Therapeutic Drug Monitoring

(TDM) protocol for pediatric

Vancomycin and Aminoglycosides

 Name Position
Prepared Clinical pharmacist: Yahya Infectious disease clinical pharmacist at
by: Mohzeri king suad medical city, MOH

Reviewed Dr: Alaa Mosly Infectious disease consultant clinical

by: pharmacist at prince sultan medical
military hospital

Dr: Heba Al-ruwaisan Infectious disease consultant clinical

pharmacist at king Faisal specialist
&Research center

Senior clinical pharmacist: Nephrology clinical pharmacist at general

Bader Al-Ghamdi pharmaceutical care administration, MOH
Senior clinical pharmacist: Internal medicine clinical pharmacist at
Alaa Mutlaq general pharmaceutical care
administration, MOH
Clinical pharmacist General clinical pharmacist at king
Mohammad al-otaibi Abdulaziz hospital Taif, MOH
Table of content:

Content Page
• Purpose, policy and procedure 4-6
• Vancomycin dosing and monitoring in Neonates and Pediatrics 7- 10
• Aminoglycosides dosing and monitoring in Neonates and Pediatrics 11-
16
 Therapeutic Drug
General Monitoring Policy and Pharmacy Department Page 4 - 3
Pharmaceutical Care Procedure
Directorate, MOH
Effective date: Revision date:
01/07/2019

1. Purpose:
To establish a standardized pharmacokinetic approach for patient receiving
drugs that are routinely monitored utilizing serum drug concentration at MOH
hospitals.

2. Definition

TDM: Therapeutic Drug Monitoring.

