“Hemodialysis, Bugs and Drugs”

1. “Hemodialysis, Bugs and Drugs” Lori-Ann Iacovino M.S., R.Ph. Holy Name Medical Center Infectious Disease Pharmacist / Pharmacy Clinical Coordinator April 14th, 2011

2. Objectives • Overview of hemodialysis (HD) associated infections • Discuss role of bacterial resistance and overuse of antimicrobials specific to the HD patient • Discuss the importance of vaccination to prevent infection • Describe the role of the health care worker and infection prevention while caring for the HD patient • Discuss what is in the pipeline with antiinfectives

3. Overview of HD associated infections • Infections are the 2nd leading cause of death in HD patients • About 30% of chronic HD patients rely on catheters for dialysis • Relative risk for bacteremia in patients with dialysis catheters is ten-fold higher than the patients with primary arteriovenous fistulas • Incidence of bacteremia in dialysis pts with indwelling catheters range from 1.6 to 8.6 per 1000 catheter days • Single most important factor contributing to infection • Accounts for 1/4th of all deaths • Leading cause of hospital admissions • HD patients are 2x more likely to get an infection than peritoneal dialysis patients U.S. Renal Data System Taylor G., Gravel D, Johnston L – Prospective surveillance for primary bloodstream infections occurring in Canadian hemodialysis units. Infect Control Hosp Epidermal 23:716-720, 2002 Marr KA: Staphylococcus aureus bacteremia in patients undergoing hemodialysis Semin Dial 13:23-29, 2000

4. Overview of HD associated infections • Most Common Sites of Infection for HD patients; • Vascular access – 57% • Local access • Blood stream • Wound – 23% • Lung – 15% • Urinary tract – 5% U.S. Renal Data System Taylor G., Gravel D, Johnston L – Prospective surveillance for primary bloodstream infections occurring in Canadian hemodialysis units. Infect Control Hosp Epidermal 23:716-720, 2002 Marr KA: Staphylococcus aureus bacteremia in patients undergoing hemodialysis Semin Dial 13:23-29, 2000

5. Vascular access associated bacteremia infection Klevens M, et al. NNI;June 2005: 37-8,43

6. Antimicrobial resistance Infections are characterized by multidrug resistant strains of bacteria • Nationwide problem • Dialysis patients are at greater risk due to a compromised immune system • Community acquired • Health Care Associated Infections (HCI) • Aka - nosocomial

7. Bloodstream Pathogens • Staph aureus/MRSA • S. aureus & S. epidermidis most frequent causing organisms • 70% of catheter related bacteremias • VISA/VRSA • Coagulase negative staphylococci • Gram negative organisms (including multi-drug resistant strains) • Acinetobacter, Pseudomonas,Stenotrophomonas • Enterococci / VRE • Fungi • Hepatitis B and C infection

8. Risk factors for blood stream infections • Intravascular access type • Indwelling catheter vs. graft or fistula • Medical comorbidities • Immunosuppression, diabetes • Frequent hospitalizations/surgeries • Other markers of severity of illness • Age, access site

9. Forces to provide guidance • CDC • CMS • Infectious Disease Society of America (IDSA) • American Society of Nephrology • National Kidney Foundations Dialysis Outcome Quality Improvement (NKF-DOQI) • Dialysis Surveillance Network (DSN) - a voluntary national surveillance system monitoring bloodstream and vascular infections. • Initiated by CDC in August 1999. Both adult and pediatric dialysis centers were invited to participate

10. Evolution of Drug Resistance in Staphylococcus aureus Penicillin Methicillin Methicillin-resistant S. aureus (MRSA) Penicillin-resistant S. aureus [1944] S. aureus [1962] Vancomycin [1997] [2002] [1990s] Vancomycin intermediate S. aureus (VISA) Vancomycin-resistant enterococci (VRE) Vancomycin resistant S. aureus CDC, MMWR 2002;51(26):565-567

11. Increased Awareness

12. “Hemodialysis; Bugs and Drugs” • VISA • Vancomycin Intermediate Staphylococcus aureus • 7 cases in the US • VRSA • Vancomycin Resistant Staphylococcus aureus • 12 cases in the U.S. • Resistance via a Gene transfer • Linked to long term use of vancomycin • Diabetes, kidney disease, previous infections with MRSA, catheters, recent hospitalizations, and recent exposure to vancomycin and other antimicrobial agents • Use of vancomycin is considered the most important risk factor for developing resistance • Continued surveillance and reporting to the CDC is vital Clinical Infectious Disease 2001

