Pediatric Dosing of Aminoglycosides and Vancomycin Based on Pharmacokinetic Concepts

1. Pediatric Dosing of Aminoglycosides and Vancomycin Based on Pharmacokinetic Concepts Marie Varela, Pharm.D., BCPS ShereneSamu, Pharm.D.

2. Objectives • Describe basic pharmacokinetic parameters for vancomycin and aminoglycosides in pediatric patients • Outline dosing strategies for aminoglycosides based on pharmacokinetic principles • Outline dosing strategies for vancomycin based on pharmacokinetic principles • Select a monitoring plan for vancomycin and aminoglycosides in pediatric patients • Select an adjusted dosing regimen based on serum concentrations for vancomycin and aminoglycosides in pediatric patients

3. Pharmacokinetics Definition: • The study of the time course of a drug and its metabolites in the body • The study of the ADME of a drug and its metabolites in the body • Absorption • Distribution • Metabolism • Excretion • Varies greatly with age groups (pediatrics, geriatrics)

4. Volume of Distribution

5. Excretion Because of the PK and PD characteristics of vancomycin and aminoglycosides, the clearance of these drugs is closely correlated to creatinine clearance

6. Estimation of Creatinine Clearance Schwartz Estimate Estimates creatinine clearance from serum creatinine, the patient's height, and a proportionality constant CrCl = (k * Ht) / Cr (Caution: formula tends to overestimate the actual creatinine clearance and should be used with caution.) http://www-users.med.cornell.edu

7. Elimination Half-life (t½) • Associated with first-order kinetics (serum concentration diminishes logarithmically over time) • Time it takes for plasma concentration to reach half of a previous concentration • Affected by metabolism and excretion • Most drugs follow first-order kinetics (including aminoglycosides and vanco)

8. Steady State • Equilibrium reached: Rate of drug in=Rate of drug out • Time to reach steady state is a function of t½

9. Graph of Multiple Dosing Q6h dosing t½ = 6 hours

10. Pharmacodynamic Concepts Affecting Dosing and Monitoring of Aminoglycosides and Vancomycin • Organism (Gram + vs. Gram -) • MIC of organism • Site of infection • Dose-response relationships of Abx • Concentration vs. time dependent bactericidal activity • PAE

11. Concentration Dependent • Aminoglycosides • CONCENTRATION dependent killing • Maximize INTENSITY of exposure • As concentration at site ↑, antimicrobial action ↑ • More pronounced responses to dosage adjustments

12. Gentamicin/TobramycinInitial Dosing Pediatrics Lexicomp 1978-2013

13. Gentamicin/TobramycinInitial Neonatal Dosing SBUH Reference: Neofax

14. Gentamicin/Tobramycin Expected Half-Life (Population Statistics) Clearance approximately equal to CrCl (≈ 5% metabolized)

15. Aminoglycosides Target Goals • Tobramycin/Gentamicin Target Serum Concentrations

16. Time Dependent • Vancomycin • TIME dependent killing • Maximize DURATION of exposure • More pronounced responses to interval adjustments

17. VancomycinInitial Dosing Pediatrics Lexicomp 1978-2013 • 10-15 mg/kg/dose q6-8 hours • Renal impairment • GFR 30-50: 10 mg/kg/dose q12h • GFR 10-29: 10 mg/kg/dose q18-24 hours • GFR < 10: 10 mg/kg/dose; re-dose based on serum concentrations

18. IV Vancomycin Initial Neonatal Dosing SBUH Dose: 10 to 15 mg/kg/dose* (*This dosing strategy targets a trough of 5-15, therefore 15 mg/kg/dose is preferred.) Reference: Neofax

19. Vancomycin Expected Half-Life(Population Statistics) Clearance approximately equal to CrCl (≈ 5% metabolized)

20. IV Vancomycin • Target Serum Concentrations Maintain trough in therapeutic range; peak inconsequential

21. IV Vancomycin • Dosing Strategies • Due to pharmacodynamic characteristics, optimal give more frequently • Want trough to remain in therapeutic range; peak inconsequential • For renal impairment, reduce frequencies

22. Why Monitor? • Constant changes in Vd and clearance • Optimize therapeutic effects • Minimize toxicity

23. When to Monitor? • At presumed steady state • Upon initiation of therapy • After a dosage/frequency adjustment • Upon significant change in weight, fluid status, renal function • After addition of a medication that may affect renal function (i.e. Ibuprofen) • Every week after achieving therapeutic serum concentrations • For vancomycin doses of > 15 mg/kg/dose q6h or > 3 g per day, recheck first therapeutic trough in 2-3 days. (Then follow above monitoring strategy thereafter.)

