Neonatal Intensive Care Drug Manual

Standard infections: 50 mg/kg/dose.

Meningitis: 100 mg/kg/dose.

Corrected Gestational Age/Postmenstrual Age	Postnatal Age	Interval
< 30+0 weeks	0–28 days	12 hourly
< 30+0 weeks	29+ days	8 hourly
30+0−36+6 weeks	0−14 days	12 hourly
30+0−36+6 weeks	15+ days	8 hourly
37+0−44+6 weeks	0−7 days	12 hourly
37+0−44+6 weeks	8+ days	8 hourly

ORAL

Treatment: 25–50 mg/kg/dose.

Prophylaxis (e.g. Urinary Tract Infection): 10–15 mg/kg/dose once a day

IM (only if IV route not possible as intramuscular route is painful)

ORAL

Add 4.6 mL of water for injection to the 500 mg vial to make 100 mg/mL solution OR

Add 9.3 mL of water for injection to the 1 g vial to make 100 mg/mL solution.

FURTHER DILUTE

Draw up 5 mL (500 mg of amoxicillin) of the above solution and add 5 mL sodium chloride 0.9% to make a final volume of 10mL with a final concentration of 50 mg/mL.

Add 2.3 mL of water for injection to the 500 mg vial to make 200 mg/mL solution.

1. Syrup 125 mg/5 mL: Add 87 mL of water for irrigation to make a final volume of 100mL with a final concentration of 125mg/5mL of suspension.

2 Syrup 250mg/5mL: Add 87 mL of water for irrigation to make a final volume of 100mL with a final concentration of 250mg/5mL of suspension.

3. Paediatric drops 100 mg/mL: Add 18 mL water for injection to make a final volume of 21mL with a final concentration of 100mg/mL.

IM injection: Only if IV route is not possible.

PO: The liquid preparation should be shaken well After mixing, administer immediately. . The dose may be mixed with milk.

Follow infectious disease/microbiology advice in case of poor therapeutic response.

PO: No significant drug-drug interaction found for neonates on oral amoxicillin.

Uncommon/rare: Neurotoxicity, electrolyte disturbances e.g. hypernatraemia due to the sodium content (3.3 mmol per gram in Amoxil IV and 2.6 mmol per gram in Fisamox IV), erythema multiforme, exfoliative skin lesions, C. difficile diarrhoea, pancytopenia, raised liver enzymes.

Amoxicillin may result in a false positive for glucose in the urine due to excessive amounts of urinary amoxicillin.

Y site: No information⁹

Y site: Aminoglycosides, ciprofloxacin, imipenem-cilastatin, midazolam, potassium chloride, sodium bicarbonate⁹

PO: The medication mixed with milk should be administered immediately.

PO: Store unreconstituted powder for oral suspension at 20–25 ⁰C. Reconstituted suspension is stable for 14 days at room temperature or if refrigerated. Refrigeration is preferred.

There are few studies of amoxicillin in the neonatal population to study effectiveness and the majority of the information is derived from studies of ampicillin. A study in two Estonian NICUs comparing ampicillin + gentamicin versus penicillin + gentamicin in the empiric therapy of neonates at risk of early-onset sepsis showed similar effectiveness in need to change antibiotics at 72 hours and/or 7-day all-cause mortality ¹. Subgroup analysis in ELBW neonates showed similar results, though NICU mortality was lower in the ampicillin group in < 26 weeks gestation neonates².

In an RCT of amoxicillin prophylaxis for prevention of catheter-related infections in newborn infants with central venous catheters, bacterial contamination of the catheter tip at removal was significantly reduced in the amoxicillin group. No significant difference was found in the incidence of invasive infection³. In a randomised, open-label, equivalence trial in Africa, oral amoxicillin was found to be equivalent to injectable procaine penicillin plus gentamicin in the treatment of neonates and young infants with fast breathing⁴.

IV amoxicillin has similar properties to ampicillin and there is little to choose between the two when given by the IV route to treat susceptible organisms⁵. Amoxicillin achieves higher serum and CSF concentrations than ampicillin⁶. Oral amoxicillin has similar properties to ampicillin. Both the antibiotics are well absorbed when given by mouth, widely distributed in body tissues (including bronchial secretions) and rapidly excreted in the urine. Oral amoxicillin has better bioavailability but can be variable in young children⁵. Oral medication can nearly always be used to complete any sustained course of treatment.¹³

Study of amoxicillin pharmacokinetics in preterm infants⁷ has shown that a q12h schedule in the first week achieves serum concentrations well above the MIC for major micro-organisms in neonatal infections. Another study⁸ in neonates older than 1 week showed that amoxicillin clearance was related to post-conceptional age and not to postnatal age with a rapid linear increase in clearance after 34 weeks post-conceptional age.