3. Functions Affected
Clinical Pharmacist Specialist, Staff Pharmacists, Pharmacy Resident and
Pharmacy Student.

4. Policy:
4.1. The Pharmacy Department has Therapeutic Drug Monitoring (TDM)
service, using the latest and most updated MOH guidelines.
4.2. The Pharmacist in-charge of the service is a qualified pharmacist.
4.3. The TDM is the use of drug concentration measurements in body fluids as
an aid to the management of drug therapy for the cure, alleviation, or
prevention of disease.
4.4. The TDM service guidelines were developed to ensure safe and efficacious
dosage regimens through the application of
pharmacokinetic/pharmacodynamics principles and determination of drug
serum concentrations.
4.5. The policy/procedure manual outlines standard guidelines which should be
followed when providing clinical pharmacokinetic monitoring of the following
drugs: aminoglycosides and vancomycin.
4.6. Educating pharmacists, physicians, nurses, and other clinical practitioners
on pharmacokinetic principles and/or appropriate indications for clinical
pharmacokinetic monitoring.
5. Procedures:
5.1 Therapeutic drug monitoring testing will be initiated by the ordering provider or
Pharmacy Department.
5.2 Upon receiving order for pharmacy to dose a specific medication, a pharmacist
will assess the patient and collect relevant information necessary to
appropriately dose/monitor the specified drug so as to achieve therapeutic drug
levels and minimize any potential risks of toxicity. Such items of information may
include. But not are limited to:
a. Indication for therapy (i.e. type and site of infection for antibiotic
dosing/monitoring consults).
b. Age.
c. Gender.
d. Height/Weight.
e. Renal/Hepatic function.
f. Estimated pharmacokinetic parameters.
g. Medication history.
h. Current/last known serum drug concentration.
5.3 The order should include the drug to be tested and, at minimum, the relative
time when the sample should be drawn (peak, trough, random). Whenever
possible, an exact time should be entered to correlate with drug administration
time.
5.4 Once all patient information, laboratory and clinical data completed, the
pharmacist in-charge start to follow sample guidelines and medication
monitoring guidelines (Attached) to monitoring medication level, patient situation
and follow-up the patient during therapy duration.
5.5 Laboratory and nursing staff will work together to determine the optimum time
for specimen collection. For TDM to be meaningful, the patient should be in
steady-state on the present dose of the drug. In general, samples should be
taken after drug dosing has continued for at least four half-lives.
5.6 Unless otherwise specified, sampling times will utilize the following definitions:
a) Trough – Immediately before the next scheduled dose.
b) Peak – 1 Hour post dose (Time to peak may be used to determine
alternative peak times).
5.7 In cases of suspected toxicity, waiting to attain steady-state is not necessary
and a random drug level may be collected to aid in clinical decision making.
5.8 The laboratory department should deal with the drug level sample as urgent
order and the result should be available in the system as soon as 1 – 2 hours
maximum.
6. Responsibility:
6.1. TDM Pharmacist:
6.1.1. Responsible for receiving order from health care professionals or
ordering and monitor the serum level during period of therapy and
report it to the head of service and the physician responsible for the
patient.
6.1.2. The working hours from 7:00 am-4:00 pm from Sunday to Thursday.
6.1.3. Responsible to monitor any new order & report it to the head of service
and the physician responsible for the patient.
7. Equation:
7.1.1. Calculate creatinine clearance with the Cockcroft-Gault equation using
an ideal body weight (IBW) or an adjusted body weight (ABW) if the
patient is obese
7.1.2. CrCL (mL/min) = (140 – age) x IBW / SCr x 72 (x 0.85 for females)
8. Definitions:
8.1.1. Pediatrics age categories:
1-Premature newborns: < 37 weeks gestational age
2-Term newborns ≥ 37 weeks gestational age.
3-Neonate 0-30 days of age.
4-Infant 31 days up to 1 year.
5-Children and adolescent more than 1 year up to 18 years.
8.1.2. Actual body weight: the use of actual body weight is recommended for
Vancomycin dosing and adjusted body weight for obese patient.
8.1.3. Ideal body weight: the use of ideal body weight is recommended for
Aminoglycoside dosing EXCEPT for neonate which actual body weight
is recommended.
8.1.4. Ideal body weight:
a-1-18 years: IBW= height2 * 1.65 ÷1000 (IBW in kg, height in cm)
b-152 cm and taller:
IBW (Male) = 39+ 2.27 (for each 2.45 cm over 152.4 cm)
IBW (female) = 42.2+2.27 (for each 2.45 cm over 152.4 cm)
8.1.5. Renal function: Vancomycin and Aminoglycoside are exclusively
eliminated through renal rout and their doses should be adjusted
according renal function. The creatinine clearance in pediatrics should
be calculated according to Schwartz equation. (bedside Schwartz
equation is validated in ≥ 1-year baby (fixed K =0.413).
 8.1.6. Schwartz equation: CrCl = K*ht (cm) *88.4/ SCr (micromole/L) where ht
is patient height.

Age K

Preterm ≤ 1yr 0.33

Full-term ≤ 1yr 0.45

2-12 yr 0.55

Name Title Date

Revised By Emad Alharbi ICU clinical 05/01/1440

pharmacist
Ahmed Al-Jaber ID clinical pharmacist 05/01/1440
Yahya Mohzeri ID clinical pharmacist 05/01/1440
Reviewed by Alaa mutlaq Internal Medicine 27/10/1440
clinical pharmacist
Approved by

