Antibiotic Dosing During Renal Failure

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Lecture to 3rd year pharmacy students in an ID elective

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Antibiotic Dosing During Renal Failure

  1. 1. Antibiotic Dosing During Renal Failure February 1, 2010 Sarah Nelson, Pharm.D. Critical Care Pharmacy Resident
  2. 2. Objectives <ul><li>Explain the necessity of dose adjustments during renal impairment </li></ul><ul><li>Demonstrate how to calculate GFR using various means </li></ul><ul><li>Compare various types of dialysis and their associated dosing adjustments </li></ul><ul><li>Utilize standard practice references to identify dosage adjustment recommendations </li></ul>
  3. 3. Kidney Disease <ul><li>Over 19 million adults have chronic kidney disease </li></ul><ul><ul><li>~80,000 new diagnoses/year </li></ul></ul><ul><li>Kidney disease is the 9 th leading cause of death </li></ul>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. 4. Importance of Renal Function <ul><li>Kidney and liver are major routes of elimination for antimicrobials & metabolites </li></ul><ul><ul><li>Most antimicrobials follow first order kinetics </li></ul></ul><ul><li>Plasma levels for antimicrobials are a function of: </li></ul><ul><ul><li>dose, bioavailability, Vd, rate of metabolism, & rate of excretion </li></ul></ul><ul><ul><li>Decreased excretion=increased plasma levels </li></ul></ul>Livornese et al. Use of antibacterial agents in renal failure. Infect Dis Clin N Am. 2004;18:551-579
  5. 5. Importance of Renal Function <ul><li>Consequences of increased plasma antimicrobial levels: </li></ul><ul><ul><li>Neurotoxicity (ex. aminoglycosides) </li></ul></ul><ul><ul><li>Nephrotoxicity (ex. vancomycin) </li></ul></ul><ul><ul><li>Thrombocytopenia (ex. TMX-SMP) </li></ul></ul><ul><li>Concentration of antimicrobials may not attain adequate levels </li></ul><ul><ul><li>Urinary tract infections </li></ul></ul><ul><ul><ul><li>Nitrofurantion </li></ul></ul></ul>
  6. 6. Renal Excretion http://www.unckidneycenter.org/images/glomerulus.jpg
  7. 7. Risk Factors/Markers of Renal Impairment <ul><li>Clinically observed: </li></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>Urine output </li></ul></ul><ul><li>Laboratory parameters: </li></ul><ul><ul><li>Serum creatinine </li></ul></ul><ul><ul><li>Urine creatinine </li></ul></ul><ul><ul><li>Urine protein </li></ul></ul><ul><ul><li>Urine RBCs </li></ul></ul>
  8. 8. Calculating GFR <ul><li>GFR: glomerular filtration rate </li></ul><ul><ul><li>Most accurate measure of kidney function </li></ul></ul><ul><ul><li>Can be directly measured but is costly and often inaccurate </li></ul></ul><ul><li>Estimate based on substances that are filtered in the glomerulus </li></ul><ul><ul><li>Must be freely filtered </li></ul></ul><ul><ul><li>Must have minimal secretion/reabsorption in renal tubules </li></ul></ul><ul><ul><li>i.e. creatinine </li></ul></ul>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. 9. Calculating GFR <ul><li>2 current techniques used to estimate renal function </li></ul><ul><ul><li>Modification of Diet in Renal Disease (MDRD) </li></ul></ul><ul><ul><ul><li>Estimates GFR </li></ul></ul></ul><ul><ul><li>Cockroft-Gault </li></ul></ul><ul><ul><ul><li>Estimates creatinine clearance (CrCl) </li></ul></ul></ul>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. 10. MDRD <ul><li>Developed as an alternate approach for staging renal disease </li></ul><ul><li>Automatically calculated by most institutional laboratory software </li></ul><ul><ul><li>Supported by NKDEP to increase detection of renal impairment </li></ul></ul><ul><li>Is not validated for use in medication dosing </li></ul><ul><ul><li>Manufacturer dosage adjustments based on creatinine clearance (Cockroft-Gault), not GFR </li></ul></ul>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. 