Group 1 Topic 1

Nadya Prafita (1511011007)

 is the discipline that applies pharmacokinetic concepts and principles in
humans in order to design individualized dosage regimens which optimize
the therapeutic response of a medication while minimizing the chance of an
adverse drug reaction
 Pharmacokinetics  absorption, distribution, metabolism, and excretion of
drugs

(Bauer, 2008: 4)
 The aminoglycoside antibiotics are widely used for the treatment of severe
gram-negative infections such as pneumonia or bacteremia, often in
combination with a β-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 are bactericidal, and the drugs exhibit
concentration dependent bacterial killing
 Antibiotics with concentration-dependent killing characteristically kill
bacteria at a faster rate when drug concentrations are higher

(Bauer, 2008:97)
 Aminoglycosides have a concentration-dependent postantibiotic effect.
 The postantibiotic effect is the phenomenon of continued bacterial killing
even though serum concentrations have fallen below the minimum
inhibitory concentration (MIC).
 Because the postantibiotic effect is concentration-dependent for the
aminoglycosides, higher drug concentrations lead to a longer postantibiotic
effect.
 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, 2008:97)
 The MIC for susceptible bacteria is higher for amikacin than it is for the other
aminoglycosides.
 Because the pharmacokinetics is similar for all these drugs, higher doses of
amikacin are needed to treat infections.
 The conventional method of dosing aminoglycoside antibiotics is to administer
multiple daily doses (usually every 8 hours).2 In order to take advantage of
concentration-dependent bacterial killing and the postantibiotic effect, extended-
interval (usually the total daily dose given once per day) aminoglycoside
administration is also a dosing option.
 Because of these two different methods of dosage administration, it is important to
identify which is being used when discussing serum concentration monitoring.

(Bauer, 2008:97)
 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.
 Because of this, a 1/2-hour waiting period is allowed for distribution to
finish if a 1/2-hour infusion is used before peak concentrations are
measured.

(Bauer, 2008:98)
 Therapeutic steadystate peak concentrations for gentamicin, tobramycin,
and netilmicin are generally 5–10 μg/mL for gram-negative infections.
 Infection sites with more susceptible bacteria, such as intraabdominal
infections usually can be treated with steady-state peak concentrations at
the lower end of this range (typically 5–7 μg/mL).
 Infection sites that are difficult to penetrate and with bacteria that have
higher MIC values, such as pseudomonal pneumonia usually require
steady-state peak concentrations in the higher end of the range (typically
8–10 μg/mL).
 When gentamicin, tobramycin, or netilmicin are used synergistically with
penicillins or other antibiotics for the treatment of gram-positive infections
such as infective endocarditis steady-state peak concentrations of 3–5
μg/mL are often times adequate.
 Therapeutic peak concentrations for amikacin are 15–30 μg/mL
 Exceeding peak steady-state concentrations of 12–14 μg/mL for
gentamicin, tobramycin, or netilmicin or 35–40 μg/mL for
amikacin when using conventional dosing leads to an increased
risk of ototoxicity.
 The types of ototoxicity that aminoglycosides cause are auditory
and vestibular, and the damage is permanent.
 Aminoglycosides accumulate in the lymph of the inner ear
causing ongoing damage to cochlear or vestibular sensory cells.

(Bauer, 2008:99)
 Aminoglycoside antibiotics exhibit concentration-dependent bacterial
killing and the postantibiotic effect is longer with higher concentrations
 investigators began studying the possibility of giving a higher dose of
aminoglycoside once daily
 these studies have shown comparable microbiologic and clinical cure rates
for many infections and about the same rate of nephrotoxicity (~5–10%) as
with conventional dosing.
 Auditory ototoxicity has not been monitored using audiometry in most of
these investigations, but loss of hearing in the conversational range as well
as signs and symptoms of vestibular toxicity have usually been assessed
and found to be similar to aminoglycoside therapy dosed conventionally.
 Based on this data, clinicians have begun using extended-interval dosing in
selected patients.

