Neonatal Pharmacokinetics

and Antibiotic Use

Brittany Logston, PharmD
September 21, 2017

Wake Forest Baptist Medical Center

Objectives

Describe general pharmacokinetic principles

Discuss neonatal sepsis treatment and
pharmacokinetics of commonly used antibiotics in
Identify and interpret the Neonatal Early-Onset Sepsis
Calculator
Review chorioamnionitis antibiotic treatment and effect
Discuss the effect of antibiotic use on the microbiome

Wake Forest Baptist Medical Center

Neonatal Pharmacokinetics

Wake Forest Baptist Medical Center

Neonatal Pharmacokinetics

Absorption
Distribution
Metabolism
Excretion

Wake Forest Baptist Medical Center Kearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67.
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
Absorption
Gastrointestinal absorption
Decreased motility
Decreased GI tract surface area
Decreased splanchnic blood flow
Gastric pH at birth is more alkaline (pH>4)

Other routes of administration

Thinner stratum corneum
Reduced skeletal-muscle blood flow and inefficient
muscular contractions

Wake Forest Baptist Medical Center Kearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67.
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
 Distribution
Higher amount of total Developmental Changes in Body Water

body water Distribiution Sites Body Fat

90

Lower amount of adipose 80

stores 70

Percent of Total Body Weight

60
Decrease in circulating
50
serum proteins
40

Competition between 30

medications and bilirubin 20

for binding sites 10

0
1
Birth 3 2mo 6 3mo 9 m
4o 1 5yr 5 6yr 10 7yr 8 yr 40
20 9 yr
Age

Wake Forest Baptist Medical Center Kearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67.
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
 Fat
Volume of Distribution Water
Drug

Adult Neonate
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 Metabolism

Phase I Phase II
CYP enzymes Conjugation
Oxidation Sulfation
Hydrolysis Glucoronidation
Hydroxylation
Reduction

Wake Forest Baptist Medical Center Kearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67.
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
 Excretion
Acquisition of Renal Function
140

Glomerular Filtration Rate (mL/min/1.73m2)

Nephrogenesis is completed by 120
36 weeks gestation 100
Rapid increase in renal clearance
80
within the first 2 weeks of life
Glomerular filtration rate reaches 60
adult values at 6-12 months of life 40

20

0
1-2 2-4 2 6 1 2 6 12
1
day 2
wk 3
mo 4
mo 5yr 6yr 7yr 8yr
Age

Wake Forest Baptist Medical Center Kearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67.
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
Half Life

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Neonatal Pharmacodynamics

Pharmacodynamics are the effect of the

medication on the body
Dependent on medication concentration at the
receptor
Correlates the drug dose with a response

Wake Forest Baptist Medical Center Kearns GL, et al. N Engl J Med. 2003 Sep 18;349(12):1157-67.
Tayman C, et al. J Pediatr Pharmacol Ther. 2011 Jul;16(3):170-84.
Neonatal Sepsis

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Neonatal Sepsis
Early Onset Sepsis
3 days of life if in the NICU
<7 days of life outside of the NICU
Pathogens
Gram Positive Gram Negative
Streptococcus agalactiae Escherichia coli
(Group B strep)
Listeria monocytogenes Klebsiella pneumoniae

Empiric Intravenous Therapy

Ampicillin
Gentamicin

Wake Forest Baptist Medical Center Sauberan J. Neonatal Sepsis. Pediatric Pharmacotherapy 2013.
McDade E. Meningitis in Infants and Children. Pediatric Pharmacotherapy 2013.
 Ampicillin
Protein Binding: 20% Renal Excretion: 79-92%

Volume of distribution Elimination Half life

Jusko WJ et al. J Pharm Sci 1973; 62:69-76.

Colburn WA, et al. J Infect Dis 1976; 134:67-69.
Clarke JT, et al. Antimicrob Agents Chemother 1974; 6:729-733.
Wake Forest Baptist Medical Center Kaplan JM, et al. J Pediatr 1974; 84:571-577.
Product Information: ampicillin IM, IV injection, ampicillin IM, IV injection. Sandoz Inc, Princeton, NJ, 2009.
Ampicillin
Body Weight Postnatal Age Dose

14 days 100 mg/kg/dose every 12 hours

<1 kg
15 to 28 days 50 mg/kg/dose every 8 hours

7 days 100 mg/kg/dose every 12 hours

1 to 2 kg
8 to 28 days 50 mg/kg/dose every 8 hours

7 days 100 mg/kg/dose every 12 hours

>2 kg
8 to 28 days 50 mg/kg/dose every 6 hours

Wake Forest Baptist Medical Center

Red Book [AAP 2015]
 Gentamicin
Protein Binding: Low (0-30%) Renal Excretion: 65 to 100%

Volume of Distribution Elimination Half Life

Tholl DA, et al. Crit Care Med 1993; 21:248-251.