11. MDRD <ul><li>2 different equations exist </li></ul><ul><ul><li>6 variable: </li></ul></ul><ul><ul><li>170 x SCr –0.999 x age –0.176 x SUN –0.170 x SAlb +0.318 x 1.180 (African American) x 0.762 (female) </li></ul></ul><ul><ul><li>4 variable: </li></ul></ul><ul><ul><li>186.3 x Scr --1.154 x age -0.203 x 1.210 (African American) x 0.742 (female) </li></ul></ul><ul><li>Units: mL/min/1.73 m 2 </li></ul><ul><li>Pros of the MDRD </li></ul><ul><ul><li>More accurate during severe renal impairment </li></ul></ul><ul><ul><li>Accounts for ethnicity </li></ul></ul><ul><li>Cons of the MDRD </li></ul><ul><ul><li>Neither address weight, height </li></ul></ul><ul><ul><li>Cannot use for dose adjustments </li></ul></ul>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. 12. Cockroft-Gault <ul><li>ESTIMATES renal function </li></ul><ul><li>Measures the rate of creatinine clearance via the glomerulus </li></ul><ul><ul><li>Creatinine: breakdown product of muscle </li></ul></ul><ul><ul><ul><li>Freely filtered </li></ul></ul></ul><ul><ul><ul><li>Fluctuates with diet, muscle mass, medications </li></ul></ul></ul><ul><li>Used when studying pharmacokinetics of medications coming/on the market </li></ul>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. 13. Cockroft-Gault <ul><li>(140 – age) x weight x 0.85 (females) </li></ul><ul><ul><li>( 72 x SCr) </li></ul></ul><ul><ul><li>Use actual body weight if patient is <IBW </li></ul></ul><ul><ul><li>Use IBW if the actual body weight is <25% above IBW </li></ul></ul><ul><ul><li>Use ABW (adjusted body weight) if the actual body weight is >25% above IBW </li></ul></ul>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. 14. Weight Calculations <ul><li>IBW females (kg)= 45.5 + 2.3(height inches - 60) </li></ul><ul><li>IBW males (kg)= 50 + 2.3(height inches - 60) </li></ul><ul><li>ABW= IBW + 0.4(actual weight – IBW) </li></ul>
  15. 15. Cockroft-Gault <ul><li>Pros to Cockroft-Gault </li></ul><ul><ul><li>Easy to make dosage recommendations </li></ul></ul><ul><ul><li>Easy to calculate </li></ul></ul><ul><li>Cons to Cockroft-Gault </li></ul><ul><ul><li>Not a true marker of renal impairment </li></ul></ul><ul><ul><li>May OVERESTIMATE renal function in elderly population </li></ul></ul><ul><ul><ul><li>Some clinicians round SCr to 1.0mg/dL </li></ul></ul></ul>
  16. 16. TIME OUT!! <ul><li>Example #1: </li></ul><ul><ul><li>36 y/o Caucasian female with renal disease due to IDDM. </li></ul></ul><ul><ul><li>Current labs: </li></ul></ul><ul><ul><li>GFR calculated with MDRD: 32 mL/min/1.73 m 2 </li></ul></ul><ul><ul><li>CrCl calculated with Cockroft-Gault: 37 mL/min/1.73 m 2 </li></ul></ul>SCr Weight Height 1.9 mg/dL 57 kg 5'3&quot;
  17. 17. Pause for the Cause! <ul><li>Example #2: 62 y/o AAM with renal disease secondary to malignant hypertension </li></ul><ul><li>Current labs: </li></ul><ul><li>Weight to use: 86 kg </li></ul><ul><li>GFR calculated with GFR: 27 mL/min/1.73 m 2 </li></ul><ul><li>CrCl calculated with Cockroft-Gault: 33 mL/min/1.73 m 2 </li></ul>SCr Weight Height 2.85 mg/dL 86 kg 5‘10&quot;
  18. 18. Which should I use? <ul><li>Both! </li></ul><ul><ul><li>Medication adjustments should be initially based on creatinine clearance (Cockroft-Gault) </li></ul></ul><ul><ul><li>Include the patient’s clinical picture when determining optimal dosing </li></ul></ul><ul><ul><li>MDRD is more accurate as the severity of renal disease increases </li></ul></ul>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. 19. Beware! <ul><li>Factors that falsely ELEVATE creatinine </li></ul><ul><ul><li>Dehydration </li></ul></ul><ul><ul><li>TMP-SMX </li></ul></ul><ul><li>Factors that falsely DECREASE creatinine </li></ul><ul><ul><li>Small muscle mass </li></ul></ul><ul><ul><li>Liver disease </li></ul></ul>
