Pharmacokinetics: Monitoring Aminoglycoside and Vancomycin Serum Levels Betty Lee, Pharm.D. Lucile Packard Children’s Hospital July 3, 2012

Pharmacokinetics: Monitoring Aminoglycoside and Vancomycin

Serum Levels

Betty Lee, Pharm.D.

Lucile Packard Children’s Hospital

July 3, 2012

Outline• Vancomycin pharmacokinetics

• Aminoglycosides pharmacokinetics

• Guidelines for monitoring aminoglycoside and vancomycin serum levels at LPCH

Vancomycin• Volume of distribution:

• An average value of 0.7 L/kg or

• For patient older than 18 years:V (L) = 0.17 (age in yr) + 0.22 (TBW in kg) + 15

• Eliminated primarily by the renal route; approximately 5% of the dose is metabolized (Vancomycin Cl ~ Clcr)

Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

Vancomycin• t1/2 elimination

• Newborns: 6-10 hours

• Infants & Children 3 months to 4 years: 4 hours

• Children > 3 years: 2.2 – 3 hours

• Adults: 5 – 11 hours; significantly prolonged with renal impairment

Lexicomp Online, June 2012

Vancomycin• Bactericidal for most gram-positive organisms,

except against enterococci

• Vancomycin-induced ototoxicity has been primarily reported in patients with vancomycin concentrations > 80 mg/L.

• As a single agent, vancomycin is associated with a low incidence of nephrotoxicity; however, when it is combined with aminoglycoside, the incidence may be as high as 30%.


Aminoglycosides• Volume of distribution is ~0.25 L/kg• Pediatric patients younger than 5 years tend to have a

larger volume of distribution, declining from an initial value of 0.5 L/kg to adult value of 0.25 L/kg

V(children 1-5 yrs) = [(0.5 L/kg) - (age in years x 0.25)] (wt in kg)

• Obese patients:

V (obese pt) = (0.25 L/kg) (IBW) + 0.1 (TBW-IBW)


5

Aminoglycosides• Aminoglycosides are eliminated almost entirely by

the renal route (Cl = Clcr)

• t1/2 elimination (Gentamicin)

• Infants < 1 week: 3 – 11.5 hours

• Infants 1 week to 6 months: 3 – 3.5 hours

• Adults: 1.5 – 3 hours

• End-stage renal disease: 36 – 70 hours

Lexicomp Online, June 2012


Aminoglycosides

• Dose based on lean weight• If total body weight (TBW) >20% ideal body weight (IBW),

use adjusted body weight

• Children (1-18 years) IBW calculation (IBW in kg, height in cm):

• IBW = (height2 x 1.65)/1000

• IBW = 2.396 x e0.01863 (height in cm)

• Adjusted body weight = IBW + [0.4 x (TBW-IBW)]


Aminoglycosides• Bactericidal activity is concentration-dependent• Postantibiotic effect that results in depressed

bacterial growth after plasma concentrations have fallen below the MIC

• Decreased risk of adaptive resistance• Saturable uptake mechanisms within the renal cortex and

inner ear indicate that extended interval dosing may also minimize the likelihood of developing nephrotoxicity and ototoxicity.

Fisman DN, Kaye KM. Once-daily dosing of aminoglycoside antibiotics. Infect Dis Clin North Am. 2000 Jun;14(2):475-87.Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Philadelphia: Lippincott Williams and Wilkins, 2010.

Once-daily Aminoglycosides

• Less intensive monitoring of serum concentrations• Nomogram developed by Nicolau D et al.

Antimicrob Agents Chemother 1995; 39:650-655.• Recommends a single level be drawn 6 to 14

hours after the dose• With extended interval dosing there should be no significant

accumulation with multiple dosing, therefore, measurements can be obtained after any dose.

Nicolau D et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:650-655.

Nicolau D et al. Antimicrob Agents Chemother 1995; 39:650-655

Nicolau D et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:650-655.

Guidelines for Monitoring Aminoglycoside and Vancomycin Serum Levels at LPCH

• Order serum levels two times a week for aminoglycoside and at least once a week for vancomycin

• Order serum creatinine once or twice per week• For patients undergoing intermittent hemodialysis,

vancomycin random levels every three to four days are indicated to ensure serum levels are greater than 10 mcg/mL (or 3 to 4 times above the MIC of the infecting organisms)

Guidelines for Monitoring Aminoglycoside and Vancomycin Serum Levels

• Vancomycin:• Order a single trough level before the 4th dose of

vancomycin• Trough is drawn within 30 minutes before the next dose

• Routine peak levels are not necessary for most patients

• Consider ordering peak level after the 3rd dose in patients with selected circumstances, such as bacterial meningitis• Peak level is drawn 60 minutes after the end of a 60-min

infusion


• Aminoglycosides:• Order peak after the 3rd dose of aminoglycosides and

trough before the 4th dose

• Peak is drawn 30 minutes after end of a 30-min infusion

• Trough is drawn within 30 minutes before the next dose

• If once-daily dosing, order a peak level 60 minutes after end of a 60-min infusion and order a random level at hour 20.


