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
Claforan Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefotaxime
Claforan Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefotaxime
CLINICAL PHARMACOLOGY
Following IM administration
of a single 500 mg or 1 g dose
of CLAFORAN to normal volunteers,
mean peak serum
concentrations of 11.7 and 20.5 µg/mL respectively were attained
within 30 minutes and declined with an elimination
half-life of approximately
1 hour. There was a dose-dependent increase in serum
levels after the IV administration
of 500 mg, 1 g, and 2 g of CLAFORAN (38.9, 101.7, and 214.4 µg/mL
respectively) without alteration in the elimination
half-life. There is no evidence
of accumulation following repetitive IV
infusion of 1 g doses every
6 hours for 14 days as there are no
alterations of serum or renal
clearance. About 60% of the administered dose
was recovered from urine during the first 6 hours following the start
of the infusion.
Approximately 20-36% of an intravenously administered dose
of 14C-cefotaxime is excreted by the kidney
as unchanged cefotaxime and 15-25% as the desacetyl derivative, the major
metabolite. The desacetyl metabolite
has been shown to contribute to the bactericidal
activity. Two other urinary
metabolites (M2 and M3) account for about 20-25%.
They lack bactericidal activity.
A single 50 mg/kg dose of CLAFORAN
was administered as an intravenous
infusion over a 10- to 15- minute period
to 29 newborn infants grouped
according to birth weight
and age. The mean half-life
of cefotaxime in infants with lower birth
weights (<1500 grams), regardless of age, was longer (4.6 hours) than
the mean half-life
(3.4 hours) in infants whose birth
weight was greater than 1500 grams. Mean serum
clearance was also smaller
in the lower birth weight
infants. Although the differences in mean
half-life values are statistically significant
for weight, they are not clinically important. Therefore, dosage
should be based solely on age. (See DOSAGE
AND ADMINISTRATION section.)
Additionally, no disulfiram-like
reactions were reported in a study conducted in 22 healthy
volunteers administered CLAFORAN and ethanol.
Microbiology
The bactericidal activity
of cefotaxime sodium results
from inhibition of cell wall
synthesis. Cefotaxime sodium
has in vitro activity against a wide range
of gram-positive and
gram-negative organisms.
CLAFORAN has a high degree
of stability in the presence
of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative
and gram-positive bacteria. Cefotaxime sodium
has been shown to be a potent
inhibitor of ß-lactamases
produced by certain gram-negative
bacteria. Cefotaxime sodium is usually active against the following microorganisms
both in vitro and in clinical
infections (see INDICATIONS AND USAGE).
Aerobes, Gram-positive:
- Staphylococcus aureus, including penicillinase
and non-penicillinase producing strains,
- Staphylococcus epidermidis, Enterococcus species,
- Streptococcus pyogenes (Group A beta-hemolytic streptococci),
- Streptococcus agalactiae (Group B streptococci),
- Streptococcus pneumoniae (formerly Diplococcus pneumoniae).
Aerobes, Gram-negative:
- Citrobacter species,
- Enterobacter species,
- Escherichia coli,
- Haemophilus influenzae (including ampicillin-resistant H.
Influenzae),
- Haemophilus parainfluenzae,
- Klebsiella species
(including K. pneumoniae),
- Neisseria gonorrhoeae (including penicillinase
and non-penicillinase producing strains),
- Neisseria meningitidis,
- Proteus mirabilis,
- Proteus vulgaris,
- Proteus inconstans Group B,
- Morganella morganii,
- Providencia rettgeri,
- Serratia species,
and
- Acinetobacter species.
NOTE: Many strains of the above organisms that are multiply resistant
to other antibiotics, e.g. penicillins, cephalosporins, and aminoglycosides,
are susceptible to cefotaxime
sodium.
Cefotaxime sodium is active
against some strains of Pseudomonas aeruginosa.
Anaerobes:
- Bacteroides species, including some strains of B. fragilis,
- Clostridium species (NOTE: Most strains of C. difficile
are resistant.),
- Peptococcus species,
- Peptostreptococcus species,
and
- Fusobacterium species (including F. nucleatum).
Cefotaxime sodium is highly
stable in vitro to four
of the five major classes of b-lactamases described
by Richmond et al., including type IIIa (TEM) which is produced by many
gram-negative bacteria.
The drug is also stable to
b-lactamase (penicillinase) produced by staphylococci.
In addition, cefotaxime sodium
shows high affinity for penicillin-binding
proteins in the cell wall, including
PBP: Ib and III.
Cefotaxime sodium also demonstrates
in vitro activity
against the following microorganisms although clinical
significance is unknown: Salmonella species (including S. typhi),
Providencia species,
and Shigella species.
Cefotaxime sodium and aminoglycosides
have been shown to be synergistic in vitro against some strains
of Pseudomonas aeruginosa.
Susceptibility Tests
Quantitative methods that require measurement of zone
diameters give the most precise estimate of antibiotic
susceptibility. One such procedure1 has been recommended for
use with discs to test susceptibility
to cefotaxime sodium. Interpretation involves correlation
of the diameters obtained in the disc
test with minimum
inhibitory concentration
(MIC) values for cefotaxime sodium.
Reports from the laboratory
giving results of the standardized single-disc susceptibility test
using a 30 µg cefotaxime sodium
disc should be interpreted according
to the following criteria:
Susceptible organisms produce zones of 20 mm
or greater, indicating that the tested organism
is likely to respond to therapy.
Organisms that produce zones of 15 to 19 mm are expected
to be susceptible if high
dosage is used or if the infection
is confined to tissues and fluids (e.g. urine) in which high antibiotic
levels are attained.
Resistant organisms produce zones of 14 mm or less,
indicating that other therapy
should be selected.
Organisms should be tested with the cefotaxime sodium disc, since cefotaxime
sodium has been shown by in
vitro tests to be active against certain strains found resistant when
other beta lactam discs are used. The cefotaxime sodium
disc should not be used for testing
susceptibility to other
cephalosporins. Organisms having zones of less than 18 mm
around the cephalothin disc are
not necessarily of intermediate susceptibility or resistant to cefotaxime
sodium. A bacterial isolate
may be considered susceptible
if the MIC value
for cefotaxime sodium is not
more than 16 µg/mL. Organisms are considered resistant to cefotaxime
sodium if the MIC is equal to
or greater than 64 µg/mL. Organisms having an MIC
value of less than 64 µg/mL
but greater than 16 µg/mL are expected to be susceptible
if high dosage is used or if
the infection is confined to tissues and fluids (e.g., urine) in which
high antibiotic levels are attained.
top