13. Infectious Disease Society of America’s first guidelines on MRSA infections • Expert panel analyzed data from 1961 • Few randomized clinical trials; mostly observational studies or small case series with expert opinion • Categories (A,B,C) for recommendation strength and grades (I,II,III) for quality of evidence • Intended for use by healthcare providers Clinical Practice Guidelines for the Treatment of Methicillin Resistant Staphylococcus aureus Infections in Adults and Children

14. Strategies to control antimicrobial resistance • Prevent Infection • Diagnose & treat infections effectively • Use antimicrobials wisely *** • Broad spectrum vs. narrow spectrum • Prevent transmission CLINICIANS HOLD THE SOLUTION

15. Diagnose & Treat Infections effectively • Monitor bacterial resistance • Culture & sensitivities (C&S) • Pt’s clinical response • Pharmacokinetic (PK) & Pharmacodynamic (PD) Principles • Therapeutic drug levels • Antibiograms

16. Diagnose & Treat Infections effectively • Cultures and sensitivities • Used in diagnosis & treatment of infections • Draw cultures before administering antibiotics • Empiric therapy * - treatment on an assumption of what particular organism maybe present. • i.e. catheters or grafts (foreign body putting the patients at risk for primarily gm+ organisms) • Once C&S’s are obtained narrow the spectrum of activity. * Potential for great abuse of antimicrobials

17. Diagnose & Treat Infections effectively • Antibiograms • Annual sensitivity data • Does your dialysis center have a problem with a particular organism and class of drugs ? • i.e. Fluoroquinolones and E.coli • Geographic locations • City to city • State to State • Obtain previous microbiolgy results on patient transfers

18. Strategies to control infections Use Antimicrobials Wisely: • Drug Selection • based on Pharmacokinetic and Pharmacodynamic principles. • Judicious use of Antimicrobials based on infection type. • Blood vs. respiratory vs. skin & soft tissue • Appropriate Dosing • Dose adjustments for renal insufficiencies and HD patients.

19. Strategies to control infections PK & PD principles are crucial for optimizing therapy and avoiding adverse drug events. By utilizing these principles we can predict bacterial resistance.

20. Pharmacokinetics Measures rise and fall of drug concentrations in the serum and tissue Absorption Distribution Metabolism Elimination t1/2 Time to eliminate 50% of the drug from the body Pharmacodynamics What the drug does to the body Incorporates kinetics Integrates microbiological activity focusing on biological effects, particular growth inhibition and killing of pathogens Concentration Dependent vs. Time Dependent (Concentration Independent) Strategies to control infections

21. “Hemodialysis; Bugs and Drugs” • Concentration dependent (AMG’s, FQ’s) • High drug concentrations will elicit a faster kill rate • AUC/MIC ratios • Post-antibiotic effects greater • Predicative parameter efficacy / resistance • Concentration independent (B-lactam’s) • Time above MIC will produce a better kill rate • time > MIC • Frequent dosing, continuous infusions

22. Concentration Dependent Aminoglycosides Gentamicin, Tobramycin Fluoroquinolones Ciprofloxacin, Levofloxacin Concentration Independent B-lactam PCN’s (Unasyn®, Timentin®, Zosyn®) Cephalosporins (Ancef®, Rocephin®, Maxipime®) Vancomycin Linezolid (Zyvox®) Commonly Prescribed Antimicrobials in the Dialysis patient

23. Pharmacokinetics • Pharmacokinetic alterations in renal failure • Absorption • Believed to be reduced • Distribution • Reduced plasma protein binding • Metabolism • Accumulation of active metabolites • Decrease in nonrenal clearance • Elimination • ↑ ½ life, ↑ accumulation, ↑ toxicity

25. * Common regimen in dialysis facilities

27. Antibiotics used to treat resistant Infections In the Dialysis Patient • Penicillins & Cephalosporins • DOC for MSSA • Recommended over vancomycin to limit the emergence of Staph aureus with reduced vanco sensitivity • PCN’s –(oxacillin, nafcillin) • Limited use – frequent administration (q6-8h) • Cefazolin (Ancef®) – most commonly used • Easy dosing - Q24-q48h dosing • Additional 500mg – 1gm dose after dialysis. • Monitor for rash • Does not have activity against Enterococcus

28. Antibiotics used to treat resistant Infections In the Dialysis Patient • Cefepime (Maxipime®) • 4th generation cephalosporin • Polymicrobial infections • MSSA, Enterobactericae, Pseudomonas aeruginosa • Easy dosing 1gm q24h, extra 1gm dose after dialysis • Doses of 2 gram after dialysis have been studied • Neurological adverse effects predominantly in the elderly with low body weight • Rash • Does not cover Enterococcus

