Download Gentamicin – Therapeutic drug monitoring

Therapeutic Drug Monitoring (TDM)
TDM is required for patients on aminoglycosides (e.g. gentamicin, amikacin,
tobramycin) and glycopeptides (e.g.vancomycin). Serum concentration
monitoring aims to avoid both excessive and sub-therapeutic concentration
thereby preventing toxicity and ensuring efficacy.
The following sections provide detailed instructions on how to dose, monitor and
administer these agents. Antibiotic doses should not be withheld pending on
antibiotic assays unless there are clinical grounds to suspect assay result will be
significantly abnormal or the patient is at risk of renal toxicity (e.g on concurrent
nephrotoxic agents).
Gentamicin
In severe Gram-negative bacterial sepsis, the addition of an aminoglycoside
antibiotic such as gentamicin broadens the spectrum of cover, specifically to
include activity against Pseudomonas aeruginosa.
Gentamicin works ‘synergistically’ in combination with -lactam antibiotics to
enhance their activity against enterococci and streptococci. Hence they are often
combined when treating endocarditis caused by these organisms.
Patient with a family history of deafness should not be given gentamicin due
to risk of irreversible otoxicity even when the drug is within therapeutic range1.
Dose recommendations
Gentamicin does not distribute well into fatty tissues therefore should be dosed
according to the patient’s ideal body weight (IBW). Use the following equations to
calculate IBW:
IBW for males (kg) = 50 + (2.3 x height in inches over 5 ft)
IBW for females (kg) = 45.5 + (2.3 x height in inches over 5 ft)
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
The following chart tabulates height against ideal body weight, and indicates the
weight above which the patient is defined as being obese:
Height
ft
5.0
5.1
5.2
5.3
5.4
5.5
5.6
5.7
5.8
5.9
5.10
5.11
6.0
6.1
6.2
6.3
6.4
IBW (kg)
cm
152
155
157
160
163
165
168
170
173
175
178
180
183
185
188
191
193
Patient Category
Obese
Between IBW and not obese
<IBW
50
52.3
54.6
56.9
59.2
61.5
63.8
66.1
68.4
70.7
73
75.3
77.6
79.9
82.2
84.5
86.8
MEN
Obese if
>kg
61
63
66
69
72
74
77
80
83
85
88
91
94
96
99
102
105
WOMEN
IBW (kg)
Obese if >
kg
45.5
47.5
50.1
52.4
54.7
57
59.3
61.6
63.9
66.2
68.5
70.8
73.1
75.4
77.7
80.0
82.3
55
58
61
63
66
69
72
74
77
80
83
85
88
91
94
96
99
Gentamicin dosage weight
Use adjusted body weight:
IBW + 0.4 (actual body weight – IBW)
Use IBW
Use actual body weight
Creatinine Clearance (CrCl)
The eGFR can be used as a quick estimate for calculating initial dose. Do not
use eGFR in patients at both extremes of weight (BMI <18.5kg/m2 or greater than
30kg/m2). The absolute glomerular filtration rate or creatinine clearance
(calculated from the Cockcroft and Gault formular- see below) should be used in
these cases.
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
*Estimated renal function (Creatinine clearance - CrCl)
Creatinine clearance may be estimated using the Cockcroft and Gault equation
below:
Male
CrCl = 1.23 (140 – age) x Weight* (kg)
Serum Creatinine (μmol/L)
Female
CrCl = 1.04 (140 – age) x Weight* (kg)
Serum Creatinine (μmol/L)
* Obese patients – those whose actual weight is 20% over their IBW, should
have their dose calculated on their adjusted IBW (see above)
This equation will not work for

Muscle wasting (patient’s CrCl will be overestimated)

Oedematous patients (use IBW)

Ascites (use IBW and consider dilutional effect on serum creatinine)

Acute renal failure. This may represent non-steady state serum creatinine
levels and may underestimate the level of renal impairment

