DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

the bile (neither is available in the U.S.). Cefotaxime is
deacetylated in vivo. The metabolite has less antimicrobial
activity than the parent compound and is excreted
by the kidneys. None of the other cephalosporins
appears to undergo appreciable metabolism.
Several cephalosporins penetrate into the CSF
in sufficient concentration to be useful for the treatment
of meningitis. These include cefotaxime, ceftriaxone,
and cefepime (see “Therapeutic Uses” section).
Cephalosporins also cross the placenta, and they are
found in high concentrations in synovial and pericardial
fluids. Penetration into the aqueous humor of the eye is
relatively good after systemic administration of thirdgeneration
agents, but penetration into the vitreous humor
is poor. Some evidence indicates that concentrations sufficient
for therapy of ocular infections owing to grampositive
and certain gram-negative microorganisms can
be achieved after systemic administration. Concentrations
in bile usually are high, with those achieved after administration
of cefoperazone and cefpiramide the highest.
Specific Agents
First-Generation Cephalosporins. Cefazolin has an antibacterial
spectrum that is typical of other first-generation
cephalosporins except that it also has activity
against some Enterobacter spp. Cefazolin is relatively
well tolerated after either intramuscular or intravenous
administration, and concentrations of the drug in
plasma after a 1-g intramuscular injection reach
64 μg/mL. Cefazolin is excreted by glomerular filtration
and is bound to plasma proteins to a great extent
(~85%). Cefazolin usually is preferred among the firstgeneration
cephalosporins because it can be administered
less frequently owing to its longer t 1/2
.
Cephalexin is available for oral administration, and it has the
same antibacterial spectrum as the other first-generation cephalosporins.
However, it is somewhat less active against penicillinase-producing
staphylococci. Oral therapy with cephalexin results in peak concentrations
in plasma of 16 μg/mL after a dose of 0.5 g; this is adequate for the
inhibition of many gram-positive and gram-negative pathogens. The
drug is not metabolized, and 70-100% is excreted in the urine.
Cephradine is similar in structure to cephalexin, and its activity
in vitro is almost identical. Cephradine is not metabolized and,
after rapid absorption from the GI tract, is excreted unchanged in
the urine. Cephradine can be administered orally, intramuscularly,
or intravenously. When administered orally, it is difficult to distinguish
cephradine from cephalexin; some authorities believe these
two drugs can be used interchangeably. Because cephradine is so
well absorbed, the concentrations in plasma are nearly equivalent
after oral or intramuscular administration.
Cefadroxil is the para-hydroxy analog of cephalexin.
Concentrations of cefadroxil in plasma and urine are at somewhat
higher levels than are those of cephalexin. The drug may be
administered orally once or twice a day for the treatment of urinary
tract infections. Its activity in vitro is similar to that of
cephalexin.
Second-Generation Cephalosporins. Second-generation
cephalosporins have a broader spectrum than do the
first-generation agents and are active against sensitive
strains of Enterobacter spp., indole-positive Proteus
spp., and Klebsiella spp.
Cefoxitin is a cephamycin produced by Streptomyces lactam
durans. It is resistant to some β-lactamases produced by gramnegative
rods. This antibiotic is less active than the first-generation
cephalosporins against gram-positive bacteria. Cefoxitin is more
active than other first- or second-generation agents (except cefotetan)
against anaerobes, especially B. fragilis. After an intramuscular dose
of 1 g, concentrations in plasma are ~22 μg/mL. The t 1/2
is ~40 minutes.
Cefoxitin’s special role seems to be for treatment of certain anaerobic
and mixed aerobic-anaerobic infections, such as pelvic inflammatory
disease and lung abscess.
Cefaclor is used orally. The concentration in plasma after oral
administration is ~50% of that achieved after an equivalent oral dose
of cephalexin. However, cefaclor is more active against H. influenzae
and Moraxella catarrhalis, although some β-lactamase-producing
strains of these organisms may be resistant.
Loracarbef is an orally administered carbacephem, similar in
activity to cefaclor, that is more stable against some β-lactamases.
The serum t 1/2
is 1.1 hours.
Cefuroxime is similar to loracarbef with broader gram-negative
activity against some Citrobacter and Enterobacter spp. Unlike
cefoxitin, cefmetazole (discontinued in the U.S.), and cefotetan,
cefuroxime lacks activity against B. fragilis. The t 1/2
is 1.7 hours,
and the drug can be given every 8 hours. Concentrations in CSF are
~10% of those in plasma, and the drug is effective (but inferior to
ceftriaxone) for treatment of meningitis owing to H. influenzae (including
strains resistant to ampicillin), N. meningitidis, and S. pneumoniae
(Schaad et al., 1990).
Cefuroxime axetil is the 1-acetyloxyethyl ester of cefuroxime.
Between 30% and 50% of an oral dose is absorbed, and the
drug then is hydrolyzed to cefuroxime; resulting concentrations in
plasma are variable.
Cefprozil is an orally administered agent that is more active
than first-generation cephalosporins against penicillin-sensitive
streptococci, E. coli, P. mirabilis, Klebsiella spp., and Citrobacter
spp. It has a serum t 1/2
of ~1.3 hours.
Third-Generation Cephalosporins. Cefotaxime is highly
resistant to many (but not the extended-spectrum product)
of the bacterial β-lactamases and has good activity
against many gram-positive and gram-negative aerobic
bacteria. However, activity against B. fragilis is poor
compared with agents such as clindamycin and metronidazole.
Cefotaxime has a t 1/2
in plasma of ~1 hour and
should be administered every 4–8 hours for serious
infections. The drug is metabolized in vivo to
desacetylcefotaxime, which is less active against most
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CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS