Ewelina Mamcarz M.D., Divya-Devi Joshi M.D.

1. Antibiotic lock versus systemic antibiotics for catheter related infections in immunocompromised pediatric patients. Ewelina Mamcarz M.D., Divya-Devi Joshi M.D.

2. Objectives • Describe indications for systemic antibiotics versus antibiotic lock therapy • Evaluate type of antibiotic and treatment duration for antibiotic lock • Timing of the antibiotic lock: early/late • Antibiotic lock as prevention of catheter associated bacteremia

3. Background: Catheter related infections • Leading cause of morbidity and mortality in critically ill hospitalized patients • Organisms: • Coagulase – negative staphylococci • Staphylococcus aureus • Gram-negative bacteria • Candida ssp.

4. Sources of infection • Colonization from the skin • Intraluminal / hub contamination • Hematologic seeding

5. Clinical evaluation -CRI • Local inflammation • Sepsis • Blood culture • Catheter dysfunction • Rapid improvement following catheter removal

6. Treatment • Type of device • Infecting pathogens • Presence of alternative venous access sites • Duration of anticipated need for access

7. Treatment • Catheter removal • Systemic antibiotics • Antibiotic lock therapy (ALT)- little evidence to support recommendation

8. Data • Guidelines from the Infectious Diseases Society of America (IDSA): CRI documented, pathogen identified-narrow spectrum systemic abx and consider ALT • Onder at al: timing of antbc locks: ALT more effective early in therapy, diminished need for catheter removal • Pervez at al: ALT for prevention of CRI: decreased incidence of CRI, improved survival of catheters

9. Antibiotic lock • First publication 1988-Messing et al • Higher concentration, longer duration of activity at the infected site without potential side-effects of systemic exposure • Concentration and intra-luminal dwell time: lack of evidence based recommendations

10. Lack of firm recommendations for individual patients • Immunocompromised population • Pathogenesis of CRI complicated • Virulence of the pathogens variable • Host factors not well defined • Lack of diversity between studied populations • Absence of compelling clinical data to form recommendations

11. Data • Uncomplicated catheter-related bacteremias: Infectious Disease Society of America – systemic antibiotics (7days) +ALT (14 days) • Local, systemic, extra-luminal CRI –ALT should be combined with systemic treatment for at least 72 hours

12. Data • Search strategy: • Pub Med (1990-2008) • Selected studies: • Pediatric patients only • Prophylaxis with ALT, • Treatment with combined therapy (SA+ALT) • 9 studies met above criteria!

13. Antibiotic-heparin lock solutions: adults and children Antimicrobial lock solutions • Active ingredient Concentration (mg⁄ L) • Vancomycin a 0.025–10 • Teicoplanin a 0.025–2.5 • Linezolid a 0.2–2 • Amikacina,b 1–10 • Gentamicin 1–10 • Ciprofloxacin 0.125–2 • Ceftazidime 0.5–2 • Amphotericin B desoxycholate 2 (in glucose 5% w⁄ v) • A: Stable for ‡ 24 h without loss of efficacy when combined with heparin 100 U⁄ mL. • B: Vancomyin 25 mg ⁄ L + amikacin 25 mg⁄ L + heparin 100 000 U⁄ L in NaCl 0.9% • Note: Standard antibiotic lock technique ampoules prepared by the hospital • pharmacy must be protected carefully against contamination with bacteria and • fungi, and should be filter-sterilized and stored in a refrigerator.

14. Data: Prevention • 3 studies: • prospective double blind study, prospective cohort study, literature review (both children and adults) • Vancomycin/heparin/ciprofloxacin, vancomycin/heparin, minocycline/ethylenediaminetetraacetate, vancomycin/teicoplanin • Results: Time to develop CRI longer with ALT, rate of total line infections decreased, no port infections or thrombotic events were observed compared to ports flushed with heparin only

15. Data: Treatment • 6 studies: • 2 case reports, 4 open pilot studies • Vancomycin/heparin, ciprofloxacin/heparin, amikacin/heparin, urokinase /vancomycin, ampicilin alone+ systemic antibiotics • 168 episodes of CRI: 143 (85%) episodes cured (negative bld cx –mean: 4days-1month),10 catheter removals, median catheter follow up -96 days,168 days (1 study),25 (15%) episodes of therapeutic failure (recurrence of febrile bacteremia),1 death.

