel J M Hale
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Brett Wagner Mackenzie
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Christian A Lux
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Kristi Biswas
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Raymond Kim
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Richard G Douglas
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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Sivaranjani M, McCarthy MC, Sniatynski MK, Wu L, Dillon JAR, Rubin JE, White AP. Biofilm Formation and Antimicrobial Susceptibility of E. coli Associated With Colibacillosis Outbreaks in Broiler Chickens From Saskatchewan. Front Microbiol 2022; 13:841516. [PMID: 35783405 PMCID: PMC9247541 DOI: 10.3389/fmicb.2022.841516] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/19/2022] [Indexed: 11/16/2022] Open
Abstract
The global poultry industry has grown to the extent that the number of chickens now well exceeds the number of humans on Earth. Escherichia coli infections in poultry cause significant morbidity and economic losses for producers each year. We obtained 94 E. coli isolates from 12 colibacillosis outbreaks on Saskatchewan farms and screened them for antimicrobial resistance and biofilm formation. Fifty-six isolates were from broilers with confirmed colibacillosis, and 38 isolates were from healthy broilers in the same flocks (cecal E. coli). Resistance to penicillins, tetracyclines, and aminoglycosides was common in isolates from all 12 outbreaks, while cephalosporin resistance varied by outbreak. Most E. coli were able to form biofilms in at least one of three growth media (1/2 TSB, M63, and BHI broth). There was an overall trend that disease-causing E. coli had more antibiotic resistance and were more likely to form biofilms in nutrient-rich media (BHI) as compared to cecal strains. However, on an individual strain basis, there was no correlation between antimicrobial resistance and biofilm formation. The 21 strongest biofilm forming strains consisted of both disease-causing and cecal isolates that were either drug resistant or susceptible. Draft whole genome sequencing indicated that many known antimicrobial resistance genes were present on plasmids, with disease-causing E. coli having more plasmids on average than their cecal counterparts. We tested four common disinfectants for their ability to kill 12 of the best biofilm forming strains. All disinfectants killed single cells effectively, but biofilm cells were more resistant, although the difference was less pronounced for the disinfectants that have multiple modes of action. Our results indicate that there is significant diversity and complexity in E. coli poultry isolates, with different lifestyle pressures affecting disease-causing and cecal isolates.
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Affiliation(s)
- Murugesan Sivaranjani
- Vaccine and Infectious Disease Organization, Saskatoon, SK, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Madeline C. McCarthy
- Vaccine and Infectious Disease Organization, Saskatoon, SK, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Michelle K. Sniatynski
- Vaccine and Infectious Disease Organization, Saskatoon, SK, Canada
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Linzhi Wu
- Vaccine and Infectious Disease Organization, Saskatoon, SK, Canada
| | - Jo-Anne R. Dillon
- Vaccine and Infectious Disease Organization, Saskatoon, SK, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Joseph E. Rubin
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Aaron P. White
- Vaccine and Infectious Disease Organization, Saskatoon, SK, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
- *Correspondence: Aaron P. White,
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Bakht M, Alizadeh SA, Rahimi S, Kazemzadeh Anari R, Rostamani M, Javadi A, Peymani A, Marashi SMA, Nikkhahi F. Phenotype and genetic determination of resistance to common disinfectants among biofilm-producing and non-producing Pseudomonas aeruginosa strains from clinical specimens in Iran. BMC Microbiol 2022; 22:124. [PMID: 35525944 PMCID: PMC9078005 DOI: 10.1186/s12866-022-02524-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 04/11/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Pseudomonas aeruginosa is a common pathogen in Hospitalized patients, and its various resistance mechanisms contribute to patient morbidity and mortality. The main aims of the present study were to assess the susceptibility of biofilm-producing and non-producing P. aeruginosa isolates to the five commonly used Hospital disinfectants, to evaluate the synergistic effect of selected disinfectants and Ethylene-diamine-tetra acetic acid (EDTA), and the effect of exposure to sub-inhibitory concentrations of Sodium hypochlorite on antimicrobial susceptibility test. RESULTS The results showed that sodium hypochlorite 5% and Ethanol 70% were the most and least effective disinfectants against P. aeruginosa, respectively. The addition of EDTA significantly increased the effectiveness of the selected disinfectants. The changes in the antibiotic-resistance profiles after exposure to sub-inhibitory concentrations of disinfectants were observed for different classes of antibiotics (Carbapenems, Aminoglycosides, Cephalosporins, Fluoroquinolones). As well as near the all isolates harbored efflux pump genes and 117 (97.5%) of isolates produced biofilm. CONCLUSION In the current study, the mixture of disinfectant and EDTA were the most suitable selection to disinfect Hospital surfaces and instruments. Also, it was clear that exposure to sub-inhibitory concentrations of Sodium hypochlorite results in resistance to some antibiotics in P. aeruginosa species. Strong and intermediate biofilm formers belonged to MDR/XDR strains. Future studies should include more complex microbial communities residing in the Hospitals, and more disinfectants use in Hospitals.
