1. 1 Vancomycin Pharmacokinetics

2. 2 Introduction Vancomycin is a glycopeptide antibiotic Mechanism of Action –Exhibits a time dependent or concentration- independent killing of bacteria. That is, it is not how high the concentration gets, but how long the concentration is above a certain level. Spectrum of Activity –Limited primarily to Gram positive organisms: severe gram-positive infections due to organisms that are resistant to other antibiotics such as methicillin- resistant staphylococci and ampicillin-resistant enterococci.

3. Introduction The mechanism of action for vancomycin is inhibition of cell wall synthesis in susceptible bacteria Many strains of Enterococcus have high MIC values for vancomycin, and for these bacteria vancomycin may only demonstrate bacteriostatic properties 3

4. Therapeutic And Toxic Concentrations Vancomycin is administered as a short-term (1 hour) intermittent intravenous infusion for doses up to 1500 mg or as a 1.5- to 2-hour intermittent intravenous infusion for larger doses (>1500 mg) Infusion rate–related side effects have been noted when shorter infusion times ( ∼ 30 minutes or less) have been used Short infusion time results in urticarial or erythematous reactions, intense flushing (known as the “red-man” or “red-neck” syndrome), tachycardia, and hypotension 4

5. Therapeutic And Toxic Concentrations Even with a 1- to 2-hour infusion time, vancomycin serum concentrations exhibit a distribution phase so that drug in the blood and in the tissues are not yet in equilibrium Because of this, a ½- to 1-hour waiting period is allowed for distribution to finish before maximum or “peak” concentrations are measured 5

6. Concentration/time plot for vancomycin 1000 mg given as a 1-hour infusion When given as a 1-hour infusion, end-of-infusion concentrations are higher because the serum and tissues are not in equilibrium A ½- to 1-hour waiting time for vancomycin distribution to tissues is allowed before peak concentrations are measured 6

7. Therapeutic And Toxic Concentrations Microbiologic cure rates are not closely associated with peak concentrations (Because vancomycin exhibits time-dependent killing) However, ototoxicity has been reported when vancomycin concentrations exceed 80 μg/mL Because vancomycin does not enter the central nervous system in significant amounts when given intravenously, steady-state peak concentrations of 50-60 μg/mL, steady-state trough concentrations of 15-20 μg/mL, or direct administration into the cerebral spinal fluid may be necessary 7

8. Therapeutic And Toxic Concentrations Trough concentrations (predose or minimum concentrations usually obtained within 30 minutes of the next dose) are usually related to therapeutic outcome for vancomycin because the antibiotic follows time-dependent bacterial killing 8

9. Therapeutic And Toxic Concentrations Optimal bactericidal effects are found at concentrations 3-5 times the organism’s MIC Average vancomycin MICs for Staphylococcus aureus and Staphylococcus epidermidis are 1-2 μg/mL  a trough steady-state concentrations equal to 5-10 μg/mL Methicillin-resistant Staphylococcus aureus (MRSA) has higher MICs. Hence, a higher steady-state trough concentrations are required to achieve a clinical cure 9

10. Therapeutic And Toxic Concentrations Vancomycin penetrates into lung tissue poorly (average serum:tissue ratio of 6:1, average epithelial lining fluid:plasma concentrations ratio of 0.68) Current treatment guidelines recommend vancomycin steady-state trough concentrations equal to: –10-15 μg/mL for lower-intensity dosing –15-20 μg/mL for complicated infections due to MRSA, such as bacteremia, endocarditis, meningitis, osteomyelitis, severe skin infections, and hospital- acquired pneumonia 10

11. Therapeutic And Toxic Concentrations Steady-state vancomycin trough levels less than 10 μg/mL are discouraged due to the possibility of lower levels contributing to treatment failure or to the development of resistance 11

12. Vancomycin-associated ototoxicity Steady-state trough vancomycin concentrations in excess of 20 μg/mL are associated with ototoxicity, and other patient risk factors include age more than 53 years and preexisting hearing loss  For this patient subgroup, the ototoxicity rate is 19% Ototoxicity can be permanent if appropriate changes in vancomycin dosing are not made 12

13. Ototoxicity: Clinical Monitoring Parameters In the clinical setting, audiometry is rarely used to detect ototoxicity because it is difficult to accomplish in severely ill patients Instead, clinical signs and symptoms of auditory (decreased hearing acuity in the conversational range, feeling of fullness or pressure in the ears, tinnitus) or vestibular (loss of equilibrium, headache, nausea, vomiting, vertigo, nystagmus, ataxia) ototoxicity are monitored at the same time intervals as serum creatinine determination 13

