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AMINOGLYCOSIDE DOSAGE

ADJUSTMENT
Group 4 :
Florence Clay Mora Sirait 1411011050
Puji Rahmi Sumarno 1411011051
Katrin Dayatri 1411011052
Dyra Eka Aulia Khaidir 1411011055
Ghina Fadhilah 1411011068
INTRODUCTION

Widely used for the treatment of severe gram-negative infections e.g.


pneumonia or bacteremia in combination with a -lactam antibiotic.
Also used for gram-positive infections e.g. infective endocarditis in
combination with penicillins
Common use gentamicin, tobramycin, netilmicin, and amikacin
Bactericidal, concentration dependent bacterial killing
Mechanism of action are binding to the 30S ribosomal subunit inhibiting
protein synthesis and misreading of mRNA causing dysfunctional protein
production
THERAPEUTIC AND TOXIC
CONCENTRATION

The conventional dosing : multiple daily doses (usually every 8 hours)


Due to its concentration-dependent bacterial killing : usually the total daily
dose given once per day (Extended-Interval Dosing)
Steady state conc. :
generally 510 g/mL (gram-negative infections)
57 g/mL (more susceptible bacteria: intra abdominal)
810 g/mL (for area that difcult to penetrate such as pseudomonal pneumonia)
35 g/mL (for combination treatment e.g. w/ penicilin for endocarditis treatment)
Amikacin: 1530 g/mL
THERAPEUTIC AND TOXIC
CONCENTRATION (cont.)

Exceeding peak steady-state conc. (> 1214 g/mL or 3540 g/mL for
amikacin) leads to an increased risk of ototoxicity (permanent auditory and
vestibular damage)
Aminoglycosides accumulate in the lymph of the inner ear causing ongoing
damage to cochlear or vestibular sensory cells
Difficult to early detect
Audiometry is required to detect high-tone hearing loss
The rst sign of auditory ototoxicity is tinnitus. Vestibular ototoxicity results
in the loss of balance, headache, ataxia, nausea, vomiting, nystagmus, and
vertigo.
THERAPEUTIC AND TOXIC
CONCENTRATION (cont.)

Trough steady state conc. above 23 g/mL or 10 g/mL for amikacin will lead
to nephrotoxicity
Aminoglycoside accumulate in the proximal tubular cells decrease the
ability of the kidney to concentrate urine decrease glomerular ltration
Occur before 35 days of therapy with proper dosing of the antibiotic
Patient usually critically ill, other sources of nephrotoxicity e.g. hypotension,
etc should be ruled out
Usually reversible
THERAPEUTIC AND TOXIC
CONCENTRATION (cont.)

Extended-Interval Dosing
Nephrotoxicity and ototoxicity also occurred just like conventional dosing bu
there is no increasing risk of toxicity
Using of this method only for selected patients such us Pseudomonas
aeruginosa infections where the organism has an expected MIC 2 g/mL,
peak concentrations between 20 and 30 g/mL and trough concentrations <1
g/mL
Differential Toxicity Among Aminoglycosides
Some clinicians believe that tobramycin is less nephrotoxic than gentamicin
or amikacin
CLINICAL MONITORING
PARAMETERS

Clinicians should always monitored patients condition and drug conc. in


plasma
In conventional dosage approaches, Aminoglycoside steady-state peak and
trough serum concentrations should be measured in 35 estimated half-lives
In extended-interval approaches serum concentrations measured after the
third dose
Serial monitoring of serum creatinine concentrations should be used to detect
nephrotoxicity
Clinical signs and symptoms of auditory or vestibular ototoxicity are also
monitored
EFFECTS OF DISEASE STATES AND CONDITIONS
ON AMINOGLYCOSIDE PHARMACOKINETICS AND
DOSING
INITIAL DOSAGE DETERMINATION
METHODS

The Pharmacokinetic Dosing Method


It can be used for both conventional and extended-interval dosing.
Pharmacokinetic parameters for the patient will be estimated using average
parameters measured in other patients with similar disease state and condition
proles
ELIMINATION RATE CONSTANT ESTIMATE
We can estimate K el by analyze relationship between creatinine clearance and
aminoglycoside elimination rate constant.
k el = 0.00293(CrCl) + 0.014
Every drugs in Aminoglycoside groups have similar pharmacokinetic properties, the same
elimination rate constant versus creatinine clearance relationship can be used for all of the
antibiotics.
INITIAL DOSAGE DETERMINATION
METHODS (cont.)

VOLUME OF DISTRIBUTION ESTIMATE


The average Vd for normal patients is 0.26 L/kg
For obese patients V = 0.26[IBW + 0.4(TBW IBW)]
For overhydrated or ascites patient V = (0.26 DBW) + (TBW DBW)
For patient with other disease conditions Vd values followed the parameter
given in Table 4-1
INITIAL DOSAGE DETERMINATION
METHODS (cont.)

STEADY-STATE CONCENTRATION SELECTION


Selected based on site and severity of infection as well as the infecting
organism
generally 510 g/mL (gram-negative infections)
57 g/mL (more susceptible bacteria: intra abdominal)
810 g/mL (for area that difcult to penetrate such as pseudomonal
pneumonia)
35 g/mL (for combination treatment e.g. w/ penicilin for endocarditis
treatment)
Amikacin: 1530 g/mL
INITIAL DOSAGE DETERMINATION
METHODS (cont.)