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Affiliation(s)
- Mehdi Bakht
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Safar Ali Alizadeh
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Sara Rahimi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Raana Kazemzadeh Anari
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohammad Rostamani
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Javadi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
- Department of Community Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Amir Peymani
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Farhad Nikkhahi
- Medical Microbiology Research Center, Qazvin University of Medical Sciences, Qazvin, Iran.
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22
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Wales A, Taylor E, Davies R. Review of food grade disinfectants that are permitted for use in egg packing centres. WORLD POULTRY SCI J 2021. [DOI: 10.1080/00439339.2022.1990741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Andrew Wales
- Department of Pathology and Infectious Diseases, School of Veterinary Medicine, University of Surrey, Guildford, UK
| | - Emma Taylor
- Department of Bacteriology, Animal and Plant Health Agency, Addlestone, Surrey, UK
| | - Robert Davies
- Department of Bacteriology, Animal and Plant Health Agency, Addlestone, Surrey, UK
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Eradication of Candida albicans Biofilm Viability: In Vitro Combination Therapy of Cationic Carbosilane Dendrons Derived from 4-Phenylbutyric Acid with AgNO 3 and EDTA. J Fungi (Basel) 2021; 7:jof7070574. [PMID: 34356953 PMCID: PMC8305162 DOI: 10.3390/jof7070574] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 01/18/2023] Open
Abstract
Candida albicans is a human pathogen of significant clinical relevance. This pathogen is resistant to different drugs, and most clinical antifungals are not effective against the prevention and treatment of C. albicans infections. As with other microorganisms, it can produce biofilms that serve as a barrier against antifungal agents and other substances, contributing to infection in humans and environmental tolerance of this microorganism. Thus, resistances and biofilm formation make treatment difficult. In addition, the complete eradication of biofilms in implants, catheters and other medical devices, is challenging and necessary to prevent relapses of candidemia. Therefore, it is a priority to find new molecules or combinations of compounds with anti-Candida biofilm activity. Due to the difficulty of treating and removing biofilms, the aim of this study was to evaluate the in vitro ability of different generation of cationic carbosilane dendrons derived from 4-phenylbutyric acid, ArCO2Gn(SNMe3I)m, to eradicate C. albicans biofilms. Here, we assessed the antifungal activity of the second generation dendron ArCO2G2(SNMe3I)4 against C. albicans cells and established biofilms since it managed to seriously damage the membrane. In addition, the combinations of the second generation dendron with AgNO3 or EDTA eradicated the viability of biofilm cells. Alterations were observed by scanning electron microscopy and cytotoxicity was assessed on HeLa cells. Our data suggest that the dendritic compound ArCO2G2(SNMe3I)4 could represent an alternative to control the infections caused by this pathogen.
