Prophylactic Antibiotic Treatment in Hemodialysis (PANTHEM)

Prophylactic Antibiotic Treatment in End Stage Kidney Disease and Central Venous Catheter as Hemodialysis Vascular Access

The purpose of this study is to assess the efficacy of prophylactic antibiotic treatment on blood stream infections and severe culture negative infections, in patients on newly started hemodialysis(HD), with a central venous catheter as vascular access.

Study Overview

• Status: Recruiting
• Conditions: Hemodialysis
• Intervention / Treatment: Drug: Amoxicillin Clavulanic 500/125mg or placebo

Detailed Description

After being informed about the study and potential risks all eligible patients, giving written informed consent will be included in the study. At week 0 patients will be randomized in a single blinded manner (participants and care providers) in a 1:1 manner to receive 500/125mg amoxicillin/clavulanic acid 30-120 minutes before each hemodialysis with a central venous catheter (CVC) as vascular access, or corresponding placebo. The timing of antibiotic administration has been established in a pilot-study in order to secure a sufficient concentration of antibiotics during the dialysis session. In case of side effects to amoxicillin/clavulanic acid, the prophylactic antibiotic will be shifted to 600mg clindamycin. Total treatment period with prophylactic antibiotics is 6 months, with a 1 year follow-up.

• Study Type: Interventional
• Enrollment (Estimated): 800
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Niels E Bruun, Professor; Phone Number: +4525159309; Email: nbru@regionsjaelland.dk
• Study Contact Backup: Name: Kasper K Iversen, Professor; Email: Kasper.Karmark.Iversen@regionh.dk

Study Locations

• Denmark
  • Capital Region
    • Copenhagen, Capital Region, Denmark, 2100
      • Not yet recruiting
      • Rigshospitalet
      • Contact: Marianne Rix, Consultant; Email: Marianne.Rix@regionh.dk
      • Contact: Anne-Lise Kamper, Consultant
    • Copenhagen, Capital Region, Denmark, 2730
      • Recruiting
      • Herlev-Gentofte Hospital
      • Contact: Henrik P Hansen, Consultant; Email: Henrik.Post.Hansen@regionh.dk
      • Contact: Kasper K Iversen, Professor
    • Hillerød, Capital Region, Denmark, 3400
      • Not yet recruiting
      • North Zealand Hospital Hillerød
      • Contact: Marianne Bertelsen, Consultant; Email: marianne.camilla.bertelsen@regionh.dk
  • Middle Region
    • Aarhus, Middle Region, Denmark, 8200
      • Not yet recruiting
      • Aarhus University Hospital
      • Contact: Jens D Jensen, Consultant; Email: jenjesen@rm.dk
  • North Region
    • Aalborg, North Region, Denmark, 9100
      • Recruiting
      • Aalborg University Hospital
      • Contact: Bo Madsen, Consultant; Email: bom@rn.dk
  • Region Sjaelland
    • Roskilde, Region Sjaelland, Denmark, 4000
      • Recruiting
      • ZUH Roskilde
      • Contact: Niels E Bruun, Professor; Phone Number: +4525159309; Email: nbru@regionsjaelland.dk
      • Contact: Rikke Borg, Consultant; Email: rbor@regionsjaelland.dk
  • Region South
    • Odense, Region South, Denmark, 5000
      • Recruiting
      • Odense University Hospital
      • Contact: Per B Jensen, Consultant; Email: Per.Bruno.Jensen@rsyd.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• End Stage Kidney Disease (ESKD) patients who receive an uncuffed or cuffed CVC for expected chronic HD, regardless of previous ESKD treatment modality (PD or KTX) and hemodialysis access (AV-fistula or AV-graft))
• ≥18 years
• Ability to understand the study background, risk and benefit of treatment and to give written informed consent

Exclusion Criteria:

• Unable to give informed consent
• Known intolerance to beta-lactam antibiotics and clindamycin
• Active infection treated with antibiotics
• Breastfeeding
• Pregnancy. In women of childbearing age, an approved birth control must be ensured at least 1 month before and during all the 6 months of antibiotic/placebo treatment.