  20. 20. Dosing in Renal Failure <ul><li>Calculate CrCl using Cockroft-gault formula </li></ul><ul><li>Use a reference to identify renal dosing parameters </li></ul><ul><li>Identify suggested dosage adjustment </li></ul><ul><li>Determine if the dose reduction is logical and appropriate for your patient </li></ul>
  21. 21. Factors to Consider when Adjusting Dose <ul><li>CrCl is a STARTING POINT! </li></ul><ul><ul><li>Remember this is just an ESTIMATE </li></ul></ul><ul><li>Toxicities of antibiotic </li></ul><ul><ul><li>Cephalosporin vs. aminoglycoside </li></ul></ul><ul><li>Clinical condition </li></ul><ul><ul><li>SCr trends, sepsis, stability of patient </li></ul></ul><ul><li>Infection being treated </li></ul><ul><ul><li>Meningitis vs. pneumonia vs. bacteremia </li></ul></ul><ul><li>Target organism </li></ul><ul><ul><li>ESBL vs. intermediate resistance vs. susceptible </li></ul></ul>
  22. 22. Stages of Kidney Disease Adapted from the National Kidney Foundation Stage Description GFR (mL/min/1.73 m 2 ) 1 Kidney damage with normal GFR ≥ 90 2 Kidney damage with mild ↓ in GFR 60-89 3 Moderate ↓ GFR 30-59 4 Severe ↓ GFR 15-29 5 Kidney Failure <15 (or dialysis)
  23. 23. Dialysis <ul><li>Use of a semi permeable membrane to remove solutes that are ineffectively cleared via the kidney during renal failure </li></ul><ul><ul><li>Pore size of membrane determines the maximum size solute that can be removed </li></ul></ul><ul><ul><ul><li>i.e. large molecules (vancomycin)=not removed </li></ul></ul></ul><ul><ul><li>Volume of distribution determines extent of removal </li></ul></ul><ul><ul><ul><li>i.e. large Vd (digoxin)=not removed </li></ul></ul></ul>Rowland, Malcolm (1995). Clinical Pharmacokinetics: Concepts and Applications . 3 rd Ed. USA: Lippincott, Williams, and Wilkins. 448-453.
  24. 24. Dialysis <ul><li>Manufacturer’s usually provide dosing recommendations </li></ul><ul><ul><li>Decrease of total dose </li></ul></ul><ul><ul><li>Increase in interval of dose (after dialysis) </li></ul></ul><ul><ul><li>Decrease of dose plus a supplemental dose after dialysis </li></ul></ul><ul><li>Use pharmacokinetics (Vd, molecule size) to make an educated guess </li></ul>Rowland, Malcolm (1995). Clinical Pharmacokinetics: Concepts and Applications . 3 rd Ed. USA: Lippincott, Williams, and Wilkins. 448-453.
  25. 25. Continuous Dialysis <ul><li>CRRT: continuous renal replacement therapy </li></ul><ul><li>Primary use in pts that are hemodynamically unstable </li></ul><ul><ul><li>ICU setting </li></ul></ul><ul><ul><li>Septic patients on ≥ 1 antimicrobial </li></ul></ul><ul><li>Slow, continuous solute removal </li></ul><ul><li>Various types (filtration, ultrafiltration, etc.) </li></ul><ul><li>Depending on type of CRRT, usually correlates with a CrCl of 50 mL/min/1.73 m 2 </li></ul><ul><li>Most references include specific information for dosing during CRRT </li></ul>Trotman et al. Antibiotic Dosing in Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy. CID . 2005;41:1159-1166
  26. 26. Adjusting Antimicrobials During Dialysis <ul><li>Determine pt’s underlying renal function </li></ul><ul><li>Determine kinetics of antimicrobial in dialysis </li></ul><ul><ul><li>Molecule size vs. filter pore size </li></ul></ul><ul><ul><li>Volume of distribution of antimicrobial </li></ul></ul><ul><li>Decrease dose as recommended/clinically appropriate </li></ul><ul><li>Check peaks/troughs as needed to avoid accumulation or toxicity </li></ul>
