Amikacin Intravenous antimicrobial prescribing guidelines

Publication: 22/09/2021

Next review: 22/09/2024

Clinical Guideline

CURRENT

ID: 7169

Approved By: Improving Antimicrobial Prescribing Group

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

INTRAVENOUS AMIKACIN ANTIMICROBIAL PRESCRIBING GUIDELINES

RESTRICTIONS TO PRESCRIBING
Amikacin is classed as a protected antimicrobial and is partially restricted therefore needs approval and an antimicrobial code from an infection specialist if used outside of specific guidelines

Please refer to the British National Formulary (BNF) or the Summary of Product Characteristics (SPC) for information on:

Dosage and routes of administration
Pharmacokinetics
Interactions
Side effects
Allergy information

Drug information
Routes of administration
Indication
Dosing regimens
Renal impairment
Special dosing considerations
Side effects
Monitoring
Therpaeutic drug monitoring
Other useful information

DRUG INFORMATION

Contraindications: Hypersensitivity to aminoglycosides or to any excipients including sodium metabisulphite. Myasthenia gravis.

Cautions: auditory disorder, vestibular disorder, patients with known mitochondrial mutations or a family history of ototoxicity, use with other nephrotoxic drugs, any pre-existing renal impairment, pregnancy and elderly.

Class of antimicrobial: Aminoglycoside

Mechanism of action: Amikacin inhibits protein production in susceptible bacteria.

Antimicrobial spectrum: Amikacin has activity against a range of Gram-negative bacteria (notably including Pseudomonas spp., Enterobacterales and A Acinetobacter spp), a range of Gram-positive bacteria and Mycobacteria. It does not have activity against anaerobic bacteria. Notably, a number of Gram-negative organisms resistant to gentamicin and tobramycin show sensitivity to amikacin in vitro.¹

Resistance: Aminoglycoside resistance may be intrinsic or acquired, and susceptibility testing should be considered before treatment with amikacin.

Elimination half-life and distribution: In normal renal function: 2-3 hours. End stage renal failure: 17-150 hours. Amikacin is concentrated in the urinary tract but is not distributed well in fatty tissues (which affects weight calculations).

ROUTES OF ADMINISTRATION

As with other aminoglycosides the route of administration is nearly always intravenous. Nebulised, intramuscular, topical amikacin can be given but advice regarding this is not included in this guideline.

Weight based calculation of dosing
Amikacin does not distribute well in fatty tissues⁵ therefore should be dosed according to the patient’s ideal body weight (IBW).

Adult patients: Ideal and adjusted body weight can be determined using an online calculator using patient’s height and actual body weight: https://www.mdcalc.com/ideal-body-weight-adjusted-body-weight

Table 1. Weight based dosing calculation
Patient body weight (CALCULATE IBW FIRST)	Weight to be used to determine amikacin dosing
Obese (> 20% of IBW)	Use ADJUSTED body weight
Between IBW and obese	Use IBW
	Use ACTUAL body weight

Neonates: For dosing in premature neonates, contact a neonatologist/infection specialist/pharmacy

Paediatric patients: If Amikacin is required in an obese child please discuss dosing with the pharmacy team.

INDICATION

Multi-resistant gram-negative infections
Mycobacterial infections on infection/respiratory specialist advice
Alternative indication on advice of infection specialist

Separate guidance is available for the following conditions:

Cystic Fibrosis^vi: Seek advice from a cystic fibrosis specialist
Mycobacteria: Refer to the TB monographs and British Thoracic Society (BTS) guidance and/or discuss with a member of the Tuberculosis Multidisciplinary Team (TB MDT)
Neutropenic Sepsis: Refer to the LTHT Neutropenic Sepsis guidelines

DOSING REGIMENS

Two regimens for amikacin are possible:

Once daily dosing
Multiple daily dosing

Once daily dosing should be the default. Potential indications for multiple daily dosing are given below. Please see section on dosing in special circumstances (e.g. renal impairment) below or consult an infection specialist/pharmacist if unsure.

Table 2. ^vii Usual initial dosing in adults and children aged 12 years or over by INDICATION
Indication	Dosing
All indications apart from the exceptions below	Single daily dosing 15mg/kg* IV every 24 hours Maximum 1.5g per day Maximum 15g per course
Endocarditis Burns >20% surface area Meningitis Pregnancy Calculated creatinine clearance <20mL/minute#	Multiple daily dosing (usually 7.5mg/kg every 12 hours) may* be needed, see below Maximum 1.5g per day Maximum 15g per course**

Table 3⁶. Usual initial dosing in children aged 1 month to 11 years by INDICATION
Indication	Dosing
All indications apart from the exceptions below	Single daily dosing 15mg/kg IV every 24 hours
Endocarditis, Burns >20% surface area, Meningitis, Calculated creatinine clearance <20mL/minute#	Multiple daily dosing (usually 7.5mg/kg every 12 hours) may* be needed see below.