Patients may be rescreened later i.e. within a time period of one month from start of HD, if exclusion criteria are reversible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active; Amoxicillin/clavulanic acid 500/125mg, tablets, will be administered before each hemodialysis for 6 months	Drug: Amoxicillin Clavulanic 500/125mg or placebo; Prophylactic antibiotic treatment; Other Names: Aurobindo
Placebo Comparator: Placebo; Placebo tablets, similar to the active drug, will be administered before each hemodialysis for 6 months	Drug: Amoxicillin Clavulanic 500/125mg or placebo; Prophylactic antibiotic treatment; Other Names: Aurobindo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with Blood stream infection (BSI)	Hospitalization for BSI	≤ 6 months after randomization
Number of patients with Severe blood culture negative infection	Hospitalization ≥ 3 days due to infection defined as: C-reactive protein (CRP) ≥ 75 and negative blood cultures, treated with iv antibiotics	≤ 6 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with BSI or severe blood culture negative infection	Each of the components in the primary endpoint	≤ 6 months after randomization
Mortality	All-cause mortality	≤ 6 months after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with Sepsis	Hospitalization due to sepsis or septic shock	≤ 6 months after randomization
Number of patients with Deep tissue infection	Infective endocarditis, osteomyelitis, and spondylodiscitis	≤ 6 months after randomization
Number of patients with Autoinfection	Frequency of BSI autoinfection	≤ 6 months after randomization
Number of patients with Clostridium difficile infection	Clostridium difficile infection - numbers and days of admission	≤ 6 months after randomization
Mortality due to infection - number of patients	Mortality due to infection	≤ 6 months after randomization
Number of CVC removals	CVC removal due to CVC infection	≤ 6 months after randomization
Use of Antibiotics in Difined Daily Doses	Total use of antibiotics in Defined Daily Doses	≤ 6 months after randomization
Healt-care economics	Health-care related economic consequences due to hospitalization and treatment of the disease	≤ 6 months after randomization
Number of patients with Extended Spectrum Beta-Lactamase (ESBL) infection	ESBL infections - number of patients and days of admission	≤ 6 months after randomization
Number of patients with Methicillin-resistant Staphylococcus aureus (MRSA) infection	MRSA infections - number of patients and days of admission	≤ 6 months after randomization
Number of patients with Carbapenemase-Producing Organisms (CPO) infection	CPO infections - number og patients and days of admission	≤ 6 months after randomization
Number of patients with Vancomycin-resistant enterococci (VRE) infection	VRE infections - number of patients and days of admission	≤ 6 months after randomization
Number of patients with Cardiovascular events	Hospitalization with acute myocardial infarction, worsening heart failure or stroke	≤ 6 months after randomization

Collaborators and Investigators

• Sponsor: Zealand University Hospital
• Investigators: Principal Investigator: Niels E Bruun, Professor, Dept. cardiology, Zealand University Hospital, Roskilde, Denmark

Publications and helpful links

General Publications

• Vogelzang JL, van Stralen KJ, Noordzij M, Diez JA, Carrero JJ, Couchoud C, Dekker FW, Finne P, Fouque D, Heaf JG, Hoitsma A, Leivestad T, de Meester J, Metcalfe W, Palsson R, Postorino M, Ravani P, Vanholder R, Wallner M, Wanner C, Groothoff JW, Jager KJ. Mortality from infections and malignancies in patients treated with renal replacement therapy: data from the ERA-EDTA registry. Nephrol Dial Transplant. 2015 Jun;30(6):1028-37. doi: 10.1093/ndt/gfv007. Epub 2015 Jan 29.
• de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, Collart F, Finne P, Heaf JG, De Meester J, Wetzels JF, Rosendaal FR, Dekker FW. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA. 2009 Oct 28;302(16):1782-9. doi: 10.1001/jama.2009.1488.
• Chaudry MS, Carlson N, Gislason GH, Kamper AL, Rix M, Fowler VG Jr, Torp-Pedersen C, Bruun NE. Risk of Infective Endocarditis in Patients with End Stage Renal Disease. Clin J Am Soc Nephrol. 2017 Nov 7;12(11):1814-1822. doi: 10.2215/CJN.02320317. Epub 2017 Oct 3.
• Nelveg-Kristensen KE, Laier GH, Heaf JG. Risk of death after first-time blood stream infection in incident dialysis patients with specific consideration on vascular access and comorbidity. BMC Infect Dis. 2018 Dec 20;18(1):688. doi: 10.1186/s12879-018-3594-7.
• Sakhuja A, Nanchal RS, Gupta S, Amer H, Kumar G, Albright RC, Kashani KB. Trends and Outcomes of Severe Sepsis in Patients on Maintenance Dialysis. Am J Nephrol. 2016;43(2):97-103. doi: 10.1159/000444684. Epub 2016 Mar 10.
• Gupta V, Yassin MH. Infection and hemodialysis access: an updated review. Infect Disord Drug Targets. 2013 Jun;13(3):196-205. doi: 10.2174/1871526511313030008.
• Aslam S, Vaida F, Ritter M, Mehta RL. Systematic review and meta-analysis on management of hemodialysis catheter-related bacteremia. J Am Soc Nephrol. 2014 Dec;25(12):2927-41. doi: 10.1681/ASN.2013091009. Epub 2014 May 22.
• Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int. 2000 Oct;58(4):1758-64. doi: 10.1111/j.1523-1755.2000.00337.x.
• Jaber BL. Bacterial infections in hemodialysis patients: pathogenesis and prevention. Kidney Int. 2005 Jun;67(6):2508-19. doi: 10.1111/j.1523-1755.2005.00364.x. No abstract available.
• Chaudry MS, Gislason GH, Kamper AL, Rix M, Dahl A, Ostergaard L, Fosbol EL, Lauridsen TK, Oestergaard LB, Hassager C, Torp-Pedersen C, Bruun NE. The impact of hemodialysis on mortality risk and cause of death in Staphylococcus aureus endocarditis. BMC Nephrol. 2018 Sep 3;19(1):216. doi: 10.1186/s12882-018-1016-0.

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2022
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: February 8, 2022
• First Submitted That Met QC Criteria: February 9, 2022
• First Posted (Actual): February 21, 2022

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 28, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Central venous catheter; Prophylactic antibiotics; Blood stream infections; Severe culture negative infections
• Additional Relevant MeSH Terms: Anti-Infective Agents; Anti-Bacterial Agents; Amoxicillin
• Other Study ID Numbers: H-20026735

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No