American Nephrology Nurses Association

Sarah Tomasello, PharmD, BCPSClinical Associate Professor

Rutgers, The State University of New JerseyClinical Specialist – Nephrology

Robert Wood Johnson University HospitalNew Brunswick, NJ

stomasel@rci.rutgers.edu

Management of Common Types of Infections in Patients Receiving

Chronic Renal Replacement Therapy

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• 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• 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?• 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

• Glycopeptide• Empiric therapy for gram+ (MRSA)• Concerns

– Resistance

• 1 gram every week• 1 gram followed by 500mg Q HD

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

• “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 BacteriaCommon to

dialysis patients

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

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

A = AbsorptionD = DistributionM = MetabolismE = Elimination/Excretion

Alterations in Kidney Dysfunction

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

Volume of Distribution (Vd)

Volume of Distribution Plasma 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

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

• Increased fluid volume – Interdialytic weight gain– Effects drug “peak”concentration

• Rapid fluid removal, – Redistribution (re-equilibrium) – Affects therapeutic drug monitoring (TDM) in

serum

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

Hemodialysis System

Hollow Fiber Dialyzer

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

• Digoxin: 781 Daltons• Vancomycin: 1,486 Daltons• Gentamicin: 149 Daltons• Cefazolin: 477 Daltons• Erythropoietin: 30,400 Daltons

Molecular Weight High Flux Dialyzer

Blood Dialysate

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

Protein Binding

Blood Dialysate

albumin

albumin

albumin

= Drug

Protein BindingUremia

albumin

albumin

albumin

albumin

albumin

Competitive inhibitors

“uremic slime”

albumin

albumin

albumin

albumin

albumin

albumin albumin

=Drug

Normal

Volume of Distribution

Tissue Compartment Plasma Compartment

Or Dialysis

Renal Elimination

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

24 967248 120 144

Dru

g C

once

ntra

tion

hours

Continuous Infusion

Steady State

GFR nl GFR

24 967248 120 144hours

Accumulation at same dose and dosing interval

kidney dysfunction

Normal function

Trough

24 967248 120 144hours

Lower dose, same dosing interval

Normal kidney function

Decreased kidney function

Max effective dose

Trough

Time (hrs)

Dru

g C

on

cen

trati

on Max effective dose

Trough

Same dose, normal kidney function

Extended interval in altered renal function

TIME Dependent KillingExample: Vancomycin HD TIW, MWF

Slope=

k

Concentration Dependent Killing

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.

This is the dosing regimen we were trying to emulate.

Dosing Tobramycin “Pre-HD”

310mg post HD

Tobramycin Course

Date Time Dose Comment

9/2 12:00 am 90 mg IVPB 1 mg/kg (4:30pm)

9/3 12:00 pm 240 mg IVPB Pre HD

9/5 5:00 am 310 mg IVPB Pre HD

9/8 12:00 pm 310 mg IVPB Post HD

*9/12 11:00 am 280 mg IVPB Post HD

*Dose was held on 9/10

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)

ConcConc

TimeTime

Pre HDPre HD HDHD End HD End HD

CCpeakpeakCCpre-HDpre-HD

Next DoseNext Dose

K off HD

K on H

Dctrough

Redistribution Phenomenon

ConcConc

Time Time

Pre HD HD End HDPre HD HD End HD

Kon H

D

Koff HD

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

• Patient technique• Provider technique• Immunocompetence• Cormorbid disease states

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

• 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• 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

• 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• 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

• 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

• Tables from ISPD guidelines 2005 update

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)

• “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

50Beathard GA et. al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21(6):528-538

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%

51

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

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:1. Microbial attachment to the catheter surface2. Adhesion, growth and aggregation of cells

into microcolonies 3. Maturation and dissemination of progeny cells

for new colony formation

52

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

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

53Beathard , et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538.

Prophylaxis of CRB

Local antiseptic applicationCatheter placementSystemic prophylactic antibioticsAspirinExit-site infection

Daily catheter site careCleansing siteBandage covering site

“Lock” solutions

54

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

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)

55

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

322.

Clinical pearlss. 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 therapyinstill post HD, dwell until next HD, aspirate,

instill fresh lock post HD repeat TIW with HDTreat for 7-14 days

56

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

• Redness, crusting, and/or exudate• NO systemic symptoms • Negative blood cultures

1. Apply topical antibiotics2. If tunnel drainage - intravenous

antibiotics 3. No response - remove the catheter.

57

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

S176-322.

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

58

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

322.

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”• 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

60

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

• 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

61

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 Formulas1. Gentamicin 5mg/ml and heparin 5000 U/mL2. Cefazolin 10 mg/ml + gentamicin 5 mg/ml+

heparin 1000 U/ml kim3. Vancomycin 25mg/mL+gentamicin sulphate

40mg/mL +heparin 5000 U/mL (al)4. 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):593-602.4.Saxena AK, Panhotra BR, Sundaram DS, et al. Nephrology. 2006; 11:299-305.

Administration of an antibiotic lock

63Image derived from: Allon M. Current management of vascular access. Clin J Am Soc

Nephrol. 2007; 2:786-800.

QUESTIONS?