Pharmacokinetics in children

Following a single intravenous administration of ceftriaxone to (premature) neonates, the following pharmacokinetic parameters have been found (Martin et al. 1984):

Age	<1 week	1-4 weeks	3-9 months
n=	4	8	8
Dose (mg/kg)	50	50-100	100
t½ (hour)	16,2	9,2	7,1
Cl (ml/min/kg)	0,37	0,77	1,03
Vd (ml/kg)	450	480	394

Gestational age and weight have no effect on the kinetics of ceftriaxone, nor is there any difference in Cmax following intravenous or intramuscular administration (Mulhall, de Louvois, and James 1985). The Cmax ranges from 134-230 mg/l after a single dose of 50 mg/kg (Mulhall, de Louvois, and James 1985, McCracken et al. 1983, Steele et al. 1983).

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

Severe bacterial infections

Intravenous Neonates, postnatal age 0 days up to 15 days [20] NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 50 mg/kg/day in 1 dose Administer slowly in at least 60 minutes Neonates, postnatal age 15 days up to 1 month [20] NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 100 mg/kg/day in 1 dose Administer slowly in at least 60 minutes 1 month up to 18 years [20] [23] [24] 100 mg/kg/day in 1 dose. Max: 2 g/day. Administer slowly in at least 30 minutes.  In exceptional situations (like bacterial endocarditis or bacterial meningitis) the maximum dose can be increased to 4 g/day Consider 2 times daily administration (every 12 hours) in Doses > 2 g/day In critically ill children with eGFR > 80 ml/min/1.73 m2 and/or MIC ≥ 0.5 mg/l    Intramuscular Neonates, postnatal age 0 days up to 15 days NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 50 mg/kg/day in 1 dose Neonates, postnatal age 15 days up to 1 month NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 100 mg/kg/day in 1 dose 1 month up to 18 years [4] [7] [9] [12] [20] 100 mg/kg/day in 1 dose. Max: 2 g/day. Dosages higher than 2 grams / day must be administered intravenously.

Neonatal gonococcal conjunctivitis

Intravenous 0 weeks up to 4 weeks NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 25 - 50 mg/kg/dose, once only. Max single dose: 125 mg/dose. Intravenous doses from 1 g or 50 mg/kg should be administered slowly over at least 30 minutes. Intramuscular 0 weeks up to 4 weeks NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 25 - 50 mg/kg/dose, once only. Max single dose: 125 mg/dose.

Prophylaxis for meningococcosis
Intramuscular 1 month up to 16 years [17] [19] 125 mg/dose, once only. 16 years up to 18 years [17] 250 mg/dose, once only.

Early (stadium II) and late (stadium III) disseminated Lyme borreliosis
Intravenous 15 days up to 12 years [15] [18] [20] 50 - 80 mg/kg/day in 1 dose. Max: 2 g/day. Duration of treatment: 14-21 days in accordance with local treatment guidelines Administer slowly in at least 30 minutes. ≥ 12 years [15] [20] 2 g/day in 1 dose Duration of treatment: 14-21 days in accordance with local treatment guidelines. Administer slowly in at least 30 minutes.

Pre-operative prophylaxis

Intravenous 1 month up to 18 years [20] 50 - 80 mg/kg/day in 1 dose. Max: 2 g/day. Administer slowly in at least 30 minutes Term neonate 0 days up to 15 days [20] NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 20 - 50 mg/kg/day in 1 dose Administer slowly in at least 60 minutes. Term neonate 15 days up to 1 month NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 50 - 80 mg/kg/day in 1 dose Administer slowly in at least 60 minutes Intramuscular 1 month up to 18 years [20] 50 - 80 mg/kg/day in 1 dose. Max: 2 g/day. Term neonate 0 days up to 15 days NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 20 - 50 mg/kg/day in 1 dose Term neonate 15 days up to 1 month [20] NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 50 - 80 mg/kg/day in 1 dose

