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Therapeutic Drug Monitoring and Pharmacokinetics of
Aminoglycosides for Pharmacists and Other Healthcare
Professionals
Purpose of this document: This document is a Section of Infectious Disease &
Pharmacy consensus statement of agreed upon dosing and drug monitoring
recommendations.
Comprehensive Antimicrobial Program (CAP) Approved Indications:
AMIKACIN-Prior approval needed and automatic review within 72 hours
A.
Prophylactic use: none.
B.
1.
C.
1.
2.
3.
Empiric use:
Seriously ill patient in whom an infection with P. aeruginosa (or other
resistant GNR) resistant to tobramycin is suspected.
Therapeutic use:
Patient with infection caused by GNR resistant to all other agents.
Patient with severe infection by an agent that requires combination
therapy and is resistant to other aminoglycosides.
Treatment of infection caused by Mycobacterium avium complex.
GENTAMICIN-Unrestricted
TOBRAMYCIN-No prior approval needed, review within 72 hours
A.
B.
Prophylactic use: none.
Empiric use:
1. In combination with cefepime for neutropenic fevers.
2. In combination with piperacillin for 48 hours when severe P. aeruginosa
infection suspected.
C.
1.
Therapeutic use:
With appropriate ß-lactam for GNR infection resistant to gentamicin,
when combination therapy is deemed necessary (e.g. P. aeruginosa)
Aminoglycoside antibiotics are active against many aerobic gram-negative bacilli
(GNB), including Pseudomonas aeruginosa. In reduced doses, gentamicin is also used as
an adjunctive synergistic agent in combination with cell wall active agents such as
vancomycin or ß-lactams for the treatment of serious infections involving many aerobic
gram positive cocci (GPC).
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Two dosing strategies are available for patients placed on aminoglycosides. These
strategies are extended interval (once daily) dosing (EID) or traditional dosing (TD).
Extended interval dosing is appropriate for patients with presumed or documented GNB
infections only. While EID is only appropriate for GNB, TD is appropriate for both
infections due to susceptible GNB (EID is the preferred method) and for synergy against
GPC. A lower dose (generally 1mg/Kg of dosing weight (DW) is preferred for synergy.
Data has shown that EID has similar efficacy and may have decreased toxicities over
traditional dosing methods. In addition, EID has the convenience of easier dosing and
has fewer drug levels to monitor.
How to Decide on an Aminoglycoside Dosing Strategy
Gentamicin, Tobramycin or Amikacin Indicated
Treating GNB
Treating GPC (gentamicin only)
Use 1mg/Kg dosing
(TD only)
EID (Preferred)
TD
I. Empiric Dosing (this step is for both TD and EID)
A. Calculate DW-All expressed in kilograms
1. Ideal body weight (IBW):
a. Males:50 + 2.3(height in inches-60)
b. Females:45.5 + 2.3(height in inches-60)
c. If IBW>Actual body weight (ACTBW) then use ACTBW as
dosing weight
B. Adjusted body weight (ADJBW ): Use if ACTBW >120% of IBW
1. ADJBW = IBW + 0.4(ACTBW - IBW)
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C. Calculate creatinine clearence (CrCL): (ml/min)
1. Use urine CrCL if available:
Urine volume (ml/24hrs)
1440
x
x
Urine creatinine (mg/dl)
Serum creatinine (mg/dl)
2. Estimated CrCL: Use Crockoft and Gault Method1
(140-age) x IBW or ADJBW x 0.85 (females only)____
72 x
SCr
D. Empiric Traditional Dosing
1. Choose a loading dose (LD), maintenance dose (MD) and interval
a. LD
1. Tobramycin or gentamicin =2mg/Kg of DW
b. MD and dosing interval: Adjust dosing interval PRN based on
the Hull-Sarubbi Nomogram
c. For synergy with cell wall active agents (gentamicin only) in the
treatment of gram positive infections, dosing is 1mg/kg Q8H
(NO LOADING DOSE NEEDED)
Hull-Sarubbi Nomogram
CrCL
Percentage of LD to use for
Dosing Interval
(ml/min)
MD
>90
84
Q8H
80
80
Q8H
70
76
Q8H
60
84
Q12H
50
79
Q12H
40
72
Q12H
30
86
Q24H
20
75
Q24-36H
<20
Give LD x1, then check random level(s)
