Medicines Q&As

Q&A 196.3

When should gentamicin levels be taken after once daily

administration?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 17th June 2013

Background
Gentamicin is the aminoglycoside of choice in the UK. All aminoglycosides are bactericidal and active
against some Gram-positive and many Gram-negative organisms (1). These antibiotics should
generally only be used for the treatment of serious infections because of their potential toxicity and
antimicrobial spectrum (2). Aminoglycosides show concentration-dependant activity (3). Most side
effects of the aminoglycosides are dose related. The important side effects are damage to the ear and
the kidney (ototoxicity and nephrotoxicity respectively) (1). Ototoxicity is irreversible whereas
nephrotoxicity is reversible (4).

The aim of aminoglycoside treatment is to achieve an initial high peak concentration to kill the micro-
organism but allow the concentration to fall to a low (trough) level between doses to avoid
accumulation and side effects (3, 4). Traditionally aminoglycoside antibiotics have been administered
as multiple daily dose regimens (2-3 divided doses over 24 hours). To check the peak and trough
levels of aminoglycosides were within the target ranges, (for gentamicin: 5-10mg/L and <2mg/L
respectively) blood samples were collected shortly after doses were given and just before the next
dose was due (1). However, therapeutic drug monitoring showed that multiple daily dosing rarely
achieved adequate peaks and often produced high trough levels (3).

Once daily administration has largely superseded multiple daily dose regimens as it is more
convenient, cost effective, leads to higher initial antibacterial concentrations at the site of infection and
provides adequate serum concentrations (1, 4, 5). Once daily administration has been shown to be at
least as effective as multiple daily dosing, and results in less nephrotoxicity (4, 5). It should be noted
that once daily administration is not suitable for all patients. Patients with infective endocarditis,
extensive burns, or renal impairment (creatinine clearance less than 20mL/minute) should be
excluded from this regimen (1, 4). With regards to renal impairment, expert opinion is that patients
presenting with a creatinine clearance of less than 60mL/minute should not receive once daily dosing
of gentamicin (6).

Monitoring peak and trough plasma concentrations is generally not suitable for once daily gentamicin
dosing. This is because the 24-hour trough concentration is unmeasurable in patients with normal
renal function using standard aminoglycoside assays. Measurement of the peak concentration is not
necessary as giving a larger once daily dose instead of 2-3 smaller doses throughout the day means
that the peak concentration will be above 10mg/L (5). If a once daily regimen is used, an alternative
method of monitoring gentamicin levels has to be applied.

Answer
The British National Formulary (BNF) recommends a once daily gentamicin dose of 5-7mg/kg per day
(1). A variety of methods exist for monitoring gentamicin plasma concentrations after once daily
administration. For most patients a predictive nomogram is the method of choice, primarily because of
its simplicity. It is not possible to use the nomogram for patients with a very high clearance of
aminoglycosides or a high volume of distribution. Examples include those with ascites, burns, cystic
fibrosis, or in other conditions such as pregnancy, where the fixed dose assumed in the construction
of the nomogram is irrelevant (4). There are some disadvantages to using a nomogram. They are
based on average pharmacokinetic parameters and they do not allow the clinician to individualise the
dosing regimens according to the type of infection or individual patient needs (7).

From the NHS Evidence website www.evidence.nhs.uk 1

 Medicines Q&As

Hartford Nomogram (7mg/kg/day)

If a once daily dose of 7mg/kg is administered, the ‘Hartford nomogram’ can be used to monitor
gentamicin plasma levels (7- 9). This nomogram has been tested in a study published in 1995. Over
2,100 patients were treated with aminoglycosides, of which gentamicin accounted for 94%. Patients
were excluded from the study if they had renal disease requiring dialysis, enterococcal endocarditis,
ascites, burns over more than 20% of the total body surface area or were pregnant. Patients
presenting with renal impairment (creatinine clearance less than 60mL/minute) were given the
aminoglycoside at a dosing interval of more than 24 hours (9).

If the Hartford nomogram is used a single random blood sample should be taken 6-14 hours after the
start of the infusion. If the gentamicin level lies below the 24-hour-line the same daily dose should be
given at 24-hour intervals. If the level falls on or above the line the dosing interval should be increased
to 36 hours or 48 hours depending on the gentamicin level measured. If the point is near the line the
authors suggest selecting the longer dosing interval. If the gentamicin concentration is off (i.e. above)
the nomogram between the 6- and 14-hour time points, the scheduled therapy should be stopped and
the drug concentration should be monitored to determine the appropriate time for administration of the
next dose (i.e. when the concentration is <1mg/L). The authors state that the measurement of
gentamicin serum samples is generally not required if the duration of gentamicin treatment is short
term unless the patient presents with varying renal function. If the duration of treatment exceeds five
days they suggest taking serum levels weekly to monitor therapy (9). In practice however serum
levels in different UK hospitals are often taken after the first infusion and then two to three times per
week (8).

