antibiotic dosing during renal failure

Antibiotic Dosing Antibiotic Dosing During Renal During Renal FailureFailureFebruary 1, 2010February 1, 2010Sarah Nelson, Pharm.D.Sarah Nelson, Pharm.D.

Critical Care Pharmacy ResidentCritical Care Pharmacy Resident

ObjectivesObjectives

Explain the necessity of dose Explain the necessity of dose adjustments during renal impairmentadjustments during renal impairment

Demonstrate how to calculate GFR using Demonstrate how to calculate GFR using various meansvarious means

Compare various types of dialysis and Compare various types of dialysis and their associated dosing adjustmentstheir associated dosing adjustments

Utilize standard practice references to Utilize standard practice references to identify dosage adjustment identify dosage adjustment recommendationsrecommendations

Kidney DiseaseKidney Disease

Over 19 million adults have chronic Over 19 million adults have chronic kidney diseasekidney disease ~80,000 new diagnoses/year~80,000 new diagnoses/year

Kidney disease is the 9Kidney disease is the 9thth leading cause leading cause of death of death

Wargo et al. Comparison of the Modification of Diet in Renal Disease and Cockroft-Gault Equations for Antimicrobial Dosage Adjustments. The Annals of Pharmacotherapy. 2006;40:1248-1253

Importance of Renal Importance of Renal FunctionFunction Kidney and liver are major routes of Kidney and liver are major routes of

elimination for antimicrobials & metaboliteselimination for antimicrobials & metabolites Most antimicrobials follow first order kineticsMost antimicrobials follow first order kinetics

Plasma levels for antimicrobials are a Plasma levels for antimicrobials are a function of:function of: dose, bioavailability, Vd, rate of metabolism, & dose, bioavailability, Vd, rate of metabolism, &

rate of excretionrate of excretion Decreased excretion=increased plasma levelsDecreased excretion=increased plasma levels

Livornese et al. Use of antibacterial agents in renal failure. Infect Dis Clin N Am. 2004;18:551-579

Importance of Renal Importance of Renal FunctionFunction

Consequences of increased plasma Consequences of increased plasma antimicrobial levels:antimicrobial levels: Neurotoxicity (ex. aminoglycosides)Neurotoxicity (ex. aminoglycosides) Nephrotoxicity (ex. vancomycin)Nephrotoxicity (ex. vancomycin) Thrombocytopenia (ex. TMX-SMP)Thrombocytopenia (ex. TMX-SMP)

Concentration of antimicrobials may not Concentration of antimicrobials may not attain adequate levelsattain adequate levels Urinary tract infectionsUrinary tract infections

NitrofurantionNitrofurantion

Renal ExcretionRenal Excretion

http://www.unckidneycenter.org/images/glomerulus.jpg

Risk Factors/Markers of Risk Factors/Markers of Renal ImpairmentRenal Impairment

Clinically observed:Clinically observed: AgeAge Urine outputUrine output

Laboratory parameters:Laboratory parameters: Serum creatinineSerum creatinine Urine creatinineUrine creatinine Urine proteinUrine protein Urine RBCsUrine RBCs

Calculating GFRCalculating GFR GFR: glomerular filtration rateGFR: glomerular filtration rate

Most accurate measure of kidney functionMost accurate measure of kidney function Can be directly measured but is costly and Can be directly measured but is costly and

often inaccurateoften inaccurate Estimate based on substances that are Estimate based on substances that are

filtered in the glomerulusfiltered in the glomerulus Must be freely filteredMust be freely filtered Must have minimal secretion/reabsorption in Must have minimal secretion/reabsorption in

renal tubulesrenal tubules i.e. creatininei.e. creatinine


Calculating GFRCalculating GFR

2 current techniques used to estimate renal 2 current techniques used to estimate renal functionfunction Modification of Diet in Renal Disease (MDRD)Modification of Diet in Renal Disease (MDRD)

Estimates GFREstimates GFR

Cockroft-GaultCockroft-Gault Estimates creatinine clearance (CrCl)Estimates creatinine clearance (CrCl)