*Higher dosing can be given for severe or resistant infections (i.e Neutropenic Sepsis) - please see BNF or BNF for Children for dosing advice or on the advice on an infection specialist
**May be exceeded in mycobacterial infection.
#See renal dosing section below

Table 4⁶. Usual initial dosing in neonates born at term

An initial loading dose of 10 mg/kg followed by 7.5 mg/kg IV every 12 hours
OR
15 mg/kg every 24 hours

Neonates: Aminoglycosides should be used with caution in neonates, and only on the advice of an infection/respiratory specialist, because of the renal immaturity of these patients.

RENAL IMPAIRMENT

Adult patients: Use https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation . Be aware that this calculation can over-estimate renal function in the elderly and those with muscle wastage.

Ensure patients are adequately hydrated to minimise the risk of renal damage.

Table 5 - Initial dosing ADULTS requiring ONCE DAILY REGIMEN in renal impairment:
Renal function (Creatinine clearance (CrCl))	Dosing
>60mL/min	15mg/kg every 24 hours
40 – 59 mL/min	15mg/kg every 36 hours
21 - 39 mL/min	15mg/kg every 48 -72 hours
<20 mL/min	Avoid – speak to an infection specialist for an alternative agent. If Amikacin is to continue use the multiple dosing regimen

Table 6² - Initial dosing ADULTS requiring MULTIPLE DAILY REGIMEN in renal impairment:
Renal function (CrCl)	Dose	Dosing interval
>50mL/min	7.5mg/kg	Every 12 hours
20-50 mL/min	5-6mg/kg	Every 12 hours
10-20 mL/min	3-4mg/kg	Every 24 hours
<10 mL/min	2mg/kg	Every 24-48hours

Please discuss with renal/ITU pharmacy if patient is on renal replacement therapy and refer to renal handbook for dosing information.

Paediatric patients: Contact pharmacy/paediatric specialist regarding dosing

SPECIAL DOSING CONSIDERATIONS

Hepatic impairment

No dose adjustments needed.¹

Pregnancy
The safety of amikacin in pregnancy has not yet been established. Amikacin should be administered to pregnant women only when there is no suitable alternative and after an assessment of the risk/benefits. There is a risk of auditory or vestibular nerve damage in the infant when aminoglycosides are used in the second and third trimesters of pregnancy^{1, 5}.

If amikacin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the foetus.

Breastfeeding
Amikacin is present at low levels in breastmilk and gut absorption is minimal, hence, it would be very unlikely to cause any adverse effects to the infant and mothers should be encouraged to continue breastfeeding normally.⁶

SIDE EFFECTS

As with other aminoglycosides, amikacin can cause nephrotoxicity, ototoxicity (vestibular or cochlear apparatus) and very rarely neuromuscular blockade, with risk of these adverse effects correlated with drug concentrations. Equally, amikacin is sometimes not appropriate when patients are on concurrent nephrotoxic or ototoxic drugs. If treatment is required, caution should be exercised in use when renal impairment exists. In order to prevent side effects, monitoring should be undertaken to monitor drug levels/ evidence of toxicity.

MONITORING

PLEASE NOTE - THERE IS A SEPARATE MONITORING PROTOCOL FOR CYSTIC FIBROSIS and MYCOBACTERIAL DISEASE.

Audiometry
Loss of hearing usually occurs first in ototoxicity and is detected by regular audiometric testing. Vertigo, loss of balance and auditory disturbances including tinnitus are also signs of ototoxicity.

Where therapy is known to be likely to exceed 5 days audiometry monitoring should be performed regardless of any reported symptoms. A baseline test should be performed prior to starting treatment (or as soon as practical after starting and definitely within 72 hours). Subsequent testing should be minimum weekly and more often if hearing loss is reported by the patient. To arrange a hearing assessment, contact the team via this email: leedsth-tr.hearingandbalance@nhs.net

Patients being treated with long term Amikacin for mycobacterial infections require baseline testing and then monthly.

Ototoxicity on audiogram is defined as a 20 dB loss from baseline at any one test frequency or a 10 dB loss at any two adjacent test frequencies. If this occurs, Amikacin should be discontinued or dosing reduced in frequency to avoid further hearing loss, although the hearing loss that has occurred is likely to be permanent. Expert advice should be sought at this point to consider a regimen change.

Renal monitoring
Patients should have a baseline renal function prior to starting treatment followed by twice weekly monitoring as a minimum whilst receiving amikacin. Consider increasing renal function monitoring if there is any renal impairment (acute or chronic) or concomitant use of nephrotoxics.

THERAPEUTIC DRUG MONITORING

Amikacin levels typically take 48 hours but can take longer to be reported. Doses should not be withheld whilst waiting for the results. Consider the latest renal function and discussing with pharmacy if there is a delay in obtaining the level.

Once daily dosing regimen⁶
Take a trough level immediately before the 2nd dose (this should be the case after any dose adjustment also). Routine peak level (post dose) monitoring is unnecessary with once daily dosing.

