
 Antimicrobial spectrum
Aminoglycosides have bactericidal activity against most gramnegative
bacteria including Acinetobacter, Citrobacter, Enterobacter, E. Coli,
Klebsiella, Proteus, Providencia, Pseudomanas, Salmonella, Serratia
and Shigella. The MIC's of gram negative bacteria are usually less
than 2 mcg/ml for gentamicin and tobramycin and 8 mcg/ml for amikacin.
Aminoglycosides are active against most strains of Staphylococcus
aureus and S. epidermidis. Most strains of enterococcus
are resistant to aminoglycosides alone, however when used in combination
with penicillins they are often effective in enterococcal endocarditis
due to synergistic antimicrobial mechanisms. Anaerobic bacteria are
universally resistant because aminoglycoside transport into cells is
oxygendependent.
 Toxicity
Aminoglycoside nephrotoxicity manifests clinically as nonoliguric renal
failure, with a slow rise in serum creatinine and a hypoosmolar urinary
output developing after several days of therapy. The reported incidence
of nephrotoxicity varies substantially between studies, averaging 6% to
10%. Nephrotoxicity rates do not vary significantly among the different
aminoglycosides.
Factors associated with nephrotoxicity include duration of treatment,
increasing age, compromised renal function, volume depletion, elevated
peak and trough levels, concurrent nephrotoxic drugs (i.e., vancomycin)
and previous exposure to aminoglycosides.
Aminoglycosides can cause permanent vestibular and/or auditory ototoxicity.
Overt otoxicity occurs in 2% to 10% of patients treated with aminoglycosides.
Factors associated with otoxicity include increasing age, duration of therapy,
elevated peak and trough levels, concurrent loop diuretics or vancomycin,
underlying disease states and previous exposure to aminoglycosides.
Vestibulotoxicity is difficult to diagnose and there is no reliable monitoring
process. Recent studies indicate a genetic predisposition to aminoglycoside
auditory ototoxicity due to a mutation of mitochondrial DNA.^{23,24}
However, this genetic component does not appear to influence aminoglycoside vestibular
ototoxicity. Gentamicin toxicity is the most common single known cause of bilateral
vestibulopathy, accounting for 1550% of all cases.^{25}
A web site, Wobblers Anonymous
presents personal testimony from patients who have suffered from this disabling ADE.
 Concentrationtoxicity relationships
For gentamicin, tobramycin and netilmicin, the risk of ototoxicity and
nephrotoxicity is increased if peak levels are consistently maintained
above 12 to 14 mcg/ml or trough levels consistently exceed 2 mcg/ml.
For amikacin, peak levels above 32 to 34 mcg/ml or trough levels greater
than 10 mcg/ml have been associated with a higher risk of ototoxicity and
nephrotoxicity.
 Concentrationefficacy relationships
The pharmacodynamic properties of aminoglycosides are:
 Concentrationdependent killing
 Significant postantibiotic effect
Aminoglycosides eliminate bacteria quickest when their concentration is
appreciably above the MIC for an organism, this is referred to as concentration
dependent activity. The aminoglycosides also exhibit a significant postantibiotic
effect (PAE). PAE is the persistent suppression of bacterial growth following
antibiotic exposure. Practically speaking this means that trough levels can drop
below the MIC of targeted bacteria for a sustained period without decreasing efficacy.
For AG's the ideal dosing regimen would maximize concentration, because
the higher the concentration, the more extensive and the faster is the degree
of bacteriocide. Therefore, the Peak/MIC ratio is an important predictor of efficacy.
It has been shown that aminoglycosides eradicate bacteria best when they achieve
a Peak/MIC ratio of at least 810. Therefore it is important to give a large enough
dose to produce a peak level 8 to 10 times greater than the MIC.
Aminoglycoside Pharmacodynamics in Vivo
Initial serum peak level

Died

Survived

< 5mcg/ml

21%

79%

>= 5mcg/ml

2%

98%

Moore et al, J Infect Dis 149: 443, 1984
Tissue penetration
Aminoglycoside concentrations in body tissues following multipledose IV administration
Body tissue