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24
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Deprey J, Baldinger A, Livet V, Blondel M, Taroni M, Lefebvre C, Goy-Thollot I, Moissonnier P, Viguier É, Pouzot-Nevoret C, Carozzo C, Cachon T. Risk factors and clinical relevance of positive urine cultures in cats with subcutaneous ureteral bypass. BMC Vet Res 2021; 17:199. [PMID: 34044828 PMCID: PMC8157650 DOI: 10.1186/s12917-021-02898-7] [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: 07/10/2020] [Accepted: 05/06/2021] [Indexed: 11/10/2022] Open
Abstract
Background The objective of the study was to report the incidence and risk factors associated with positive urine bacterial cultures as well as long-term outcome in cats with subcutaneous ureteral bypass (SUB) devices. Results Medical records of cats that underwent SUB device placement were retrospectively reviewed. Signalment of the cat, laterality of the ureteral obstruction, surgery, anesthesia and hospitalization duration, bacterial culture results and follow-up data were retrieved. Thirty-two cats met the inclusion criteria. Four cats (12.5%) had a positive intraoperative culture, with two of them being treated successfully. Ten cats out of 28 (35.7%) were documented with a positive urine culture during follow-up period, with a median time between discharge and identification of the first positive urine culture of 159 days (range 8–703 days). Bacteriuria resolved in 60% of cats (6/10). Escherichia coli was the most common organism, isolated in 4 out of 10 postoperative urine cultures. Overall, subclinical bacteriura was documented for 6 of 32 (18.8%) cats and 5 of 32 (15.6%) cats displayed clinicals signs suggestive of persistent UTI. One cat had subclinical bacteriuria. Three cats died during the follow-up period. There was a significant difference between negative and positive urine bacterial culture groups in median hospitalization duration (5 days versus 6 days, P = 0.022) and in median body condition score (5/9 versus 4/9, P = 0.03). Cats with a longer hospital stay and with a lower body condition score were more likely to have a positive urine culture during follow-up period. Conclusions SUB device placement surgery is associated with complications such as chronic bacteriuria. Bacteriuria in our study resolved with appropriate antibiotic treatment in more than half of cats. Risk factors identified for positive urine culture were a longer hospitalization duration and a decreased body condition score.
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Affiliation(s)
- Julie Deprey
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France. .,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France.
| | - Arnaud Baldinger
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Véronique Livet
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Margaux Blondel
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Mathieu Taroni
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Cynthia Lefebvre
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France
| | - Isabelle Goy-Thollot
- Intensive Care Unit (SIAMU), Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France.,Université de Lyon, Veterinary Campus of VetAgro Sup, APCSe, F-69280, Marcy l'Etoile, France
| | - Pierre Moissonnier
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Éric Viguier
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Céline Pouzot-Nevoret
- Intensive Care Unit (SIAMU), Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France.,Université de Lyon, Veterinary Campus of VetAgro Sup, APCSe, F-69280, Marcy l'Etoile, France
| | - Claude Carozzo
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
| | - Thibaut Cachon
- Department of Small Animal Surgery, Vetagro Sup, Campus Vétérinaire de Lyon, Marcy l'Etoile, France.,Research Unit ICE, UPSP 2011.03.101, Université de Lyon, Veterinary Campus of VetAgro Sup, Marcy l'Etoile, France
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25
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Talathi S, Mezoff E, Galloway D, Rahhal R. Anticipated impact of recent ethanol lock shortage and price increase on practice among pediatric intestinal rehabilitation programs across the United States. JPEN J Parenter Enteral Nutr 2021; 46:319-323. [PMID: 33914379 DOI: 10.1002/jpen.2128] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND Ethanol lock use has been associated with significantly lower rates of central line-associated bloodstream infection (CLABSI) in children with intestinal failure. Concerns have been raised among intestinal rehabilitation program providers regarding the impact of recent changes in cost and availability of ethanol locks in the US. METHODS We conducted a survey among the members of the North American Society For Pediatric Gastroenterology, Hepatology & Nutrition Intestinal Rehabilitation Special Interest Group (NASPGHAN IR-SIG) regarding practice changes among providers to tackle this issue and the anticipated effect on CLABSI rates. RESULTS The results show that the vast majority of US participants use ethanol locks in their population with intestinal failure, with most anticipating or already experiencing reduction in access to ethanol locks. Most worrisome is that more than half of participating programs expect an increase in CLABSI rates in this vulnerable patient population as a consequence of limited access to ethanol locks. CONCLUSION Further multicenter prospective studies to assess the efficacy of alternative locking agents, besides ethanol, are needed in order to have readily available and affordable options for CLABSI prevention in the future.