DOSAGE COMPUTATION
INITIAL DOSAGE DETERMINATION
METHODS (cont.)

Hull and Sarubbi Nomogram


Method
it should be used only in patients who only
have renal dysfunction and/or obesity as
complicating factors and only when
conventional dosing is to be used
1. Compute patients creatinine clearance
(CrCl) using Cockcroft-Gault method. Use
Salazar-Cocoran method if weight >30%
above IBW 4. Select maintenance dose (as percentage of
2. Use patients weight if within 30% of IBW, loading dose) to continue peak serum
otherwise use adjusted dosing weight concentrations indicated above according to
=IBW+[0.40(TBW IBW)] desired dosage interval and the patients
3. Select loading dose in mg/kg to provide creatinine clearance. To maintain usual
peak serum concentrations in range listed peak/trough ratio, use dosage intervals in clear
below for the desired aminoglycoside areas.
antibiotic:
INITIAL DOSAGE DETERMINATION
METHODS (cont.)

Hartford Nomogram Method


for Extended-Interval Dosing
is designed for use when extended
interval dosing is desired. This
nomogram also incorporates a
method to adjust aminoglycoside
doses based on serum
concentration feedback
Extended-interval doses obtained
from the literature for patients with
normal renal function are 47
mg/kg/d for gentamicin,
tobramycin, or netilmicin and 1120
mg/kg/d for amikacin
INITIAL DOSAGE DETERMINATION
METHODS (cont.)
Literature-based
recommended dosing
is a commonly used method to prescribe
initial doses of aminoglycosides to
pediatric patients
If serum creatinine values are available,
estimated creatinine clearance can be
computed using equations that are
specic for pediatric patients
age 01 year, CrClest = (0.45 Ht) / SCr
age 120 years, CrClest = (0.55 Ht) / SCr
Doses for infants and children are:
amikacin 1522.5 mg/kg/d IV or IM given
every 8 hours, gentamicin or tobramycin
7.5 mg/kg/d IV or IM given every 8 hours
USE OF AMINOGLYCOSIDE SERUM
CONCENTRATIONS TO ALTER
DOSAGES

Aminoglycoside serum concentrations are measured in many patients to ensure that


therapeutic, nontoxic levels are present.
However, not all patients may require serum concentration monitoring e.g. the case
for surgical prophylaxis
Important patient parameters (fever curves, white blood cell counts, serum creatinine
concentrations, etc.) should be followed
How to alter the dosages:
simple dosage ratio follow linear pharmacokinetics
pharmacokinetic concepts
Sawchuk-Zaske method
area under the concentration-time curve
Bayesian pharmacokinetic computer programs
Linear Pharmacokinetics Method

D new / Css,new = Dold / Css,old or D new = (Css,new / Css,old) D


old,
where D is the dose, Cs
The advantages of this method are that it is quick and simple. The
disadvantages are steady-state concentrations are requireds is the steady-
state peak
Pharmacokinetic Concepts Method

The following steps are used to compute


new aminoglycoside doses:
1. Draw a rough sketch of the serum log
concentration/time curve by hand,
keeping tract of the relative time
between the serum concentrations
(Figure 4-5).
2. Since the patient is at steady state,
the trough concentration can be
extrapolated to the next trough value
time (Figure 4-5).
3. Draw the elimination curve between
the steady-state peak concentration
and the extrapolated trough
concentration. Use this line to
estimate half-life.
Sawchuk-Zaske Method

STANDARD SAWCHUK-ZASKE METHOD


The standard version of the Sawchuk-Zaske method does not require steady-state
concentrations

STEADY-STATE SAWCHUK-ZASKE METHOD: PEAK/TROUGH VERSION


If a steady-state peak and trough aminoglycoside concentration pair is available for a
patient
Area Under the Curve Method

Recommended method
Usually, the AUC method is used with extended-interval aminoglycoside dosing
The steady-state area under the concentration-time curve during the dosage interval
(AUCss) is computed using the following equation

The dose is adjusted to attain the target AUCss using linear pharmacokinetics:
D new = (AUCss,new / AUCss,old) D old
BAYESIAN PHARMACOKINETIC COMPUTER
PROGRAMS

The most reliable computer programs use a nonlinear regression algorithm that incorporates
components of Bayes theorem
Briey, the patients drug dosage schedule and serum concentrations are input into the
computer.
The computer program has a pharmacokinetic equation preprogrammed for the drug and
administration method (oral, intravenous bolus, intravenous infusion, etc.).
Typically, a one-compartment model is used, although some programs allow the user to
choose among several different equations.
Using population estimates based on demographic information for the patient (age, weight,
gender, renal function, etc.) supplied by the user, the computer program then computes
estimated serum concentrations at each time there are actual serum concentrations.
Kinetic parameters are then changed by the computer program, and a new set of estimated
serum concentrations are computed
These pharmacokinetic parameters can then be used to compute improved dosing schedules
for patients
REFFERENCE

Bauer, Larry A. 2008. Applied Clinical Pharmacokinetics. USA: McGraw Hill Companies