(Bauer, 2008:100)
 Because of the extremely high peak concentrations obtained during
extended-interval dosing of aminoglycosides, it can be difficult to
understand why increased toxicity is not seen in patients.
 The hypothesized reason is that both nephrotoxicity and ototoxicity are due
to accumulation of aminoglycoside in the relevant tissue.
 Because the dosage interval is prolonged in extended-interval
administration, aminoglycoside concentrations are low for a long period of
time and may allow for diffusion of drug out of tissue and into the blood
which avoids drug accumulation in the ear and kidney.
 Also, some of the uptake mechanisms into the ear and kidney may be
saturable, so that high peak serum concentrations of aminoglycosides may
not result in high renal or ear tissue concentrations.
 Because of the high peak concentrations achieved using extended-interval
dosing, surgical and intensive care patients should be monitored for this
possible adverse effect.

(Bauer, 2008:100)
 The aminoglycosides are eliminated almost completely (≥90%) unchanged
in the urine primarily by glomerular filtration
 These antibiotics are usually given by short-term (1/2–1 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, 2008:102)
 Manufacture recommended doses for conventional dosing in patients with
normal renal function are
◦ 3–5 mg/kg/d for gentamicin and tobramycin,
◦ 4–6 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.
 Extended-interval doses obtained from the literature for patients with
normal renal function are
◦ 4–7 mg/kg/d for gentamicin, tobramycin, or netilmicin
◦ 11–20 mg/kg/d for amikacin.

(Bauer, 2008:102)
a. The pharmacokinetic dosing method is the most flexible of the
techniques.
 It allows for individualized target serum concentrations to be chosen for a
patient, so it can be used for both conventional and extended-interval
dosing. Also, each pharmacokinetic parameter can be customize to reflect
specific disease states and conditions present in the patient
b. The Hull and Sarubbi nomogram uses the dosing concepts in the
pharmacokinetic dosing method  target concentration ranges
consistent with conventional dosing only, fixed volume of distribution
parameter in the normal range, limited dosage interval selection (no
longer than 24 hours).
 Thus, 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.

(Bauer, 2008:110)
c. The Hartford nomogram has similar strengths and weaknesses when
compared to the Hull and Sarubbi nomogram, but is designed for use
when extendedinterval dosing is desired.
 This nomogram also incorporates a method to adjust aminoglycoside
doses based on serum concentration feedback.
d. Literature-based recommended dosing is a commonly used method to
prescribe initial doses of aminoglycosides to pediatric patients.
 Doses are based on those that commonly produce steady-state
concentrations within the therapeutic range, although there is a wide
variation in the actual concentrations for a specific patient.

(Bauer, 2008:110)
 The goal of initial dosing of aminoglycosides is to compute the
best dose possible for the patient given their set of disease states
and conditions that influence aminoglycoside pharmacokinetics
and the site and severity of the infection.
 In order to do this, pharmacokinetic parameters for the patient
will be estimated using average parameters measured in other
patients with similar disease state and condition profiles

(Bauer, 2008:110)
 Aminoglycosides are almost totally eliminated unchanged in the urine, and
there is a good relationship between creatinine clearance and aminoglycoside
elimination rate constant
 This relationship allows the estimation of the aminoglycoside elimination rate
constant for a patient which can be used to compute an initial dose of the
antibiotic.
K e  0.0293(CrCl )  0.014
Ke = aminoglycside elimination rate constant in h-1
CrCl = creatinine clearance in mL/min

 A limitation in using elimination rate constant as the elimination parameter in

this relationship is that it is a hybrid pharmacokinetic constant whose value
can be influenced by either clearance or volume of distribution (ke = Cl/V).