*Ann Intern Med 1978; 89: 612-618
2. When is it appropriate to obtain serum aminoglycoside levels?
a. Utilization of serum aminoglycoside concentrations may be used
to help ensure adequate levels are achieved at the site of infection,
for those patients with altered pharmacokinetics and in populations
that are at increased risk to help avoid or identify toxicity. It is
important to keep in mind that acute renal failure can occur even if
drug levels are closely monitored, although the risk is clearly
greater in those patients with levels outside the therapeutic range.2,3
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b. Populations who DO NOT require serum aminoglycoside levels:
1. Predicted duration of therapy less than 5 days with the
following characteristics
a. Stable, normal renal function
b. No concurrent nephrotoxins
c. Not volume depleted
d. Absence of hypotension or impaired renal
perfusion
2. For those that require serum levels, a peak and a trough
should be obtained after 4-5 half lives (typically the 3rd
or 4th maintenance dose) and subsequently every 7 days,
with lack of efficacy, signs of toxicity or with a 25%
change in serum creatinine or CrCL.
3. Special Populations
a. Neonates
Postconseptual Age
(weeks)
Postnatal Age
(days)
Gent or Tobra
Dose (mg/Kg/dose)
Amikacin Dose
(mg/Kg/dose)
Dosing Interval
(hours)
< 29
0-28
>28
0-14
>14
0-7
0-7
>7
>7
2.5
3
3
2.5
4
4
-
7.5
10
10
7.5
7.5
7.5
24
24
24
12
24
12
24
8
30-36
>37
*All Pediatric dosing based on The Harriet Lane Handbook, Sixth edition
a. Infants and Children
1. Gentamicin and Tobramycin
i. 2 to 2.5mg/Kg every 8 hours
2. Amikacin
i. 5 to 7.5mg/Kg every 8 hours
c. Ascites-Patients receiving aminoglycosides who have ascites
typically have a larger volume of distribution (VD) than the normal
population, due to the hydrophilic nature of the drug class. The
VD in patients who have ascites typically is 0.3-0.35 L/Kg versus
~0.25L/Kg in the normal population4. Serum levels should be
monitored closely.
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d. Elderly patients- More than 85% of the elimination of all
aminoglycosides is accounted for by renal clearance. Therefore, it
is not unexpected that linear regression models have shown a direct
correlation between CrCL and the aminoglycoside elimination rate
constant5 Similarly, pharmacokinetic studies have found a direct
relationship between age and diminished renal function, although,
to date no firm relationship has been established between age and
decreased aminoglycoside clearance 6,7. Given this information,
dosing should be based on CrCL not age. One must also keep in
mind that the elderly have a higher incidence of dehydration and
decreased plasma proteins (albumin) that may influence
aminoglycoside dosing, so serum levels should be monitored
closely. Ultimately, after the clinician reaches a dose they think is
appropriate based on the methods provided, they should review the
patients clinical situation, weight and renal function and decided if
the dose is acceptable. The ID pharmacist may be consulted as
needed.
e. Burn patients-Patients with burns of greater than 20% of their
body should NOT be placed on EID of aminoglycosides8. This is
due to the unpredictability of the drug clearance and volume of
distribution in this patient population9. It is apparent that large
variations in dosages and dosing intervals may be needed to
achieve therapeutic levels of aminoglycosides. Many patients may
require either increased dosages or more frequent dosing intervals
to achieve their target serum levels, or both. However, this should
not be interpreted as a steadfast rule. Early research by Zaske and
colleagues has shown that patients receiving individualized dosing
regimens have a statistically significant reduction in mortality
compared to patients who receive a standard dosing regimen10.
Patients placed on aminoglycosides with burns greater than 20% of
their body should receive a traditional dosing regimen and serum
levels with the 3rd maintenance dose. Patients who are started on
aminoglycosides within 48 hours of a > 20% burn injury should
have levels drawn with the 3rd maintenance dose and with the 6th 9th maintenance dose due to the changing burn pharmacokinetics
before and after 48 hours8. Patients placed on aminoglycosides
after a > 20% burn injury should be dosed at 3mg/Kg every 8
hours (adjust dosing interval based on CrCl), and serum levels
should be monitored closely11.