Acute otitis media

Intramuscular Term neonate 0 days up to 15 days [20] NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 50 mg/kg/dose, once only. term neonate 15 days up to 1 month [20] NOTE: Only if there is no hyperbilirubinaemia (see warnings and precautions) 50 mg/kg/dose, once only. In seriously ill child or after failure of initial dose: continue treatment during 3 days.  1 month up to 18 years and < 40 kg [20] 50 mg/kg/dose, once only. Max: 2 g/day. In seriously ill child or after failure of initial dose: continue treatment during 3 days 1 month up to 18 years and ≥ 40 kg 2 g/dose, once only. In seriously ill child or after failure of initial dose: continue treatment during 3 days

Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: dose adjustment not necessary
GFR <10 ml/min/1.73m2: maximal 2 g/day.

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

Thrombophlebitis, fever, nausea, vomiting, diarrhoea, vaginal candidiasis, abnormal blood counts, headaches and temporary elevated liver enzymes. Rare: convulsions, pseudomembranous colitis.

(Reversible) precipitation in the kidneys or urinary tract (especially in children >3 years) has been reported, especially when treated with high doses and in the presence of other risk factors such as fluid restriction or bedriddenness. In some cases, this led to ureteral obstruction, (postrenal) acute renal failure and / or anuria.

 

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

Contra-indications in children

Due to the high incidence of hyperbilirubinaemia in the newborn, ceftriaxone is contraindicated in these situations. If use of a 3rd generation cephalosporin is indicated, a safer alternative is preferred, e.g. cefotaxime. If the period of hyperbilirubinaemia is over and there are no underlying liver diseases, ceftriaxone can also be used in neonates.

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

Ceftriaxone should not be mixed with or administered concomitantly with intravenous solutions that contain calcium. The solutions may be given successively as long as the infusion line is flushed thoroughly. In neonates of younger than 28 days, the combination is contraindicated: ceftriaxone may not be administered along with intravenous administration of solutions that contain calcium.

Cephalosporins can in general be given to patients who are hypersensitive to penicillin, although cross-reactions have been reported. Special care is indicated in patients who previously had anaphylactic responses to penicillins.
Ceftriaxone is not effective against bacteria that cause atypical pneumonia or against various other bacterial species that can cause pneumonia, including P. aeruginosa.
Be aware of the occurrence of symptoms that could indicate that gallstones are forming. Stopping the treatment with ceftriaxone in these symptomatic cases must be assessed by the treating specialist.
Pseudomembranous colitis may occur during antibiotic use. If pseudomembranous colitis develops, the ceftriaxone treatment should be discontinued and an appropriate therapy started.
Once the patient no longer has a fever, the treatment should be continued for at least a further three days. Treatment for at least 10 days is needed in infections caused by Streptococcus pyogenes

Interactions

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

• ANTIINFECTIVES FOR SYSTEMIC USE
• ANTIBACTERIALS FOR SYSTEMIC USE

OTHER BETA-LACTAM ANTIBACTERIALS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

First-generation cephalosporins
	Cefazolin Related Medicines Menu">	J01DB04
	Cephalexin Related Medicines Menu">	J01DB01

Second-generation cephalosporins
	Cefuroxime (as the sodium salt), cefuroxime (as cefuroxime axetil) Related Medicines Menu">	J01DC02

Third-generation cephalosporins
	Cefixim Related Medicines Menu">	J01DD08
	Cefotaxime (as the sodium salt) Related Medicines Menu">	J01DD01
	Ceftazidim + Avibactam Related Medicines Menu">	J01DD52
	Ceftazidime Related Medicines Menu">	J01DD02

