Neonatal Intensive Care Drug Manual

The Antimicrobial Stewardship Team has listed this drug under the following category: Restricted.

Excipients: Sodium citrate, sodium metabisulfite.

Infants with perinatal asphyxia and on therapeutic hypothermia: Increase dose interval by 12 hours [1-3].

Infants treated with cyclo-oxygenase inhibitors (indomethacin or ibuprofen): Increase dose interval by 12 hours [1-3]

Intramuscular injection

Step 1: Add 1 mL (250 mg) of amikacin to 9 mL of sodium chloride 0.9% to make a 25 mg/mL solution.

Step 2: FURTHER DILUTE

Draw up 3 mL (75 mg) of this solution and add 12 mL of sodium chloride 0.9% to make a final volume of 15mL with a final concentration of 5 mg/mL.

≥ 1.5 kg: No dilution required.

IM: May be given if IV route not available.

For infants on continuing treatment, perform early trough and peak levels (prior to and 1 hour after the second amikacin dose). Target peak levels 24–35 mg/L and troughs <5 mg/L [2].

Assess renal function.

Myasthenia Gravis¹³

CAUTION in patients with pre-existing renal impairment, auditory or vestibular impairment, hypocalcaemia, depressed neuromuscular transmission.

Gastrointestinal: Amikacin has been associated with Clostridium difficile diarrhoea; discontinue use if suspected.

Immunological: Allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic reactions, may occur in patients with sulfite sensitivity as preparation contains sodium metabisulfite.

Neurological: Use caution in patients with parkinsonism; muscle weakness may be aggravated.

Neurotoxic and/or nephrotoxic agents: Avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic antibiotics, including other aminoglycosides, polymyxin B, colistin, cisplatin, vancomycin, amphotericin B, clindamycin and cephalosporins.

Anaesthetics/neuromuscular blocking agents or medications with neuromuscular blocking activity: succinylcholine, tubocurarine, decamethonium, halogenated hydrocarbon inhalation anaesthetics, opioid analgesics and massive transfusions with citrate anticoagulated blood may increase neuromuscular blockade. Treatment with anticholinesterase agents or calcium salts may help to reverse the blockade.

Penicillins: Aminoglycosides are inactivated by solutions containing penicillins. Ensure line is adequately flushed between antibiotics.

The diluted solution is stable for 24-hours at room temperature.

The most recent Cochrane review on one dose per day compared to multiple doses per day for gentamicin in neonates found insufficient evidence from the currently available RCTs to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However, a 'once a day' gentamicin regimen was superior to a 'multiple doses a day' regimen in achieving higher peak concentrations while avoiding toxic trough concentrations [5].

Sherwin 2009, in a cohort study, reported a peak/MIC ratio of <8 predicted treatment failure [6].

Safety: Toxicity is thought to be related to the Area Under the time versus concentration Curve (AUC), reflected by the trough concentration [2]. For amikacin, historical data (prospective clinical trials 1975–1982) suggest an incidence of cochlear, vestibular and renal toxicity of 13.9%, 2.8%, and 9.4% in adults [7]. This high incidence may relate to the practice of using multiple doses per day regimens. Although short-term renal toxicity in human neonates has been reported, there is consistently a lower rate of ototoxicity and nephrotoxicity in neonates when compared to adults [2]. The most recent Cochrane review on one dose per day compared to multiple doses per day for gentamicin in neonates found (pooled, all dosing regimens) the incidence of ototoxicity was 1.4% (n = 3/214) with no cases (n = 0/348) of nephrotoxicity (increased creatinine or decreased creatinine clearance) [5]. Limited reports have not identified a link between amikacin pharmacokinetics and ototoxicity in neonates [2]. However, extrapolated from other populations, to avoid adaptive resistance and toxicity, it is recommended higher doses should be combined with extended interval dosing [2].

Pharmacokinetics/pharmacodynamics: Sherwin 2009, in a cohort study, reported a peak/MIC ratio of <8 predicted treatment failure [6]. Allegaert 2007 reported weight explained 47.3% of drug clearance; post menstrual age 25.2%; co-administration of a nonselective cyclo-oxygenase inhibitor 3.5%; renal function 7.6% and being born SGA, 1.7%. Renal drug clearance was significantly lower in preterm neonates born SGA [8], infants on cyclo-oxygenase inhibitors [2, 3, 9] and infants with perinatal asphyxia [2]. Labaune 2001 [10] reported validation of an individualised dosing regimen for neonates in the first two days of life to target attainment of C_max/MIC ratio >10 using a simplified once-a-day regimen with target peak serum concentrations obtained in 62–80% of patients after the first dose and in 80–100% after the second dose, and trough concentrations were obtained in 100%.