Tissue/serum ratio

CSF

0.08  0.25

Pleural fluid

1

Synovial fluid

0.9

Saliva

0.05

Urine

> 500

Nix et al, 1991
Pharmacokinetic parameters
When given by IV infusion over 30 minutes, aminoglycosides follow a 3compartment
pharmacokinetic model; alpha (distribution), ß (elimination), and gamma
(tissue release). When infused over one hour, the distribution phase is usually
not observed. The gamma phase begins approximately sixteen hours post infusion,
drug that was tissue bound to various organs is released. The amount released
from tissue is very small, but does accumulate over time, contributing to AG toxicity.
Although this model accurately represents the time course of AG serum levels,
it cannot be used clinically because of its complexity. Therefore, the simpler
one compartment model is widely used, and does, in fact, accurately predict
serum AG levels.
Volume of distribution
The average Vd of AG's in otherwise healthy adults is 0.26 L/kg (range: 0.20.3).
Although AG's do not distribute into adipose tissue, they do enter the extracellular
fluid contained therein. Therefore, obese patients require a correction in the weight
used for Vd calculation: LBW + 40% of weight above LBW. Patients with cystic fibrosis
have a markedly increased Vd of 0.35 L/kg due to increases in extracellular fluid
brought about by the disease process. Patients with ascites have additional
extracellular fluid because of accumulation of ascitic fluid, which increases the
Vd to approximately 0.32 L/kg. ICU patients may have a Vd 2550% above normal.
Elimination rate
AG elimination is closely correlated with creatinine clearance, the average value
for the slope is between 0.0024 and 0.0029 and the yintercept is typically 0.01 to 0.015.
Cystic fibrosis patients show a 50% increase in elimination rate. A major
body burn increases the basal metabolic rate resulting in a marked increase in
AG elimination. ICU patients are often hyper metabolic and therefore eliminate
AG's more rapidly.
Dosing methods
Achieving therapeutic serum levels of aminoglycosides early in the
course of treatment is critical to therapeutic success. Dosing error
on the high side is preferable to the risks of undertreatment. An
adequate loading dose is critical for rapid attainment of therapeutic
peak levels.
The method of
Sarrubi and Hull^{4} utilizes serum creatinine,
lean body weight, age, and sex to estimate creatinine clearance.
This method considers more patient variables, which may improve
the estimation of aminoglycoside elimination. Lesar et al found
that the Sarubbi and Hull nomogram achieved therapeutic concentrations
in 78% of patients.^{9} Tsubaki and Chandler evaluated 5 methods
for determining initial dosing requirements for gentamicin. They
concluded that the Sarubbi and Hull method was the most accurate.^{22}
However, dosing nomograms are initial guidelines only. They
can produce substantial variations in serum concentrations and
should be subsequently adjusted based on serum level determinations
and clinical response.
Dosage regimens necessary to achieve therapeutic aminoglycoside
serum concentrations can be quantitatively determined by using
simple pharmacokinetic principles. Individualized pharmacokinetic
parameters are determined from the patient's serum concentration
versus time data. Sawchuk and Zaske have described a method for
establishing multiple infusion regimens based on individually
calculated pharmacokinetic parameters.^{3} Lesar, et al found that
this individualized method achieved therapeutic concentrations
in 90% of patients.^{9}
For evaluation of serum level data, methods incorporating Bayesian
principles appear to give the best overall predictive performance
compared with traditional methods of vancomycin dosage adjustment.
The Bayesian approach combines both population and patientspecific
information (i.e., serum level data) in predicting dosage requirements.
Extendedinterval aminoglycoside dosing has
gained popularity in recent years. This simplified dosing method is
appropriate in young, otherwise healthy patients with sepsis. However,
there are many patient groups who are not candidates for this dosing
methodology: the elderly, CrCl less than 30, dialysis, pregnancy, endocarditis, cystic
fibrosis, ascites, neutropenia, infants, 20% or greater BSA burns, history of hearing
loss or vestibular dysfunction, gram positive infections (when aminoglycoside
is used for synergy), or mycobacterial infections.
II. Monitoring parameters
 The following patient parameters should be monitored
during aminoglycoside therapy:
 Aminoglycoside peak and trough levels
Obtain levels 24 hours after initiating therapy,
at steady state (approximately four halflives), and every
2 to 3 days.
 BUN and serum creatinine
Measure every two days, or every day in unstable
renal function.
 Weight
Weigh patient every two to seven days.
 Urine output
Measure and monitor urine output daily
 Baseline and weekly audiograms, and check for
tinnitus or vertigo daily.
 Therapeutic serum concentrations (mcg/ml)
 Gent/Tobra/Netilmicin Amikacin/Kanamycin
Peak
Serious infection: 68
LifeThreatening infection: 810
Trough
Serious infection: 0.51.5
LifeThreatening infection: 1 <2
 Amikacin/Kanamycin
Peak
Serious infection: 2025
LifeThreatening infection: 2530
Trough
Serious infection: 14
LifeThreatening infection: 48
III. Precautions
 Proper timing of serum sampling is critical.
The trough sample should be obtained 30 minutes prior to the dose.
Measure the peak level 15 to 30 minutes after completion of the IV
infusion to avoid the distributive phase. Measure the peak level 90
