Dosage / Interval - Neonatal Intensive Care Drug Manual

Dosage / Interval
Standard infections: 50 mg/kg/dose. Dosing interval as per table below
Meningitis: 100 mg/kg/dose. Dosing interval as per table below
Method
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Interval
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Corrected Gestational Age/Postmenstrual Age
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Postnatal Age
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< 30+0 weeks
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0–28 days
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12 hourly
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< 30+0 weeks
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29+ days
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8 hourly
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30+0 −36+6 weeks
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0−14 days
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12 hourly
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30+0−36+6 weeks
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15+ days
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8 hourly
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37+0−44+6 weeks
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0−7 days
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12 hourly
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37+0−44+6 weeks
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8+ days
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8 hourly
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≥ 45+0 weeks
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0+ days
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6 hourly
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Maximum Daily Dose
400 mg/kg/day
Route
IV
IM (only if IV route not possible as intramuscular route is painful)
Preparation/Dilution
IV:
Add 4.7 mL of water for injection to the 500 mg vial for reconstitution to make 100 mg/mL solution OR
Add 9.3 mL of water for injection to the 1 g vial for reconstitution to make 100 mg/mL solution.
FURTHER DILUTE:
Draw up 5 mL (500 mg of ampicillin) of solution and add 5 mL sodium chloride 0.9% to make a final volume of 10mL with a concentration of 50 mg/mL solution OR
Draw up 3 mL (300 mg of ampicillin) of solution and add 7 mL sodium chloride 0.9% to make a final volume of 10mL with a concentration of 30 mg/mL solution
IM:
Add 1.7 mL of water for injection to the 500 mg vial for reconstitution to make 250 mg/mL solution OR
Add 3.3 mL of water for injection to the 1 g vial for reconstitution to make 250 mg/mL solution.
Administration
IV: Infusion over 30 minutes.
Separate from aminoglycosides by clearing the lines with a flush as ampicillin inactivates them. Higher doses (meningitis) should be diluted to 30 mg/mL and infused over 30 minutes.
Monitoring
Plasma concentrations not usually required; however may be useful for infections caused by bacteria with high Minimum Inhibitory Concentration (MIC).
Contraindications
Hypersensitivity reactions can occur in ampicillin-treated infants younger than 6 months of age but are rarely reported in neonates.
Precautions
Hypersensitivity to penicillin derivatives.
In renal impairment the excretion of ampicillin will be delayed. In infants with severe renal impairment it may be necessary to reduce the total daily dose.
Drug Interactions
Aminoglycosides including gentamicin should not be mixed with ampicillin when both drugs are given parenterally as inactivation occurs. Ensure line is adequately flushed between antibiotics.
Adverse Reactions
Allergic reactions – maculopapular or urticarial rash, fever (rare in neonates).
Other: Diarrhoea; CNS excitation or seizures with very large doses reported in adults; and prolonged bleeding time with repeated doses.
Compatibility
Fluids: Sodium chloride 0.9%.
Y site: Aciclovir, amifostine, anidulafungin, aztreonam, bivalirudin, dexmedetomidine, esmolol, filgrastim, foscarnet, granisetron, heparin sodium, labetalol, linezolid, magnesium sulfate, morphine sulfate, pethidine, potassium chloride, remifentanil.
Incompatibility
Fluids: Glucose and glucose containing solutions, fat emulsions.
Y site: Amino acid solutions, adrenaline hydrochloride, aminoglycosides – amikacin, gentamicin, tobramycin; aminophylline, atropine, buprenorphine, caspofungin, chlorpromazine, clindamycin, dobutamine, dolasetron, dopamine, ergometrine, fluconazole, ganciclovir, haloperidol lactate, hydralazine, ketamine, lincomycin, metoclopramide, midazolam, mycophenolate mofetil, ondansetron, pentamidine, prochlorperazine, promethazine, protamine, sodium bicarbonate, tranexamic acid, verapamil.
Stability
Administer immediately; discard unused portion of reconstituted solution.
Storage
Store below 25°C
Protect from light.
Special Comments
Clearance is primarily by the renal route. Clearance increases with increasing gestational age and postnatal age. Serum half-life is longer in premature infants and infants younger than 7 days.
