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Management of Common Types of Infections in Patients Receiving Chronic Renal Replacement Therapy. American Nephrology Nurses Association . Sarah Tomasello, PharmD, BCPS Clinical Associate Professor Rutgers, The State University of New Jersey Clinical Specialist – Nephrology

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american nephrology nurses association

Management of Common Types of Infections in Patients Receiving Chronic Renal Replacement Therapy

American Nephrology Nurses Association

Sarah Tomasello, PharmD, BCPS

Clinical Associate Professor

Rutgers, The State University of New Jersey

Clinical Specialist – Nephrology

Robert Wood Johnson University Hospital

New Brunswick, NJ

stomasel@rci.rutgers.edu

outline of presentation
Outline of Presentation
  • Infections in patients on hemodialysis
    • Risk factors
    • Common “Bugs and Drugs”
    • Pharmacokinetic parameters and alterations
    • Administration and dosing
    • Monitoring therapy and altering regimen
  • Catheter related infections
  • Peritonitis
risk factors for infection
Risk factors for Infection
  • Weakened immune function
    • Immunosuppressive agents, uremia
  • Indwelling catheters
    • Vascular Access
      • Catheter > AVG (arteriovenous graft) > AVG (arteriovenous fistula)
    • Presence as well as manipulation
  • Dialysis unit exposure
    • Care givers, patients
  • Comorbidities
    • Diabetes (~50%)
issues related to hemodialysis
Issues Related to Hemodialysis
  • Intermittent clearance
    • Generally three times a week
      • Vascular access
  • Type of filters
    • “High-Flux”
  • Filter re-use
  • Dialysis adequacy
    • Time on HD
    • Blood flow rate
common drugs used and why
Common Drugs Used and Why?
  • Cephalosprins
    • Cefazolin, ceftazadime, ceftriaxone,
  • Quinolones
    • Levofloxacin, ciprofloxacin
  • Vancomycin
  • Aminoglycosides?
    • Gentamicin, tobramycin, amikacin
  • Long half-life (t ½)in ESRD patients
  • Can be dosed with/right after hemodialysis
  • What about “The WEEKEND”?
vancomycin
Vancomycin
  • Glycopeptide
  • Empiric therapy for gram+ (MRSA)
  • Concerns
    • Resistance
  • 1 gram every week
  • 1 gram followed by 500mg Q HD
vanco
Vanco
  • “Mississippi mud”
  • Crystalline Degradation Product 1 (CDP1)
  • Higher trough for resistant organisms or hard to penetrate areaaas
  • Assays
    • high performance liquid chromatography (HPLC)
    • Fluorescence polarization immunoassays (FPIA)

Hu et al. Ther Drug Monitor 12 562-569, 1990

vancomycin toxicities
Vancomycin Toxicities
  • “Red Man’s” Syndrome
  • Ototoxicity
  • Nephrotoxicity
  • Increased risk of toxicity with aminoglycoside antibiotics
  • Thrombocytopenia

Rybak et al. Antimicrob Agents Chemother 1999;43:1549-1555

types of bacteria common to dialysis patients
Types of BacteriaCommon to dialysis patients

bioweb.uwlax.edu/.../whatisbacteria.htm

properties of dialyzable drug
Properties of Dialyzable Drug*
  • Molecular weight
    • High-flux may eliminate drugs up to 5000 daltons
  • Vd
    • > 1 L/kg not readily dialyzed
    • Must be water soluble
  • Protein Binding
    • Highly protein bound (>96%) not as dialyzable
      • Watch “narrow therapeutic window” agents
      • Or saturated plasma proteins (toxicologic emergencies)

* May be removed during dialysis

pharmacokinetic parameters

Pharmacokinetic Parameters

A = Absorption

D = Distribution

M = Metabolism

E = Elimination/Excretion

Alterations in Kidney Dysfunction

absorption and bioavailability
Absorption and Bioavailability
  • DECREASED
    • Altered GI emptying (diabetes)
    • Altered pH (H2 antagonists, proton pump
    • Edema of GI tract (fluid overload) inhibitors, antacids)
    • Drug Interactions (antacids, iron, etc…)
  • INCREASED
    • Decreased first pass effect
    • Decreased metabolism by uremic toxins
    • Decreased enzymatic activity in kidney, liver, GI tract

FOR ORAL MEDICATION ADMINISTRATION ONLY

volume of distribution vd
Volume of Distribution (Vd)
  • Plasma Protein Binding
    • Albumin is major plasma protein
    • Acidic drugs bind to albumin
      • Phenytoin, valproic acid, salicylates
    • Changes in albumin effect Vd
      • Alterations in binding sites

Increased free concentrations (more effect?)

vs

Increased rate of clearance? (excreted more rapidly?)