minutes after an IM injection. Drawing the peak too soon will result
in inaccurate analysis.
Drawing at exactly the right time is not as important as having the
lab note the exact times that the samples were drawn. Also,
have the nurse note the exact times that the sample infusion
was started and when it ended. Please be aware of the widespread
policy of nursing personnel to record a dose as having been given
exactly as ordered if it is given within 30 minutes of the recorded
time. This will lead to significant errors in analysis, have everyone
record the exact times.
This issue cannot be stressed enough. Inaccurate recording of drug
administration times and lab draw times are the greatest source of
calculation error, having a greater effect than pharmacy preparation
error or lab assay error.
 Outliers
In general the Bayesian approach to the determination of individual drugdosage
requirements performs better than other approaches. However, outlying patients
in a population (ie, those patients whose pharmacokinetic parameters lie outside
of the 95th percentile of the population) may be put at risk. As is always the case,
the computerized algorithms outlined below can only assist in the decisionmaking
process and should never become a substitute for rational thought or informed
judgement.
IV. Program procedure
Before calculating an initial dose or analyzing serum level data,
enter the target peak and trough levels and the standard length
of infusion.
 Initial dosing
The program calculates an ideal dose and interval, the user enters
a practical dose and interval. The program then displays estimated
steadystate peak and trough serum levels.
 Dosage adjustment based on serum levels
Enter the current dosage regimen, date and time of sample infusion
and date and time of serum level(s). The program calculates an ideal
maintenance dose and the user enters a practical maintenance dose and
interval. The program then displays estimated steadystate peak and
trough serum levels.
The program supports six different serum level analysis methods for the
onecompartment model:
V. Aminoglycoside dosing flow chart
VI. Pharmacokinetic formulas
The aminoglycoside model is not hardcoded into the program. The parameters are
found in the drug model database and are fully usereditable. You can tailor each
drug model to fit your patient population, or you can create your own models.
A. Initial dosing
An initial dose, prior to serum level measurement, is based solely on the population model
As stated above, the pk models supplied with the program may be edited, also multiple models
of the same drug may be added to reflect different patient populations.
 Determine dosing weight (DW)
DW = LBW + ((ABW  LBW) x CF)
where ABW = actual weight
CF is a correction factor for obesity, usually 40%, but literature values vary:
 Amikacin = 38%
 Gentamicin = 43%
 Kanamycin = no correction
 Netilmicin = 50%
 Tobramycin = 58%
 Determine loading dose (LD)
Gentamicin, Tobramycin, Netilmicin: LD = 2mg/kg DW
Amikacin & Kanamycin: LD = 7.5mg/kg DW
 Determine maintenance dose (MD)
 Estimate elimination rate (Kel)
Kel = 0.01 + (CrCl x 0.0024)
 Estimate Volume of distribution (Vd)
Vd = 0.27 L/kg x DW
 Calculate ideal maintenance dose (IMD)
IMD = Kel x Vd x Cptmax x (1  e^{Kel x tau} / 1  e^{Kel x tinf})
 User selects practical dosage and interval
 Calculate expected peak & trough levels
Peak = (MD / t_{inf }x Vd x Kel ) x (1  e^{Kel x tinf} /1  e^{Kel x tau} )
Trough = Peak * e^{Kel x (tau  tinf)}
where tinf = length of infusion
B. Adjusting maintenance dose using Sawchuk and Zaske's method
Patient specific pharmacokinetic parameters are calculated using the proven
pharmacokinetic method of Sawchuk and Zaske.^{3}
 Determine elimination rate (Kel)
Kel = (ln Cpmax/Cpmin') / time between samples
where Cpmax = Peak level
Cpmin'= Trough after dose
 Determine Volume of distribution (Vd)
VD = [(Dose/tinf) / kel] x (1 e^{Kel x tinf}) / Cpmax  (Cpmin x e^{Kel x t'} )
where Cpmax = Peak levelCpmin = Trough level before the dose
t' = hours between time Cpmin drawn and end of infusion
 Determine ideal dosing interval (tau)
tau = tinf + (1 /Kel) x ln (Cptmax/Cptmin)
where Cptmin = Target trough
Cptmax = Target peak
 Determine ideal maintenance dose (IMD)
IMD = Kel x Vd x Cptmax x (1  e^{Kel x tau} / 1  e^{Kel x tinf})
 User selects practical dosage and interval
 Calculate expected peak & trough levels
CPssmax = (MD / t_{inf }x Vd x Kel ) X (1  e^{Kel x tinf} /1  e^{Kel x tau} )
CPssmin = Peak * e^{Kel x (tau  tinf)}
C. Adjusting maintenance dose using Bayesian 1compartment model
 Minimize Bayesian function
The Bayesian method uses populationderived pharmacokinetic
parameters (ie., Vd and kel) as a starting point and then
adjusts those parameters based on the serum level results, taking
into consideration the variability of the populationderived
parameters and the variability of the drug assay procedure. To
achieve that end, the least squares method based on the Bayesian
algorithm estimates the parameters which minimize the following
function:^{11}
 Determine ideal dosing interval (tau)
Same as Sawchuk and Zaske's method
 Determine ideal maintenance dose
Same as Sawchuk and Zaske's method
 User selects practical dosage and interval
 Calculate expected peak & trough levels
Same as Sawchuk and Zaske's method
D. Extended interval method  Initial dose
 Determine dosing weight (DW)
Same as Sawchuk and Zaske's method
 Determine maintenance dose (MD)
MD = DW x QDdose
where QDdose is:
 Amikacin, kanamycin = 15 mg/kg
 Gentamicin, Tobramycin, Netilmicin = 5 mg/kg
 Determine interval
The initial interval is based on estimated creatinine clearance:
CrCl