f. Critically ill/surgery patients-Critically ill patients who have
undergone surgery may receive EID aminoglycosides based on the
Hartford Nomogram guidelines. Frequently, patients in this
subpopulation who receive aminoglycosides (EID and TD) will
have sub-therapeutic serum levels initially. This is due to the large
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VD that is commonly seen in this patient population. Typical
VD’s are 0.3-0.4 L/Kg as compared to ~0.25L/Kg seen in patients
with normal pharmacokinetics12-14. Some traditional dosing studies
suggest a larger initial dose (such as 3mg/Kg) might be necessary
in critically ill patients, but no consensus has been reached on this
issue as of yet15. To complicate the clinical picture, these patients
commonly present with renal insufficiency or even acute renal
failure. Serum levels should be drawn with the 3rd or 4th
maintenance dose to ensure they are within the therapeutic range.
e. Cystic fibrosis (CF)- The renal clearance of aminoglycosides is
considerably accelerated in CF patients for unclear reasons,
requiring starting doses that are approximately triple (usually
3mg/Kg Q8h) those normally recommended. Volumes of
distribution are also increased and are thought to be from a lack of
adipose tissue in CF patients (and a resultant increase in the
percentage of hydrophilic tissue). It is critically important to
measure peak and trough blood levels soon after the initiation of
treatment because considerable variation exists in clearance rates.
Extrapolation of EID in CF patients is uncertain. Pharmacokinetic
studies of once-daily tobramycin in CF patients showed that the
time spent with serum levels less than the minimal inhibitory
concentration was significantly longer than in non-CF
individuals16. Pending the results of ongoing multicenter trials, a
general recommendation for once daily dosing of aminoglycosides
in these patients cannot yet be made. Some practitioners, who
specialize in the treatment of older CF patients here at DHMC
routinely, do use tobramycin EID (10mg/Kg). Nevertheless, the
current available data show a clear consensus that CF patients
exhibit a larger VD and enhanced clearance in comparison to nonCF patients for many antibiotics, including aminoglycosides.17,18
E. Empiric Dosing Using EID (Hartford Nomogram)
1. Should NOT be used in the following populations
a. < 13 y/o
b. Allergy to aminoglycosides
c. Ascites
d. CRCL<20 ml/min
e. Synergy for gram-positive infections
f. Extensive burns (>20% of BSA)
g. Pregnancy
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2. Dosing
a. Tobramycin and gentamicin =7mg/Kg based on DW
3. Initial dosing interval
a. Initial dosing interval should be based on CrCL as described in
the table below. Obtain a random level 6-14 hours after the start
of a 1 hour infusion, except as noted
b. Q24H Regimens-If duration of therapy is expected to be > 5
days, a random level should be obtained after the first or second
dose and weekly thereafter. A Random level is necessary after the
first dose if the regimens expected duration is < 5 days and:
i. Receiving concurrent nephrotoxic agent(s)
ii. Changing renal function
iii. Quadriplegic or amputee
iv. Patient is in an ICU
c. Q36H Regimens- A random level should be obtained after the
first or second dose and then weekly thereafter.
d. Q48H Regimens- A random level should be obtained after the
first dose and then weekly thereafter.
CrCl
>60
40-60
20-40
<20
Dosing Interval
Q24H
Q36H
Q48H
Use traditional dosing and
follow serial levels
II. Dosing Modifications based on level(s) obtained (TD)
A. Traditional Dosing using the Sawchuk-Zaske method19
1. Find elimination constant (Ke)
Ke = lnC1 - lnC2___
t1-t2
2. Find T1/2 (Want dosing interval to be 2-3 x T1/2)
T1/2= 0.693
Ke
3. Find real peak (Cmax) and trough (Cmin)
Cmax= __C1_____
e-Ke(t”)
Cmin= Cmax (e-Ke(T-t’) )
Symbol
Meaning
(D)
(t’)
Dose (mg)
Infusion duration (hr)
(T)
Dosing interval (hr)
(t)
Time since infusion
completion (hr)
(t”)
Time since
completion of
infusion when C1
drawn (hr)
Volume of
distribution (L)
(Vd)
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4. Find volume of distribution (Vd) in liters
Vd= ___ Dose (mg) x (1-e-Ke(t’) )
t’*Ke (Cmax – Cmin e-Ke(t’) )
5. Find new dose (mg) based on peak level (from chart below)
Dose= Cmax (desired) * Ke*Vd*(1-e-Ke(T) )*t’
1-e-Ke(t’)
6. Calculate new peak and trough
Cmax(new)= _____Dose(mg)* (1-e-Ke(t’) )_______
t’*Ke*Vd (1-e-ke(T) )
Cmin(new)= Cmax (e-Ke(T-t’) )
Gentamicin and Tobramycin Target Serum Levels for Specific Disease States/Etiologies
Infection Type
Target Peak
Target Trough
Gram-positive infections
4 mg/L
<2 mg/L
Most gram-negative infections
6-8 mg/L
<2 mg/L
Gram-negative pneumonia
8-10 mg/L
<2 mg/L
UTI
4-6 mg/L
<2 mg/L
Cystic Fibrosis
10-12 mg/L
<2 mg/L
P. aeurgenosa (non-UTI)
9-11 mg/L
<2 mg/L
Amikacin
15-30 mg/L
<8 mg/L
*amikacin serum levels are a send out
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B. Dosing Modifications based on level(s) obtained (EID)
1. Evaluate using the Hartford Nomogram below
a. If the level falls in the area designated q24h, q36h or q48h the
dosing interval should be adjusted as needed.