Two recent pharmacokinetic studies have reported attainment of therapeutic peak and trough levels for modelled amikacin regimens [2, 11]. The regimens had similar rates of attainment of target concentrations with the regimen assessed by Hughes et al [11] considered the preferable regimen for ease of implementation by the ANMF group (Table 1).

Hughes 2017 [11] targeted peak concentrations 20 to 35 mg/L with sub- and supra-therapeutic peak concentrations were defined as <20 mg/L and >35 mg/L, respectively; and supra-therapeutic trough concentrations >8 mg/L using the regimen in table 1. They reported 12% peak concentrations >35 mg/L and 2% trough concentrations >8mg/L.

Table 1
–Postmenstrual age	Postnatal age	Dose
≤29 weeks	0–7 days	14 mg/kg, q48h
	8–28 days	12 mg/kg, q36h
	≥29 days	12 mg/kg, q24h
30–34 weeks	0–7 days	12 mg/kg, q36h
	≥8 days	12 mg/kg, q24h
≥35 weeks	All	12 mg/kg, q24h

Smits 2017 [2, 3] targeted trough concentrations of 1.5–3 mg/L and peak concentrations of 24–35 mg/L. They reported 98% of peak concentrations in target zone >20 mg/L (90% 24–35 mg/L) and 90% of troughs in target zone <5 mg/L (53% <3 mg/L) using the regimen in Table 2. Cristea 2017 retrospectively quantified the impact of perinatal asphyxia treated with therapeutic hypothermia on amikacin clearance in neonates and reported amikacin clearance decreased by 40.6%. A 12-hour increase in the dosing interval while keeping the amikacin dose (milligram per kilogram) unchanged, had a minimal impact on the peak concentrations but improved the attained trough concentrations [1]. Smits 2015 reported attainment of therapeutic targets when dose intervals were increased by 10 hours for infants on ibuprofen [3].

2. Smits A, Kulo A, van den Anker J, Allegaert K. The amikacin research program: a stepwise approach to validate dosing regimens in neonates. Expert Opin Drug Metab Toxicol. 2017;13:157-66.

3. Smits A, De Cock RF, Allegaert K, Vanhaesebrouck S, Danhof M, Knibbe CA. Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice. Antimicrob Agents Chemother. 2015;59:6344-51.

4. Li JY, Chen SQ, Yan YY, Hu YY, Wei J, Wu QP, Lin ZL, Lin J. Identification and antimicrobial resistance of pathogens in neonatal septicemia in China-A meta-analysis. Int J Infect Dis. 2018;71:89-93.

5. Rao SC, Srinivasjois R, Moon K. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev. 2016;12:CD005091.

6. Sherwin CMT, Svahn S, Van Der Linden A, Broadbent RS, Medlicott NJ, Reith DM. Individualised dosing of amikacin in neonates: A pharmacokinetic/ pharmacodynamic analysis. European Journal of Clinical Pharmacology. 2009;65:705-13.

7. Kahlmeter G, Dahlager JI. Aminoglycoside toxicity - a review of clinical studies published between 1975 and 1982. J Antimicrob Chemother. 1984;13 Suppl A:9-22.

8. Allegaert K, Anderson BJ, van den Anker JN, Vanhaesebrouck S, de Zegher F. Renal drug clearance in preterm neonates: relation to prenatal growth. Ther Drug Monit. 2007;29:284-91.

9. Allegaert K. The impact of ibuprofen or indomethacin on renal drug clearance in neonates. J Matern Fetal Neonatal Med. 2009;22 Suppl 3:88-91.

10. Labaune JM, Bleyzac N, Maire P, Jelliffe RW, Boutroy MJ, Aulagner G, Putet G. Once-a-day individualized amikacin dosing for suspected infection at birth based on population pharmacokinetic models. Biol Neonate. 2001;80:142-7.

11. Hughes KM, Johnson PN, Anderson MP, Sekar KC, Welliver RC, Miller JL. Comparison of Amikacin Pharmacokinetics in Neonates Following Implementation of a New Dosage Protocol. J Pediatr Pharmacol Ther. 2017;22:33-40.

12. Micromedex accessed 09/05/2019: https://www.micromedexsolutions.com.acs.hcn.com.au/micromedex2/librarian?acc=36422

13. MIMS online accessed 09/05/2019: https://www.mimsonline.com.au.acs.hcn.com.au/Search/Search.aspx

14. Australian Injectable Drugs Handbook, 7th Edition, Society of Hospital Pharmacists of Australia 2019.