Vancomycin dosing and monitoring in Neonates and Pediatrics

Vancomycin is a glycopeptide antibiotic that has activity against gram-positive

organisms, including MRSA and Enterococcus. It has activity against MSSA, although it
is inferior to the penicillinase-resistant penicillins (eg, oxacillin).
Dosing of vancomycin:
a. Neonatal Dose:
 The calculated dose should be rounded to the whole number for patients
weighing less than 1 Kg, and to nearest 5 for the patients weighing more than or
equal to 1 Kg.
• Adjust subsequent doses to achieve an AUC/MIC >400. In institution in which
AUC calculation is not feasible, trough concentration 10 to 12 mg/ml is very
highly likely (>90%) to achieve the goal of AUC (AUC/MIC >400) in neonate.
• Loading dose: All patients: IV: 20mg/kg once, followed by maintenance dose.
 • Maintenance dose:
 Renal function-based dosing:
Gestational age Serum creatinine Dose
<0.5 mg/dl 15mg/kg/dose every 12 hours
0.5 to 0.7mg/dl 20mg/kg/dose every 24 hours
≤28 weeks 0.8 to 1mg/dl 15mg/kg/dose every 24 hours
1.1 to1.4mg/dl 10mg/kg/dose every 24 hours
>1.4mg/dl 15mg/kg/dose every 48 hours
Gestational age Serum creatinine Dose
<0.7 mg/dl 15mg/kg/dose every 12 hours
0.7 to 0.9mg/dl 20mg/kg/dose every 24 hours
>28 weeks 1 to 1.2mg/dl 15mg/kg/dose every 24 hours
1.3 to1.6mg/dl 10mg/kg/dose every 24 hours
>1.6mg/dl 15mg/kg/dose every 48 hours
Serum creatinine concentrations normally fluctuate and are partly influenced by transplacental maternal
creatinine in the first week after birth. Cautious use of creatinine-based dosing strategy with frequent
reassessment of renal function and vancomycin serum concentrations are recommended in neonates ≤7
days old.

 Weight-directed dosing:
Body Postnatal Dose
weight age
<1.2kg ≤ 28 days 15mg/kg/dose every 18 to 24 hours
1.2 to < 7 days 10 to 15mg/kg/dose every 12 to 18 hours
2 kg
≥ 7 days 10 to 15mg /kg/dose every 8 to 12 hours
>2 kg < 7 days 10 to 15 mg/kg/dose every 8 to 12 hours
≥ 7 days 10 to 15mg/kg/dose every 6 to 8 hours

b. Infant, children and adolescent:

• Loading dose: 25mg/kg based on current actual body weight.
 Should be administered to all patients with normal renal function, initiating
vancomycin therapy for complicated infection and suspected or documented
MRSA infection.
 May also be considered in cases where rapid attainment of target serum
concentration is desired.
• Maintenance dose (MD):
 15 to 20 mg/kg/dose every 6 hours to be given as IV infusion over 2 hours
(based on type of infection).
 Adjust subsequent dose to achieve a target AUC/MIC >400. In institution in
which AUC calculation is not feasible, trough concentration 10 t 15 mg/ml for
mild infection and 15 to 20 mg/ml for severe infection.
 The calculated dose should be rounded to the nearest 10.

• Dose adjustment in renal impairment:

GFR Infants children adolescent

30 to 50 ml/min/1.37 m2 10 to 15 mg/kg/dose every 12 hours

10 to 29 ml/min/1.37 m2 10 to 15 mg/kg/dose every 18 to 24 hours

<10 ml/min/1.37 m2 10 to 15 mg/kg/dose once, check

Intermittent hemodialysis vancomycin random level after 24-48 hr, re-
Peritoneal dialysis (PD) dose with 10mg/kg/dose when the level is
less than 10-15 mg/ml.
Continuous renal replacement 10 to 15 mg/kg/dose every 12 to 24 hours
therapy (CRRT)

• Target trough concentration:

-Recent pediatric literatures suggested serum trough goal of 10 to 20 mg/L may
not correlate well with AUC/MIC ratio > 400 in pediatric patients.
Desired serum concentrations; a 24-h AUC: MIC of 400 mg·h/L is
recommended based on adult studies of invasive MRSA infections. In
situations in which AUC calculation is not feasible, a trough concentration 10–12
mg/L is very highly likely (90%) to achieve the goal AUC target in neonates when
the MIC is 1 mg/L and 10 to 15 mg/ml for mild infection or 15 to 20 mg/ml for
severe infection in pediatric patients.
• Neonate:
Type of infection Target trough concentration
Infection in neonate Target trough concentration: 10 to 12
mg/ml