(Bauer, 2008:110)
 Because gentamicin, tobramycin, netilmicin, and amikacin have similar
pharmacokinetic properties, the same elimination rate constant versus
creatinine clearance relationship can be used for all of the antibiotics.
 For example, the estimated elimination
 rate constant for an individual with a creatinine clearance of 10 mL/min is
0.043 h−1 which yields an estimated half-life of 16 hours
 [ke = 0.00293(CrCl) + 0.014 = 0.00293 ⋅ (10 mL/min) + 0.014 = 0.043 h−1;
t1/2 = 0.693/(0.043 h−1) = 16 h].
 Taking the patient’s renal function into account when deriving initial doses
of aminoglycoside antibiotics is the single most important characteristic to
assess.

(Bauer, 2008:111)
 The average volume of distribution for patients without disease states and
conditions that change this parameter is 0.26 L/kg.
 Thus, for a nonobese 70-kg patient, the estimated volume of distribution
would be 18.2 L (V = 0.26 L/kg ⋅ 70 kg = 18.2 L).
 If a patient weighs less than their ideal body weight, actual body weight is
used to estimate volume of distribution.
 For patients whose weight is between their ideal body weight and 30%
over ideal weight, actual body weight can be used to compute estimated
volume of distribution, although some clinicians prefer to use ideal body
weight for these individuals.

(Bauer, 2008:111)
 In patients who are more than 30% above their ideal body
weight, volume of distribution (V) estimates should include
both ideal and actual total body weighs using the following
equation:
 V = 0.26[IBW + 0.4(TBW − IBW)]
V = Volume of distribution,
IBW = ideal body weight in kilograms,
TBW= total body weight in kilograms.

(Bauer, 2008:111)
 in patients who are overhydrated or have ascites, their dry body weight
(weight without the extra fluid) can be used to provide an improved
volume of distribution estimate (V in L) using the following formula:
 V = (0.26 ⋅ DBW) + (TBW − DBW)

DBW = the patient’s dry body weight

TBW = the patient’s actual total body weight.

(Bauer, 2008:111)
 When given by intravenous injection over less than 1 hour,
aminoglycosides follow a threecompartment pharmacokinetic model
 After the end of infusion, serum concentrations drop rapidly because of
distribution of drug from blood to tissues (α or distribution phase).
 If aminoglycosides are infused over 1 hour, the distribution phase is not
usually observed.

(Bauer, 2008:112)
 intravenously administered aminoglycosides are given over 1/2–1 hour as
intermittent continuous infusions.
 Generally, infusion equations should be used if the patient has a creatinine
clearance greater than 30 mL/min.
 For creatinine clearances of 30 mL/min or less, very little aminoglycoside
is eliminated during infusion and waiting period times, and intravenous
bolus equations accurately compute peak concentrations.

(Bauer, 2008:112)
 Aminoglycoside steady-state peak (Cssmax) and trough (Cssmin) serum
concentrations are chosen to treat the patient based on the type, site, and
severity of infection as well as the infecting organism.
 Steady-state versions of one-compartment model intermittent intravenous
infusion

 
Cssmax  k0 / k eV  1  e  k et ' / 1  e  k e 
 
 ke  t ' 
C min ss  C max ss
k0 = the infusion rate
ke = the elimination rate constant
V = the volume of distribution,
t =the drug infusion time
τ = the dosage interval

(Bauer, 2008:112)
 Intravenous bolus

 
Cssmax  D / V  e  k et / 1  e  k e 
D = the antibiotic dose
k 
V = the volume of distribution Cssmax  Cssmax e e
Ke= the elimination rate constant,
t =the time Cssmax was measured
τ = the dosage interval
 equations are chosen based on the patient’s renal function to compute the
required doses needed to achieve desired aminoglycoside concentrations.
 Note that intermittent intravenous infusion equations will work well
regardless of the patient’s creatinine clearance.
 However, the intravenous bolus equations are easier to solve, save time,
and are less likely to invoke a computational error