CrCl can overestimate renal function in the elderly, consider 20% reduction of
calculated CrCl for patients >80 years of age
Gentamicin Regimens
Gentamicin may be administered in several ways:
1. Single stat dose/Once-daily regimen (see page 4-6)
2. Multiple daily dose synergistic regimens (e.g. in endocarditis) in adults:
1mg/kg 12 hourly (see page 7)
3. Conventional multiple daily dose therapeutic regimen: 3-5mg/kg in divided
doses (8 hourly). Note: Once daily gentamicin regimen has largely
superseded multiple daily dose regimens however may be used in
certain circumstances (see page 8-9)
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
1. Single-dose (STAT) and Once daily (OD) gentamicin regimen
(a) 5mg/kg once daily
Dose: 5mg/kg OD
(Maximum daily dose: 480mg)
Administration: in 100ml normal saline or glucose 5% infused over 60mins
Single-dose or once-daily administration in patients without pre-existing renal
impairment is as effective as multiple daily dosing.
There are various advantages in using a single daily dose of aminoglycoside:

high peaks are more effective in achieving bacterial kill

long post-antibiotic effect therefore not necessary to have levels above the
mean inhibitory concentration (MIC) all day

reduced risk of nephrotoxicity due to washout period allowed by infrequent
dosing

no greater risk of ototoxicity.

monitoring of levels is simpler

less nursing time required to administer the antibiotic
Indications for OD regimen
Exclusions for OD regimen
 Severe sepsis of unknown cause
and/or oliguria
 Intra-abdominal sepsis
 Urological sepsis
 Hospital-acquired pneumonia
 Significant renal impairment
 Pregnant patients
 Endocarditis
 Patients with cystic fibrosis
 Patients with severe burns
Most patients will need ONLY ONE DOSE of gentamicin when given in this way
and in combination with a -lactam or other appropriate agent (the latter agent
should be continued as clinically indicated).
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
A second dose MAY be given after a 24-hour
interval if there is no clinical improvement, and providing the renal function has
not become impaired. In this case, it is not necessary to check the serum level of
gentamicin before giving the second dose.
Should once-daily gentamicin be required for more than two doses, this should
be guided by serum trough levels. Unless use for treatment of specific conditions
i.e infective endocarditis and neutropenic sepsis, gentamicin should not be given
> 5 days as this increase the risk of toxicity.
(b) Reduced dose regimen in renal impairment (3mg/kg)
Dose: 3mg/kg OD
Administration: in 100ml normal saline or glucose 5% infused over 60mins
This may be used in patients with severe sepsis and renal impairment (GFR
<60ml/min).
In patients receiving ≥ 2 doses, a post dose gentamicin level should be collected
18 – 24 hours after the last dose (i.e a pre-dose level).
Subsequent doses can be given when pre-dose level is <1mg/L.
Monitoring level for once daily regimen

Aim for a pre-dose (trough) level of < 1mg/L.

Take a pre-dose level (18-24 hours) before giving the next dose. Clearly
mark on the request form how many hours after the dose the sample has
been taken.

Unless patients are at risk of nephrotoxicity due to pre-existing renal
impairment or are receiving multiple nephrotoxic agents (e.g some
chemotherapy agents). Do not wait for the result to come back before
giving the next dose, adjust the regimen around the next and subsequent
dose if applicable.

Post dose (peak) levels are not required.

When the first dose of gentamicin has been given in the evening or night,
the level should be taken by 1500hr the following day if this falls within 1824 hour window and sent for analysis immediately.
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
Serum levels
Action
Trough level

Continue current regimen.
< 1mg/L

Provided renal function is stable, and continued
gentamicin administration is required, monitor
gentamicin levels twice weekly i.e. after the 1 st and 3rd
or 4th dose.
Trough level
Provided renal function is unchanged increase the dosing
interval to 36 - 48 hours.
1 – 2mg/L
Trough level
> 2mg/L
Omit next dose, re-assay in 24hours. Re-dose if clinically
indicated when levels fall ≤ 1mg/L but extend the dosing
interval accordingly for subsequent doses.

If a patient’s renal function is poor or deteriorates, await assay result
and give dose when level <1mg/L.

Always monitor renal function carefully by checking urine output daily and
serum creatinine levels 2 – 3 times per week, especially for courses longer
than 5 days duration.