b. If the level falls directly on a line choose the longer of the two
dosing intervals
c. If the 6-14 hour post level is < 2 mg/L then use TD
d. For amikacin double the serum concentrations on the Y axis of
the nomogram
III. Monitoring the patient- In addition to serum levels the following information should
be monitored daily.
A. Laboratory parameters
1. Serum creatinine (or CrCL)
a. Monitor for trends and adjust doses based on Hartford or Hall
& Sarubbi Nomogram if not following serum drug levels
2. Blood urea nitrogen
a. BUN / Scr ratio of > 20 may indicate a pre-renal state
(dehydration) representing a smaller VD and subsequent
increased levels
3. White blood cell count (WBC)
a. Trends in WBC count help evaluate physiologic response to
treatment
4. Microbiology
a. Gram stain results
i. Aminoglycosides are mainly effective against GNB, but
may be used as an adjunctive agents for GPC
b. Culture and sensitivity results
i. Culture
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1. These results should be reviewed to identify the
species of the microorganism.
ii. Sensitivities
1. Identifies in vitro activity of antibiotics against a
specific microorganism
B. Monitor for Adverse Drug Reactions (ADR)
1. Nephrotoxicity (Acute tubular necrosis)
a. Nephrotoxicity has ranged from 5% to 25% in clinical trials. It
is important to note that the criteria used to define
nephrotoxicity influences the incidence reported in these trials.
b. The risk of nephrotoxicity may be less with EID (Murry et al,
1999)
c. Concurrent use of other nephrotoxins, dehydration, pre-existing
renal dysfunction, prolonged therapy and increased trough
concentrations appear to increase the risk of nephrotoxicity
b. Recommended course of action is to withdraw the offending
agent(s) and risk/benefit should be discussed with the physician
2. Ototoxicity
a. Serious adverse effects on both vestibular and auditory
branches of the eighth cranial nerves have been reported in
varying ranges (3%-14%) based on the criteria used
b. This toxicity is primarily seen in patients with renal impairment
(especially if dialysis is required), patients on high doses and/or
prolonged therapy, dehydration, and previous/concurrent
exposure to other ototoxic agents
c. Symptoms include dizziness, vertigo, ataxia, tinnitus, roaring in
the ears and hearing loss, which, may be irreversible.
d. Hearing loss is usually manifested initially by diminution of
high-tone acuity
c. Recommended course of action is to withdraw the offending
agent(s) and risk/benefit should be discussed with the physician
3. Other Neurotoxicity
a. Peripheral neuropathy, numbness, skin tingling, muscle
twitching, convulsions, and a myasthenia gravis-like syndrome
are all rare occurrences
b. Recommended course of action is to withdraw the offending
agent(s) and risk/benefit should be discussed with the physician
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References
1. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum
creatinine. Nephron 1976:16;31-41.
2. Humes, HD. Aminoglycoside nephrotoxicity. Kidney Int 1988; 33:900.
3. Moore, RD, Smith, CR, Lipsky, JJ, et al. Risk factors for nephrotoxicity in
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pharmacokinetics. J Clin Pharmacol 1984; 24:43-6
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14. Oparaoji E, Cornwell E, Hekmak E, et al. Aminoglycoside volume of distribution
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Pharmacokinet 1998;35:313–329
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Pharmacol Ther 1977;21;3:362-369
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