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Affiliation(s)
- Saurabh Talathi
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, OU Center for Pediatric Intestinal Rehabilitation, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Ethan Mezoff
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Center for Intestinal Rehabilitation and Nutrition Support, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - David Galloway
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Riad Rahhal
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Iowa, Iowa City, Iowa, USA
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26
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Abstract
Biofilms are aggregates formed as a protective survival state by microorganisms to adapt to the environment and can be resistant to antimicrobial agents and host immune responses due to chemical or physical diffusion barriers, modified nutrient environments, suppression of the growth rate within biofilms, and the genetic adaptation of cells within biofilms. With the widespread use of medical devices, medical device-associated biofilms continue to pose a serious threat to human health, and these biofilms have become the most important source of nosocomial infections. However, traditional antimicrobial agents cannot completely eliminate medical device-associated biofilms. New strategies for the treatment of these biofilms and targeting biofilm infections are urgently required. Several novel approaches have been developed and identified as effective and promising treatments. In this review, we briefly summarize the challenges associated with the treatment of medical device-associated biofilm infections and highlight the latest promising approaches aimed at preventing or eradicating these biofilms.
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27
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Sivaranjani M, Liu F, White AP. Synergistic activity of tetrasodium EDTA, ethanol and chlorhexidine hydrochloride against planktonic and biofilm cells of clinically relevant pathogens. J Glob Antimicrob Resist 2020; 24:148-157. [PMID: 33383260 DOI: 10.1016/j.jgar.2020.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/12/2020] [Accepted: 12/08/2020] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Biofilms associated with implantable medical devices and wounds are clinically relevant, often requiring repeated use of antibiotics without success. A search for non-antibiotic antimicrobial and antibiofilm solutions is warranted, in line with antimicrobial stewardship. Our study aimed to evaluate the broad-spectrum antimicrobial efficacy of tetrasodium EDTA, ethanol and chlorhexidine hydrochloride (HCl) alone and in combination against clinically relevant planktonic and biofilm cells of bacterial and fungal pathogens. METHODS MICs and MBCs were determined for tetrasodium EDTA, ethanol and chlorhexidine HCl against planktonic cells of test pathogens. The MBEC Assay® biofilm inoculator device was used to evaluate the biofilm eradication ability of test antimicrobials alone and in combination against clinically relevant pathogens. The checkerboard microbroth dilution assay was performed to analyze the synergism between test antimicrobials. RESULTS Against planktonic cells, the combination of tetrasodium EDTA with ethanol or chlorhexidine HCl resulted in synergistic to indifferent activity, with no antagonism observed. Against mature biofilms, all combinations were synergistic. The MBEC of each test antimicrobial was decreased from 4- to -64-fold when used in combination as compared to when agents were used alone. We optimised the concentration of antimicrobials to achieve rapid eradication of pre-formed biofilms. A triple combination of 3% tetrasodium EDTA, 20% ethanol and 2.5 μg/mL chlorhexidine HCl completely eradicated 48-h-old biofilms of all test strains within 2 h. CONCLUSION All three antimicrobial agents can be used together for prevention and treatment of biofilms and biofilm-related infections. The observed in vitro efficacy should be tested further through in vivo and clinical studies.