24. Time to Draw • Peak (aminoglycosides only) 30 minutes after dose completely infused • Trough (all drugs) 30 minutes before the next dose is due

25. How to Interpret Lab Results • Questions to ask yourself • Was the initial dosing appropriate? (considering renal function etc.) • Was the trough drawn at presumed steady state? • For unexpected high concentrations, was it possible the trough was drawn after the start of the infusion or from a line that may not have been flushed? • Was it actually drawn at the time documented in the system? • Should the level be redrawn?

26. Gentamicin Conventional Dosage Adjustment Guidelines

27. Gentamicin Dosage Adjustment Guidelines • If peak is in desired range and trough is high, DECREASE THE FREQUENCY. • After rechecking serum concentrations, may be necessary to increase dose with next adjustment. • If peak is in desired range and trough is low, most likely no adjustment is necessary.

28. Vancomycin Dosage Adjustment Guidelines

29. Common Myth • Adjust the dose by 10% • Is this an appropriate recommendation? • In what situation, if ever, would this apply?

30. Calculating Actual Half-Lifeto choose best dosage interval K = ln C1 C2 Δ Time t½ = 0.693/K K=elimination rate constant Δ Time = hours • Can be done from random levels if spaced far enough apart (one number at least twice the other) • Can be done from peak and trough if at steady state

31. Communication Verbal Progress notes Sign outs

32. Patient Specific Data Female 20 years old ABW 76.6 kg IBW 52.4 kg SCr 0.6 CrCl 123 mL/min Case 1 • Reason for visit • Chronic CSF leak • Comes to ER with symptoms of bending down, having rhinorrhea • Started on vancomycin • Trough goal = 15-20 mcg/mL

33. Case 1

34. Case 1 • Pharmacy recommendation on 2/5/10 • Draw a level on 2/6/10 AM • If level ≤ 10 mcg/mL, give 1 g Q8H • If level 11-12 mcg/mL, give 1.5 g Q12H • If 13-15 mcg/mL, give 1.2 g Q12h

35. Case 1

36. Patient Specific Data Female 2 years old ABW 17.5 kg IBW 17.3 kg SCr 0.3 CrCl 177 mL/min Case 2 • Reason for admission • Lethargy • Mental status changes • Fever • Started on gentamicin • R/O sepsis (gram negative coverage)

37. Case 2 • Target Serum Concentrations • Peak: 6-10 mcg/mL • Trough: < 2 mcg/mL • Gentamicin Dose: 2.5 mg per kg q8h

38. Case 2

39. Case 2 • Dosage Adjustment • Want peak 6 or greater • If 43 mg yields peak of 5.2, what dose would bring it to 6? • Use linear proportion as long as interval is unchanged

40. Case 2 • Dosage Adjustment Continued • What effect would that have on trough (if dose was increased to 49 mg q8h)? • If 43 mg yields a trough of 1.3 mcg/mL, 49 mg would bring it to what trough?

41. Case 2 • What if trough calculated to greater than 2? • Answer: increase the interval • Monitoring • After dosage change, repeat peak and trough around 3rd dose of the new regimen

42. Case Study Term neonate DOB: 1/25/12 Diagnosis: chorioamnionitis Weight 3.65 kg Start antibiotics: ampicillin gentamicin

43. Case 3 ( 1) Gentamicin Gentamicin ordered: 14.6 mg q 24 hours Dosed at 4 mg per kg

44. Questions: Was this dosed properly? What criteria are used to determine if this was dosed properly? What level(s) will be drawn to properly monitor this drug? What serum concentrations are we targeting?

45. Gentamicin Dosing PMA is theequivalent to Gestational Age plus Postnatal Age

46. Case 3 (2) Gentamicin Dose given each morning for 3 doses

47. Question: What time should the peak be drawn? What time should the trough be drawn?

48. Case 3 (3) Gentamicin

49. Case 3 (4) Gentamicin

50. Question: What is your evaluation of this peak? How do we proceed from here?