Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Flucloxacillin

Generic name
Flucloxacillin
Brand name
ATC Code
J01CF05

Pharmacokinetics in children

The following mean ± SD pharmacokinetic parameters have been found after one or multiple IV doses of 25-50 mg/kg in 66 neonates and infants [Adrianzén Vargas 2004, Pullen 2006]:

Age t½ (hours) Cl (l/kg/hour) Vd (l/kg)
Neonates/infants 2.6 ± 1.6 0.12-0.18 0.45

Flucloxacillin is poorly absorbed after oral administration. The oral absorption in adults is approx. 55% (on an empty stomach), in children approx. 48%. (Herngren 1987) The absorption of flucloxacillin is significantly hindered when food is taken at the same time.

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

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Available formulations

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Dosages

Severe bacterial infections
  • Oral
    • Term neonate
      • 100 mg/kg/day in 3 doses.
      • Directions for administration:

        1 hour before or 2 hours after a meal

      • When dosing 3 times daily, maintain a dosing interval of 8 hours. 

    • 1 month up to 18 years and < 30 kg
      • 100 mg/kg/day in 3 doses.
      • Directions for administration:

        1 hour before or 2 hours after a meal. Take with a large glass of water to prevent esophageal discomfort and do not lie down immediately after taking.

      • When dosing 3 times daily, maintain a dosing interval of 8 hours. 

    • 1 month up to 18 years and ≥ 30 kg
      • 3.000 mg/day in 3 doses.
      • Directions for administration:

        1 hour before or 2 hours after a meal. Take with a large glass of water to prevent esophageal discomfort and do not lie down immediately after taking.

    • Term neonate
      [9]
      • 100 mg/kg/day in 3 doses.
      • Directions for administration:

        1 hour before or 2 hours after a meal

      • When dosing 3 times daily, maintain a dosing interval of 8 hours. 

  • Intravenous
    • < 1 week and weight at birth < 2000 g
      • 50 mg/kg/day in 2 doses.
        • In infections caused by S. aureus, the dosage must be increased to 150 mg/kg/day in 3 doses.
        • The total daily dose can also be administered as a continuous infusion. An intermittent dose should be administered as a loading dose.
    • < 1 week and weight at birth ≥ 2000 g
      • 75 mg/kg/day in 3 doses.
        • In infections caused by S. aureus, the dosage must be increased to 150 mg/kg/day in 3 doses.
        • The total daily dose can also be administered as a continuous infusion. An intermittent dose should be administered as a loading dose.
    • 1 week up to 4 weeks and weight at birth < 2000 g
      • 75 mg/kg/day in 3 doses.
        • In infections caused by S. aureus, the dosage must be increased to 150 mg/kg/day in 3 doses.
        • The total daily dose can also be administered as a continuous infusion. An intermittent dose should be administered as a loading dose.
    • 1 week up to 4 weeks and weight at birth ≥ 2000 g
      • 100 mg/kg/day in 4 doses.
        • In infections  caused by S. aureus, the dosage must be increased to 150 mg/kg/day in 3 doses
        • The total daily dose can also be administered as a continuous infusion. An intermittent dose should be administered as a loading dose.
    • 1 month up to 12 years
      • 100 mg/kg/day in 4 doses. In case of therapy failure or increased renal clearance, increase to max: 200mg/kg/day in 6 doses, but not exceeding 12 g/day. Maximum dosage per gift: 2 g/dose.
        • In the case of hypoalbuminemia, the free fraction of flucloxacillin may be elevated, resulting in increased efficacy. Dose reduction may be necessary.
        • The total daily dose may also be administered as a continuous infusion. An intermittent dose should be administered as a loading dose.
    • 12 years up to 18 years
      • 6 g/day in 4 doses. Max single dose: 2 g/dose. In case of therapy failure or increased renal clearance, increase to max 12 g/day in 6 doses.
        • In the case of hypoalbuminemia, the free fraction of flucloxacillin may be elevated, resulting in increased efficacy. Dose reduction may be necessary.
        • The total daily dose may also be administered as a continuous infusion.  An intermittent dose should be administered as a loading dose.
Infection in cystic fibrosis
  • Intravenous
    • 1 month up to 18 years
      • 150 - 200 mg/kg/day in 4 - 6 doses. Max: 12 g/day.

