CLINICAL

PHARMACOCINETICS OF
AMINOGLYCOSIDE ANTIBIOTIC

Kelompok 1 (Kelas B)
Fadilla Septria Zelli1411011006
Lili Wahyuni 1411011023
Firlicia Ayuning 1411011024
Octy Aisyahharma 1411011038
Della Sucitra HC 1411011042
THE AMINOGLYCOSIDE
ANTIBIOTICS
The aminoglycoside antibiotics are widely used for the
treatment of severe gram-negative infections such as
pneumonia or bacteremia, often in combination with a
-lactam antibiotic.
Aminoglycosides are also used for gram-positive

infections such as infective endocarditis in combination

with penicillins when antibiotic synergy is required for
optimal killing. Aminoglycoside antibiotics available in
the United States that are in common use include
gentamicin, tobramycin, netilmicin, and amikacin.

(Bauer, 2008)
MECHANISMS OF ACTION

The mechanisms of action for aminoglycosides

are binding to the 30S ribosomal subunit
inhibiting protein synthesis and misreading of
mRNA causing dysfunctional protein production.

(Bauer, 2008)
DRUG INTERACTION
Most important drug interactions are pharmacodynamic,
and not pharmacokinetic, in nature. Vancomycin,
amphotericin B, cyclosporin, and furosemide enhance the
nephrotoxicity potential of the aminoglycosides.
When these drugs are administered concurrently with an

aminoglycoside, serum creatinine concentrations should be

monitored on a daily basis.
Loop diuretics, including furosemide, bumetanide, and
ethacrynic acid, can cause ototoxicity, and an increased
incidence of this adverse effect has been reported when
aminoglycosides have been coadministered.

(Bauer, 2008)
 Aminoglycosides have intrinsic nondepolarizing
neuromuscular blocking activity and may prolong
the effects of neuromuscular blocking agents such
as succinylcholine.
As previously discussed, penicillins (primarily

penicillin G, ampicillin, nafcillin, carbenicillin,

ticarcillin) can inactivate aminoglycosides in vivo
and in blood specimen tubes intended for the
measurement of aminoglycoside serum
concentrations. These two classes of drugs can
also inactive each other in intravenous
administration bags and syringes and should not
be mixed together.

(Bauer, 2008)
THERAPEUTIC AND TOXIC
CONCENTRATIONS
The convensional method of dosing aminoglycoside
antibiotics is to administer multiple daily doses (usually
every 8 hours).
Conventional Dosing

Aminoglycoside antibiotics are given as short-term (1/2

1 hour) infusions.
If a 1-hour infusion is used, maximum end of infusion

peak concentrations are measured when the infusion is

completed.
If a 1/2-hour infusion is used, serum concentrations

exhibit a distribution phase so that drug in the blood and

in the tissues are not yet in equilibrium.

(Bauer, 2008)
 Extended-Interval Dosing
Because aminoglycoside antibiotics exhibit
concentration-dependent bacterial killing and the
postantibiotic effect is longer with higher
concentrations, there is possibility of giving a
higher dose of aminoglycoside once daily. The new
once a day dose has shown almost same desired
and side effect as the conventional dosing.
Extended-interval dosing has been using in
selected patients.
(Bauer, 2008)
 Toxicity among Aminoglycoside
Gentamicin accumulates to a greater extent in kidney
tissue when compared to tobramycin.
Because doses of amikacin are larger than for
gentamicin and tobramycin, amikacin in renal
accumulation must be adjusted for dosage differences.
When this is done, amikacin accumulation patterns
are similar to gentamicin. Based on these
accumulation profiles and associated clinical data and
other trials, some believe that tobramycin is less
nephrotoxic than gentamicin or amikacin.
(Bauer, 2008)
CLINICAL MONITORING
PARAMETERS
Clinicians should always consult the patients
chart to confirm that antibiotic therapy is
appropriate for current microbiologic cultures
and sensitivities
Aminoglycoside steady-state peak and trough
serum concentrations should be measured in 35
estimated half-lives when the drug is given using
conventional dosage approaches.