Moranville, M et al. Implications of using modification of diet in renal disease versus Cockroft-Gault equations for renal dosing adjustments. Am J Health-Syst Pharm. 2009;66:154-161

MDRDMDRD Developed as an alternate approach for Developed as an alternate approach for

staging renal diseasestaging renal disease Automatically calculated by most Automatically calculated by most

institutional laboratory softwareinstitutional laboratory software Supported by NKDEP to increase detection of Supported by NKDEP to increase detection of

renal impairmentrenal impairment Is not validated for use in medication Is not validated for use in medication

dosingdosing Manufacturer dosage adjustments based on Manufacturer dosage adjustments based on

creatinine clearance (Cockroft-Gault), not GFRcreatinine clearance (Cockroft-Gault), not GFR


MDRDMDRD 2 different equations exist2 different equations exist

6 variable: 6 variable: 170 x SCr170 x SCr–0.999–0.999 x age x age–0.176–0.176 x SUN x SUN–0.170 –0.170 x SAlbx SAlb+0.318+0.318 x 1.180 x 1.180

(African American) x 0.762 (female)(African American) x 0.762 (female) 4 variable: 4 variable:

186.3 x Scr186.3 x Scr--1.154--1.154 x age x age -0.203-0.203 x 1.210 (African American) x x 1.210 (African American) x 0.742 (female)0.742 (female)

Units: mL/min/1.73 mUnits: mL/min/1.73 m22

Pros of the MDRD More accurate during severe renal impairmentMore accurate during severe renal impairment Accounts for ethnicityAccounts for ethnicity

Cons of the MDRDCons of the MDRD Neither address weight, heightNeither address weight, height Cannot use for dose adjustmentsCannot use for dose adjustments

Golik et al. Comparison of Dosing Recommendations for Antimicrobial Drugs Based on Two Methods for Assessing Kidney Function: Cockroft-Gault and Modification of Diet in Renal Disease. Pharmacotherapy. 2008;28(9):1125-1132

Cockroft-GaultCockroft-Gault

ESTIMATES renal functionESTIMATES renal function Measures the rate of creatinine clearance Measures the rate of creatinine clearance

via the glomerulusvia the glomerulus Creatinine: breakdown product of muscleCreatinine: breakdown product of muscle

Freely filteredFreely filtered Fluctuates with diet, muscle mass, medicationsFluctuates with diet, muscle mass, medications

Used when studying pharmacokinetics of Used when studying pharmacokinetics of medications coming/on the marketmedications coming/on the market



(140 – age) x weight(140 – age) x weight x 0.85 (females) x 0.85 (females)

( 72 x SCr)( 72 x SCr)

Use actual body weight if patient is <IBWUse actual body weight if patient is <IBW Use IBW if the actual body weight is Use IBW if the actual body weight is

<25% above IBW<25% above IBW Use ABW (adjusted body weight) if the Use ABW (adjusted body weight) if the

actual body weight is >25% above IBWactual body weight is >25% above IBW

Golik et al. Comparison of Dosing Recommendations for Antimicrobial Drugs Based on Two Methods for Assessing Kidney Function: Cockroft-Gault and Modification of Diet in Renal Disease. Pharmacotherapy. 2008;28(9):1125-1132

Weight CalculationsWeight Calculations

IBWIBWfemales females (kg)= 45.5 + 2.3(height(kg)= 45.5 + 2.3(heightinches inches - 60)- 60)

IBWIBWmalesmales(kg)= 50 + 2.3(height(kg)= 50 + 2.3(heightinches inches - 60)- 60)

ABW= IBW + 0.4(actual weight – IBW)ABW= IBW + 0.4(actual weight – IBW)


Pros to Cockroft-GaultPros to Cockroft-Gault Easy to make dosage recommendationsEasy to make dosage recommendations Easy to calculateEasy to calculate

Cons to Cockroft-GaultCons to Cockroft-Gault Not a true marker of renal impairmentNot a true marker of renal impairment May OVERESTIMATE renal function in May OVERESTIMATE renal function in

elderly populationelderly population Some clinicians round SCr to 1.0mg/dLSome clinicians round SCr to 1.0mg/dL

TIME OUT!!TIME OUT!! Example #1: Example #1:

36 y/o Caucasian female with renal disease due to 36 y/o Caucasian female with renal disease due to IDDM. IDDM.