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Affiliation(s)
- Murugesan Sivaranjani
- Vaccine and Infectious Disease Organization, Saskatoon, Saskatchewan, Canada; Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Fangning Liu
- Vaccine and Infectious Disease Organization, Saskatoon, Saskatchewan, Canada
| | - Aaron P White
- Vaccine and Infectious Disease Organization, Saskatoon, Saskatchewan, Canada; Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
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Candida albicans as an Essential "Keystone" Component within Polymicrobial Oral Biofilm Models? Microorganisms 2020; 9:microorganisms9010059. [PMID: 33379333 PMCID: PMC7823588 DOI: 10.3390/microorganisms9010059] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 02/06/2023] Open
Abstract
Background: Existing standardized biofilm assays focus on simple mono-species or bacterial-only models. Incorporating Candida albicans into complex biofilm models can offer a more appropriate and relevant polymicrobial biofilm for the development of oral health products. Aims: This study aimed to assess the importance of interkingdom interactions in polymicrobial oral biofilm systems with or without C. albicans, and test how these models respond to oral therapeutic challenges in vitro. Materials and Methods: Polymicrobial biofilms (two models containing 5 and 10 bacterial species, respectively) were created in parallel in the presence and absence of C. albicans and challenged using clinically relevant antimicrobials. The metabolic profiles and biomasses of these complex biofilms were estimated using resazurin dye and crystal violet stain, respectively. Quantitative PCR was utilized to assess compositional changes in microbial load. Additional assays, for measurements of pH and lactate, were included to monitor fluctuations in virulence "biomarkers." Results: An increased level of metabolic activity and biomass in the presence of C. albicans was observed. Bacterial load was increased by more than a factor of 10 in the presence of C. albicans. Assays showed inclusion of C. albicans impacted the biofilm virulence profiles. C. albicans did not affect the biofilms' responses to the short-term incubations with different treatments. Conclusions: The interkingdom biofilms described herein are structurally robust and exhibit all the hallmarks of a reproducible model. To our knowledge, these data are the first to test the hypothesis that yeasts may act as potential "keystone" components of oral biofilms.
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29
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Hill J, Garner R. Efficacy of 4% tetrasodium ethylenediaminetetraacetic acid (T-EDTA) catheter lock solution in home parenteral nutrition patients: A quality improvement evaluation. J Vasc Access 2020; 22:533-539. [DOI: 10.1177/1129729820946916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Introduction: A functioning and reliable central venous access device is fundamental for home parenteral nutrition patients to administer essential nutrition. Complications of central venous access devices including occlusion, microbial colonization, and biofilm formation are problematic and sometimes life-threatening. A novel lock solution, 4% tetrasodium ethylenediaminetetraacetic acid, has properties that may reduce such complications. Purpose: The aim of this study was to determine the safety, efficacy, and cost implications of implementing 4% tetrasodium ethylenediaminetetraacetic acid to prevent catheter-related complications in home parenteral nutrition patients. Methods: A pre- and post-intervention study was carried over 36 months (12 months pre; 24 months post) by the British Columbia Home Parenteral Nutrition Program in Vancouver, Canada, where 4% tetrasodium ethylenediaminetetraacetic acid was implemented for patients at high risk for central venous access device occlusion and catheter-related infection. Patients were included in the study if they had previous central venous access device complications. The outcomes evaluated were central line-associated bloodstream infection, catheter occlusion requiring thrombolytic treatment, and catheter replacements. Results: In total, 22 out of 105 patients met the inclusion criteria. Two patients were excluded from analyses due to non-adherence and concomitant use of other lock solutions. Post intervention, 20 home parenteral nutrition patients experienced significant reduction in the central line-associated bloodstream infection rate (pre = 1.918/1000 catheter days; post = 0.563/1000 catheter days; p = 0.04) There were no occlusion events reported post intervention. Conclusion: For home parenteral nutrition patients, 4% tetrasodium ethylenediaminetetraacetic acid lock solution effectively reduces the risk of central venous access device complications including occlusions and catheter-related infections.