(Bauer, 2008)
 When extended-interval aminoglycoside therapy
is used, several different monitoring techniques
can be used. Some clinicians measure steady-
state peak and trough concentrations while
others measure two steady-state postdose
concentrations.
Serial monitoring of serum creatinine
concentrations should be used to detect
nephrotoxicity.
In the clinical setting, audiometry is rarely used

to detect ototoxicity because it is difficult to

accomplish in severely ill patients. Instead,
clinical signs and symptoms of auditory or
vestibular ototoxicity are monitored at the same
time intervals as serum creatinine
determination.
CLINICAL PHARMACOKINETICS
PARAMETERS
The aminoglycosides are eliminated almost completely
(90%) unchanged in the urine primarily by glomerular
filtration.
These antibiotics are usually given by short-term (1/21

hour) intermittent intravenous infusions, although they

can be given intramuscularly. When aminoglycosides
are given intramuscularly, they exhibit very good
bioavailability of 100% and are rapidly absorbed with
maximal concentrations occurring about 1 hour after
injection. Exceptions to this situation are patients who
are hypotensive or obese.
(Bauer, 2008)
 Oral bioavailability is poor (<10%) so systemic
infections cannot be treated by this route of
administration. Plasma protein binding is low
(<10%).
Manufacture recommended doses for conventional

dosing in patients with normal renal function are

35 mg/kg/d for gentamicin and tobramycin, 46
mg/kg/d for netilmicin, and 15 mg/kg/d for
amikacin. These amounts are divided into three
equal daily doses for gentamicin, tobramycin, or
netilmicin, or two or three equal daily doses for
amikacin.
(Bauer, 2008)
EFFECTS OF DISEASE STATES AND
CONDITIONS ON AMINOGLYCOSIDE
PHARMACOKINETICS AND DOSING
Disease state and conditions that alter
aminoglycoside pharmacokinetics
(Bauer, 2008)
Initial doses for neonates are based on birth weight
and age
INITIAL DOSAGE DETERMINATION
METHODS
Pharmacokinetics Dosing Method
Hull and Sarubbi Nomogram

Hartford Nomogram

Literature-Based Recommended Dosing

(Bauer, 2008)
PHARMACOKINETICS DOSING
METHOD
Elimination rate constant estimate
Volume of distribution estimate

Selection of appropriate pharmacokinetics model

and equation
Steady state concentration selection

Dosage computation

(Bauer, 2008)
Example
JM is a 50-year-old, 70-kg (5 ft 10 in) male with
gram-negative pneumonia. His current serum
creatinine is 0.9 mg/dL, and it has been stable
over the last 5 days since admission. Compute a
gentamicin dose for this patient using
conventional dosing.

(Bauer, 2008)
1. Estimate creatinine clearance.
.This patient has a stable serum creatinine and is
not obese. The Cockcroft-Gault equation can be
used to estimate creatinine clearance:
CrClest = [(140 age)BW] / (72 SCr)
= [(140 50 y)70 kg] / (72 0.9 mg/dL)
= 97 mL/min
2. Estimate elimination rate constant (ke) and
half-life (t1/2).
ke = 0.00293(CrCl) + 0.014
= 0.00293(97 mL/min) + 0.014 = 0.298 h1
t1/2 = 0.693/ke = 0.693/0.298 h1 = 2.3 h
3. Estimate volume of distribution (V).
The patient has no disease states or conditions
that would alter the volume of distribution from
the normal value of 0.26 L/kg:
V = 0.26 L/kg (70 kg) = 18.2 L
4. Choose desired steady-state serum
concentrations.
Gram-negative pneumonia patients treated with
aminoglycoside antibiotics require steady-state
peak concentrations (Cssmax) equal to 810
g/mL; steady-state trough (Cssmin)
concentrations should be <2 g/mL to avoid
toxicity. Set Cssmax = 9 g/mL and Cssmin = 1
g/mL.
5. Use intermittent intravenous infusion
equations to compute dose
Calculate required dosage interval () using a 1-
hour infusion:
= [(ln Cssmax ln Cssmin) / ke] + t
= [(ln 9 g/mL ln 1 g/mL) / 0.298 h1] + 1 h
= 8.4 h
 Aminoglycoside doses should be rounded to the
nearest 510 mg. This dose would be rounded to
170 mg. (Note: g/mL = mg/L, and this
concentration unit was substituted for Cssmax so
that unnecessary unit conversion was not
required.)
The prescribed maintenance dose would be 170
mg every 8 hours.
6. Compute loading dose (LD), if needed.
Loading doses should be considered for patients
with creatinine clearance values below 60
mL/min.
LD = k0/(1 eke)
= 170 mg / [1 e(0.298 h1)(8 h)] = 187 mg
One compartment model equations used with
aminoglycoside antibiotics

(Bauer, 2008)
Pharmacokinetics constant computations utilizing a one
compartment model for aminoglycoside antibiotics

(Bauer, 2008)
Equations used to compute individualized dosage
regimens for various routes administration used with
aminoglycoside antibiotics

(Bauer, 2008)
HULL & SARUBBI NOMOGRAM
METHOD
For patients who do not have disease states or
conditions that alter volume of distributions, the only
two patient-specific factors that change when using the
pharmacokinetics dosing method is patient weight and
creatinine clearance.
Because of this, it is possible to make a simple

nomogram to handle uncomplicated patients with a

standard volume of distribution.
(Bauer, 2008)
 The Hull & Sarubbi aminoglycoside dosing
nomogram is a quick and efficient way to apply
pharmacokinetic dosing concepts without using
complicated pharmacokinetic equation. With a
simple modification, it can also be used for obese
patients

(Bauer, 2008)
HARTFORD NOMOGRAM
Hartford nomogram for extended-interval dosing
Extended-interval dosing is now a mainstream method
used to administer aminoglycoside antibiotics.
Conventional dosing is still preferred for endocarditis
patients because the aminoglycoside is usually used for
antibiotic synergy.
The Hartford nomogram includes a method to adjust
doses based on gentamicin serum concentration.
(Bauer, 2008)
LITERATURE-BASED
RECOMMENDED DOSING
Because of the large amount of variability in
aminoglycoside pharmacokinetics, even when
concurrent disease states and conditions are
identified, many clinicians believe that the use of
standard aminoglycoside doses for pediatric
patients is warranted.
The original computation of these does was based

on the pharmacokinetics dosing methods

described in the previous section, and
subsequently modified based on clinical
experience.
(Bauer, 2008)
 In general, the expected aminoglycoside steady
state serum concentration used to compute these
doses were similar to those for adults given
conventional dosing.
Suggested initial aminoglycoside doses for
various pediatric patients are listed in the Effects
of Disease States and Conditions on
aminoglycoside pharmacokinetics & Dosing
section
(Bauer, 2008)
USE OF AMINOGLYCOSIDE
SERUM CONCENTRATIONS TO
ALTER DOSAGES
LinearPharmacokinetics Method
Sawchuk-Zaske Method