Current labs:Current labs:

GFR calculated with MDRD: 32 mL/min/1.73 mGFR calculated with MDRD: 32 mL/min/1.73 m22

CrCl calculated with Cockroft-Gault: 37 mL/min/1.73 mCrCl calculated with Cockroft-Gault: 37 mL/min/1.73 m22

SCr Weight Height

1.9 mg/dL 57 kg 5'3"

Pause for the Cause!Pause for the Cause! Example #2: 62 y/o AAM with renal disease secondary Example #2: 62 y/o AAM with renal disease secondary

to malignant hypertensionto malignant hypertension Current labs:Current labs:

Weight to use: 86 kgWeight to use: 86 kg

GFR calculated with GFR: 27 mL/min/1.73 mGFR calculated with GFR: 27 mL/min/1.73 m22

CrCl calculated with Cockroft-Gault: 33 mL/min/1.73 mCrCl calculated with Cockroft-Gault: 33 mL/min/1.73 m22

SCr Weight Height

2.85 mg/dL 86 kg 5‘10"

Which should I use?Which should I use?

Both!Both! Medication adjustments should be initially Medication adjustments should be initially

based on creatinine clearance (Cockroft-based on creatinine clearance (Cockroft-Gault)Gault)

Include the patient’s clinical picture when Include the patient’s clinical picture when determining optimal dosingdetermining optimal dosing

MDRD is more accurate as the severity of MDRD is more accurate as the severity of renal disease increases renal disease increases


Beware!Beware!

Factors that falsely ELEVATE creatinineFactors that falsely ELEVATE creatinine DehydrationDehydration TMP-SMXTMP-SMX

Factors that falsely DECREASE creatinineFactors that falsely DECREASE creatinine Small muscle massSmall muscle mass Liver diseaseLiver disease

Dosing in Renal FailureDosing in Renal Failure

1.1. Calculate CrCl using Cockroft-gault Calculate CrCl using Cockroft-gault formulaformula

2.2. Use a reference to identify renal dosing Use a reference to identify renal dosing parametersparameters

3.3. Identify suggested dosage adjustmentIdentify suggested dosage adjustment

4.4. Determine if the dose reduction is Determine if the dose reduction is logical and appropriate for your patientlogical and appropriate for your patient

Factors to Consider when Factors to Consider when Adjusting DoseAdjusting Dose

CrCl is a STARTING POINT!CrCl is a STARTING POINT! Remember this is just an ESTIMATERemember this is just an ESTIMATE

Toxicities of antibioticToxicities of antibiotic Cephalosporin vs. aminoglycosideCephalosporin vs. aminoglycoside

Clinical conditionClinical condition SCr trends, sepsis, stability of patientSCr trends, sepsis, stability of patient

Infection being treatedInfection being treated Meningitis vs. pneumonia vs. bacteremiaMeningitis vs. pneumonia vs. bacteremia

Target organismTarget organism ESBL vs. intermediate resistance vs. susceptibleESBL vs. intermediate resistance vs. susceptible

Stages of Kidney DiseaseStages of Kidney DiseaseStageStage DescriptionDescription GFR (mL/min/1.73 mGFR (mL/min/1.73 m22))

11 Kidney damage with Kidney damage with normal GFRnormal GFR

≥≥9090

22 Kidney damage with Kidney damage with mild ↓ in GFRmild ↓ in GFR

60-8960-89

33 Moderate ↓ GFRModerate ↓ GFR 30-5930-59

44 Severe ↓ GFRSevere ↓ GFR 15-2915-29

55 Kidney FailureKidney Failure <15 (or dialysis)<15 (or dialysis)

Adapted from the National Kidney Foundation

DialysisDialysis

Use of a Use of a semi permeablesemi permeable membrane to membrane to remove solutes that are ineffectively remove solutes that are ineffectively cleared via the kidney during renal failurecleared via the kidney during renal failure Pore size of membrane determines the Pore size of membrane determines the

maximum size solute that can be removedmaximum size solute that can be removed i.e. large molecules (vancomycin)=not removedi.e. large molecules (vancomycin)=not removed