Interval

60 and above

24 hours

40 to 59

36 hours

30 to 39

48 hours

Less than 30

Use traditional dosing method

E. Extended interval method  Adjust maintenance dose
 Determine interval
Obtain a midinterval drug level 6 to 16 hours after the initial dose, then
evaluate the level using the interval adjustment nomogram. If the 6 to 16
hour level is undetectable and the infection is not responding, consider
changing to a traditional dosing method.
The three interval break points on the Hartford interval adjustment nomogram (illustrated below) are the
approximate decay curves from a 7mg/kg gentamicin dose. These decay curves were calculated using a one
compartment model with a volume of distribution of 0.25 L/kg and an elimination rate calculated
from creatinine clearances of 25, 40, and 60 ml/min for 48, 36, and 24 hour intervals respectively.
The authors of the Hartford nomogram then flattened these decay curves to simplify the nomogram.
To use the Hartford nomogram for 15mg/kg doses of amikacin, multiply the druglevel scale by a factor of two. ^{5}
It is important to note that the Hartford interval adjustment nomogram is only valid for a
7mg/kg dose. A nomogram for the less aggressive dose of 5mg/kg was developed by a consensus
panel (illustrated below). The consensus panel argues that the 48 hour interval should be abandoned and that patients with
a CrCl less than 40ml/min should be dosed by traditional pharmacokinetic methods. To use the consensus
nomogram for 15mg/kg doses of amikacin, multiply the druglevel scale by a factor of three. ^{20}
The consensus panel also suggests that younger patients with excellent renal function may require Q 12
hour dosing. A 5mg/kg dosing algorithm for this subpopulation has been proposed by Urban and Craig (illustrated below).
To use the Urban and Craig nomogram for 15mg/kg doses of amikacin, multiply the druglevel scale by a factor of three.^{21}
Some have questioned the validity of all ODA nomograms because they are based on onecompartment parameters
derived from traditional dosing methods. Some pk studies have shown that the pharmacokinetics of aminoglycosides
at high doses differ significantly from those at traditional doses. Therefore, it is argued that nomograms based
on an assumption of similar kinetics are invalid.
^{22}
VII. Bibliography
 Devine B.
Gentamicin therapy.
Drug Intell Clin Pharm. 1974;8:650655.
 Sarubbi FA, Hull JW.
Gentamicin serum concentrations: pharmacokinetic predicitions.
Ann Intern Med 1976;85:183189.
[ PubMed ]
 Sawchuk RJ, Zaske DE, Cipolle RJ, Wargin WA, Strate RG.
Kinetic model for gentamicin dosing with the use of individual patient parameters.
Clin Pharmacol Ther 1977;21;3:362369.
[ PubMed ]
 Sarubbi FA, Hull JW.
Amikacin serum concentrations: prediction of levels and dosage guidelines.
Ann Intern Med 1978;89:612618.
[ PubMed ]
 Nicolau DP, Freeman CD, Belliveau PP, Nightingale CH, Ross JW, Quintiliani R.
Experience with a oncedaily aminoglycoside program administered to 2,184 adult patients.
Antimicrob Agents Chemo 1995;29;3:650655.
[ PubMed ]
 Blouin RA, et al.
Tobramycin pharmacokinetics in morbidly obese patients.
Clin Pharmacol Ther 1979;26:508513.
[ PubMed ]
 Bauer LA, et al.
Amikacin pharmacokinetics in morbidly obese patients.
Am J Hosp Pharmacy 1980;37:519522.
 Korsager S.