(Bauer, 2008:112)
 Aminoglycoside peak steady-state concentrations are selected based on site
and severity of infection as well as the infecting organism.
 Severe infections, such as gram-negative pneumonia or septicemia, or
infections with organisms that have a high minimum inhibitory
concentration (MIC) such as Pseudomonas aeruginosa (typical MIC ≈ 2
μg/mL for gentamicin, tobramycin, or netilmicin) generally require peak
steady-state serum concentrations of 8–10 μg/mL for gentamicin,
tobramycin, or netilmicin or 25–30 μg/mL for amikacin when using
conventional dosing.
 Moderate infections at sites that are easier to penetrate or with organisms
that display lower MIC values, such as intraabdominal infections are
usually treated with peak gentamicin, tobramycin, or netilmicin steady-
state serum concentrations equal to 5–7 μg/mL or with amikacin peak
steady-state serum concentrations equal to 15–25 μg/mL.

(Bauer, 2008:113)
 Similar target peak steady-state concentrations for extended-interval
aminoglycoside dosing are less established although concentrations 20–30
μg/mL have been suggested for Pseudomonas aeruginosa and other serious
infections including pulmonary exacerbations in cystic fibrosis patients.
 Desirable concentrations for steady-state trough concentrations are chosen
based on avoidance of potential toxicity.
 For conventional dosing, steady-state trough concentrations should be
maintained <2 μg/mL for tobramycin, gentamicin, and netilmicin or <5–7
μg/mL for amikacin.
 Using extended-interval dosing, steady-state trough concentrations should
be <1 μg/mL for gentamicin, tobramycin, and netilmicin.

(Bauer, 2008:113)
 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, 2008:113)
 Patient has a stable Scr and not obese.
 The Cockcroft-Gault equation can be used to estimate Clcr:
 CrClest = [(140−age)BW]/(72*SCr)
= [(140−50y)70kg]/(72*0.9 mg/dL)
= 97mL/min

(Bauer, 2008:113)
(Bauer, 2008:114)
 ke vs Crcl relationship is used to estimate the gentamicin
elimination rate for this patient:
 ke = 0.00293(CrCl) + 0.014
= 0.00293(97 mL/min) + 0.014
= 0.298 h−1

 t1/2 = 0.693/ke
= 0.693/0.298 h−1 = 2.3 h
 The patient has no disease states or conditions that would
alter the Vd from the normal value of 0.26 L/kg
V = 0.26 L/kg (70 kg) = 18.2 L

To avoid toxicity
 Gram (-) pneumonia patients treated with AMG require:
Steady-State peak conc (Cssmax) : 8–10μg/mL
Steady-State trough conc (Cssmin): <2μg/mL

 Set Cssmax = 9 μg/mL

Cssmin = 1 μg/mL
To avoid toxicity
 Gram (-) pneumonia patients treated with AMG require:
SS peak conc (Cssmax) : 8–10μg/mL
SS trough conc (Cssmin) : <2μg/mL

 Set Cssmax = 9 μg/mL

Cssmin = 1 μg/mL
 Calculate required dosage interval (τ) using a 1-hour infusion:

  ln Cssmax  ln Cssmin / ke   t

= [(ln 9 μg/mL−ln 1μg/mL) / 0.298 h−1] + 1h
= 8.4h
 Dosage intervals should be rounded to clinically acceptable intervals
of 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 72
hours, and multiples of 24 hours thereafter,whenever possible.
 In this case, the dosage interval would be rounded to 8 hours.
 steady-state peak concentrations are similar if drawn immediately
after a 1-hour infusion or 1/2 hour after a 1/2-hour infusion, so the
dose could be administered either way.
  
k0  Cssmax keV 1  e  k e / 1  e  k et ' 
1

k0  (9mg / L .0,298 h . 18,2L) 1  e  
 0.298h 1 8 h 
/1 e  
 0.298h 1 1h 
 172mg
 Aminoglycoside doses should be rounded to the nearest 5–10 mg. This
dose would be rounded to 170 mg. (Note: μg/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.