• Infant, children and adolescent:

Type of infection Target trough concentration
Uncomplicated infection: soft and skin infection 10-15 mg/l
 Complicated infection (endocarditis, 15-20mg/l
osteomyelitis, bacteremia, pneumonia and
meningitis)

• Monitoring:
 Rational:
Therapeutic drug monitoring (TDM) of vancomycin is very essential to ensure
efficacy, prevent development of resistance and toxicity.
The AUC/MIC >400 is the most accurate and appropriate pharmacodynamic
target to monitor vancomycin efficacy in pediatrics.
Trough is most practical method for monitor vancomycin efficacy.

Clinical situation Obtain When to

trough obtain
Empiric short course (<3 days) therapy (≥51ml/min, stable No -
renal function, hemodynamic stable)
Empiric therapy ≥ 3 days Yes 30 mins
before 4th
dose
Empiric therapy (neonate, cystic fibrosis, Yes 30 mins
hematology/oncology, CrCl 10-50ml/min unstable renal before 4th
function, hemodynamic unstable. dose
<10 ml/min No-do Within 24-48
AKI random hours of
Intermittent hemodialysis level initial dose.
Peritoneal dialysis (PD)
CRRT

 Renal function monitoring:

Monitor renal function for nephrotoxicity three time per week and more
frequently when vancomycin combined with another nephrotoxic drugs
(piperacillin- tazobactam, aminoglycoside. furosemide, tacrolimus, cyclosporin,
acyclovir, amphotericin B …etc.).

 Infusion related reaction monitoring:

Monitor for infusion related event, including hypotension and red man syndrome.
Rapid IV administration (<60 minutes) may increase risk of red man syndrome
and may result in hypotension, flushing, erythema, urticaria, pruritus and cardiac
arrest.
  CBC monitoring:
Periodic monitoring for CBC should be done to screen for neutropenia and
thrombocytopenia in patient with prolong vancomycin therapy or those whose
receive concomitant drug that cause bone marrow suppression.

Aminoglycosides dosing and monitoring in Neonates and

Pediatrics
- Aminoglycosides are widely used for systemic treatment of gram-negative
infections or for synergy in the treatment of certain gram-positive infections.
- Aminoglycosides demonstrate concentration-dependent killing of pathogens.
- Aminoglycosides have two way for administration, traditional approach for
parenteral aminoglycoside dosing involve administration of a weight-based dose
divided in two to three times daily and extended- interval aminoglycoside (also
known as once-daily aminoglycoside) utilize a higher weight-based dose
administered at an extended interval every 24 hour or longer for those with renal
dysfunction.

1-connventional / traditional dosing:

A- Initial dose:
Initial dose for neonate and infant < 2 months of age is based on
gestational age and postnatal age:

Empiric Dosage (mg/kg/dose) by Gestational and Postnatal Age

<30 weeks 30-34 weeks ≥ 35 weeks

Medication Route 0-14 >14 day 0-10 >10 0-7 >7 days
day days days days
Amikacin IV, IM 15 15 15 15 25 17.5 q24h
q48h q24h q24h q24h q24h
Gentamicin IV, IM 5q 48h 5q 36h 5 q36h 5 q36h 4 q24h 5 q24h

Initial dose in infant >2 months, children and adolescents:

• Gentamicin
 Infection Gentamicin dose
Septicemia, meningitis, other CNS 2 to 2.5mg/kg/dose every 8 hours
infection, biliary tract infection,
endocarditis, pneumonia
infection in cystic fibrosis 3.3mg/kg/dose every 8 hours

• Amikacin
Infection Amikacin dose
General dosing, severe, susceptible 15 to 22.5 mg/kg/day divided every 8 hours
infection
CNS infection 20 to 30 mg/kg/dose divided every 8 hours
infection in cystic fibrosis 10mg/kg/dose every 8 hours

Aminoglycoside starting dose and prolonged interval in patient with renal

impairment or on dialysis:

