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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
(Bauer, 2008)
MECHANISMS OF ACTION
(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
(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
(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
(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
Hartford Nomogram
(Bauer, 2008)
PHARMACOKINETICS DOSING
METHOD
Elimination rate constant estimate
Volume of distribution estimate
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
(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
(Bauer, 2008)
LINEAR PHARMACOKINETICS METHOD
concentration
D is the aminoglycoside dose
(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