“Hemodialysis, Bugs and Drugs”

Lori-Ann Iacovino M.S., R.Ph.Holy Name Medical Center

Infectious Disease Pharmacist / Pharmacy Clinical Coordinator

April 14th, 2011

1. Overview of hemodialysis (HD) associated infections

2. Discuss role of bacterial resistance and overuse of antimicrobials specific to the HD patient

3. Discuss the importance of vaccination to prevent infection

4. Describe the role of the health care worker and infection prevention while caring for the HD patient

5. Discuss what is in the pipeline with antiinfectives

Objectives

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

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

0

2

4

6

8

10

12

Fistula Graft CuffedCatheter

Non-cuffed

catheter

Port

Rate Per100patientmonths

Klevens M, et al. NNI;June 2005: 37-8,43

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 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

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

Risk factors for blood stream infections

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

S. aureus

Penicillin

[1944] Penicillin-resistantS. aureus

Evolution of Drug Resistance in Staphylococcus aureus

Methicillin

[1962]

Methicillin-resistant

S. aureus (MRSA)

Vancomycin-resistantenterococci (VRE)

Vancomycin

[1990s]

[1997]

Vancomycinintermediate

S. aureus(VISA)

[2002]

VancomycinresistantS. aureus

CDC, MMWR 2002;51(26):565-567

Increased Awareness

“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

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

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.

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 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)

“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 patientConcentration 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

Believed to be reduced Distribution

Reduced plasma protein binding Metabolism

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.

1g IV once, then 0.5-1g IV after HD*

Empirical therapy before final culture and sensitivity result MSSA (if allergic to cephalosporins), MRSA, CNS*, Streptococcus spp, 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 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 PatientAminoglycosides (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 PatientAminoglycosides 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 PatientLinezolid (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 (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

Antibiotics used to treat resistant Infections In the Dialysis PatientOther 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

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 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)

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

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

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

???