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Clinical Pharmacokinetics of VANCOMYCIN Mohd Bin Makmor Bakry, Ph. D, RPh Senior Lecturer in Clinical Pharmacokinetics of VANCOMYCIN Mohd Bin Makmor Bakry, Ph. D, RPh Senior Lecturer in Clinical Pharmacy Faculty of Pharmacy Universiti Kebangsaan Malaysia Kuala Lumpur

INTRODUCTION • • Inhibits bacterial cell wall synthesis Time-dependent effect Gram positive bacteria Indications INTRODUCTION • • Inhibits bacterial cell wall synthesis Time-dependent effect Gram positive bacteria Indications : • Documented infections: • • Methicillin/Cephalosporin-Resistant Staphycoccal infection. Penicillin/Cephalosporin-Resistant Streptococcal infection. Staphy. /Strep. infection in patient allergic to penicillin. Staphy. infection in patient with renal disease undergoing hemodialysis. • Penicillin-Resistant Diphtheroid infection. • Severe antibiotic-associated enterocolitis.

 • Indications (cont’) : • Empiric Therapy: • • • Suspected MRSA nosocomial • Indications (cont’) : • Empiric Therapy: • • • Suspected MRSA nosocomial infection. Meningitis in patient who had neurosurgery. Neutropenic febrile patient not responding or allergic to penicillin. • Suspected Staphy. infection in patient with renal disease undergoing hemodialysis. • Prophylaxis: • Endocarditis in patient allergic to penicillin. • Prosthetic valve placement in patient allergic to penicillin.

ADVERSE DRUG REACTION • • Ototoxicity (tinnitus, fullness in the ear) Nephrotoxicity • An ADVERSE DRUG REACTION • • Ototoxicity (tinnitus, fullness in the ear) Nephrotoxicity • An increase in Sr. Cr of 0. 5 mg/d. L or greater, or as 50% increase from baseline. • Occurs at a rate of 5% with Vancomycin alone and increase to 22% with addition of Aminoglycosides. • Red-Man Syndrome (hypotension, upper body • Cutaneous reaction (urticaria, angioedema, erythema) Neutropenia (within 15 – 30 days of drug initiation) Fever • • maculopapular rash)

PHARMACOKINETIC CHARACTERISTICS • • Two- or three-compartment model. Bioavailability • Per oral < 5% PHARMACOKINETIC CHARACTERISTICS • • Two- or three-compartment model. Bioavailability • Per oral < 5% • Intravenous 100% • • Protein binding 30 – 55% Excretion • Renal: >90% unchanged in urine

KEY PARAMETERS • Ctarget • F Vd CLVanco t½ Ke • • Conventionally P KEY PARAMETERS • Ctarget • F Vd CLVanco t½ Ke • • Conventionally P = 40 – 50 mg/L T = 10 – 15 mg/L Continuous infusion Cavess = 12 – 18 mg/L <0. 05 PO 0. 7 (0. 5 – 1. 0) (L/kg) 0. 65 CLCr x 0. 06 (L/H) 7 (H) 0. 00083(CLCr) + 0. 0044 (H-1) *CLCr in ml/min

INITIATING VANCOMYCIN • Cultures • Appropriate C&S obtain within 48 hrs before starting therapy. INITIATING VANCOMYCIN • Cultures • Appropriate C&S obtain within 48 hrs before starting therapy. • Antibiotic therapy modified (if necessary) within 24 hrs of the C&S results. • Renal Function • Estimated CLCr within 24 hrs of initiating therapy. • Monitoring CLCr every 3 – 5 days during therapy.

INITIATING VANCOMYCIN (CONT’) • Dosage Regimen & Monitoring Needs • Conventional dosing • Peak INITIATING VANCOMYCIN (CONT’) • Dosage Regimen & Monitoring Needs • Conventional dosing • Peak & Trough concentration method • Continuous infusion • Trough concentration method

INITIATING VANCOMYCIN (CONT’) • Conventional Dosage Regimen • • • Initial per dose is INITIATING VANCOMYCIN (CONT’) • Conventional Dosage Regimen • • • Initial per dose is between 10 – 15 mg/kg body wt Dosage interval based on estimated CLCr. Rate of infusion not more than 20 mg/min. Adjustment based on measured levels. Serum Drug Concentration • • Levels taken at steady-state. If stable renal function, repeat trough levels once a week. Trough levels obtained if with other nephrotoxic drugs. Trough and peak levels obtained if: • Not responding to therapy. • Altered physiologic parameters

INITIATING VANCOMYCIN (CONT’) • Continuous Infusion Regimen • Infusion rate is based on estimated INITIATING VANCOMYCIN (CONT’) • Continuous Infusion Regimen • Infusion rate is based on estimated CLCr and targeted Cavess (15 mg/L). • Rate of infusion, Ro (mg/H) Ro = CLvanco. Cavess = Vd. Ke. Cavess • Adjustment based on measured Cavess