29. Antibiotics used to treat resistant Infections In the Dialysis Patient • Vancomycin • Glycopeptide • Used against gram positive pathogens • Enterococcus spp (bacteriostatic) • MRSA, MSSA (bacteriocidal), Staph coag -) • PCN allergic pts • Concentration independent • Concentrations should exceed the MIC • Monitor vancomycin levels – random vs. trough vs. peak • Dialysis patients target random levels 15mcg/ml. • Levels of 20mcg/ml (not common practice) • Hard to treat infections endocarditis, osteomyelitis

30. Antibiotics used to treat resistant Infections In the Dialysis Patient Vancomycin (con’t) • Higher-permeability (high flux) membranes, • Significant vancomycin removal 25%-50%. • New dosing 1gram load followed by 500mg each HD • Administered last 1 hour of the session • Minimize risk red man syndrome – related to infusion time • Monitor CBC - neutropenia • Increased use of Vanco leads to resistance • Reducing the use of Vanco is the best method of preventing Vanco resistance • Initiatives for appropriate use of Vanco • CDC – 1996 nationwide campaign launched. • Appropriate vs. inappropriate

31. Antibiotics used to treat resistant Infections In the Dialysis Patient Aminoglycosides (Gentamicin, Tobramycin) • Common pathogens: gram positive and gram negative pathogens • Combination tx with Vanco commonly used • Most common choice for empiric treatment for febrile HD patients • Bacteriocidal for most pathogens • Bacteriostatic for Enterococcus & Streptococcus spp. • Commonly used in combo with ampicillin or vancomycin • Bacteriocidal in combination • Concentration dependent • Once daily dosing not used in HD patients • Limited nonrenal clearance

32. Antibiotics used to treat resistant Infections In the Dialysis Patient Aminoglycosides • Dose 1.5-2.0mg/kg IV × 1, then 1.0-1.5mg/kg IV after HD • Concerns for ototoxicity and loss of residual renal fx. • High flux dialyzers • Unpredictable clearance • Post dialysis levels are recommended

33. Antibiotics used to treat resistant Infections In the Dialysis Patient Linezolid (Zyvox®) – oxazolidinones Bacteriostatic • Common pathogens VRE, Staphylococcus aureus, Staph coag neg • Should be Considered 2nd line agent for patients with MRSA infections refractory or intolerant to vancomycin • Very expensive • ID restrictions • Available IV or po • Alternative oral agents • trimethoprim-sulfamethoxazole (Bactrim) • Dose 600mg IV every 48h • Dose after dialysis – no supplemental dosing • High incidence of thrombocytopenia in HD patients • 80% vs. 40% in non-ESRD pts • Monitor for anemia ??? • Optic & peripheral neuropathy • Serotonin syndrome

34. Antibiotics used to treat resistant Infections In the Dialysis Patient Daptomycin (Cubicin®) – cyclic lipopeptide • Dose 6-8 mg/kg IV every 48 hours • Bacteriocidal • Common pathogens MRSA, VRE, and coag negative staph • Should be Considered 2nd line agent for patients with MRSA infections refractory or intolerant to vancomycin • Concentration dependent • Dose after dialysis • No supplemental dosing needed • Very expensive • ID restrictions • Monitor for skeletal muscle toxicity, unexplained myopathy & elevations in creatine phosphokinase (CPK)

35. Antibiotics used to treat resistant Infections In the Dialysis Patient • Ceftaroline- 5th generation cephalosporin • Only indicated for skin and soft tissue infections and MSSA pneumonia • Bacteriocidal • Dose adjustments are required for patients with CrCl of 50mL/min or less • HD patients- 200 mg every 12 hours; give after hemodialysis • Restriction to ID physicians • Common pathogens • Acute bacterial skin and soft tissue infections: MRSA, Streptococcus. pyogenes, Streptococcus. agalactiae, Eschericia. coli, Klebsiella oxytoca, and Klebsiella pneumoniae • Community acquired pneumonia: MSSA, Haemophilus. influenzae, Klebsiella. pneumoniae, Klebsiella. oxytoca, and Eschericia. coli.

