TDM of vancomycin(Antibiotic)

Introduction

• Antibacterial, tricyclic glycopeptide antibiotic.

• used to treat gram-positive infection caused by: - methicillin resistant staphylococci - ampicillin resistant enterococci.

Mechanism of action• Vancomycin acts by inhibiting cell wall synthesis

of bacteria. • Vancomycin binds to the building blocks of the

peptidoglycan

• it prevents the transpeptidase from acting on these newly formed blocks

• prevents cross-linking of the peptidoglycan layer.

Major brands and strengths

Brands Contains Dosage forms

Vancard Vancomycin HCl USP 500mg/vial Inj Vancomin Vancomycin HCl USP 500mg/vial or 1 g/ vial Inj

Vancomycin HCl 500mg/ vial Inj

Vanmycin Vancomycin HCl Inj

Pharmacokinetic data

• Bioavailability Negligible (oral)

• Metabolism Excreted unchanged

• Half-life 4–11 hours (adults) 6-10 days (renal impairment)

• Excretion Renal

• Volume of distribution 0.5-1 L/kg

• Clearance 7L/hr (85% renal clearance)

Uses of vancomycin

• Endocarditis• Meningitis• Osteomyelitis• Respiratory Tract Infections• Skin and skin structure infections• Clostridium difficile-associated Diarrhea

andColitis• Staphylococcal Enterocolitis

Administration and dosage

• Administration - orally - slow infusion• Dose - Normal: 15 to 20 mg/kg - Toxicity dose: Greater than 4g/day - Staphyloccal enterocolitis: 500 mg – 2

g/day PO divided TID/QID - renal impairment: 15 mg / kg initially

Side effects

• Hives (Rashes)• Ototoxicity• Hypotension• Fever, chills, body aches, flu

symptoms• Red man syndrome• Anemia and insomnia in patient

older than 65 years• Nephrotoxicity and intestinal

nephritis.

Drug interactions

• with other ototoxic and/or nephrotoxic drugs

• Aminoglycosides• Amphotericin B• Bacitracin• Polymyxin B• Anesthetics

Clinical pharmacokinetics

Absorption IV or orally IM route is not used Distribution Vd is 0.5 to 1.0 l/kg Metabolism not metabolized to a greater extent 80 to 90% of IV administered drug can

be recovered unchanged in urine Excretion CLV = 0.65 xCLCr x total

body weight

TDM of vancomycin

“measurement of medication levels in blood”

Conditions & altered PK parameters for TDM of vancomycin:

Vancomycin therapy for longer than 5 days Impaired renal function Impaired hepatic function Pregnancy Obese Severe burns Concomitant therapy with nephrotoxic drugs

Clinical signs and symptoms of toxicity

red man syndrome (erythema,flushing,pruritis) Angioedema LeucopeniaThrombocytopenia Ototoxicity Nephrotoxicity

Analytical methods for vancomycin monitoring:

Immunoassay: 1) microbiologic assay 2) fluorescence immune assay technique.

Chromatographic method HPLC

Timing of monitoring

• Serum is preferred specimen.• Sample should be taken after

third dose (usually fourth dose)• which is obtained in 3 to 5

days

precautions

• Careful observation of the patient overgrowth of non susceptible microorganisms

• monitoring of renal function (with amino glycosides)

nephrotoxicity

• periodic monitoring of the leukocyte count (In Case of prolonged therapy)

neutropenia

• vancomycin should be infused at a rate 10 mg/minute

'red-man' syndrome

Dosing Guidelines

• Initial vancomycin doses: →actual body weight

• Subsequent dosage: → actual serum

concentrations

Dose

Normal dose 15-20 mg/kg (250 mg) IV 1000 mg

Neonates IV: Loading dose of 15 mg/kg

Infants and Children IV: usual start dose 15mg/kg 6 hourly Maximum recommended 2g/dose

Adults 15 mg/kg (based on

[ABW]/dose maximum of 2 g/dose

Dose adjustment a/c to trough levels

• dosing interval is adjusted, based on the steady state trough concentration

• trough levels >10 mg/L.(i.e. 15-20mg/L)

• Low trough levels: Increase dose and/or reduce interval (ie: give more frequently).

• High trough levels: Increase interval (give less frequently) first, and/or reduce dose.

Continued…

•  Level <5 increase dose by 50-100% (eg 10 to 20 mg/kg/dose).

• Level 5-10 increase dose by 20%

• Level >20 increase dose interval (eg from 6 to 8 hourly). Recheck level prior to next dose

and administer if within target range.

Dosage regimen calculation

2 approaches to calculate this. 1st approach includes:1st step pharmacokinetic parameters:

Kel = 0.009 + (CLcr x 0.0022)

Vd = DW x Vdperkg

tau = tinf + [ln(Cptmax / Cptmin) / Kel]

2nd stepmaintenance dose:

MD = Kel x Vd x Cptmax x (1 - e-Kel x tau / 1 - e-Kel x tinf)

Continued…

2nd approach includes:

Creatinine Clearance Clcr (females) = (140 – age) x IBW*/Scr (μmol/L) Clcr (males) = Clcr (females) x 1.2

IBW Calculation:

IBW = 50 + 2.3 × inches over 60 (for men)

IBW = 45 + 2.3 × inches over 60 (for women)

ABW = IBW + 0.4 × actual wt – IBW DW = 0.4 (ABW – IBW) + IBW (if ABW

> IBW)

Case study

B.C., > a 65 - year old , > 45 kg male

past medical history: > diabetes mellitus, > hypertension > hospital-aquired , nafcillin-resistant S.aureus

infection . > serum creatinine of 2.2 mg / dL, >.( Note that Vd = 0.7L/kg ) > Cpss (avg) = 20 mg/L

 

calculation of the pharmacokinetic parameters Vd = DW x Vdperkg

= 0.7 L / kg. * 45 kg. 31.5 L

CLcr = (140 – Age ) (weight) / (72) (SrCrss) = (140 – 65 ) (45)/ (72) (2.2) 21.3 ml/min

Cl = (0.65)(CLcr )*(total body wt) =(0.65)(0.475 ml/kg/min)(45 kg) 0.83 L/h

Kd = Cl / Vd = 0.83 L/h / 31.5 L 0.026 hr -1

t 0.5 = (0.693) (Vd) / Cl = (0.693) (31.5 L) / 0.83 L/hr 26 hr

Further calculations

Initial plasma concentration: Cpo = (S) (F) (loading dose) / Vd = (1) (1) (15 mg/kg) / 0.7 L/Kg = 21 mg/L ~20mg/L

Loading Dose : Loading dose = (Vd) (Cp) / (S) (F) = (31.5 L) (30 mg/L) / (1) (1) = 945mg or ~1000mg

Maintenance Dose : Maintenance dose = (Cl) (Cpss ave) (t) / (S)

(F) =(0.83 L/hr) (20mg/L) (1hr) / (1)

(1) = 17 mg