Gentamicin/Tobramycin

Amikacin

Trough < 2 mcg/ml < 10 mcg/mlPeak 4-10 mcg/ml 20-30 mcg/mlPeak (synergy) 3-5 mcg/ml N/APeak (CF patients) 8-12 mcg/ml N/AOnce-daily Peak 15-25 mcg/ml 30-55 mcg/mlOnce-daily Random(at 18-20 hours)

<1 mcg/ml <5 mcg/ml

Trough *10-20 mcg/ml

Peak 25-40 mcg/ml

Aminoglycosides

Vancomycin

*For patients with meningitis or osteomyelitis, the goal trough levels should be 15-20 mcg/ml .

Viscoli C, Dudley, M et al. Serum Concentrations and safety of single daily dosing of amikacin in children undergoing bone marrow transplantation. Journal of Antimicrobial Chemotherapy 1991 27, Suppl. C,113-120.Trujillo H, Robledo J et al. Single daily dose amikacin in paediatric patients with severe Gram-negative infections. Journal of Antimicrobial Chemotherapy 1991 27, Suppl. C, 141-147.

Some Useful PK Formulas• K = ln (C1 / C2 ) (t2 – t1)• K = Cl V

• t1/2 = 0.693 / K

• For steady state, bolus model :

Dose = (Css1 ) (V) (1- e-Kτ ) (e-Kt1 )


Some Useful PK Formulas

• CLcr for Children = (K) (Height in cm) (BSA) (ml/min) SCrss (1.73m2)

where the K value is based on the infant/child’s age:

Age K

Preterm infants up to 1 year 0.33

Full-term infants up to 1 year 0.45

1-12 years 0.55

13-21 years female 0.55

13-21 years male 0.70


Some Useful PK Formulas

• BSA in m2 = Patient’s weight in kg (1.73 m2)

• CLcr for males = (140 - Age) (Weight) (ml/min) (72) (SCrss)

• CLcr for females = (0.85) (140 - Age) (Weight) (ml/min) (72) (SCrss)


70 kg

0.7

Clinical Calculators• Clinical calculator available at LPCH Intranet:

Lane Library Specialty Portals Pharmacy-Calculators Drug Levels-Vancomycin & Aminoglycoside Pharmacokinetics

•http://medcalc.com.laneproxy.stanford.edu/pk/

•Other calculators available at Pharmacy Network: Pharmacy Network Pharmacokinetic Monitoring• CF Kinetics - by Dr. Carlos Milla

• NICU Drug Kinetics - by Dr. William Benitz

Additional Information

• Area Under the Curve (AUC) = area under the plasma drug concentration vs. time curve• AUC = dose administered/drug clearance

• AUC (mg.hr/L)= C0 = initial concentration (mg/L) k elimination rate

constant (hr-1)

• Gentamicin and Tobramycin:• AUC24 = 70 – 100 mg.hr/L

• Cystic fibrosis patients: tobramycin AUC24 ~ 100 to 125

Prescott WA Jr, Nagel JL. Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis. Pharmacotherapy 2010 Jan;30(1):95-108.

CF Kinetics - by Dr. Carlos Milla

NICU - Drug Kinetics

Additional Information

• Vancomycin—some oncology or ICU patients may need up to q 6 hour dosing

• Never give aminoglycoside more frequent than q 8 hour

• Aminoglycoside—if long term therapy, need hearing test

References• Michael E. Winter. Basic Clinical Pharmacokinetics. 5th

edition. Lippincott Williams & Wilkins, 2010.

• Nicolau D et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39:650-655.

References

• Rybak M, Lomaestro B, Rotschafer JC et al. Therapeutic monitoring of Vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm 2009;66:82-98.

• Prescott WA Jr, Nagel JL. Extended-interval once-daily dosing of aminoglycosides in adult and pediatric patients with cystic fibrosis. Pharmacotherapy 2010 Jan;30(1):95-108.

Documents

Pharmacokinetics: Monitoring Aminoglycoside and Vancomycin Serum Levels Betty Lee, Pharm.D. Lucile Packard Children’s Hospital July 3, 2012