“Hemodialysis, Bugs and Drugs” Lori-Ann Iacovino M.S., R.Ph. Holy Name Medical Center Infectious Disease Pharmacist / Pharmacy Clinical Coordinator April 14th, 2011 Objectives 1. 2. 3. 4. 5. 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 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 tenfold 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 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 Vascular access associated bacteremia infection 12 10 Rate Per 8 100 patient 6 months 4 2 0 Fistula Graft Cuffed Catheter Klevens M, et al. NNI;June 2005: 37-8,43 Noncuffed catheter Port 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 Bloodstream Pathogens Staph aureus/MRSA S. aureus & S. epidermidis most frequent causing organisms VISA/VRSA Coagulase negative staphylococci Gram negative organisms (including multi-drug resistant strains) 70% of catheter related bacteremias Acinetobacter, Pseudomonas,Stenotrophomonas Enterococci / VRE Fungi Hepatitis B and C infection Risk factors for blood stream infections Intravascular access type Medical comorbidities Indwelling catheter vs. graft or fistula Immunosuppression, diabetes Frequent hospitalizations/surgeries Other markers of severity of illness Age, access site 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 Evolution of Drug Resistance in Staphylococcus aureus Penicillin Methicillin S. aureus  Penicillin-resistant S. aureus    Methicillinresistant S. aureus (MRSA) Vancomycin [1990s] Vancomycin resistant S. aureus Vancomycin intermediate S. aureus (VISA) CDC, MMWR 2002;51(26):565-567 Vancomycin-resistant enterococci (VRE) Increased Awareness “Hemodialysis; Bugs and Drugs” VISA VRSA Vancomycin Resistant Staphylococcus aureus 12 cases in the U.S. Resistance via a Gene transfer Linked to long term use of vancomycin Vancomycin Intermediate Staphylococcus aureus 7 cases in the US 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 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 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 Diagnose & Treat Infections effectively Monitor bacterial resistance Culture & sensitivities (C&S) Pt’s clinical response Pharmacokinetic (PK) & Pharmacodynamic (PD) Principles Therapeutic drug levels Antibiograms 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 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 Strategies to control infections Use Antimicrobials Wisely: Drug Selection Judicious use of Antimicrobials based on infection type. based on Pharmacokinetic and Pharmacodynamic principles. Blood vs. respiratory vs. skin & soft tissue Appropriate Dosing Dose adjustments for renal insufficiencies and HD patients. 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. Strategies to control infections Pharmacokinetics Measures rise and fall of drug concentrations in the serum and tissue Absorption Distribution Metabolism Elimination t1/2 Pharmacodynamics What the drug does to the body Time to eliminate 50% of the drug from 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) “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 Commonly Prescribed Antimicrobials in the Dialysis patient Concentration Dependent Aminoglycosides Gentamicin, Tobramycin Fluoroquinolones Ciprofloxacin, Levofloxacin Concentration Independent B-lactam PCN’s (Unasyn®, Timentin®, Zosyn®) Cephalosporins (Ancef®, Rocephin®, Maxipime®) Vancomycin Linezolid (Zyvox®) Pharmacokinetics Pharmacokinetic alterations in renal failure Absorption Distribution Reduced plasma protein binding Metabolism Believed to be reduced Accumulation of active metabolites Decrease in nonrenal clearance Elimination ↑ ½ life, ↑ accumulation, ↑ toxicity Antimicrobial dosing and clinical use Antimicrobial Dosing Clinical use Cefazolin 1-2g IV after HD 3g IV if 2days until next session MSSA, Streptococcus spp Cefepime 2g IV after HD MSSA, Streptococcus spp, Enterobacteriacea, Pseudomonas aeruginosa Vancomycin 25-30mg/kg IV loading (not>2g) then as needed after HD based on levels. Empirical therapy before final culture and sensitivity result MSSA (if allergic to cephalosporins), MRSA, CNS*, Streptococcus spp, Enterococcus spp 1g IV once, then 0.5-1g IV after HD* Tobramycin/ Gentamicin Ototoxicity, predialysis concentration of 26mg/L for gram positive synergy Difficult to optimize dosing for Pseudomonas aerugenosa (consider use of fluoroquinolones or cefepime) Linezolid 600mg IV or po q12h (after HD) MRSA, MSSA, CNS, VRE, Streptococcus spp (including S. pneumoniae) Daptomycin 6-8mg/kg IV q48h after HD on dialysis days MRSA, MSSA (if allergic to cephalosporins), CNS*, Streptococcus spp, Enterococcus spp * Common regimen in dialysis facilities Antimicrobial monitoring and limitation Antimicrobial Monitoring Limitation Cefazolin Rash No activity against Enterococcus spp. Cefepime Rash, neurotoxicity No activity against Enterococcus spp. Vancomycin Rash, red-man syndrome*, CBC for neutropenia, Vancomycin trough levels between 15-20mcg/ml Emerging resistance in Staphylococcus spp and Enterococcus spp. Tobramycin/ Gentamicin Ototoxicity, predialysis concentration of 2-6mg/L for gram positive synergy Difficult to optimize dosing for Pseudomonas aerugenosa (consider use of fluoroquinolones or cefepime) Linezolid CBC for anemia and thrombocytopenia Risk of cytopenia in HD patients Daptomycin Myalgia, creatinine phosphokinase concentration Active but not approved for VRE related infections, not to be used for pulmonary infections 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 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 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 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 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 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 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 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) 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. 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 (vancomycinsusceptible 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 Antibiotics used to treat resistant Infections In the Dialysis Patient Other antimicrobials: Antifungals Antivirals Fluconazole (Diflucan®) Acyclovir (Zovirax®) Anti HIV-lamivudine (Epivir®), Stavudine (Zerit®) Antituberculosis Ethambutol (Myambutol®), isoniazid (INH) Appropriate dosing is crucial in optimizing patient care 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 Preventing Infections Patients with renal failure have an increased risk of infection Vaccination – healthcare professionals / patients Influenza Hepatitis B Inactivated influenza vaccine should be given annually Live attenuated influenza vaccine is contraindicated Vaccination vs. booster Pneumococcal Every 5 years (maximum 2 doses in a lifetime) Preventing Infections Adapted from CDC. Recommendations for Preventing Transmission of Infections Among Chronic Hemodialysis Patients. MMWR 2001;50 (No. RR-5):Table 3 Antibiotic line therapy Heparin +/- Antibiotic Antibiotic line lock initial management of suspected catheter related bacteremia controversial Varying data on doses, concentrations IDSA 2009 guidelines 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 Common Dosing for Antibiotic Line Lock 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 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 ??? 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 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 “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 Pipeline 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. Bad bugs, New drugs Clostridium difficile (C.difficile) Most common hospital acquired diarrhea Increased prevalence amongst HD patients Vancomycin (po) vs. Metronidazole (IV & po) Fidaxomicin (Dificid®) 4/6/2011 – Anti-Infective Drug Advisory Committee Voted unanimously for FDA approval Expected FDA approval 2nd quarter 2011 Non inferior to vancomycin Improved cure rates without occurrence (4 weeks) Reducing C difficile infection occurrence by 47% Conclusion Antimicrobial Therapy is widely used in HD patients. Resistance is on the rise, therefore it is imperative that all health care providers play an active role in education, treatment and prevention of all types of infections in order to preserve our treatment options. Newer antibiotics are available for gram positive infections but should be used with caution to prevent resistance. 4 Strategies for controlling antimicrobial resistance is the key to beating the bugs ! Anybody want to guess what type of infection ? MRSA Enterococcus faecalis “Hemodialysis; Bugs and Drugs” QUESTIONS ???