Creatinine clearance Gentamicin Amikacin

ml/min
30 to 50 2.5mg/kg/dose/every 5 to 7.5 mg/kg/dose every 12 to
12 to 18 hours 18 hours
10 to 29 2.5mg/kg/dose/every 5 to 7.5 mg/kg/dose every 18 to
18 to 24 hours 24 hours
<10 2.5mg/kg/dose/every 5 to 7.5 mg/kg/dose every 48 to
48 to 72 hours 72 hours
Intermittent 2mg/kg/dose, re-dose 5mg/kg/dose, re-dose as
hemodialysis (IHD) as indicated by serum indicated by serum concertation
concertation
Peritoneal dialysis 2 mg/kg/dose, re- 5mg/kg/dose, re-dose as
dose as indicated by indicated by serum concertation
serum concertation
CRRT 2 to 2.5 mg/kg/dose 7.5mg/kg/dose every 12 hours
every 12 to 24 hours

• Therapeutic drug monitoring:

- Timing:
 A trough level should be obtained immediately before administration of 3rd dose.
 A peak level should be obtained 30 minutes after the end of 3rd dose infusion.

- Target trough and peak of gentamicin:

 Type of infection Target trough Target peak
Serious infection < 2mg/L 6 to 8mg/L
Life threatening < 2 mg/L 8 to 10 mg/L
infection
Urinary tract infection < 2 mg/L 4 to 6mg/ml
Synergy against < 2 mg/L 3to 5 mg/ml
gram- positive
organism

- Target trough and peak of Amikacin:

Type of infection Target trough Target peak

Serious infection <10mg/ml 20 to 25 mg/ml
Life threatening infection <10mg/ml 25 to 40 mg/ml
Urinary tract infection <10mg/ml 15 o 20 mg/ml

- Interpretation and action in response to the result of:

 Gentamicin

Trough Peak Meaning Action

<2 mg/L 3 to 10mg/L Within target Continue same regimen and
check again after 3-4 days
>2mg/L Any result High trough Withhold next dose -recheck
the level in 24 hours and if the
result <2 mg/L resume the
regimen with less frequent
interval (e.g. Q8 to Q12). Re-
check the trough and peak
around 3rd dose.
<2 mg/L >10mg/L High peak Reduce the dose by 25% and
continue same interval. Re-
check trough and peak
around 3rd dose

 Amikacin

Trough Peak Meaning Action

<10mg/L 20 to 40mg/l Within target Continue the same regimen.
≥10mg/L Any result High trough Withhold next dose -recheck
the level in 24 hours and if the
 result <10 mg/L resume the
regimen with less frequent
interval (e.g. Q8 to Q12). Re-
check the trough and peak
around 3rd dose.
<10mg/L >40mg/L High Peak Reduce the dose by 25% and
continue same interval. Re-
check trough and peak
around 3rd dose

• Others monitoring parameters:

 Serum creatinine should be measured at least every other day while patient on
aminoglycosides therapy.
 Check CBC twice weekly.

2- Once-Daily Dosing of Aminoglycosides:

- Aminoglycosides demonstrate concentration-dependent killing of pathogens,
suggesting a potential benefit to higher serum concentrations achieved with
once-daily dosing.
- Regimens giving the daily dosage as a single infusion, rather than as
traditionally split doses every 8 hours, are effective and safe for normal hosts
and immune-compromised hosts with fever and neutropenia and may be less
toxic.
- Experience with once-daily dosing in children is increasing, with similar
encouraging results as noted for adults.
- A recent Cochrane review for children (and adults) with cystic fibrosis
comparing once-daily with 3-times–daily administration found equal efficacy
with decreased toxicity in children.
- Once-daily dosing should be considered as effective as multiple, smaller
doses per day and is likely to be safer for children; therefore, it should be the
preferred regimen for treatment.