Lackner TE, et al. DICP 1990; 24:29-32.
Postovsky S, et al. Pediatr Hematol Oncol 1997; 14:547-554.
Shevchuk YM, et al. DICP 1990; 24:273-276.
Hayani KC, et al. J Pediatr 1997; 131:76-80.
Sawchuck RJ, et al. J Pharmacokinet Biopharm 1976; 4:183.
Murphy JE, et al. Am J Health Syst Pharm 1998; 55:2280-2288.
Hayani KC, et al. J Pediatr 1997; 131:76-80.
Wake Forest Baptist Medical Center Product Information: gentamicin intramuscular injection solution, intravenous injection solution, gentamicin
intramuscular injection solution, intravenous injection solution. Fresenius Kabi USA, LLC. Lake Zurich, IL, 2013.
Gentamicin

PMA Postnatal Dose Interval

(weeks) (days) (mg/kg) (hours)

0 to 7 5 48
29 8 to 28 4 36
29 4 24

0 to 7 4.5 36
30 to 34
8 4 24

35 ALL 4 24

Wake Forest Baptist Medical Center

Stolk LM, et al. Ther Drug Monit Aug, 2002; 24(4): 527-531.
 Neonatal Early-Onset Sepsis Calculator
Incidence of Early-Onset Sepsis

Gestational Age

Highest maternal antepartum temperature

Time from rupture of membranes

Maternal GBS status

Type of intrapartum antibiotics

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https://neonatalsepsiscalculator.kaiserpermanente.org
Neonatal Early-Onset Sepsis Calculator

Type of intrapartum antibiotics

Broad spectrum antibiotics >4 hours prior to birth
Broad spectrum antibiotics 2-3.9 hours prior to birth
GBS specific antibiotics >2 hours prior to birth
No antibiotics or any antibiotics <2 hours prior to birth

Wake Forest Baptist Medical Center

https://neonatalsepsiscalculator.kaiserpermanente.org
Neonatal Early-Onset Sepsis Calculator
Results

Wake Forest Baptist Medical Center

https://neonatalsepsiscalculator.kaiserpermanente.org
Neonatal Early-Onset Sepsis Calculator
Results

Risk/1000 Births Clinical Recommendations Vital Recommendations

0.40 No culture, no antibiotics Routine Vitals
Vitals every 4 hours for
0.41-3 Blood Culture
24 hours
Strongly consider starting
>3 Vitals per NICU
empiric antibiotics

Wake Forest Baptist Medical Center

https://neonatalsepsiscalculator.kaiserpermanente.org
Neonatal Early-Onset Sepsis Calculator
Example
Criteria Decision
Incidence of Early onset sepsis 0.5/1000 live births
Gestational age 35 weeks, 1 day
Highest maternal antepartum temperature 98o
ROM 3 hours
Maternal GBS status Negative
Type of intrapartum antibiotics No antibiotics

Wake Forest Baptist Medical Center

https://neonatalsepsiscalculator.kaiserpermanente.org
Neonatal Sepsis
Late Onset Sepsis
> 3 days of life if in the NICU
7-30 days of life outside of the NICU
Pathogens
Gram Positive Gram Negative Fungi
Staphylococcus aureus Escherichia coli Candida species
Coagulase-negative staphylococcus Enterobacter species
Enterococcus species Serratia species
Pseudomonas aeruginosa

Empiric Intravenous Therapy

Vancomycin
Gentamicin

Wake Forest Baptist Medical Center Sauberan J. Neonatal Sepsis. Pediatric Pharmacotherapy 2013.
McDade E. Meningitis in Infants and Children. Pediatric Pharmacotherapy 2013.
 Vancomycin
Protein Binding: 55% Renal Excretion: 80-100%

Volume of Distribution Elimination Half Life

Machado JK, et al. Clinics (Sao Paulo) 2007; 62(4):405-410.

