Antibiotic Dosing During Renal Failure

Lecture to 3rd year pharmacy students in an ID elective

1. Antibiotic Dosing Antibiotic Dosing
During Renal During Renal
FailureFailureFebruary 1, 2010February 1, 2010
Sarah Nelson, Pharm.D.Sarah Nelson, Pharm.D.
Critical Care Pharmacy ResidentCritical Care Pharmacy Resident

2. 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

3. 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 9
thth
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

4. 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

5. 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

6. Renal ExcretionRenal Excretion
http://www.unckidneycenter.org/images/glomerulus.jpg

7. Risk Factors/Markers Risk Factors/Markers
of Renal Impairmentof Renal 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

8. 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
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

9. 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

10. 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
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

11. 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 m
22
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

12. Cockroft-GaultCockroft-Gault
ESTIMATES renal functionESTIMATES renal function
Measures the rate of creatinine Measures the rate of creatinine
clearance via the glomerulusclearance via 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
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

13. Cockroft-GaultCockroft-Gault
(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

14. Weight CalculationsWeight Calculations
IBWIBW
females females (kg)= 45.5 + 2.3(height(kg)= 45.5 + 2.3(height
inches inches - 60)- 60)
IBWIBW
malesmales(kg)= 50 + 2.3(height(kg)= 50 + 2.3(height
inches inches - 60)- 60)
ABW= IBW + 0.4(actual weight – IBW)ABW= IBW + 0.4(actual weight – IBW)

15. Cockroft-GaultCockroft-Gault
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

16. 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 m
22
CrCl calculated with Cockroft-Gault: 37 mL/min/1.73 mCrCl calculated with Cockroft-Gault: 37 mL/min/1.73 m
22
SCr Weight Height
1.9 mg/dL 57 kg 5'3"

17. 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 m
22
CrCl calculated with Cockroft-Gault: 33 mL/min/1.73 mCrCl calculated with Cockroft-Gault: 33 mL/min/1.73 m
22
SCr Weight Height
2.85 mg/dL 86 kg 5‘10"

18. 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
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

19. 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

20. 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

21. Factors to Consider Factors to Consider
when Adjusting Dosewhen Adjusting 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

22. Stages of Kidney Stages of Kidney
DiseaseDisease
StageStage DescriptionDescription GFR (mL/min/1.73 mGFR (mL/min/1.73 m
22
))
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

23. 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. 3
rd
Ed.
USA: Lippincott, Williams, and Wilkins. 448-453.

24. 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. 3
rd
Ed.
USA: Lippincott, Williams, and Wilkins. 448-453.

25. 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 m
22
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

26. Adjusting Adjusting
Antimicrobials During Antimicrobials During
DialysisDialysis
1.1.Determine pt’s underlying renal functionDetermine pt’s underlying renal function
2.2.Determine kinetics of antimicrobial in Determine kinetics of antimicrobial in
dialysisdialysis
Molecule size vs. filter pore sizeMolecule size vs. filter pore size
Volume of distribution of antimicrobialVolume of distribution of antimicrobial
Decrease dose as Decrease dose as
recommended/clinically appropriaterecommended/clinically appropriate
Check peaks/troughs as needed to Check peaks/troughs as needed to
avoid accumulation or toxicityavoid accumulation or toxicity

27. 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’

28. Example #1: Example #1:
FluconazoleFluconazole
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

29. Example #1: Example #1:
FluconazoleFluconazole
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 m
22
Cockroft-Gault: 16 ml/min/1.73 mCockroft-Gault: 16 ml/min/1.73 m
22

30. Example #1: Example #1:
FluconazoleFluconazole
DiflucanDiflucan
®®
package insert states: package insert states:
Recommended Dose: 100mg PO dailyRecommended Dose: 100mg PO daily

31. 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/dL1.1mg/dL1.1mg/dL1.24mg/dL1.24mg/dL1.45mg/dL1.45mg/dL
WeightWeight HeightHeight UOUO
87 kg87 kg 5’4”5’4” 44 mL/hour44 mL/hour

32. 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 m
22
Cockroft-Gault: 37 mL/min/1.73 mCockroft-Gault: 37 mL/min/1.73 m
22

33. 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

34. Example #3: Example #3:
LevofloxacinLevofloxacin
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

35. Example #3: Example #3:
LevofloxacinLevofloxacin
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 m
22
Cockroft-Gault: 45 mL/min/1.73 mCockroft-Gault: 45 mL/min/1.73 m
22

36. Example #3: Example #3:
LevofloxacinLevofloxacin

37. Example #3: Example #3:
LevofloxacinLevofloxacin
Recommended dose: 750mg every other dayRecommended dose: 750mg every other day

38. 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