FYI! FYI!

volume of distribution plasma protein binding cont
Volume of DistributionPlasma Protein Binding (cont.)
  • Alpha-1-acid glycoprotein (AAG)
    • Binds basic drugs
    • AAG up-regulated in kidney disease
    • “Expect” a decreased free-fraction
      • This has not been observed in vitro studies

FYI! FYI!

causes of hypoalbuminemia
Causes of Hypoalbuminemia
  • Malnutrition
  • Nephrotic syndrome
  • Liver disease
  • Accumulation of competitive inhibitors
    • Uremic toxins
    • Metabolites

(Normal serum albumin concentration ~4g/dL)

clinical significance of changes in volume of distribution water
Clinical Significance of Changes in Volume of Distribution: WATER
  • Increased fluid volume
    • Interdialytic weight gain
    • Effects drug “peak”concentration
  • Rapid fluid removal,
    • Redistribution (re-equilibrium)
    • Affects therapeutic drug monitoring (TDM) in serum
hemodialyzer
Hemodialyzer
  • Selectively permeable membrane
  • Solute (drug) molecules pass through “selectively” based on MW and size
  • Composed of many types of fibers
  • Blood flows through 5000-20,000 hollow fibers
  • Dialysate flows on outside of fibers
definitions
Definitions
  • Diffusion- passive movement of particles from high concentration to low concentration. Limited by filter.
  • Ultrafiltration- Removal of plasma water by a procedure
  • Convection-movement of particles with movement of water in which they are dissolved. Due to ultrafiltration, also limited by filter
mw of common drugs
MW of Common Drugs
  • Digoxin: 781 Daltons
  • Vancomycin: 1,486 Daltons
  • Gentamicin: 149 Daltons
  • Cefazolin: 477 Daltons
  • Erythropoietin: 30,400 Daltons
molecular weight high flux dialyzer
Molecular Weight High Flux Dialyzer

Blood

Dialysate

MW cutoff < 5,000 daltons (up to 20,000?)

protein binding
Protein Binding

albumin

albumin

albumin

Blood

Dialysate

= Drug

protein binding1
Protein Binding

Normal

Uremia

albumin

albumin

albumin

albumin

albumin

albumin

albumin

albumin

albumin

albumin

albumin

albumin

“uremic slime”

=Drug

Competitive inhibitors

volume of distribution
Volume of Distribution

Tissue Compartment

Plasma Compartment

Renal Elimination

Or Dialysis

optimizing therapy
Optimizing Therapy
  • Altering dose and dosing interval depends on efficacy and toxicity parameters
    • Peak effect for efficacy
      • aminoglycosides
    • Trough effect for efficacy/toxicity
      • digoxin, antiepileptics, aminoglycosides
    • Steady state for efficacy
      • antihypertensive agents
      • beta-lactam antibiotics
slide27

GFR

nl GFR

Continuous Infusion

Drug Concentration

Steady State

24

hours

48

72

96

120

144

slide28

kidney dysfunction

Accumulation at same dose and dosing interval

Drug Concentration

Normal function

Trough

24

hours

48

72

96

120

144

slide29

Lower dose, same dosing interval

Normal kidney function

Decreased kidney function

Drug Concentration

Max effective dose

Trough

24

96

hours

48

72

120

144

slide30

Same dose, normal kidney function

Extended interval in altered renal function

Max effective dose

Drug Concentration

Trough

Time (hrs)

time dependent killing
TIME Dependent Killing

Example: Vancomycin

HD TIW, MWF

Slope=k

slide33

This is the dosing regimen we were trying to emulate.

Matsuo et al. "Administration of Aminoglycosides to Hemodialysis Patients Immediately before Dialysis: a New Dosing Modality." Antimicrobial Agents and Chemotherapy 41.12 (1997): 2597-601. Print.

tobramycin course
Tobramycin Course

*Dose was held on 9/10

drug dosing for hemodialysis
Drug Dosing for Hemodialysis
  • Use recommendations from literature*
    • Dose for CrCl < 10-15 ml/min on HD
    • IV IDEALLY given TIW during/after HD
    • Supplemental dose post-HD if needed
  • Daily Dialysis
    • Very little literature (use professional judgment)
  • MONITOR
    • Subjective and objective efficacy and toxicity
    • Therapeutic drug monitoring if available (and PK calculations)

*See previous slides 30-32

drug levels in hd dialyzable
Drug Levels in HD (Dialyzable)