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Affiliation(s)
- Jocelyn Hill
- BC Home Parenteral Nutrition Program, St. Paul’s Hospital, Providence Health Care, Vancouver, BC, Canada
| | - Rachel Garner
- BC Home Parenteral Nutrition Program, St. Paul’s Hospital, Providence Health Care, Vancouver, BC, Canada
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30
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31
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Daoud DC, Wanten G, Joly F. Antimicrobial Locks in Patients Receiving Home Parenteral Nutrition. Nutrients 2020; 12:nu12020439. [PMID: 32050544 PMCID: PMC7071146 DOI: 10.3390/nu12020439] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/02/2020] [Accepted: 02/03/2020] [Indexed: 12/12/2022] Open
Abstract
Catheter-related bloodstream infection (CRBSI) is one of the most common and potentially fatal complications in patients receiving home parenteral nutrition (HPN). In order to prevent permanent venous access loss, catheter locking with an antimicrobial solution has received significant interest and is often a favored approach as part of the treatment of CRBSI, but mainly for its prevention. Several agents have been used for treating and preventing CRBSI, for instance antibiotics, antiseptics (ethanol, taurolidine) and, historically, anticoagulants such as heparin. Nonetheless, current guidelines do not provide clear guidance on the use of catheter locks. Therefore, this review aims to provide a better understanding of the current use of antimicrobial locking in patients on HPN as well as reviewing the available data on novel compounds. Despite the fact that our current knowledge on catheter locking is still hampered by several gaps, taurolidine and ethanol solutions seem promising for prevention and potentially, but not proven, treatment of CRBSI. Additional studies are warranted to further characterize the efficacy and safety of these agents.
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Affiliation(s)
- Dane Christina Daoud
- Department of Medicine, Division of Gastroenterology, Centre Hospitalier de l’Universite de Montreal (CHUM), Centre de Recherche du Centre Hospitalier de l’Universite de Montreal (CRCHUM), 1051 Rue Sanguinet, Montreal, Québec, H2X 3E4, Canada
- Correspondence: ; Tel.: +1-514-467-5931
| | - Geert Wanten
- Intestinal Failure Unit, Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands;
| | - Francisca Joly
- Center for Intestinal Failure, Department of Gastroenterology and Nutritional Support, Reference Centre of Rare Disease MarDI, Hopital Beaujon, University of Paris Inserm UMR 1149, 92110 Clichy, France;
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LaRusso K, Schaack G, Fung T, McGregor K, Long J, Dumas MP, Attari Z, Yousef Y, Girgis H, Raghunathan R, Sant'Anna A, Emil S. Should you pick the PICC? Prolonged use of peripherally inserted central venous catheters in children with intestinal failure. J Pediatr Surg 2019; 54:999-1004. [PMID: 30795912 DOI: 10.1016/j.jpedsurg.2019.01.052] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 01/27/2019] [Indexed: 11/30/2022]
Abstract
PURPOSE Prolonged central vascular access is a source of significant morbidity in children with intestinal failure (IF). In an effort to decrease morbidity, our multidisciplinary IF team has primarily used peripherally inserted central catheters (PICCs) for these patients. We compared outcomes of PICCs to Broviacs®. METHODS A review of children with IF (2006-2018) at an academic children's hospital was conducted. INCLUSION CRITERIA total parenteral nutrition duration >42 days or small bowel length < 25% of total for gestational age. Complications/1000 catheter days were extracted, and a Poisson model was used to compare complications between PICCs and Broviacs®. RESULTS Thirty-seven patients with IF were included, accounting for 19,452 catheter days. There were 209 PICCs (1.2-4F) and 39 Broviacs® (2.7-7F). The median duration of overall PICC access/patient was 166 days (range: 35 days-8 years). Incidences of central line associated blood stream infection and venous thrombosis were 3.95 and 0.55 per 1000 catheter days, respectively. There were no significant differences in complication rates per line per catheter day between PICCs and Broviacs® on multivariate analysis. Broviacs® showed a trend towards increased of catheter-related hospital admissions when compared to PICCs. CONCLUSIONS PICCs in children with intestinal failure have similar complication rates to Broviacs® but may reduce catheter-related hospital admissions. Use of tunneled PICCs and increasing experience with this vascular access method may allow it to realize its potential advantages. LEVEL OF EVIDENCE Retrospective study, level III.
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Affiliation(s)
- Kathryn LaRusso
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Geraldine Schaack
- Nursing Education, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Tiffany Fung
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Kevin McGregor
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada
| | - Justin Long
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Marie-Pier Dumas
- Nursing Education, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Zahia Attari
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Yasmine Yousef
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Hidy Girgis
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Rajam Raghunathan
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Ana Sant'Anna
- Division of Pediatric Gastroenterology and Nutrition, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
| | - Sherif Emil
- Division of Pediatric General and Thoracic Surgery, The Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
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