Urban-Craig Nomogram (5mg/kg/day)

If a once daily dose of 5mg/kg is used, the ‘Urban-Craig nomogram’ can be applied to monitor and
interpret gentamicin levels (8, 10). This nomogram was published by two American researchers in
1997. Exclusion criteria for its use include patients presenting with a creatinine clearance of less than
20mL/minute, pregnant women, neonates, severe burns, anasarca, cystic fibrosis, meningitis and
endocarditis. The authors suggest that the frequency of drug administration should be extended to
more than every 24 hours in patients with renal impairment (creatinine clearance less than
60mL/minute).

From the NHS Evidence website www.evidence.nhs.uk 2

 Medicines Q&As

Using this nomogram, levels should be taken 8-12 hours after the dose. Depending on where the
level lies, the dosing interval should be maintained or modified. In contrast to the Hartford nomogram,
there is the option to decrease the dosing interval to every 12 hours for patients with unusually low
drug levels after dosage. The authors recommend that monitoring of drug concentration is not needed
in patients presenting with adequate renal function in whom the expected duration of therapy is under
5 days. It is however recommended to obtain levels in patients at greater risk of drug toxicity or
potential for clinical failure. For patients with normal renal function checking the drug level after the
first dose can confirm the appropriate dosing interval. If therapy is required for more than 5 days the
authors suggest monitoring drug levels weekly and serum creatinine at least every 3 days (10).

Using both nomograms it is essential that the time the gentamicin infusion was started and the time
the serum level was taken are documented accurately on the drug chart and on the microbiology
request form.

Summary
 Once daily dosing of gentamicin has been shown to be at least as effective as and not more toxic
than a multiple daily dosing regimen.
 Monitoring peak and trough levels with once daily dosing is generally not suitable.
 For most patients a nomogram is the method of choice in order to confirm or modify dosing
intervals.
 For a daily dose of 7mg/kg/day the Hartford nomogram can be used. Gentamicin levels should be
taken 6-14 hours after the start of the infusion.
 For a daily dose of 5mg/kg/day the Urban-Craig nomogram can be used. Gentamicin levels
should be taken 8-12 hours after the dose.
 It is essential that the time the gentamicin infusion was started and the time the sample was taken
are documented accurately.

Limitations
This Q&A only looks at adult patients with normal renal function (creatinine clearance above
60mL/minute). Only once daily gentamicin administration is considered. The maximum daily dose and
the maximum duration of treatment have not been included. The dose determining weight has not
been included. The appropriateness for individual infections and patients has not been investigated.
The method of administration has not been included. No critical evaluation of the nomograms has
been performed.

From the NHS Evidence website www.evidence.nhs.uk 3

 Medicines Q&As

References
1. Ryan R, editor. British National Formulary. London: British Medical Association and The Royal
Pharmaceutical Society of Great Britain; June 2013. Accessed 17.06.13 via http://www.bnf.org
2. Sweetman S, editor. Martindale: The Complete Drug Reference. Aminoglycosides. Date of
revision of the text 25.05.10. Accessed 17.06.13 via www.medicinescomplete.com.
3. Thomson A. Why do therapeutic drug monitoring. Pharmaceutical Journal 2004, 273: 153-155.
4. Sweetman S, editor. Martindale: The Complete Drug Reference. Gentamicin sulfate. Date of
revision of the text 12.02.13. Accessed 17.06.13 via www.medicinescomplete.com.
5. Barclay ML, Kirkpatrick CMJ et al. Once daily aminoglycoside therapy. Is it less toxic than multiple
daily dosing and how should it be monitored? Clinical Pharmacokinetics 1999; 36 (2): 89-98.
6. Personal communication. Consultant Pharmacist: Critical Care. Southampton General Hospital.
30.07.13
7. Winter ME. Basic Clinical Pharmacokinetics. 5th ed. Lippincott Williams & Wilkins; 2010.p.137,
144-145.
8. UKMi Discussion Group. Accessed 17/06/2013 via http://list.ecompass.nl/listserv/cgi-
bin/wa?A0=MI-UK
9. Nicolau DP, Freeman CD et al. Experience with a Once-daily Aminoglycoside Program
Administered to 2,184 Adult Patients. Antimicrobial Agents and Chemotherapy 1995; 39: 650-655.
10. Urban AW, Craig WA. Daily dosage of Aminoglycosides. Current Clinical Topics in Infectious
Diseases 1997; 17:236-55.

Quality Assurance
Prepared by
Mark Cheeseman, East Anglia Medicines Information Service (based on earlier work by Kerstin
Weber)

Date this version prepared

17th June 2013

Checked by
Katie Smith, East Anglia Medicines Information Service

Date of check
1st August 2013

Search strategy
Medline: "exp GENTAMICINS" + "DRUG MONITORING" [Limit to: Latest Update and Publication
Year 2009-Current]
Embase: "exp GENTAMICIN" + "exp DRUG MONITORING" [Limit to: Latest Update and Publication
Year 2009-Current];
Cochrane: “gentamicin” + “monitoring”; “aminoglycoside” + “monitoring”;
NHS Evidence: “gentamicin drug monitoring” [limited to last 3 years]
In-house database/ resources
UKMi Discussion Group
Clinical experts/ professional bodies (Mark Tomlin, Consultant Pharmacist: Critical Care)

From the NHS Evidence website www.evidence.nhs.uk 4