 Rational:
extended interval dosing has become preferred method of administration of
aminoglycoside for following reasons:
- Aminoglycoside is concentration depended killer.
- Increase drug -free period.
- Takes advantage of post-antibiotic effect of aminoglycoside.
- Less nephrotoxic.
- Less frequent.
 - Less monitoring.

 Exclusion criteria:
- Neonatal patient (Gestational age < 44 weeks)
- Pediatric patient with significant renal dysfunction (<20ml/min).
- Patient on hemodialysis and peritoneal dialysis.
- Patient with alteration in volume of distribution:
1- burn patient (>20% body surface area).
2- Patient with ascites
- When aminoglycoside used as synergistic to treat gram-positive infection.
- Patient known with auditory/ vestibular disease.
- Patient with osteomyelitis. (lack of evidence)
 Dosing:
-Gentamicin

Infection Gentamicin
usual dose 4.5 to 7.5 mg/kg/dose every 24 hours
infection in cystic fibrosis 10 to 12 mg/kg/dose every 24 hours

-Amikacin

Infection Amikacin
usual infection 15 to 22.5mg/kg/dose every 24 hours
infection in cystic fibrosis 30 to 35mg/kg/dose every 24 hours

 Therapeutic drug monitoring:

• Timing:
- Trough level should be checked before second dose.
- Dose of aminoglycoside should not be given to patient who are at increased risk
of nephrotoxicity unless trough level result within target.
- Trough level should be checked every 3-4 days thereafter, unless trough level
not within target.

• Target trough:

Drug Target trough

Gentamicin <1mg/L
Amikacin <5mg/L
• Interpretation and action in response to result of:

- Gentamicin

Trough Mean Action

<1mg/ml Within target Continue same regimen and recheck every
3-4 days
1-2mg/ml Slightly high Provided renal function is unchanged
increase the dose interval to 36 to 48 hours.
>2mg/ml high Check when the level was taken.
Omit next dose, re-assay in 24 hours.
Re-dose if clinically indicated when level fall≤
1mg/l but extend the dosing interval
accordingly for subsequent doses.

- Amikacin
Trough Mean Action
<5mg/ml Within target Continue same regimen and recheck every
3-4 days
≥5mg/ml high Check when the level was taken.
Omit next dose, re-assay in 24 hours.
Re-dose if clinically indicated when level fall≤
1mg/l but extend the dosing interval
accordingly for subsequent doses.

• Monitoring:
 Serum creatinine should be measured at least every other day while patient on
aminoglycosides therapy.
 Check CBC twice weekly.
• References:
1. Micromedex Neofax Essentials 2014
2. Pediatric and Neonatal Lexicomp Drug Information System. Online version
(accessed Jan 21st, 2018)
3. Infectious disease data base. Lexicomp Drug Information System. Online version
(accessed Jan 21st, 2018)
4. Rybak, M., Lomaestro, B., Rotschafer, J., Moellering, R., Craig, W., Billeter, M.,
Dalovisio, J. and Levine, D. (2009). Vancomycin Therapeutic Guidelines: A
Summary of Consensus Recommendations from the Infectious Diseases Society
of America, the American Society of Health-System Pharmacists, and the Society
of Infectious Diseases Pharmacists. Clinical Infectious Diseases, 49(3), pp.325-
327.
5. Van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of
vancomycin-induced nephrotoxicity associated with dosing schedules that
maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents
Chemother. 013;57:734-744.
6. Therapeutic Guidelines Limited. Antibiotic Expert Group. Therapeutic guidelines:
antibiotic. 15 ed Melbourne, Vic.: Therapeutic Guidelines. Limited; 2014. xxxi 687 p.
7. Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Loui A. Back to the
future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis.
2007;45(6):753-60 .
8. Giotis ND,. Baliatsa DV, Extended-interval aminoglycoside Contopoulos-Ioannidis DG
Ioannidis JP administration for children: a meta-analysis. Pediatrics. 2004;114(1):e111-