“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
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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 [1944] Penicillin-resistant
S. aureus
[1962]
[1997]
[2002]
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

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VRSA

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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

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Prevent Infection
Diagnose & treat infections effectively
Use antimicrobials wisely ***

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Broad spectrum vs. narrow spectrum
Prevent transmission
CLINICIANS HOLD THE SOLUTION
Diagnose & Treat Infections effectively

Monitor bacterial resistance

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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

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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

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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

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Absorption
Distribution
Metabolism
Elimination
t1/2

Pharmacodynamics

What the drug does to the body

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
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)

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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
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Pharmacokinetic alterations in renal failure
Absorption

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Distribution

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Reduced plasma protein binding
Metabolism

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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

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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®)
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4th generation cephalosporin
Polymicrobial infections

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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

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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)
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Hard to treat infections endocarditis, osteomyelitis
Antibiotics used to treat resistant
Infections In the Dialysis Patient
Vancomycin (con’t)

Higher-permeability (high flux) membranes,
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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

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Most common choice for empiric treatment for febrile HD
patients

Bacteriocidal for most pathogens
Bacteriostatic for Enterococcus & Streptococcus spp.
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Commonly used in combo with ampicillin or vancomycin
Bacteriocidal in combination
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Concentration dependent
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Once daily dosing not used in HD patients
Limited nonrenal clearance
Antibiotics used to treat resistant
Infections In the Dialysis Patient
Aminoglycosides
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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
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Very expensive

ID restrictions

Available IV or po

Alternative oral agents

trimethoprim-sulfamethoxazole (Bactrim)
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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
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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
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HD patients- 200 mg every 12 hours; give after hemodialysis

Restriction to ID physicians
Common pathogens
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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)
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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

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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
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Antivirals
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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

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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:

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
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
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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

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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
???
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Antimicrobial Resistance How Can We Beat The Bugs ?