In a study¹⁰, early switching to the oral route in asymptomatic full-term newborns with early onset GBS disease maintained serum amoxicillin concentrations within the therapeutic range. The dose used in that study was 200–300 mg/kg/day in 4 divided doses. All the concentrations were in the therapeutic range with the lower dose. Another pharmacokinetic study in 6–13 days old neonates concluded that amoxicillin should be useful for oral treatment of neonatal infections caused by susceptible micro-organisms in infants who are not critically ill. The dose used was 50 mg/kg twice a day.¹¹
Recommendation:

Amoxicillin can be used as a substitute for benzylpenicillin or ampicillin for suspected, early-onset, neonatal sepsis in combination with an aminoglycoside. When amoxicillin is used in combination with an aminoglycoside for the treatment of meningitis, it is recommended that the dose be doubled from 50 to 100 mg/kg/dose.¹² This is in keeping with similar recommendations for benzylpenicillin and ampicillin based on high minimum bactericidal concentration of group B streptococci and high inocula of the organisms in neonatal meningitis. (Level of evidence 5, Grade of recommendation D).

2. Metsvaht T, Ilmoja ML, Parm U, Merila M, Maipuu L, Muursepp P et al. Ampicillin versus penicillin in the empiric therapy of extremely low-birthweight neonates at risk of early onset sepsis. Pediatr Int 2011;53:873–80

3. Harms K, Herting E, Kron M, Schiffmann H, Schulz-Ehlbeck H. Randomized, controlled trial of amoxicillin prophylaxis for prevention of catheter-related infections in newborn infants with central venous silicone elastomer catheters. J Pediatr 1995; 127: 615-9

4. African Neonatal Sepsis Trial (AFRINEST) group, Tshefu A, Lokangaka A, Ngaima S, Engmann C, Esamai F, Gisore P et al. Oral amoxicillin compared with injectable procaine benzylpenicillin plus gentamicin for treatment of neonates and young infants with fast breathing when referral is not possible: a randomised, open-label, equivalence trial. Lancet 2015; 385: 1758-66

5. Neonatal Formulary: Drug use in pregnancy and the first year of life. 7^th Ed. 2015: 76-7

6. Fanos V, Dall’Agnola A. Antibiotics in neonatal infections: A Review. Drugs 1999; 58: 405-27

7. Huisman-de Boer J, van den Anker JN, Vogel M, Goessens WHF, Schoemaker RC, de Groot R. Amoxicillin pharmacokinetics in preterm infants with gestational ages of less than 32 weeks. Antimicrob Agents Chemother 1995; 39: 431-4

8. Pullen J, Driessen M, Stolk LML, Degraeuwe PLJ, van Tiel FH, Neef C et al. Amoxicillin pharmacokinetics in (preterm) infants aged 10 to 52 days: Effect of postnatal age. Ther Drug Monit 2007; 29: 376-80

9. Australian Injectable Drugs Handbook, 6th Ed accessed on www.aidh.hcn.com.au on 26th July 2016.

10. Gras-Le Guen C, Boscher C, Godon N, Caillon J, Denis C, Nguyen JM et al. Therapeutic amoxicillin levels achieved with oral administration in term neonates. Eur J Clin Pharmacol 2007; 63: 657-62

11. Lonnerholm G, Bengtsson S, Ewald U. Oral pivampicillin and amoxycillin in newborn infants. Scand J Infect Dis 1982; 14: 127-30.

12. McMullan BJ, Andresen D, Blyth CC, Avent ML, Bowen AC, Britton PN, Clark JE, Cooper CM, Curtis N, Goeman E, Hazelton B, Haeusler GM, Khatami A, Newcombe JP, Osowicki J, Palasanthiran P, Starr M, Lai T, Nourse C, Francis JR, Isaacs D, Bryant PA, ANZPID-ASAP group. Antibiotic duration and timing of the switch from intravenous to oral route for bacterial infections in children: systematic review and guidelines. Lancet Infect Dis 2016;16(8):e139-52.