  27. 27. References <ul><li>Package Insert </li></ul><ul><li>Online Resources </li></ul><ul><ul><li>Up-to-Date/Lexi-comp </li></ul></ul><ul><ul><li>Micromedex </li></ul></ul><ul><ul><li>Facts & Comparisons </li></ul></ul><ul><li>Sanford Guide </li></ul><ul><li>‘ The Green Book’ </li></ul>
  28. 28. Example #1: Fluconazole <ul><li>A.Y. is a 46 y/o AAF who was recently admitted for cadaveric kidney transplant. The transplant protocol calls for antifungal coverage (fluconazole 200mg PO daily) for 6 months as the patient tapers off immunosuppressive medications. </li></ul><ul><li>Labs: </li></ul><ul><ul><li>Height: 5’6” </li></ul></ul><ul><ul><li>Weight: 68 kg </li></ul></ul><ul><ul><li>SCr: 4.68 mg/dL </li></ul></ul><ul><ul><li>UO: 40 cc/hr </li></ul></ul>
  29. 29. Example #1: Fluconazole <ul><li>Weight: </li></ul><ul><ul><li>IBW: 59.3 kg </li></ul></ul><ul><ul><li>% above IBW: 14% </li></ul></ul><ul><ul><li>Use ABW for calculation </li></ul></ul><ul><li>Calculated renal function: </li></ul><ul><ul><li>MDRD: 12 mL/min/1.73 m 2 </li></ul></ul><ul><ul><li>Cockroft-Gault: 16 ml/min/1.73 m 2 </li></ul></ul>
  30. 30. Example #1: Fluconazole <ul><li>Diflucan ® package insert states: </li></ul><ul><li>Recommended Dose: 100mg PO daily </li></ul>
  31. 31. Example #2: Pip/Tazo <ul><li>72 y/o Hispanic female initially admitted for an acute decompensation of CHF, develops a Klebsiella pneumoniae UTI. Sensitivities come back, resistant to everything except Zosyn. The team asks you for a recommendation . . . . </li></ul><ul><li>Labs: </li></ul>1/19 1/20 1/22 1/23 Scr 0.9mg/dL 1.1mg/dL 1.24mg/dL 1.45mg/dL Weight Height UO 87 kg 5’4” 44 mL/hour
  32. 32. Example #2: Pip/Tazo <ul><li>Weight </li></ul><ul><ul><li>IBW: 54.7 kg </li></ul></ul><ul><ul><li>% above Ideal: 59% </li></ul></ul><ul><ul><li>Use ABW!!! (67.6 kg) </li></ul></ul><ul><li>Calculated Renal Function </li></ul><ul><ul><li>MDRD: 38 mL/min/1.73 m 2 </li></ul></ul><ul><ul><li>Cockroft-Gault: 37 mL/min/1.73 m 2 </li></ul></ul>
  33. 33. Example #2: Pip/Tazo <ul><li>Package Insert: </li></ul><ul><li>Recommended Dose: </li></ul><ul><ul><li>2.25gm IV every 6 hours </li></ul></ul>
  34. 34. Example #3: Levofloxacin <ul><li>A 55 y/o Asian male is admitted for community-acquired pneumonia. It is decided that his condition warrants IV antibiotics. The physician wants you to recommend an appropriate dose of levofloxacin </li></ul><ul><li>Labs: </li></ul><ul><ul><li>Height: 5’7” </li></ul></ul><ul><ul><li>Weight: 67 kg </li></ul></ul><ul><ul><li>SCr: 1.75 mg/dL </li></ul></ul>
  35. 35. Example #3: Levofloxacin <ul><li>Weight </li></ul><ul><ul><li>IBW: 66.1 kg </li></ul></ul><ul><ul><li>% above Ideal: 1% </li></ul></ul><ul><ul><li>Use actual body weight </li></ul></ul><ul><li>Calculated Renal Function </li></ul><ul><ul><li>MDRD: 43 mL/min/1.73 m 2 </li></ul></ul><ul><ul><li>Cockroft-Gault: 45 mL/min/1.73 m 2 </li></ul></ul>
  36. 36. Example #3: Levofloxacin
  37. 37. Example #3: Levofloxacin <ul><li>Recommended dose: 750mg every other day </li></ul>
  38. 38. Conclusions <ul><li>Antimicrobial dose adjustments must be made to avoid supratherapeutic serum levels and toxicity in renal failure </li></ul><ul><li>Cockroft-Gault equation should be used to determine antimicrobial dose adjustments </li></ul><ul><li>MDRD is useful in pts with severe renal failure </li></ul><ul><li>The clinical picture should be utilized to determine the correct antimicrobial dose </li></ul>

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