Administration of gentamicin to obese patients.
Int J Clin Pharmacol Ther Tox 1980;18,12:549553.
[ PubMed ]
 Lesar TS, Rotschafer JC, Strand LM, Solem LD, Zaske DE.
Gentamicin dosing errors with four commonly used nomograms.
JAMA 1982;248(10);11901193.
[ PubMed ]
 Sheiner LB, Beal S.
Bayesian individualization of pharmacokinetics: simple implementation and comparison with nonBayesian methods.
J Pharm Sci 1982 71:13441348.
[ PubMed ]
 Matzke GR, Burkle WS, Lucarotti RL.
Gentamicin and tobramycin dosing guidelines: an evaluation.
Drug Intell Clin Pharm. 1983;17:425432.
 Burton ME, Brater DC, Chen PS, Day RB, Huber PJ, Vasko MR.
A Bayesian feedback method of aminoglycoside dosing.
Clin Pharmacol Ther 37:349357, 1985.
[ PubMed ]
 Burton ME, Chow MS, Platt DR, Day RB, Brater DC, Vasko MR.
Accuracy of Bayesian and SawchukZaske dosing methods for gentamicin.
Clin Pharm 1986;5:143149.
[ PubMed ]
 Fant WK.
Controversies in antimicrobial therapy: Pitfalls in monitoring aminoglycoside therapy.
AJHP 1986:43:641645.
 Chrystyn H.
Validation of the use of Bayesian analysis in the optimization of gentamicin therapy.
Drug Intell Clin Pharm. 1988 22:4953.
[ PubMed ]
 Donahue T, Yates DJ.
Predictability of aminoglycoside serum levels dosed by a pharmacy protocol.
Hospital Pharmacy 1988:23;1125
 Rodvelt KA, Zokufa H, Rotschafer JC.
Aminoglycoside pharmacokinetic monitoring: An integral part of patient care?
Clin Pharm 1988:7:608613.
[ PubMed ]
 Okamoto MP, Chi A, et al.
Comparison of two microcoputer Bayesian pharmacokinetic programs for predicting serum gentamicin concentrations.
Clin Pharm 1990 9:70811.
[ PubMed ]
 Tsubaki T, Chandler MHH.
Evaluating new and traditional methods for aminoglycoside dosing with various degrees of renal function.
Pharmacotherapy 1994; 14:330336.
[ PubMed ]
 Anaizi N. Oncedaily dosing of aminoglycosides.
A consensus document. Int J Clin Pharmacol Ther. 1997 Jun;35(6):2236.
 Urban AW, Craig WA. Daily dosage of Aminoglycosides. Current Clinical Topics in Infectious Diseases Vol 17,
JS Remington & MN Swartz, Eds. Blackwell Science, Malden, MA, 1997.
Full text from ClinRx.Com
 Demczar DJ, Nafziger AN, Bertino JS. Pharmacokinetics of Gentamicin at Traditional versus High
Doses: Implications for OnceDaily Aminoglycoside Dosing. Antimicrob Agents Chemother. 1997 41:11151119.
[ PubMed ]
 Casano RA, Johnson DF, Bykhovskaya Y, Torricelli F, Bigozzi M, FischelGhodsian N.
Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications.
Am J Otolaryngol. 1999 MayJun;20(3):1516.
[ PubMed ]
 Hutchin T, Cortopassi G. Proposed molecular and cellular mechanism for aminoglycoside ototoxicity.
Antimicrob Agents Chemother. 1994 Nov;38(11):251720
Full text from aac.asm.org
 Hain, TC. Bilateral vestibulopathy. July 2007.
 DE Nix, et al.
Antibiotic Tissue Penetration and Its Relevance: Impact of Tissue Penetration on Infection Response.
Antimicrob Agents Chemother. 1991 Oct; 35(10): 1953–1959.
[ PubMed ]
VIII. Recommended Reading
 Ambrose PJ, Winter ME. Aminoglycosides. In: Winter ME. Basic clinical pharmacokinetics, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004.
 Bauer, Larry A. Applied Clinical Pharmacokinetics. McGrawHill. 2001.
 Evans W, Schentag J, Jusko J (eds): Applied Pharmacokinetics 3rd edition. San Francisco, CA. Applied Therapeutics, 1992.
IX. Additional WWW Resouces