      • The total daily dose can also be administered as a continuous infusion. An intermittent dose should be administered as a loading dose.

  • Oral
    • 1 month up to 18 years
      • 50 - 100 mg/kg/day in 3 - 4 doses. Max: 6 g/day.
      • Directions for administration:

        1 hour before or 2 hours after a meal. Take with a large glass of water to prevent esophageal discomfort and do not lie down immediately after taking.
Bacterial infections
  • Oral
    • 1 month up to 12 years
      • 25 - 50 mg/kg/day in 3 doses. Max: 1.500 mg/day.
      • Directions for administration:

        1 hour before or 2 hours after a meal. Take with a large glass of water to prevent esophageal discomfort and do not lie down immediately after taking.

      • When dosing 3 times daily, maintain a dosing interval of 8 hours. 

    • 12 years up to 18 years
      • 1.500 mg/day in 3 doses.
      • Directions for administration:

        1 hour before or 2 hours after a meal, Take with a large glass of water to prevent esophageal discomfort and do not lie down immediately after taking.

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Renal impaiment in children > 3 months

Oral use: 
Intravenous use: adjusting the dose is not necessary.

  • GFR ≥10: adjusting dose is not necessary.
  • GFR <10: dose adjustment is only necessary when using a high IV dose of flucloxacillin (150-200 mg/kg/day) for a prolonged period; after 10 days of treatment, dose reduction should be considered.
Clinical consequences

In impaired renal function, the t½ of flucloxacillin and its active hydroxymethyl metabolite is prolonged. Dosage adjustment is necessary only when using high-dose flucloxacillin for an extended period in patients with very severely impaired renal function.

Clinical effects:
Neurotoxicity, e.g., convulsions, occurs with high intravenous doses. Flucloxacillin is largely excreted with the urine; approx. 55% of the orally administered dose in unchanged form, approx. 10% as the active metabolite 5-hydroxymethylflucloxacillin and approx. 5% as inactive metabolites. Flucloxacillin is strongly protein-bound. In critically ill patients, hypoalbuminemia may occur, resulting in reduced protein binding and therefore a higher free fraction while the total concentration may remain the same. In flucloxacillin, protein binding may decrease from 95% to 30%. The increased free concentration may cause toxicity to occur earlier, but also increases clearance leading to a decrease in total concentration.

TDM:
Consider monitoring drug concentration levels of flucloxacillin particularly to avoid undertreatment. TDM is only useful if the sensitivity (MIC) of the micro-organism to be controlled is also known. With flucloxacillin, it should be noted that some methods use oxacillin as a reference substance. It is questionable whether the result for oxacillin can be translated 1:1 to flucloxacillin.

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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, nausea, vomiting, diarrhoea.    As a result of high dosages: neutropenia, leukopenia.

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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

Crossover sensitivity and crossover resistance with other β-lactam antibiotics such as cephalosporins can occur. Caution is needed in impaired liver function and where there is porphyria in the previous history. If pseudomembranous colitis develops, the flucloxacillin treatment should be discontinued and appropriate therapy started.

The taste of the suspension is very unpleasant: use capsules where possible. (Baguley 2012)

Sodium benzoate, in suspension, may exacerbate jaundice in neonates < 4 weeks.

In children under 6 months of age, the serum concentration may be relatively higher due to delayed renal clearance. Special attention is required in neonates due to the risk of hyperbilirubinemia; after parenteral high dose flucloxacillin can induce kernicterus in a yellow colored infant by displacing bilirubin from the protein binding sites.

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Interactions

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

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Penicillins with extended spectrum
J01CA04
J01CA01
J01CA11
J01CA08
Beta-lactamase sensitive penicillins
J01CE08
J01CE01
J01CE05
J01CE02
J01CE10
Beta-lactamase resistant penicillins
J01CF01
J01CF02
J01CF02
Combinations of penicillins, incl. beta-lactamase inhibitors
J01CR02
J01CR01, J01CR04
J01CR05
J01CR04