Cpeak

Cpre-HD

K off HD

Conc

K on HD

Next Dose

ctrough

Pre HDHDEnd HD

Time

redistribution phenomenon
Redistribution Phenomenon

Koff HD

Kon HD

Conc

Pre HD HD End HD

Time

points to remember
POINTS TO REMEMBER
  • MONITOR!!!
    • Therapeutic drug levels (if appropriate)
      • MUST be taken at the proper times
    • Subjective and objective signs of efficacy and toxicity
    • Watch for idiosyncratic or “expected” adverse drug events
risk factors for infection in peritoneal dialysis
Risk factors for Infection in Peritoneal Dialysis
  • Patient technique
  • Provider technique
  • Immunocompetence
  • Cormorbid disease states
peritonitis
Peritonitis
  • Incidence
    • 1 episode for every 12-24 patient months
  • Signs and Symptoms
    • Cloudy drainage
    • Abdominal pain
    • Fever
    • Nausea/vomiting
    • Fever > 37ºC
  • Diagnostic criteria
    • Dialysate WBC count > 100/mm3 (> 50% PMNs)
    • Organism on culture?
drug regimens to treat peritonitis
Drug Regimens to Treat Peritonitis
  • Several review articles on drug delivery using intraperitoneal route (IP)
    • Watch for compatibility issues*
  • Use International Society of PD Guidelines for the treatment of PD related peritonitis**
  • Use primary literature

*Intraperitoneal administration of drugs in peritoneal dialysis patients: A review of compatibility and guidance for clinical use peritoneal dialysis international 2009;29:5–15

.**International ad hoc committee on peritoneal dialysis related infections. International society for peritoneal dialysis - guidelines for the treatment of peritonitis in adults. Peritoneal dial int 2005;25:107-131.

treatment of peritonitis
Treatment of Peritonitis
  • Give intraperitoneally (IP) if possible
  • Empiric therapy
  • Cover both gram positive and negative
  • Combination first and third generation cephalosporin
    • Cefazolin and ceftazidime
  • Narrow coverage based on culture report
    • not always cultured
  • Complications
    • Fibrosis and scarring
peritoneal dialysis catheter infections
Peritoneal Dialysis Catheter Infections
  • Incidence
    • Once per 1-2 patient years
  • Organisms
    • staph aureus, staph epi, pseudomonas
  • Prophylaxis for nasal carriers of Staphylococcus aureus?
    • rifampin 300 mg BID x 5 days every three months
    • intranasal mupiricin BID x 5 days every month
    • exit-site mupiricin topically every day
pd dialyzability factors
PD Dialyzability Factors
  • Inflamed peritoneum during infection
  • Blood flow - may affect drug transfer
  • Dwell time
  • Residual renal function
  • Dialysate dextrose concentration- increase causes more ultrafiltration
  • Generally, high drug absorption but low drug clearance for PD
dosing drugs for patients on pd
Dosing Drugs for Patients on PD
  • Molecular size- not as important as HD, increased permeability
  • PB- highly PB not removed
  • Vd- Increased Vd means less removed, more absorbed into the body
  • Water solubility- required for removal
  • Ionization- highly ionized neither absorbed or removed
common agents to treat peritonitis
Common Agents to Treat Peritonitis
  • Tables from ISPD guidelines 2005 update
issues related to ip administration
Issues Related to IP Administration
  • Patient education
  • Compatibility
  • Clearance
    • Increased peritoneal membrane permeability during acute infection
    • Decreased permeability with fibrosis and sclerosis secondary to infection and inflammation
catheter related bacteremia crb
Catheter-Related Bacteremia (CRB)
  • “Biofilm infection”
  • Catheter removal creates a requirement for the use of temporary catheters and risk of their associated complications
    • Multiple procedures, hospitalization period, increased costs
    • Loss of central venous entry site
  • Dialysis patients must continue to receive dialysis treatments, therefore, catheter removal is not a feasible option

Beathard GA et. al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21(6):528-538

incidence of crb
Incidence of CRB
  • Rate is less than uncuffed catheters
    • Tunneled catheters: 1.6-5.5 episodes/1000 days
    • Uncuffed cathers: 3.8-6.6 episodes/1000 days
  • Morbidity and mortality due to metastatic infections: 3.2%-50%

Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538

pathogenesis
Pathogenesis
  • >99.9% bacteria grow as aggregated “sessile communities” attached to surfaces
  • Hallmark of biofilm-related infections: resistance to anti-microbials and host defenses
  • Develop in steps:
    • Microbial attachment to the catheter surface
    • Adhesion, growth and aggregation of cells into microcolonies
    • Maturation and dissemination of progeny cells for new colony formation

Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538

risk factors
Risk factors
  • Skin and nasal colonization with staphylococcus
  • Catheter hub colonization
  • Prolonged duration of usage
  • Thrombosis
  • History of previous CRB
  • Frequency of catheter manipulation
  • Diabetes mellitus
  • Iron over-load
  • immunocompromised

Beathard , et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538.

prophylaxis of crb
Prophylaxis of CRB
  • Local antiseptic application
  • Catheter placement
  • Systemic prophylactic antibiotics
  • Aspirin
  • Exit-site infection
    • Daily catheter site care
      • Cleansing site
      • Bandage covering site
  • “Lock” solutions

Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538.

diagnosis
Diagnosis
  • + blood culture
  • No other apparent source of infection
  • Symptomatic patient
  • Isolation of the same organism from a semiquantitative culture of the catheter tip (>15 colony-forming units)

National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Vascular Access. Am J Kidney Dis 2006; 48: S176-322.

clinical pearls
Clinical pearls
  • s. aureus, pseudomonas or candida species
    • Remove catheter
  • Other gram- or coagulase- staph. organisms
    • adjunctive antibiotic lock therapy for 3 weeks AND/OR
    • guidewire catheter exchange
  • Catheter locks to be used WITH systemic anti-microbial therapy
    • instill post HD, dwell until next HD, aspirate, instill fresh lock post HD repeat TIW with HD
  • Treat for 7-14 days

Mermel, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 49:1-45.

exit site infections
Exit Site Infections
  • Redness, crusting, and/or exudate
  • NO systemic symptoms
  • Negative blood cultures
    • Apply topical antibiotics
    • If tunnel drainage - intravenous antibiotics
    • No response - remove the catheter.

National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Vascular Access. Am J Kidney Dis 2006; 48: S176-322.

treatment crb
Treatment CRB
  • Intravenous antibiotics
  • Remove the catheter
    • Symptomatic >36 hours
    • Patient is unstable.
  • Stable, asymptomatic
    • Change catheter over a guidewire
    • Minimum of 3 weeks of systemic antibiotic therapy
  • New permanent access
    • Placed AFTER course of antibiotics AND
    • Blood cultures, have been negative for at least 48 hours

National Kidney Foundation: KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Vascular Access. Am J Kidney Dis 2006; 48: S176-322.

empiric treatment
Empiric Treatment
  • Cefazollin OR vancomycin plus gram-negative rod coverage

(Vancomycin plus gentamicin)

  • Vancomycin: 20 mg/kg loading dose, then 500 mg each subsequent dialysis session
  • Gentamicin (or tobramycin): 1mg/kg, not to exceed 100mg after each dialysis session
  • Ceftazidime: 1g IV after each dialysis session
cath lock
“Cath lock”
  • Concentrated antibiotic solution with/without anticoagulant agent. Dwelled in lumen of the dialysis catheter at the end of each dialysis session until the beginning of next session
  • Goal: sterilize the catheter biofilm while salvaging the catheter
  • Antibiotic concentrations must be 100-1000 times greater to kill sessile bacteria within a biofilm

Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 49:1-45.

antibiotic lock solutions
Antibiotic lock solutions
  • Success rate
    • 87%–100% gram-negative pathogens
    • 75%– 84% Staphylococcus epidermidis
    • 40%–55% for hemodialysis-associated CRBSI due to S. aureus
  • Clinical success of salvaging the catheter and eradicating CRB depends upon the bacterial pathogen involved

Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Inf Dis. 2009; 49:1-45.

examples of cath lock formulas
Examples of Cath-Lock Formulas
  • Gentamicin 5mg/ml and heparin 5000 U/mL
  • Cefazolin 10 mg/ml + gentamicin 5 mg/ml+ heparin 1000 U/ml kim
  • Vancomycin 25mg/mL+gentamicin sulphate 40mg/mL +heparin 5000 U/mL (al)
  • Cefotaxime (10mg/ml) and heparin 5000 U/mL
  • 1. McIntyre CW, et al. Kidney International. 2004; 66:801-805.
  • 2.Kim SH, et al. Kidney International 2006; 69:161-164.
  • 3. Al-Hwiesh AK. Saudi J Kidney Dis Transplant. 2008; 19(4):593-602.
  • Saxena AK, Panhotra BR, Sundaram DS, et al. Nephrology. 2006; 11:299-305.
administration of an antibiotic lock
Administration of an antibiotic lock

Image derived from: Allon M. Current management of vascular access. Clin J Am Soc Nephrol. 2007; 2:786-800.