Pharmacokinetics in children

The studies by Metsvaht et al. and Muller et al. show that the clearance of benzylpenicillin in neonates increases as the bodyweight increases. The following pharmacokinetic parameters have been observed in children:
 

Age	T½	Cl (ml/min/kg)	V (l/kg)
Neonates < 1 week, < 2000 g	4-6 hours	1.2-1.5	0.41-0.64
Neonates < 1 week, > 2000 g	2-3 hours
Neonates 1-4 weeks, < 2000 g	2-3 hours
Neonates 1-4 weeks, > 2000 g	0.5-2 hours
> 1 month	0.5-1.2 hours

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

CAUTION:
Intravenous 0 years up to 18 years INFUSION RATE Doses > 2 mln. IU:  inject slowly (0.5 mln IU/min), to avoid electrolyte imbalance and convulsions.

Infection, sepsis

Intravenous 1 week up to 4 weeks and weight at birth < 2000 g [1] [5] [6] [7] 75.000 IU/kg/day in 3 doses. 1 week up to 4 weeks and weight at birth ≥ 2000 g [1] [5] [6] [7] 100.000 IU/kg/day in 4 doses. 1 month up to 18 years [1] [4] 100.000 - 400.000 IU/kg/day in 4 - 6 doses. Max: 24.000.000 IU/day. The daily dose may be administerd as a continuous infusion.  < 1 week and weight at birth < 2000 g [2] [5] [6] [7] 50.000 IU/kg/day in 2 doses. < 1 week and weight at birth < 2000 g 50.000 IU/kg/day in 2 doses. < 1 week and weight at birth < 2000 g [2] [5] [6] [7] 50.000 IU/kg/day in 2 doses. < 1 week and weight at birth ≥ 2000 g 75.000 IU/kg/day in 3 doses. < 1 week and weight at birth ≥ 2000 g [1] [5] [6] [7] 75.000 IU/kg/day in 3 doses.

Meningitis

Intravenous < 1 week and weight at birth < 2000 g [1] [3] [5] [6] [7] 100.000 IU/kg/day in 2 doses.   < 1 week and weight at birth ≥ 2000 g [1] [3] [5] [6] [7] 150.000 IU/kg/day in 3 doses.   1 week up to 4 weeks and weight at birth < 2000 g [1] [3] [5] [6] [7] 150.000 IU/kg/day in 3 doses.   1 week up to 4 weeks and weight at birth ≥ 2000 g [1] [3] [5] [6] [7] 200.000 IU/kg/day in 4 doses.   1 month up to 18 years [1] [3] 250.000 - 400.000 IU/kg/day in 4 - 6 doses. Max: 12.000.000 IU/day. The daikly dose may be administerred as a continuous infusion.

Early neuroborreliosis
Intravenous < 9 years [9] 200.000 - 400.000 IU/kg/day in 6 doses. Max: 18.000.000 IU/day. Duration of treatment: 14 days ≥ 9 years [9] 12.000.000 - 20.000.000 IU/day in 6 doses. Duration of treatment: 14 days

Lyme meningitis
Intravenous ≥ 9 years [9] 12.000.000 - 20.000.000 IU/day in 6 doses. Duration of treatment: 14 days

Congenital syphilis
Intravenous Term neonate [10] [11] [13] Initial dose: The first 7 days after the birth 100.000 IU/kg/day in 2 doses. Maintenance dose: 150.000 IU/kg/day in 3 doses. For 3 days. Treatment after consultation of pediatric infectiologist.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Adjustment not necessary

GFR 30-50 ml/min/1.73 m2

Adjustment not necessary

GFR 10-30 ml/min/1.73 m2

generalized recommendations cannot be given. An assessment must be made per patient of the desired effect against the risks of side effects on overdosing and failure of the therapy on underdosing.

GFR < 10 ml/min/1.73 m2

generalized recommendations cannot be given. An assessment must be made per patient of the desired effect against the risks of side effects on overdosing and failure of the therapy on underdosing.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Hypersensitivity reactions, fever. Muscle necrosis and inflammation at the injection site can occur after intramuscular administration; thrombophlebitis can occur after intravenous administration. Further as a result of high doses: interstitial nephritis, abnormal blood counts, blood clotting disorders.

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Cross-allergies and cross-resistance can occur between penicillins and (to a lesser extent) with cephalosporins. Allergic reactions of the skin and mucous membranes can sometimes only occur after 48 hours. The treatment should be discontinued in such cases. Take account of the sodium content when giving high doses. Do not administer high doses in cases of renal insufficiency because of the danger of neurotoxicity, tubular necrosis and anuria.

 

 

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Penicillins with extended spectrum
	Amoxicillin Related Medicines Menu">	J01CA04
	Ampicillin Related Medicines Menu">	J01CA01

Beta-lactamase sensitive penicillins
	Benzathine benzylpenicillin Related Medicines Menu">	J01CE08
	Phenoxymethylpenicillin Related Medicines Menu">	J01CE02

Beta-lactamase resistant penicillins
	Kloksacillin Related Medicines Menu">	J01CF02

Combinations of penicillins, incl. beta-lactamase inhibitors
	Amoxicillin + clavulanic acid Related Medicines Menu">	J01CR02
	Piperacillin (as the sodium salt) / tazobactam (as the sodium salt) Related Medicines Menu">	J01CR05

References

1. Hartwig NC, et al, Vademecum pediatrische antimicrobiële therapie, 2005
2. American Academy of Pediatrics, Committee on Infectious Diseases, Red Book; Report of the Committee on Infectious Diseases, Elk Grove Village, IL:, 2003, 26th ed
3. American Academy of Pediatrics Committee on Infectious Diseases, Treatment of Bacterial Meningitis, Pediatrics, 1988, 81, 904-7
4. Jacobson SJ, et al, A randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children., Arch Pediatr Adolesc Med, 1997, 151, 701-4
5. Metsvaht T, et al, Pharmacokinetics of penicillin g in very-low-birth-weight neonates, Antimicrob Agents Chemother, 2007, 51, 1995-2000
6. McCracken GH Jr, et al, Clinical pharmacology of penicillin in newborn infants, J Pediatr, 1973, 82, 692-8
7. Muller AE, et al, Pharmacokinetics of penicillin G in infants with a gestational age of less than 32 weeks, Antimicrob Agents Chemother, 2007, 51, 3720-5
8. Prober CG, et al, The use of antibiotics in neonates weighing less than 1200 grams, Pediatr Infect Dis J, 1990, 9, 111-21
9. CBO, Richlijn Lymeziekte, www.cbo.nl, 2013, 71-85
10. HJC de Vries et al., Nederlandse Vereniging voor Dermatologie en Venereologie (NVDV). Richtlijn SOA voor de tweede lijn, www.huidarts.info, 2012, 94
11. National Institute for Public Health and the Environment | RIVM - National coordination Infectious disease control, Guideline Syphilis, 03-02-2023
12. AWMF, Deutsche Gesellschaft für Neurologie, Leitlinien für Diagnostik und Therapie in der Neuroborreliose, 2018
13. Ikuta T et al., Administration of intravenous benzylpenicillin in 13 infants born to mothers with syphilis infection: A case series, J Infect Chemother, 2021, 27(11), 1662-1664

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