Wake Forest Baptist Medical Center Evans WE, et al. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, 3rd. Applied Therapeutics, Inc, Vancouver, WA, 1992.
Product Information: vancomycin HCl IV injection, vancomycin HCl IV injection. APP Pharmaceuticals, LLC, Schaumburg, IL, 2011.
 Vancomycin

Body Weight Postnatal Age Dose Frequency

<1.2 kg 28 days 15 mg/kg/dose Every 18 to 24 hours
<7 days 10 to 15 mg/kg/dose Every 12 to 18 hours
1.2 to 2 kg
>7 days 10 to 15 mg/kg/dose Every 12 to 18 hours
>2 kg <7 days 10 to 15 mg/kg/dose Every 8 to 12 hours
7 days 10 to 15 mg/kg/dose Every 6 to 8 hours

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Red Book [AAP 2009]
Chorioamnionitis and Antibiotic Effects
on Neonates

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Chorioamnionitis Treatment
Thought to provide bactericidal concentrations of
antibiotics to the fetus
Treatment
Recommended therapy
Ampicillin and gentamicin
Penicillin allergy
Cefazolin and gentamicin
Severe penicillin allergy
Clindamycin and gentamicin

Wake Forest Baptist Medical Center

Tita AT, Andrews WW. Clin Perinatol. 2010 Jun;37(2):339-54.
Effects of Chorioamnionitis Antibiotics
Ampicillin:
Detectable in amniotic fluid, cord blood, and serum in the
infant
Concentration exceeding MIC of:
E Coli: 4 hours
Listeria: 8 hours
Group B Strep: 8 hours
Gentamicin:
Levels in the cord blood reaching approximately 40%
those of maternal serum levels
Tita AT, Andrews WW. Clin Perinatol. 2010 Jun;37(2):339-54.
Kraybill EN, et al. Am J Obstet Gynecol 1980; 138(pt 1):793-796.
Weinstein AJ, et al. Am J Obstet Gynecol 1976; 124:688-691.
Wake Forest Baptist Medical Center Philipson A, et al. N Engl J Med 1973; 288:1219
Hannay WT: Cephazolin in obstetrics. Scot Med J 1975; 20:175..
Effects of Chorioamnionitis Antibiotics

Cefazolin: Adequate concentrations are

achieved in amniotic fluid, cord blood, and
placental tissue

Clindamycin: Levels in cord blood peak

reaching approximately 45% of maternal serum
concentrations

Tita AT, Andrews WW. Clin Perinatol. 2010 Jun;37(2):339-54.

Kraybill EN, et al. Am J Obstet Gynecol 1980; 138(pt 1):793-796.
Weinstein AJ, et al. Am J Obstet Gynecol 1976; 124:688-691.
Wake Forest Baptist Medical Center Philipson A, et al. N Engl J Med 1973; 288:1219
Hannay WT: Cephazolin in obstetrics. Scot Med J 1975; 20:175..
Microbiome Changes

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Microbiome Changes
Early Complications
Disrupts the balance of pathogenic bacteria
and beneficial bacteria

Increased Decreased
Enterobacteriaceae Bifidobacteriaceae
Actinobacteria Bacteroidetes
Proteobacteria Bacilli
Lactobacillales

Wake Forest Baptist Medical Center Gibson MK, et al. Curr Opin Microbiol. 2015 Oct;27:51-6.
Hartz LE, et al. . Adv Neonatal Care. 2015 Oct;15(5):324-35.
Microbiome Changes

Long-term Complications
Continued imbalance
Increase the risk of necrotizing enterocolitis
Increase resistance to antibiotics
Increase in asthma rate in children
Antibiotic usage within the first 6 months of life has
been linked to obesity

Wake Forest Baptist Medical Center Gibson MK, et al. Curr Opin Microbiol. 2015 Oct;27:51-6.
Hartz LE, et al. . Adv Neonatal Care. 2015 Oct;15(5):324-35.
Questions

Wake Forest Baptist Medical Center

Neonatal Pharmacokinetics
and Antibiotic Use
Brittany Logston, PharmD
September 21, 2017

Wake Forest Baptist Medical Center

Meropenem

Body Weight Postnatal Dose Interval

(kg) (days) (mg/kg) (hours)
14 20 12
2 15 to 28 20 8
29 to 60 30 8
14 20 8
>2
15 to 60 30 8

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Ceftazidime

Body Weight Postnatal Dose Interval

(kg) (days) (mg/kg) (hours)

14 50 12
<1
15 to 28 50 8-12

7 50 12
1-2
8 to 28 50 8-12
7 50 12
>2
8 to 28 50 8

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Cefepime

Body Weight Postnatal Dose Interval

(kg) (days) (mg/kg) (hours)

0-14 50 12
<1
14 50 8

0 to 7 50 12
1 to 2
8 50 8

2 ALL 50 8

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Piperacillin-Tazobactam

Body Weight Postnatal Dose Interval

(kg) (days) (mg/kg) (hours)

14 100 12
<1
15 to 28 100 8

7 100 12
1
8 to 28 100 8

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Clindamycin

Body Weight Postnatal Dose Interval

(kg) (days) (mg/kg) (hours)

14 5 12
<1
15 to 28 5 8

7 5 12
1-2
8 to 28 5 8
7 5 8
>2
8 to 28 5 6

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