14. Ototoxicity: Clinical Monitoring Parameters When high vancomycin concentrations are needed for therapeutic reasons (trough >20 μg/mL, peak >50-60 μg/mL), assessment of renal function and auditory/vestibular function should be conducted on a daily basis 14

15. Vancomycin-associated nephrotoxicity Trough vancomycin steady-state concentrations of more than 15 μg/mL are related to an increased incidence of nephrotoxicity, with reported rates as high as 30%-35% Coadministration of an aminoglycoside with vancomycin may double the risk of developing renal toxicity 15

16. Vancomycin-associated nephrotoxicity Many patients receiving vancomycin are critically ill, so other sources of renal dysfunction, such as: –Dehydration –Hypotension –Other nephrotoxic drug therapy (such as aminoglycosides, amphotericin B, loop diuretics, or immunosuppressants) Other sources of renal dysfunction should be ruled out before the diagnosis of vancomycin- induced renal damage is made in a patient 16

17. Vancomycin-associated nephrotoxicity In contrast to ototoxicity, vancomycin-related nephrotoxicity is usually reversible with a low incidence of residual damage if the antibiotic is withdrawn or doses appropriately adjusted soon after renal function tests change With adequate patient monitoring and dosage adjustments, the only result of vancomycin nephrotoxicity may be transient serum creatinine increases of 0.5-2.0 mg/dL 17

18. Nephrotoxicity: Clinical Monitoring Parameters Serial monitoring of serum creatinine concentrations should be used to detect nephrotoxicity A baseline serum creatinine concentration is obtained before vancomycin therapy is initiated and three times weekly during treatment An increasing serum creatinine test on two or more consecutive measurement occasions indicates that more intensive monitoring of serum creatinine values, such as daily, is needed 18

19. Nephrotoxicity: Clinical Monitoring Parameters If serum creatinine measurements increase more than 0.5 mg/dL over the baseline value (or >25%-30% over baseline for serum creatinine values >2 mg/dL) and other causes of declining renal function have been ruled out (other nephrotoxic drugs or agents, hypotension, etc): –Alternatives to vancomycin therapy should be given –Intensive vancomycin serum concentration monitoring should be initiated to ensure that excessive amounts of vancomycin do not accumulate in the patient 19

20. Clinical Monitoring Parameters Measurement of serial white blood cell counts and body temperatures is useful to determine the efficacy of antibiotic therapy Favorable response to antibiotic treatment is usually indicated by high white blood cell counts decreasing toward the normal range and body temperatures approaching normal Clinicians should also be aware that immunocompromised patients with a bacterial infection may not be able to mount a fever or elevated white blood cell count 20

21. Clinical Monitoring Parameters Any specific infection site tests or procedures resolving: –In pneumonia patients the chest x-ray should be resolving –In patients with infective endocarditis the size of the bacterial vegetation on the heart valve should be decreasing –In patients with a wound infection the wound should be less inflamed with less purulent discharge 21

22. Clinical Monitoring Parameters Vancomycin steady-state serum concentrations should be measured in 3-5 estimated half-lives A useful clinical rule is to measure serum concentrations after the third dose Steady-state serum concentrations, in conjunction with clinical response, are used to adjust the antibiotic dose, if necessary 22

23. Clinical Monitoring Parameters While some clinicians continue to monitor both steady-state peak and trough vancomycin serum concentrations, most individuals advocate the measurement of just a steady-state trough concentration The reasoning behind this approach is that vancomycin follows time-dependent bacterial killing, and the efficacy of the drug should be most closely related to the minimum serum concentration encountered over the dosage interval 23

24. 24 PK Parameters Vancomycin is almost completely eliminated unchanged in the urine primarily by glomerular filtration (≥90%) This antibiotic is given by short-term (1 hour) intermittent intravenous infusion Intramuscular administration is usually avoided because this route has been reported to cause tissue necrosis at the site of injection Oral bioavailability is poor (<10%) so systemic infections cannot be treated by this route of administration Plasma protein binding is ~ 55% The recommended dose for vancomycin in patients with normal renal function is 30 mg/kg/d given as 2 or 4 divided daily doses In normal weight adults, the dose is usually 2 g/d given as 1000 mg every 12 hours

25. 25 PK Parameters

26. 26 PK Parameters PK profile can be characterized by a 2- compartment pharmacokinetic profile In patients with normal creatinine clearance, vancomycin has an α- distribution phase of ∼ 30 min to 1 h and a β -elimination half-life of 6–12 h

27. 27 Clearance estimate Cl = 0.695(CrCl) + 0.05 where Cl is vancomycin clearance in mL/min/kg and CrCl is creatinine clearance in mL/min/kg. The weight factor that is used for all individuals, including obese patients, is total body weight (TBW).