 • Lake’s Method INITIATING VANCOMYCIN (CONT’) • Target serum levels: T = 5 • Lake’s Method INITIATING VANCOMYCIN (CONT’) • Target serum levels: T = 5 – 10 mg/L (30 min before the next infusion) P = 20 – 30 mg/L (15 min after the end of infusion) • Maintenance dose (per dose) = 8 mg/kg (LBW) • To be give at Q H interval: CLCr (ml/min) (H) >90 6 70 – 89 8 46 – 69 12 30 – 45 18 15 – 29 24

INITIATING VANCOMYCIN (CONT’) • Rodvold’s Method • Target serum levels: T = 5 – INITIATING VANCOMYCIN (CONT’) • Rodvold’s Method • Target serum levels: T = 5 – 10 mg/L (30 min before the next infusion) P = 30 – 40 mg/L (15 min after the end of infusion) • Daily maintenance dose Dose (mg/kg TBW per 24 H) = (0. 227(CLCr) + 5. 67 • Interval: CLCr (ml/min) >65 46 – 65 20 – 39 10 – 19 (H) 8 12 24 48

ADJUSTING THE DOSAGE REGIMEN ln Cp Cmax Cpostdose C*predose ti Ct, max C* Cmin ADJUSTING THE DOSAGE REGIMEN ln Cp Cmax Cpostdose C*predose ti Ct, max C* Cmin t

ADJUSTING THE DOSAGE REGIMEN (CONT’) • Sawchuck-Zaske Method (Conventional/Multiple short infusion) • Determine the ADJUSTING THE DOSAGE REGIMEN (CONT’) • Sawchuck-Zaske Method (Conventional/Multiple short infusion) • Determine the t½ Ke = ln (Cpeak/Ctrough) / (ttrough – tpeak) t½ = 0. 693 / Ke • Determine the Vd Vd = R o x 1 – e-Keti. Ke (Cmax – (Cmine-Keti) *Ro = mg/H infusion • Determine the new = ln (Cmax desired / Cmin desired) + ti Ke

ADJUSTING THE DOSAGE REGIMEN (CONT’) • Sawchuck-Zaske Method (cont’) • Determine the Ronew ( ADJUSTING THE DOSAGE REGIMEN (CONT’) • Sawchuck-Zaske Method (cont’) • Determine the Ronew ( ) Ronew = Ke Vd Cmax desired x 1 – e-Keti • Predict Ct, max at t after the end of infusion and Cmin Ct, max = Ro x 1 – e-Keti x e-Ket Ke (Cmax – (Cmine-Ke ) Cmin = Ct, maxe-Ke( - (ti – t)

ADJUSTING THE DOSAGE REGIMEN (CONT’) • Continuous Infusion Method • Determine the CLvanco* = ADJUSTING THE DOSAGE REGIMEN (CONT’) • Continuous Infusion Method • Determine the CLvanco* = Ro / achieved Cavess • Determine the new Ro (mg/H) Ro = CLvanco* x targeted Cavess

EXAMPLE OF CASES CASE 1 • Mr. AD, 62 years old patient was diagnosed EXAMPLE OF CASES CASE 1 • Mr. AD, 62 years old patient was diagnosed to have MRSA and allergic to penicillin, Body weight is 98 kg and height is 165 cm. Lab results: Sr. Cr 95 mol/L, Urea 8. 5 Suggest the best Vancomycin dosage regimen to achieve Cpeak = 40. 0 mg/L and Ctrough = 10. 0 mg/L. Estimate the dose to be given through continuous infusion, Cp = 15 mg/L

CASE 2 • Mrs. PS, 55 years old patient was diagnosed to have MRSA CASE 2 • Mrs. PS, 55 years old patient was diagnosed to have MRSA sepsis. Body weight is 85 kg and height is 170 cm. Given Short Inf. for 0. 5 H Vancomycin 500 mg Q 8 H Lab results: C&S S. aureus. , Sr. Cr 150 mol/L, Urea 9. 2, Cpeak = 40 mg/L, Ctrough = 24. 0 mg/L Adjust the Vancomycin dose regimen to achieve Cpeak = 40. 0 mg/L and Ctrough = 10. 0 mg/L.

CASE 3 • Mrs. SP, 40 years old patient was diagnosed to have endocarditis CASE 3 • Mrs. SP, 40 years old patient was diagnosed to have endocarditis and allergic to penicillin. Body weight is 45 kg and height 165 cm. Given Short Inf. for 1 H Vancomycin 750 mg Q 12 H Lab results: C&S S. aureus. , Sr. Cr 120 mol/L, Urea 9. 0, Cpeak = 30 mg/L, Ctrough = 22. 0 mg/L The doctor would like to change the method of administration to continuous infusion for 24 hours and targeted Cp = 15 mg/L. Suggest new dosage regimen to reach this later target and when to start this new regimen?

CASE 4 • Mr. IZ, 50 years old patient was diagnosed with Co. NS CASE 4 • Mr. IZ, 50 years old patient was diagnosed with Co. NS and allergic to penicillin. Body weight is 60 kg and height 150 cm. Given continuous infusion of Vancomycin 80 mg/H Lab results at day 3: Sr. Cr 200 mol/L (120 mol/L at D 1), Cave = 26. 0 mg/L The doctor would like to change the method of administration to conventional method and targeted Ctrough = 10 mg/L. Suggest new dosage regimen to reach this later target and when to start this new regimen?

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