Hemodialysis, Bugs and Drugs

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Hemodialysis, Bugs and Drugs

• Lori-Ann Iacovino M.S., R.Ph.
• Holy Name Medical Center
• Infectious Disease Pharmacist / Pharmacy Clinical
  Coordinator
• April 14th, 2011

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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

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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 23716-720, 2002
• Marr KA Staphylococcus aureus bacteremia in
  patients undergoing hemodialysis Semin Dial
  1323-29,
• 2000

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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 23716-720, 2002
• Marr KA Staphylococcus aureus bacteremia in
  patients undergoing hemodialysis Semin Dial
  1323-29,
• 2000

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Vascular access associated bacteremia infection
Klevens M, et al. NNIJune 2005 37-8,43
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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

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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

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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

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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

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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 200251(26)565-567
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Increased Awareness
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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

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• Infectious Disease Society of Americas 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

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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

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Diagnose Treat Infections effectively

• Monitor bacterial resistance
• Culture sensitivities (CS)
• Pts clinical response
• Pharmacokinetic (PK) Pharmacodynamic (PD)
  Principles
• Therapeutic drug levels
• Antibiograms

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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 CSs are obtained narrow the spectrum of
  activity.
• Potential for great abuse of antimicrobials

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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

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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.

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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.

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Strategies to control infections

• 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)

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Hemodialysis Bugs and Drugs

• Concentration dependent (AMGs, FQs)
• High drug concentrations will elicit a faster
  kill rate
• AUC/MIC ratios
• Post-antibiotic effects greater
• Predicative parameter efficacy / resistance
• Concentration independent (B-lactams)
• Time above MIC will produce a better kill rate
• time gt MIC
• Frequent dosing, continuous infusions

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Commonly Prescribed Antimicrobials in the
Dialysis patient

• Concentration Dependent
• Aminoglycosides
• Gentamicin, Tobramycin
• Fluoroquinolones
• Ciprofloxacin, Levofloxacin
• Concentration Independent
• B-lactam PCNs (Unasyn, Timentin, Zosyn)
• Cephalosporins (Ancef, Rocephin, Maxipime)
• Vancomycin
• Linezolid (Zyvox)

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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

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Common regimen in dialysis facilities
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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
• PCNs (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

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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

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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

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Antibiotics used to treat resistant Infections In
the Dialysis Patient

• Vancomycin (cont)
• 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

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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

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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

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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

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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)

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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.

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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 lt30 mL/minute 10 mg/kg every 48
  hours.
• HD and pts with Cr Cl lt10 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

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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

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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

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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)

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Preventing Infections
Adapted from CDC. Recommendations for Preventing
Transmission of Infections Among Chronic
Hemodialysis Patients. MMWR 200150 (No.
RR-5)Table 3
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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 gt Enterococcus gt Staph aureus
• In combination with systemic antibiotics

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Common Dosing for Antibiotic Line Lock
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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

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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
  ???

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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

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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 

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• 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

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Pipeline
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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 Americas 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.

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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

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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 !

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Anybody want to guess what type of infection ?

• MRSA

• Enterococcus faecalis

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Hemodialysis Bugs and Drugs

• QUESTIONS
• ???