28. 28 Volume of distribution estimate The average volume of distribution of vancomycin is 0.7 L/kg The weight factor that is used to calculate vancomycin volume of distribution for obese patients is ideal body weight (IBW) Thus, for an 80-kg patient, the estimated vancomycin volume of distribution would be 56 L: V = 0.7 L/kg ⋅ 80 kg = 56 L For a 150-kg obese patient with an ideal body weight of 60 kg, the estimated vancomycin volume of distribution is 42 L: V = 0.7 L/kg ⋅ 60 kg = 42 L.

29. 29 Elimination rate constant and half- life estimates The vancomycin elimination rate constant (ke) is computed using the estimated clearance and volume of distribution values for the drug in the following equation: ke = Cl/V Vancomycin half-life would be calculated using the equation that relates elimination rate constant and half-life: t1/2 = 0.693/ke

30. 30 Time of Sampling Peak concentration: 0.5-1 hr after end of the infusion Trough within 30 min prior to dose Target concentrations should be at steady- state (after 3-5 half-lives or 24 to 30 hours after initiation of therapy with normal renal function; approximately after the fourth dose in adults)

31. 31 Reference Range The reference range for vancomycin trough levels is 10-20 µg/mL (15-20 µg/mL for complicated infections such as those with hospital acquired pneumonia in institutions with high MICs for methicillin- resistant S. aureus (MRSA)) The reference range for vancomycin peak levels is 20-40 µg/mL (at 1hr after end of 1hr infusion)

32. 32 Appropriate pharmacokinetic model and equations Although Vancomycin is given as an intravenous infusion, intravenous bolus equations are used to predict peak vancomycin concentrations Generally, when the half-life is 5 or more times the duration of infusion, intravenous bolus equations accurately predict peak vancomycin concentrations (the error in predicting concentration is 6.8% or less)

33. 33 Initial dosage determination 1.Calculate CrCl 2.Calculate Cl 3.Calculate Vd 4.Calculate Ke 5.Calculate Tau: T: infusion duration, t’: time of Cmax relative to infusion end 6.Calculate the dose:

34. 34 Use Of Vancomycin Serum Concentrations To Alter Dosages Linear Pharmacokinetics Method Pharmacokinetic Concepts Method

35. 35 Linear Pharmacokinetics Method Requirements: one trough steady state concentration If Tau was fixed then: If dose was fixed:

36. 36 Pharmacokinetic Concepts Method Requirements: 2 concentrations obtained at steady-state: C1 and C2 at t1 and t2 1.Calculate K 2.Calculate Vd: using C1 and t1 (t1 is the time relative to end of infusion):

37. 37 Pharmacokinetic Concepts Method 3.Calculate Tau: T: infusion duration, t’: time of Cmax relative to infusion start 4.Calculate the dose:

38. 38 Examples JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus (MRSA) wound infection. His current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days since admission. Compute a vancomycin dose for this patient

39. 39

40. 40 Vancomycin therapeutic range for Ctrough is 10-20 mg/L and for Cmax 20-40 mg/L Practical dosing interval is 8 or 12 hours. Tau would be rounded to 12 hours Vancomycin doses should be rounded to the nearest 100–250 mg. This dose would be rounded to 1000 mg

41. 41 Predicted SS concentrations are:

42. 42

43. 43 Example 2 JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus (MRSA) pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days since admission. A vancomycin dose of 1000 mg (infused over 1 hr) every 12 hours was prescribed and expected to achieve steady-state peak and trough concentrations equal to 35 μg/mL and 15 μg/mL, respectively. Steady-state peak and trough concentrations were measured and equaled 22 μg/mL and 10 μg/mL, respectively. Calculate a new vancomycin dose that would provide a steady-state trough of 15 μg/mL.

44. 44 Linear PK Approach The recommended dose is 1500 mg every 12 hrs. The predicted new Cmax is:

45. 45 Pharmacokinetic Concepts Method

46. 46

47. 47 Example 3 JM is a 50-year-old, 70-kg (5 ft 10 in) male with a methicillin-resistant S. aureus (MRSA) pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days since admission. A vancomycin dose of 1000 mg (infused over 1 hr) every 12 hours was prescribed and expected to achieve steady-state peak and trough concentrations equal to 35 μg/mL and 15 μg/mL, respectively. Steady-state concentrations at 6 and 7 hours post infusion were 22 μg/mL and 10 μg/mL, respectively. Is it necessary for the dose to be adjusted?

48. 48