Risk of toxicity increases when duration of the treatment course exceeds 5
days. Prolonged courses of gentamicin must only be given only when
there is a clear clinical need e.g. endocarditis.
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
2. Multiple daily dose synergistic regimen for infective endocarditis
All cases of infective endocarditis must be referred to a cardiologist.
Dose: 1mg/kg every 12 hours (Max 240mg/day)
Administration:
IV injection in 10-20ml saline or glucose 5% over at 3–5 mins
IV infusion in 50ml normal saline or glucose 5% infused slowly over 20mins – 30mins
Gentamicin is given in low doses primarily for its synergistic effect with -lactam
antibiotics. Regular monitoring of serum levels is important to ensure that there is
enough present throughout a 24-hour period to act with the -lactam.
Because gentamicin may be given for several weeks in this context, it is also
important to ensure that the drug is being adequately renally excreted. Baseline
audiometry is recommended for patients who require extended treatment (>2
weeks) with this agent.
Monitoring levels for multi-dose synergistic regimen

Take pre-dose (trough level) sample before giving the 3rd or 4th dose after
commencement. This should also be the case after any dose adjustment.

Post-dose (peak level) should be taken ONE HOUR after the end of the
infusion.

For streptococcal/enterococcal endocarditis infections aim for:
Pre-dose levels: <1mg/L
Post-dose levels: 3-5mg/L
Serum levels
Pre-dose level <1mg/L
Post-dose level around 3-5mg/L
Action
 Continue current regimen
 Re-check levels after a further 3 or 4 doses
Pre-dose level <1mg/L




Post dose level <3mg/L

Pre-dose level >2mg/L
Post dose level 5mg/L or above
Omit further doses until level <1mg/L
Increase the dosing interval to 24-hourly
Re-check levels after a further 3 or 4 doses
Increase dose and remain on 12-hourly
dosing interval
Re-check levels after a further 3 or 4 doses
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
3. Conventional multiple dose therapeutic regimen
Multiple daily doses therapeutic regimen has largely been superseded by once
daily gentamicin regimen (see section 1) and is generally not recommended
except for pregnant patients, patients with cystic fibrosis or severe burns.
Dose: 3-5mg/kg in divided doses (8 - 12 hourly)
Administration:
IV injection in 10-20ml saline or glucose 5% over at 3–5 mins
IV infusion in 50ml normal saline or glucose 5% infused slowly over 20mins – 30mins
Monitoring levels for conventional multi-dose therapeutic regimen

Both pre and post dose levels are required.

Take pre-dose (trough level) sample before giving the 3rd or 4th dose after
commencement. This should also be the case after any dose adjustment.

Pre-dose (trough level) should be taken 8 or 12 hours after the previous
dose for tds and bd regimens respectively

Post-dose (peak level) should be taken ONE HOUR after the end of the
infusion.

Aim for pre-dose (trough) level < 2mg/L

For most infections, aim for post-dose level of 5 – 10mg/L.
Pre-dose level
<2mg/L
2- 3mg/L
>3mg/L
Action

Continue current regimen. Ensure the patient is responding
clinically.

Further pre-dose level to be monitored twice weekly so long
renal function is stable
Increase dosing interval i.e. from tds to bd provided renal function
is unchanged.

Further gentamicin doses should be withheld until level
<1mg/L.

If further doses are required, re-start with increased
interval/decreased dose.
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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Therapeutic Drug Monitoring (TDM)
Post-dose level
Action
Below target
range

Check previous dose(s) have been given as prescribed.

If the low post-dose level appears genuine, gentamicin is subtherapeutic. Consider increasing the dose.
Level is high

Ensure level is not taken via an intravenous catheter that is
used for the administration of the antibiotic as this will give
false high level.

Consider reducing the dose (and the dose frequency). Final
action dependent on trough level also.
Pre and Post Action
dose levels
Pre-dose level <
2mg/L (normal)
Reduce the dose
Post dose level
is above target
range
Both pre-dose
and post-dose
levels are above
target range

Omit next dose

Review need for further gentamicin

Consider increasing the interval between doses

Restart gentamicin when pre-dose level <2mg/L
Reference:
1. S Rahman, E Russell, C Harry et al. Hearing in 44e45 year olds with
m.1555A>G, a genetic mutation predisposing to aminoglycoside-induced
deafness: a population based cohort study. BMJ open, 2012.
Gentamicin prescribing guidelines – updated 27th Mar 2014, AL
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