Volume of distribution determines extent of Volume of distribution determines extent of removalremoval i.e. large Vd (digoxin)=not removedi.e. large Vd (digoxin)=not removed

Rowland, Malcolm (1995). Clinical Pharmacokinetics: Concepts and Applications. 3rd Ed.USA: Lippincott, Williams, and Wilkins. 448-453.

DialysisDialysis

Manufacturer’s usually provide dosing Manufacturer’s usually provide dosing recommendationsrecommendations Decrease of total doseDecrease of total dose Increase in interval of dose (after dialysis)Increase in interval of dose (after dialysis) Decrease of dose plus a supplemental dose Decrease of dose plus a supplemental dose

after dialysisafter dialysis

Use pharmacokinetics (Vd, molecule Use pharmacokinetics (Vd, molecule size) to make an educated guesssize) to make an educated guess

Rowland, Malcolm (1995). Clinical Pharmacokinetics: Concepts and Applications. 3rd Ed.USA: Lippincott, Williams, and Wilkins. 448-453.

Continuous DialysisContinuous Dialysis CRRT: continuous renal replacement therapyCRRT: continuous renal replacement therapy Primary use in pts that are hemodynamically Primary use in pts that are hemodynamically

unstableunstable ICU settingICU setting Septic patients on ≥ 1 antimicrobialSeptic patients on ≥ 1 antimicrobial

Slow, continuous solute removalSlow, continuous solute removal Various types (filtration, ultrafiltration, etc.)Various types (filtration, ultrafiltration, etc.) Depending on type of CRRT, usually correlates Depending on type of CRRT, usually correlates

with a CrCl of 50 mL/min/1.73 mwith a CrCl of 50 mL/min/1.73 m22

Most references include specific information for Most references include specific information for dosing during CRRTdosing during CRRT

Trotman et al. Antibiotic Dosing in Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy. CID. 2005;41:1159-1166

Adjusting Antimicrobials Adjusting Antimicrobials During DialysisDuring Dialysis

1.1. Determine pt’s underlying renal functionDetermine pt’s underlying renal function2.2. Determine kinetics of antimicrobial in Determine kinetics of antimicrobial in

dialysisdialysis1.1. Molecule size vs. filter pore sizeMolecule size vs. filter pore size2.2. Volume of distribution of antimicrobialVolume of distribution of antimicrobial

3.3. Decrease dose as Decrease dose as recommended/clinically appropriaterecommended/clinically appropriate

4.4. Check peaks/troughs as needed to Check peaks/troughs as needed to avoid accumulation or toxicityavoid accumulation or toxicity

ReferencesReferences

Package InsertPackage Insert Online ResourcesOnline Resources

Up-to-Date/Lexi-compUp-to-Date/Lexi-comp MicromedexMicromedex Facts & ComparisonsFacts & Comparisons

Sanford GuideSanford Guide ‘‘The Green Book’The Green Book’

Example #1: FluconazoleExample #1: Fluconazole A.Y. is a 46 y/o AAF who was recently admitted A.Y. is a 46 y/o AAF who was recently admitted

for cadaveric kidney transplant. The transplant for cadaveric kidney transplant. The transplant protocol calls for antifungal coverage protocol calls for antifungal coverage (fluconazole 200mg PO daily) for 6 months as (fluconazole 200mg PO daily) for 6 months as the patient tapers off immunosuppressive the patient tapers off immunosuppressive medications. medications.