Evidence summary
1. Effectiveness:
A 2 hospital crossover study comparing ampicillin versus penicillin combined with gentamicin in the empiric therapy of extremely low-birth weight neonates at risk of early onset sepsis showed similar effectiveness in change of antibiotics at 72 hours and/or 7-day all-cause mortality. 11, 12
A systematic review comparing the effectiveness and safety of penicillin or ampicillin-chloramphenicol versus third generation cephalosporin in patients with community-acquired suspected acute bacterial meningitis found 12 trials enrolling infants under 1 year of age. There were no significant differences between the groups in the risk of death, deafness, or treatment failure; there were significantly decreased risks of culture positivity of CSF after 10 to 48 hours and increases in the risk of diarrhoea between the groups (RD 8%; 95% CI 3% to 13%) with third generation cephalosporin. 13
2. Dose: There are no clinical trials comparing standard versus high dose ampicillin in neonates with sepsis or meningitis. Clinical trials reporting effectiveness of regimens including ampicillin for meningitis reported use of daily doses of ampicillin ≥ 200 mg/kg/day.13 Doses of ampicillin of 200 mg/kg/day result in adequate CSF concentrations for treatment of enterococcus and Listeria monocytogenes.10, 14
Recommendation:
When ampicillin 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 (Level of evidence III-2, Grade of recommendation B).
References
1. Espaze EP, Reynaud AE. Antibiotic susceptibilities of Listeria: in vitro studies. Infection. 1988;16 Suppl 2:S160–4.
2. Lamont RF, Sobel J, Mazaki-Tovi S, Kusanovic JP, Vaisbuch E, Kim SK, Uldbjerg N, Romero R. Listeriosis in human pregnancy: a systematic review. Journal of perinatal medicine. 2011;39:227–36.
3. Townsend RS. In vitro inactivation of gentamicin by ampicillin. American journal of hospital pharmacy. 1989;46:2250–1.
4. Daly JS, Dodge RA, Glew RH, Keroack MA, Bednarek FJ, Whalen M. Effect of time and temperature on inactivation of aminoglycosides by ampicillin at neonatal dosages. Journal of perinatology. 1997;17:42–5.
5. Roberts JK, Stockmann C, Constance JE, Stiers J, Spigarelli MG, Ward RM, Sherwin CM. Pharmacokinetics and pharmacodynamics of antibacterials, antifungals, and antivirals used most frequently in neonates and infants. Clinical pharmacokinetics. 2014;53:581-610.
6. Sieniawaska M, Wroblewska-Kaluzewska M, Wierzbowska-Lange B, Korniszewska J, Kazmirowska Z, Suska A, Janecki J. [Serum levels of cephalothin, ampicillin and cloxacillin in children with and without renal failure]. Pediatria polska. 1974;49:133–41.
7. Hodgman T, Dasta JF, Armstrong DK, Visconti JA, Reilley TE. Ampicillin-associated seizures. Southern medical journal. 1984;77:1323–5
8. Sheffield MJ, Lambert DK, Henry E, Christensen RD: Effect of ampicillin on the bleeding time of neonatal intensive care patients. J Perinatol 2010Aug;30(8):527–30.
9. Axline SG, Yaffe SJ, Simon HJ. Clinical pharmacology of antimicrobials in premature infants. II. Ampicillin, methicillin, oxacillin, neomycin, and colistin. Pediatrics. 1967;39:97–107.
10. Kaplan JM, McCracken GH, Jr., Horton LJ, Thomas ML, Davis N. Pharmacologic studies in neonates given large dosages of ampicillin. The Journal of pediatrics. 1974;84:571–7.
11. Metsvaht T, Ilmoja ML, Parm U, Maipuu L, Merila M, Lutsar I. Comparison of ampicillin plus gentamicin vs. penicillin plus gentamicin in empiric treatment of neonates at risk of early onset sepsis. Acta paediatrica. 2010;99:665–72.
12. Metsvaht T, Ilmoja ML, Parm U, Merila M, Maipuu L, Muursepp P, Julge K, Sepp E, Lutsar I. Ampicillin versus penicillin in the empiric therapy of extremely low-birthweight neonates at risk of early onset sepsis. Pediatrics international : official journal of the Japan Pediatric Society. 2011;53:873–80.
13. Prasad K, Kumar A, Gupta PK, Singhal T. Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis. The Cochrane database of systematic reviews. 2007:CD001832
14. Tessin I, Trollfors B, Thiringer K, Larsson P. Ampicillin-aminoglycoside combinations as initial treatment for neonatal septicaemia or meningitis. A retrospective evaluation of 12 years' experience. Acta paediatrica Scandinavica. 1991;80:911–6.
15. MIMSOnline March 2015.
16. Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.acs.hcn.com.au/ (cited: 03/2015.
17. Australian Injectable Drugs Handbook, 6th Edition, Society of Hospital Pharmacists of Australia 2014.
18. Neofax accessed on www.neofax.micromedex.solutions.com on 29th July 2015.
Original version Date: 08/08/2015
Author: NeoMed Consensus Group
Current Version number: 3
Current Version Date: 26/2/2021
Risk Rating: Low
Due for Review: 26/2/2026
Approval by: DTC
Approval Date: TBA
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