Pre-dose (trough) level (Target <5mg/L)
Level (mg/L)	Interpretation	Comment
≤5	Continue current regimen	Continue at current dose Provided renal function is stable and amikacin is continuing, monitor pre-dose levels twice weekly.
≥5	Potentially toxic accumulation	Check the level has been taken at the correct time i.e. between 18-24 hours after the previous dose. A level taken <18 hours is not a true trough level If the level is taken at the correct time, omit next dose, re-take in 24 hours THEN Re-dose if clinically indicated when levels fall ≤ 5mg/L but INCREASE the dosing interval accordingly for subsequent doses; the dosing interval depends on the CrCl (see table above for dosing in renal impairment)

Multiple daily dosing regimen⁶
If a patient is on a multiple daily dosing regimen additional post dose levels should be taken (1 hour after a dose is completed). For the multiple daily dosing, levels should be taken before and after the third dose, this should be the case after any dose adjustment also.

Pre-dose (trough) level (Target <10mg/L)
Level (mg/L)	Interpretation	Comment
<10 - in normal range	Continue current regimen	Continue at current dose Provided renal function is stable and amikacin is continuing, monitor pre-dose levels twice weekly.
>10 - level is high	Potentially toxic accumulation	Level should be taken 12 hours after previous dose for twice daily dosing (or after 8 hours for three times daily dosing), just before the next dose is due If pre-dose level appears genuine, withhold further doses until level is <10mg/L If further doses are required, re-start with increased interval/decreased dose (see below; consult pharmacy if advice needed) Check patient’s renal function as high pre-dose level may coincide with reduced renal function.
Post-dose level: Target 20-30 mg/L
Level (mg/L)	Interpretation	Comment
≤30 - in normal range	Continue current regimen	Continue at current dose Provided renal function is stable and amikacin is continuing, monitor post dose levels twice weekly
>30 - level is high	Potentially toxic accumulation	Check the level has been taken correctly, it must be taken one hour after the dose has been administered If genuine, reduce the dose and the dose frequency. Final action dependent on trough level also (see below) Check patient’s renal function

Pre and Post-dose level combinations
Level (mg/L)	Action
Pre-dose level > 10 mg/L (high) Post dose level is in range (≤30mg/L)	Contact Pharmacy Infection Team
Pre-dose level < 10 mg/L (normal) Post dose level is above target range (>30mg/L)	Reduce the dose Contact Pharmacy Infection Team for advice
Both pre-dose (>10mg/L) and post-dose levels (>30mg/L) are above target range	Review need for further amikacin. Omit next dose Consider reducing the dose frequency Retake levels and restart when pre-dose level < 10mg/L Check renal function and confirm correct dose Contact Pharmacy Infection Team for advice

ANY OTHER USEFUL INFORMATION

Discharge information:if being discharged with OPAT/CIVAS team please refer to the OPAT monographs for the requirements on discharge: http://www.leedsformulary.nhs.uk/docs/CIVAS%20Drug%20Monographs.pdf?UNLID=689299657202132113954

MHRA warning January 2021: https://www.gov.uk/drug-safety-update/aminoglycosides-gentamicin-amikacin-tobramycin-and-neomycin-increased-risk-of-deafness-in-patients-with-mitochondrial-mutations

Provenance

Record:	7169
Objective:
Clinical condition:
Target patient group:
Target professional group(s):	Pharmacists Secondary Care Doctors
Adapted from:

Evidence base

Medicines.org.uk. 2021. Amikacin 250 mg/ml Injection - Summary of Product Characteristics (SmPC) - (emc). [online] Available at: [Accessed 15 March 2021].
Ashley C, Currie A, eds. The Renal Drug Handbook, 4th ed London, Radcliffe Publishing, 2014
Bauer, L., Blouin, R., Griffen, W., Record, K. and Bell, R., 1980. Amikacin Pharmacokinetics in Morbidly Obese Patients. American Journal of Health-System Pharmacy, 37(4), pp.519-522.
Daschner, F., Reiss, E. and Engert, J., 1977. Distribution of Amikacin in Serum, Muscle, and Fat in Children After a Single Intramuscular Injection. Antimicrobial Agents and Chemotherapy, 11(6), pp.1081-1083.
Grayson, M.L., Cosgrove, S.E., Crowe, S.M., Grayson, M.L., Hope, W., McCarthy, J.S., Mills, J., Mouton, J.W., & Paterson, D.L. (Eds.). (2017). Kucers’ The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic, and Antiviral Drugs (7th ed.). CRC Press.
Joint Formulary Committee. (2020). British national formulary 79. London: BMJ Publishing and the Royal Pharmaceutical Society.
TB DRUG MONOGRAPHS. 2021. Amikacin. [online] Available at: [Accessed 30 May 2021].
http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=3968#Amikacin
Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006-. Amikacin. [Updated 2018 Oct 31]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501703/
Mandell, G., Bennett, J., & Dolin, R. (2015). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Elsevier Churchill Livingstone.

Approved By

Improving Antimicrobial Prescribing Group

Document history

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