Area Under the Curve Method

(Bauer, 2008)
LINEAR PHARMACOKINETICS METHOD

Because aminoglycoside antibiotics follow linear,

dose-proportional pharmacokinetics, steady-state
serum concentrations change in proportion to
dose according to the following equation: Dnew /
Css,new = Dold / Css,old or Dnew = (Css,new /
Css,old)Dold, where D is the dose,Css is the
steady-state peak or trough concentration.
Example
JM is a 50-year-old, 70-kg (5 ft 10 in) male
with gram-negative pneumonia. His current
serum creatinine is 0.9 mg/dL, and it has been
stable over the last 5 days since admission. A
gentamicin dose of 170 mg every 8 hours was
prescribed and expected to achieve steady-state
peak and trough concentrations equal to 9
g/mL and 1 g/mL, respectively. After the
third dose, steady-state peak and trough
concentrations were measured and were 12
g/mL and 1.4 g/mL, respectively. Calculate a
new gentamicindose that would provide a
steady-state peak of 9 g/mL.
1. Estimate creatinine clearance.
CrClest = [(140 age)BW] / (72 SCr)
= [(140 50 y)70 kg] / (72 0.9 mg/dL)
= 97 mL/min
2. Estimate elimination rate constant (ke) and half-
life (t1/2).
ke = 0.00293(CrCl) + 0.014
= 0.00293(97mL/min) + 0.014 = 0.298 h1
t1/2 = 0.693 / ke = 0.693 / 0.298 h1 = 2.3 h
3. Compute new dose to achieve desired
serum concentration.
Dnew = (Css,new / Css,old)Dold
= (9 g/mL / 12 g/mL) 170 mg = 128 mg,
round to 130 mg
The new suggested dose would be 130 mg every
8 hours to be started at next scheduled dosing
time.
4. Check steady-state trough concentration
for new dosage regimen.
Css,new = (Dnew / Dold)Css,old
= (130 mg / 170 mg) 1.4 g/mL = 1.1
g/mL
SAWCHUK-ZASKE METHOD
The sawchuk-zaske method of adjusting
aminoglycoside doses was among the first
techniques available to change doses using serum
concetrations.
The standard sawchuk-zaske method conduct a
small pharmacokinetics experiment using 3-4
aminoglycoside serum concetrations obtained
during a dosage interval and does not require
steady state conditions.
(Bauer, 2008)
The equation

= [(ln Cssmax ln Cssmin) / ke] + t

Where, C1 is the first measured steady-state
concentration
ke is the elimination rate constant,

C2 is the second measured steady-state

concentration
D is the aminoglycoside dose

t is the infusion time

Cssmax is the steady-state peak concentration, and

Cssmin is the steady-state trough concentration.

AREA UNDER THE CURVE METHOD

Most often, the AUC method is used with extended-

interval aminoglycoside dosing.
Different therapeutic AUC values have been suggested
by various investigations studying this dosing method.

(Bauer, 2008)
DOSING STRATEGIES
Initial dose and dosage adjustment techniques using
serum concentrations can be used in any combination
as long as the limitations of each method are observed.
Some dosing approaches link together logically when
considered according to their basic approaches or
philosophies.
Dosage strategies that follow similar pathways are

given in Tables 4-5A and 4-5B

(Bauer, 2008)
SPECIAL DOSING CONSIDERATIONS
Hemodialysis Dosing
Aminoglycoside antibiotics are eliminated by
dialysis, so renal failure patients receiving
hemodialysis must have aminoglycoside dosage
regimens that take dialysis clearance into
account.
 Use of Aminoglycoside Serum
Concentrations to Alter Dosages
The intradialysis elimination rate constant can
be determined by obtaining postdose
(Cpostdose(1)) and predialysis (Cpredialysis)
concentrations [ke = (Cpostdose(1)
Cpredialysis) / t, where t is the time between
the two concentrations], the fraction of drug
eliminated by dialysis can be computed using
predialysis and postdialysis (Cpostdialysis)
concentrations (fraction eliminated =
[(Cpredialysis Cpostdialysis) / Cpredialysis],
and the volume of distribution can be calculated
using postdialysis and postdose concentrations [V
= D / (Cpostdose(2) Cpredialysis)].
Once individualized pharmacokinetic parameters
have been measured, they can be used in the
same equations used to compute initial doses in
the previous section in place of average,
population pharmacokinetic parameters and used
to calculate individualized doses for dialysis
patients. For instance, a clinician may wish to
measure the elimination rate constant or volume
of distribution for a patient, but elect to use an
average population estimate for fraction of drug
removed by the artificial kidney.
REFERENCE
Bauer,L.A. 2008. Applied Clinical
Pharmacokinetics Second Edition. New
York: Mc Graw Hill Companies
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