Labs:Labs: Height: 5’6”Height: 5’6” Weight: 68 kgWeight: 68 kg SCr: 4.68 mg/dLSCr: 4.68 mg/dL UO: 40 cc/hrUO: 40 cc/hr

Example #1: FluconazoleExample #1: Fluconazole Weight:Weight:

IBW: 59.3 kgIBW: 59.3 kg % above IBW: 14%% above IBW: 14% Use ABW for calculationUse ABW for calculation

Calculated renal function:Calculated renal function: MDRD: 12 mL/min/1.73 mMDRD: 12 mL/min/1.73 m22

Cockroft-Gault: 16 ml/min/1.73 mCockroft-Gault: 16 ml/min/1.73 m22

Example #1: FluconazoleExample #1: Fluconazole

DiflucanDiflucan®® package insert states: package insert states:

Recommended Dose: 100mg PO dailyRecommended Dose: 100mg PO daily

Example #2: Pip/TazoExample #2: Pip/Tazo 72 y/o Hispanic female initially admitted for an 72 y/o Hispanic female initially admitted for an

acute decompensation of CHF, develops a acute decompensation of CHF, develops a Klebsiella pneumoniae Klebsiella pneumoniae UTI. Sensitivities come UTI. Sensitivities come back, resistant to everything except Zosyn. The back, resistant to everything except Zosyn. The team asks you for a recommendation . . . . team asks you for a recommendation . . . .

Labs:Labs:

1/191/19 1/201/20 1/221/22 1/231/23

ScrScr 0.9mg/dL0.9mg/dL 1.1mg/dL1.1mg/dL 1.24mg/dL1.24mg/dL 1.45mg/dL1.45mg/dL

WeightWeight HeightHeight UOUO

87 kg87 kg 5’4”5’4” 44 mL/hour44 mL/hour

Example #2: Pip/TazoExample #2: Pip/Tazo

WeightWeight IBW: 54.7 kgIBW: 54.7 kg % above Ideal: 59%% above Ideal: 59% Use ABW!!! (67.6 kg)Use ABW!!! (67.6 kg)

Calculated Renal FunctionCalculated Renal Function MDRD: 38 mL/min/1.73 mMDRD: 38 mL/min/1.73 m22

Cockroft-Gault: 37 mL/min/1.73 mCockroft-Gault: 37 mL/min/1.73 m22

Example #2: Pip/TazoExample #2: Pip/Tazo Package Insert:Package Insert:

Recommended Dose: Recommended Dose: 2.25gm IV every 6 hours2.25gm IV every 6 hours

Example #3: LevofloxacinExample #3: Levofloxacin

A 55 y/o Asian male is admitted for A 55 y/o Asian male is admitted for community-acquired pneumonia. It is community-acquired pneumonia. It is decided that his condition warrants IV decided that his condition warrants IV antibiotics. The physician wants you to antibiotics. The physician wants you to recommend an appropriate dose of recommend an appropriate dose of levofloxacinlevofloxacin

Labs:Labs: Height: 5’7”Height: 5’7” Weight: 67 kgWeight: 67 kg SCr: 1.75 mg/dLSCr: 1.75 mg/dL


WeightWeight IBW: 66.1 kgIBW: 66.1 kg % above Ideal: 1%% above Ideal: 1% Use actual body weightUse actual body weight

Calculated Renal FunctionCalculated Renal Function MDRD: 43 mL/min/1.73 mMDRD: 43 mL/min/1.73 m22

Cockroft-Gault: 45 mL/min/1.73 mCockroft-Gault: 45 mL/min/1.73 m22


Recommended dose: 750mg every other dayRecommended dose: 750mg every other day

ConclusionsConclusions

Antimicrobial dose adjustments must be Antimicrobial dose adjustments must be made to avoid supratherapeutic serum made to avoid supratherapeutic serum levels and toxicity in renal failurelevels and toxicity in renal failure

Cockroft-Gault equation should be used to Cockroft-Gault equation should be used to determine antimicrobial dose adjustmentsdetermine antimicrobial dose adjustments

MDRD is useful in pts with severe renal MDRD is useful in pts with severe renal failurefailure

The clinical picture should be utilized to The clinical picture should be utilized to determine the correct antimicrobial dosedetermine the correct antimicrobial dose

antibiotic dosing during renal failure

Documents

renal dosing adjustments

renal failure

renal tubules

overestimate renal function

detection of renal impairment

renal excretion http

age x weight x

cockroftgault easy