A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Pediatric Gentamicin Pharmacology, Pharmacokinetics, Studies, Metabolism - Pediatric Gentamicin
Pediatric Gentamicin Pharmacology, Pharmacokinetics, Studies, Metabolism - Pediatric Gentamicin
CLINICAL PHARMACOLOGY
After Intramuscular administration
of Pediatric Gentamicin Sulfate Injection, peak serum
concentrations usually occur between 30 and 60 minutes and serum
levels are measurable for 6 to 12 hours. In
infants, a single dose
of 2.5 mg/kg usually provides a peak serum
level in the range of
3 to 5 mcg/mL. When gentamicin
is administered by intravenous
infusion over a two-hour
period, the serum concentrations
are similar to those obtained by intramuscular administration. Age
markedly affects the peak concentrations: In
one report, a 1 mg/kg dose
produced mean peak concentrations
of 1.58, 2.03, and 2.81 mcg/mL in patients 6 months to 5 years old,
5 to 10 years old, and over 10 years old, respectively.
In infants one week to six months of age, the half-life
is 3 to 3½ hours. In
full-term and large premature
infants less than one weak
old, the approximate
serum half-life
of gentamicin is
5½ hours. In small,
premature infants, the half-life
is inversely related to birth
weight. In premature
infants weighing less than 1500 grams, the half-life
is 11½ hours; in those weighing 1500 to 2000 grams, the half-life
is 8 hours; in those weighing over 2000 grams, the half-life
is approximately 5 hours. While some variation
is to be expected due to a number
of variables such as age, body
temperature, surface
area and physiologic differences,
the individual patient
given the same dose tends
to have similar levels in repeated determinations.
Gentamicin, like all aminoglycosides, may accumulate in the serum
and tissues of patients treated with higher doses and for prolonged
periods, particularly in the presence of impaired or immature
renal function. In patients
with immature or impaired
renal function, gentamicin
is cleared from the body
more slowly than in patients with normal
renal function. The more
severe the impairment,
the slower the clearance. (Dosage must be adjusted.)
Since gentamicin
is distributed in extracellular
fluid, peak serum
concentrations may be lower than usual in patients who have a large
volume of this fluid.
Serum concentrations of gentamicin
in febrile patients
may be lower than those in afebrile
patients given the same dose. When body
temperature returns
to normal, serum
concentrations of the drug
may rise. Febrile and anemic states may be associated with a shorter
than usual serum half-life.
(Dosage adjustment is usual ly not necessary.) In
severely burned patients, the half-life may be significantly decreased
and resulting serum concentrations
may be lower than anticipated from the mg/kg dose.
Protein binding studies have indicated that the degree
of gentamicin binding is low; depending upon the methods used for
testing, this may be between 0 and 30%.
In neonates less than 3 days old, approximately 10% of the administered
doses is excreted in 12 hours; in infants 5 to 40 days old, approximately
40% is excreted over the same period. Excretion of gentamicin
correlates with postnatal
age and creatinine
clearance. Thus, with increasing postnatal age and concomitant
increase in renal maturity,
gentamicin is excreted
more rapidly. Little, if any, metabolic transformation
occurs; the drug is excreted principally by glomerular
filtration. After several days of treatment, the amount of gentamicin
excreted in the urine
approaches, but does not equal, the daily dose
administered. As with other
aminoglycosides, a small amount of the gentamicin
dose may be retained in
the tissues, especially in the kidneys. Minute quantities of aminoglycosides
have been detected in the urine
of some patients weeks after drug
administration
was discontinued. Renal clearance
of gentamicin is
similar to that of endogenous
creatinine.
In patients with marked impairment
of renal function, there
is a decrease in the concentration
of aminoglycosides in urine
and in their penetration into defective
renal parenchyma. This
decreased drug excretion,
together with the potential
nephrotoxicity of aminoglycosides, should be considered when treating
such patients who have
urinary tract
infections. Probenecid does not affect
renal tubular
transport of gentamicin.
The endogenous creatinine
clearance rate
and the serum creatinine
level have a high correlation
with the half-life
of gentamicin in
serum. Results of these tests may serve as guides for adjusting
dosage in patients with
renal impairment
(see DOSAGE AND ADMINISTRATION).
Following parenteral
administration, gentamicin
can be detected in serum, lymph, tissues, sputum,
and in pleural, synovial, and peritoneal
fluids. Concentrations in renal
cortex sometimes may
be eight times higher than the usual serum
levels. Concentrations in bile, in general, have been low and have
suggested minimal biliary
excretion. Gentamicin crosses the peritoneal as well as the placental
membranes. Since aminoglycosides diffuse
poorly into the subarachnoid
space after parenteral
administration, concentrations of gentamicin
in cerebrospinal
fluid are often low and
dependent upon dose, rate of penetration, and degree
of meningeal infl ammation. There is minimal penetration of gentamicin
into ocular tissues following
intramuscular
or intravenous administration.
MICROBIOLOGY
In vitro tests have demonstrated that gentamicin
is a bactericidal antibiotic which acts by inhibiting normal
protein synthesis
in susceptible microorganisms. It is active against a wide variety
of pathogenic bacteria including Escherichia
coli, Proteus species
(indole-positive and Indole-negative), Pseudomonas aeruginosa,
species of the Klebsiella-Enterobacter-Serratia
group, Citrobacter species
and Staphylococcus species
(including penicillin- and methicillin-resistant strains).
Gentamicin is also active in vitro against species
of Salmonella and Shigella, The following bacteria
are usually resistant to aminoglycosides: Streptococcus pneumoniae,
most species of streptococci
, particularly group D and anaerobic
organisms, such as Bacteroides
species or Clostridium
species.
In vitro studies have shown that an aminoglycoside
combined with an antibiotic
that interferes with cell
wall synthesis
may act synergistically
against some group D streptococcal
strains. The combination of gentamicin and penicillin
G has a synergistic
bactericidal effect
against virtually all strains of Streptococcus faecalis and
its varieties ( S. faecalis var. liquifaciens, S. faecalis var.
zymogenes), S. faecium and S. durans. An
enhanced killing effect
against many of these strains has also been shown in vitro with
combinations of gentamicin
and ampicillin, carbenicillin, nafcillin, or oxacillin.
The combined effect
of gentamicin and
carbenicillin is synergistic
for many strains of Pseudomonas aeruginosa. In vitro synergism
against other gram-negati ve organisms has been shown with combinations
of gentamicin and
caphalosporins. Gentamicin may be active against clinical isolates
of bacteria resistant
to other aminoglycosides. Bacteria resistant to one aminoglycoside
may be resistant to one or more other aminoglycosides. Bacterial
resistance to gentamicin
is generally developed slowly.
Susceptibility Testing
If the disc method
of susceptibility
testing used is that described by Bauer et al (Am J Clin Path 45:493,
1966: Federal Register 37:20527-20529,1972), a disc
containing 10 mcg of gentamicin
should give a zone of inhibition
of 15 mm or more to indicate
susceptibility
of the infecting organism. A zone
of 12 mm or less indicates
that the infecting organism
is likely to be resistant. Zones greater than 12 mm
and less than 15 mm indicate
intermediate susceptibility. In
certain conditions it may be desirable to do additional susceptibility
testing by the t.b. or
agar dilution
method; gentamicin substance
is available for this purpose.
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