36. Antibiotics used to treat resistant Infections In the Dialysis Patient • Telavancin (Vibativ) • Lipopeptide • No blood levels are required • Bactericidal • Indicated for complicated skin and skin structure infections • MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, or Enterococcus faecalis (vancomycin-susceptible isolates only). • CrCl 10 to <30 mL/minute: 10 mg/kg every 48 hours. • HD and pts with Cr Cl <10 mL/minute, • No specific recommendations for dose adjustment. • In patients with impaired renal function • the solubilizer can accumulate • Clinical cure rates are lower in patients with impaired renal function • Restriction to ID physicians

37. Antibiotics used to treat resistant Infections In the Dialysis Patient Other antimicrobials: • Antifungals • Fluconazole (Diflucan®) • Antivirals • Acyclovir (Zovirax®) • Anti HIV-lamivudine (Epivir®), Stavudine (Zerit®) • Antituberculosis • Ethambutol (Myambutol®), isoniazid (INH) Appropriate dosing is crucial in optimizing patient care

39. Preventing Infections • Hand Washing • Crucial to an effective Infection Control Program • Single most important factor • Health care provider • Patients should be educated about the importance of their role in infection control upon admission to a dialysis center/hospital and at least annually thereafter. • Soap & water vs. Alcohol based hand rub

40. Preventing Infections • Patients with renal failure have an increased risk of infection • Vaccination – healthcare professionals / patients • Influenza • Inactivated influenza vaccine should be given annually • Live attenuated influenza vaccine is contraindicated • Hepatitis B • Vaccination vs. booster • Pneumococcal • Every 5 years (maximum 2 doses in a lifetime)

41. Preventing Infections Adapted from CDC. Recommendations for Preventing Transmission of Infections Among Chronic Hemodialysis Patients. MMWR 2001;50 (No. RR-5):Table 3

42. Antibiotic line therapy Heparin +/- Antibiotic • Antibiotic line lock • IDSA 2009 guidelines • initial management of suspected catheter related bacteremia • controversial • Varying data on doses, concentrations • Most common antibiotics, cefazolin, gentamicin, cefipime • Success is limited • Sensitive organisms • Success primary function of infecting organism • Staph Coag neg > Enterococcus > Staph aureus • In combination with systemic antibiotics

43. Common Dosing for Antibiotic Line Lock

44. Preventing Infection Hemodialysis: • Use catheters only when essential • Maximize use of fistulas/grafts • Remove catheters when they are no longer essential • Hand Hygiene • Vaccinate • Antibiotic line lock therapy Heparin + Antibiotic

45. Preventing Infection • For HD patients who are nasal Staphylococcus aureus carriers with catheter blood related infections, • Routine use of nasal mupirocin (Bactroban®) or rifampin is recommended by IDSA • Controversial • Mupirocin concern for resistance • avoid with polyurethane catheters due to catheter degradation. • Recommendations for reducing HD access related infections • NKF-DOQI – Povidone-iodine (Betadine®) or mupirocin ointment at HD catheter exit sites after catheter placement and each dialysis treatment. • CDC apply povidone-iodine routinely to exit sites • Silver coated catheters vs. Biofilm (chlorhexidine) patch vs. chlorhexidine solution ???

46. Preventing Infection • Vancomycin should not be 1st line agent for MSSA catheter related infections • Guidelines should be in place • Clinical presentation / clinical Hx • R/O systemic infection • Is antimicrobial use warranted ? • Options include Chlorhexidine vs. Betadine topical ointment at the exit site • Appropriate selection of antibiotic • Cefazolin vs. Vancomycin

47. Antibiotic Timeline • 1936 Sulfa drugs  • 1940  Beta-lactams  • 1949 Chloramphenicol, Tetracyclines  • 1950 Aminoglycosides  • 1952 Macrolides  • 1962 Quinolones, Streptogramins  • 2000 Oxazolidinones  • 2003 Lipopeptides  • 2005 Glycylcyclines  • 2007 Mutilins

48. “The lack of new antibiotics in the pipeline threatens to leave physicians around the world without the tools they need to effectively treat” -Richard Whitley, MD, IDSA President

49. Pipeline

50. Bad bugs, New drugs • IDSA developed the Antimicrobial availability task force • Concerned about lack of initiative in research for antimicrobials • Calls for 10 new antibiotics by 2020 • Collaborative Efforts by • American Academy of Pediatrics, • American Gastroenterological Association, • Trust for America’s Health, • The Society for Healthcare Epidemiology of America, • The Pediatric Infectious Disease Society, • The Michigan Antibiotic Resistance Reduction Coalition, • The National Foundation for Infectious Diseases • The European Society of Clinical Microbiology and Infectious Diseases.