Carbapenems
	Meropenem Related Medicines Menu">	J01DH02

References

1. Arguedas A, et al, Safety and tolerability of ertapenem versus ceftriaxone in a double-blind study performed in children with complicated urinary tract infection, community-acquired pneumonia or skin and soft-tissue infection, Int J Antimicrob Agents, 2009, 33, 163-7
2. Biner B, et al, Ceftriaxone-associated biliary pseudolithiasis in children, J Clin Ultrasound, 2006, 34, 217-22
3. Bor O, et al, Ceftriaxone-associated biliary sludge and pseudocholelithiasis during childhood: a prospective study, Pediatr Int., 2004, 46, 322-4
4. Craig JC, et al, Ceftriaxone for paediatric bacterial meningitis: a report of 62 children and a review of the literature, N Z Med J., 1992, 105, 441-4
5. Dowell SF, et al, Acute otitis media: management and surveillance in an era of pneumococcal resistance--a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group, Pediatr Infect Dis J, 1999, 18, 1-9
6. James J, et al, Ceftriaxone--clinical experience in the treatment of neonates, J Infect., 1985, 11, 25-33
7. Karageorgopoulos DE, et al, Short versus long duration of antibiotic therapy for bacterial meningitis: a meta-analysis of randomised controlled trials in children, Arch Dis Child., 2009, 94, 607-14
8. Leibovitz E, et al, Bacteriologic and clinical efficacy of one day vs. three day intramuscular ceftriaxone for treatment of nonresponsive acute otitis media in children, Pediatr Infect Dis J., 2000, 19, 1040-5
9. Martin E, et al, Pharmacokinetics of ceftriaxone in neonates and infants with meningitis., J Pediatr, 1984, 105, 475-81
10. Mohkam M, et al, Ceftriaxone associated nephrolithiasis: a prospective study in 284 children., Pediatr Nephrol, 2007, 22, 690-4
11. Mulhall A, et al, Pharmacokinetics and safety of ceftriaxone in the neonate, Eur J Pediatr, 1985, 144, 379-82
12. Nathan N, et al, Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study, Lancet., 2005, 366, 308-13
13. No authors listed, Ceftriaxone in the treatment of meningitis, gonococcal infections and other serious bacterial infections. Infectious Diseases and Immunization Committee, Canadian Paediatric Society., CMAJ., 1990, 142, 450-2
14. Schaad UB, The cephalosporin compounds in severe neonatal infection, Eur J Pediatr, 1984, 141, 143-6
15. CBO, Richtlijn Lymeziekte, www.cbo.nl, 2013, 71-85
16. HEXAL, SmPC Ceftriaxon HEXAL® (44418.00.00/44419.00.00/44420.00.00), 09/2016
17. LCI, Richtlijn Meningokokken-meningitis en -sepsis, www.lci.rivm.nl, 2019, Jan
18. AWMF, Deutsche Gesellschaft für Neurologie, Leitlinien für Diagnostik und Therapie in der Neuroborreliose, https://www.awmf.org/leitlinien/aktuelle-leitlinien.html, 2018
19. Van de Beek, D, et al., ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2016, 22, Suppl 3: 37­ - 62
20. Fresenius Kabi, Nederland BV, SmPC ceftriaxon (RVG 100048) 12 Jun 2019, www.geneesmiddeleninformatiebank.nl
21. Steele, R. W., et al, Pharmacokinetics of ceftriaxone in pediatric patients with meningitis, Antimicrob Agents Chemother, 1983, 23(2), 191-4
22. McCracken, G. H. et al, Ceftriaxone pharmacokinetics in newborn infants., Antimicrob Agents Chemother, 1983, 23(2), 341-
23. Tang Girdwood, S., et al., Population Pharmacokinetic Modeling of Total and Free Ceftriaxone in Critically Ill Children and Young Adults and Monte Carlo Simulations Support Twice Daily Dosing for Target Attainment. , Antimicrobial agents and chemotherapy, 2022, 66(1), , e0142721
24. Hartman SJF, et al. , Pharmacokinetics and Target Attainment of Antibiotics in Critically Ill Children: A Systematic Review of Current Literature, Clin Pharmacokinet., 2020, Feb;59(2), 173-205

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