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References

  1. Hartwig NC, et al, Vademecum pediatrische antimicrobiële therapie, 2005
  2. Adrianzén Vargas MR, et al, Pharmacokinetics of intravenous flucloxacillin and amoxicillin in neonatal and infant cardiopulmonary bypass surgery., Eur J Cardiothorac Surg, 2004, 25, 256-60
  3. Beardsmore CS, et al, Pulmonary function in infants with cystic fibrosis: the effect of antibiotic treatment., Arch Dis Child, 1994, 71, 133-7
  4. Price JD, et al, Flucloxacillin in the treatment of infectious conditions in children., Curr Med Res Opin., 1975, 3, 77-82
  5. Pullen J, et al, Population pharmacokinetics and dosing of flucloxacillin in preterm and term neonates., Ther Drug Monit., 2006, 28, 351-8
  6. Rodriguez-Solares A, et al, A comparative study of the efficacy, safety and tolerance of azithromycin, dicloxacillin and flucloxacillin in the treatment of children with acute skin and skin-structure infections, J Antimicrob Chemother., 1993, 31, 103-9
  7. Steer JA, et al, Teicoplanin versus flucloxacillin in the treatment of infection following burns., J Antimicrob Chemother., 1997, 39, 383-92
  8. Weaver LT, et al, Prognosis in cystic fibrosis treated with continuous flucloxacillin from the neonatal period, Arch Dis Child, 1994, 70, 84-9
  9. Aurobindo Pharma B.V., SmPC Floxapen suspensie (RVG 14314) 09-02-2021, www.geneesmiddeleninformatiebank.nl
  10. Aurobindo Pharma B.V., SmPC Floxapen injectie (RVG 05990) 19-09-2019, www.geneesmiddeleninformatiebank.nl
  11. Baguley D et al, Prescribing for children - taste and palatability affect adherence to antibiotics: a review. , Arch Dis Child, 2012, Mar;97(3), 293-7
  12. Bons SCS et al., NHG-Standaard Bacteriële huidinfecties (Tweede herziening)
  13. PUREN Pharma, SmPC Staphylex 250, 500 mg Kapseln (6007657.01.00, 6007657.00.00), 12.2017
  14. Altamedics, SmPC Flucloxacillin Altamedics 500 mg Hartkapseln (91384.00.00), 2018
  15. NKFK Workinggroup Acute Kidney Impairment, Extrapolation of KNMP risk analysis "Impaired renal function" for adults to children, 20 Dec 2021
  16. Ibrahim, L. F.,et al, Efficacy and safety of intravenous ceftriaxone at home versus intravenous flucloxacillin in hospital for children with cellulitis (CHOICE): a single-centre, open-label, randomised, controlled, non-inferiority trial, Lancet Infect Dis, 2019, 19 (5), 477-486
  17. Ibrahim, L. F.,et al, Evaluating an admission avoidance pathway for children in the emergency department: outpatient intravenous antibiotics for moderate/severe cellulitis., Emerg Med J, 2017, 34 (12, 780-785
  18. Herngren, L. et al., Pharmacokinetics of free and total flucloxacillin in newborn infants, Eur J Clin Pharmacol, 1987, 32 (4):, 403-9
  19. Howden, B. P. et al, The efficacy of continuous infusion flucloxacillin in home therapy for serious staphylococcal infections and cellulitis., J Antimicrob Chemother, 2001, 48 (2), 311-4
  20. Landersdorfer, C. B. et al., Population pharmacokinetics at two dose levels and pharmacodynamic profiling of flucloxacillin, Antimicrob Agents Chemother, 2007, 51 (9), 3290-7
  21. Leder, K. et al, The clinical efficacy of continuous-infusion flucloxacillin in serious staphylococcal sepsis, J Antimicrob Chemother, 1999, 43 (1), 113-8
  22. Ulldemolins, M.et al, Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics, J Antimicrob Chemother, 2010, 65 (8), 1771-8
  23. Wilkes, S. et al, Population pharmacokinetic modelling of total and unbound flucloxacillin in non-critically ill patients to devise a rational continuous dosing regimen, Int J Antimicrob Agents, 2019, 53 (3), 310-317
  24. Baguley D et al, Prescribing for children - taste and palatability affect adherence to antibiotics: a review., Arch Dis Child, 2012, Mar;97(3), 293-7
  25. Bons SCS et al., NHG-Standaard Bacteriële huidinfecties (Tweede herziening)

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