16. ALT Evidence based guidelines -Significance • Decrease in mortality and morbidity related to catheter related infections • Limit use of systemic antibiotic • Prevent resistance • Improve quality of life • Lack of serious complications • Cost effective?

17. References • Chatzinikolaou I, Zipf TF, Hanna H, Umphrey J, Roberts WM, Sherertz R, Hachem R, Raad I. Minocycline-ethylenediaminetetraacetate lock solution for the prevention of implantable port infections in children with cancer.Clin Infect Dis. 2003 Jan 1;36(1):116-9. Epub 2002 Dec 11. • Henrickson KJ, Axtell RA, Hoover SM, Kuhn SM, Pritchett J, Kehl SC, Klein JP. Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: A randomized, multicenter, double-blind trial. J Clin Oncol. 2000 Mar;18(6):1269-78 . • van de Wetering MD, van Woensel JB. Prophylactic antibiotics for preventing early central venous catheter Gram positive infections in oncology patients. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD003295 . • Fernandez-Hidalgo N, Almirante B, Calleja R, Ruiz I, Planes AM, Rodriguez D, Pigrau C, Pahissa A. Antibiotic-lock therapy for long-term intravascular catheter-related bacteraemia: results of an open, non-comparative study. J Antimicrob Chemother. 2006 Jun;57(6):1172-80. Epub 2006 Apr 5 .

18. References • De Sio L, Jenkner A, Milano GM, Ilari I, Fidani P, Castellano A, Gareri R, Donfrancesco A. Antibiotic lock with vancomycin and urokinase can successfully treat colonized central venous catheters in pediatric cancer patients. Pediatr Infect Dis J. 2004 Oct;23(10):963-5 . • Bernardi M, Cavaliere M, Cesaro S. The antibiotic-lock therapy in oncoematology pediatric unit . Assist Inferm Ric. 2005 Jul-Sep;24(3):127-31. • Viale P, Pagani L, Petrosillo N, Signorini L, Colombini P, Macri G, Cristini F, Gattuso G, Carosi G. Antibiotic lock-technique for the treatment of catheter-related bloodstream infections. J Chemother. 2003 Apr;15(2):152-6. • Gattuso G, Tomasoni D, Ceruti R, Scalzini A. Multiresistant Stenotrophomonas maltophilia tunneled CVC-related sepsis, treated with systemic and lock therapy. J Chemother. 2004 Oct;16(5):494-6 . • Mermel LA, Farr BM, Sherertz RJ, Raad II, O'Grady N, Harris JS, Craven DE; Infectious Diseases Society of America; American College of Critical Care Medicine; Society for Healthcare Epidemiology of America . Guidelines for the management of intravascular catheter-related infections Clin Infect Dis. 2001 May 1;32(9):1249-72. Epub 2001 Apr 3 .

19. References • Elwood RL, Spencer SE . Successful clearance of catheter-related bloodstream infection by antibiotic lock therapy using ampicillin. Ann Pharmacother. 2006 Feb;40(2):347-50. Epub 2006 Jan 31. • Simon A, Bode U, Beutel K . Diagnosis and treatment of catheter-related infections in paediatric oncology: an update. Clin Microbiol Infect. 2006 Jul;12(7):606-20. • Band JD. Pathogenesis of and risk factors for central venous catheter-related infections. Diagnosis of central venous catheter –related bloodstream infections. Treatment of central venous catheter-related infections. www. uptodate. Com. • Bagnall-Reeb H. Evidence for the use of the antibiotic lock technique. J Infus Nurs. 2004 Mar-Apr;27(2):118-22. • Robinson JL, Tawfik G, Roth A . Barriers to antibiotic lock therapy in children with intravascular catheter-related bloodstream infections. Pediatr Infect Dis J. 2005 Oct;24(10):944 .