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

manifest cross-reactivity to a member of the other class.
Immunological studies have demonstrated cross-reactivity in as many
as 20% of patients who are allergic to penicillin, but clinical studies
indicate a much lower frequency (~1%) of such reactions. There are
no skin tests that can reliably predict whether a patient will manifest
an allergic reaction to the cephalosporins.
Patients with a history of a mild or a temporally distant reaction
to penicillin appear to be at low risk of rash or other allergic
reaction following the administration of a cephalosporin. However,
patients who have had a recent severe, immediate reaction to a
penicillin should be given a cephalosporin with great caution, if at
all. A positive Coombs reaction appears frequently in patients who
receive large doses of a cephalosporin. Hemolysis usually is not
associated with this phenomenon, although it has been reported
and has been associated with fatalities. Cephalosporins have produced
rare instances of bone marrow depression, characterized by
granulocytopenia.
The cephalosporins have been implicated as potentially
nephrotoxic agents, although they are not nearly as toxic to the
kidney as the aminoglycosides or the polymyxins. Renal tubular
necrosis has followed the administration of cephaloridine in doses
>4 g/day; this agent is no longer available in the U.S. Other
cephalosporins are much less toxic and, when used by themselves
in recommended doses, rarely produce significant renal toxicity.
High doses of cephalothin (no longer available in the U.S.) have
produced acute tubular necrosis in certain instances, and usual
doses (8-12 g/day) have caused nephrotoxicity in patients with preexisting
renal disease. There is good evidence that the concurrent
administration of cephalothin and gentamicin or tobramycin act
synergistically to cause nephrotoxicity, especially in patients >60
years of age. Diarrhea can result from the administration of
cephalosporins and may be more frequent with cefoperazone, perhaps
because of its greater biliary excretion. Intolerance to alcohol
(a disulfiram-like reaction) has been noted with cephalosporins that
contain the methylthiotetrazole (MTT) group, including cefotetan,
cefamandole, moxalactam, and cefoperazone (the latter three are
no longer available in the U.S.). Serious bleeding related either to
hypoprothrombinemia owing to the MTT group, thrombocytopenia,
and/or platelet dysfunction has been reported with several
β-lactam antibiotics.
Therapeutic Uses. The cephalosporins are used
widely and are therapeutically important antibiotics.
Clinical studies have shown cephalosporins to be
effective as both therapeutic and prophylactic agents.
Unfortunately, a wide array of bacteria is resistant to
their activity.
The first-generation cephalosporins are excellent agents for
skin and soft tissue infections owing to S. pyogenes and methicillinsusceptible
S. aureus. A single dose of cefazolin just before surgery
is the preferred prophylaxis for procedures in which skin flora are the
likely pathogens (Medical Letter, 2006). For colorectal surgery,
where prophylaxis for intestinal anaerobes is desired, the secondgeneration
agent cefoxitin is preferred.
The second-generation cephalosporins generally have been
displaced by third-generation agents. They have inferior activity
against penicillin-resistant S. pneumoniae compared with either the
third-generation agents or ampicillin and therefore should not be
used for empirical treatment of meningitis or pneumonia. The oral
second-generation cephalosporins can be used to treat respiratory
tract infections, although they are suboptimal (compared with oral
amoxicillin) for treatment of penicillin-resistant S. pneumoniae
pneumonia and otitis media. In situations where facultative gramnegative
bacteria and anaerobes are involved, such as intra-abdominal
infections, pelvic inflammatory disease, and diabetic foot
infection, cefoxitin and cefotetan both are effective.
The third-generation cephalosporins, with or without aminoglycosides,
have been considered to be the drugs of choice for serious
infections caused by Klebsiella, Enterobacter, Proteus, Providencia,
Serratia, and Haemophilus spp. Ceftriaxone is the therapy of choice
for all forms of gonorrhea and for severe forms of Lyme disease.
The third-generation cephalosporins cefotaxime or ceftriaxone are
used for the initial treatment of meningitis in nonimmunocompromised
adults and children >3 months of age (in combination with
vancomycin and ampicillin pending identification of the causative
agent) because of their antimicrobial activity, good penetration into
CSF, and record of clinical success. They are the drugs of choice for
the treatment of meningitis caused by H. influenzae, sensitive
S. pneumoniae, N. meningitidis, and gram-negative enteric bacteria.
Cefotaxime has failed in the treatment of meningitis owing to resistant
S. pneumoniae; thus vancomycin should be added (Quagliarello
and Scheld, 1997). Ceftazidime plus an aminoglycoside is the treatment
of choice for Pseudomonas meningitis. Third-generation
cephalosporins, however, lack activity against L. monocytogenes and
penicillin-resistant pneumococci, which may cause meningitis. The
antimicrobial spectra of cefotaxime and ceftriaxone are excellent for
the treatment of community-acquired pneumonia, i.e., pneumonia
caused by some pneumococci (achievable serum concentrations
exceed MICs for many or most penicillin-resistant isolates), H.
influenzae, or S. aureus.
The fourth-generation cephalosporins are indicated for the
empirical treatment of nosocomial infections where antibiotic resistance
owing to extended-spectrum β-lactamases or chromosomally
induced β-lactamases are anticipated. For example, cefepime has
superior activity against nosocomial isolates of Enterobacter,
Citrobacter, and Serratia spp. compared with ceftazidime and
piperacillin. However KPC- or metallo-β-lactamase expressing
strains are resistant to cefepime.
OTHER β-LACTAM ANTIBIOTICS
Important therapeutic agents with a β-lactam structure
that are neither penicillins nor cephalosporins have
been developed.
Carbapenems
Carbapenems are β-lactams that contain a fused β-lactam
ring and a five-member ring system that differs
from the penicillins because it is unsaturated and contains
a carbon atom instead of the sulfur atom. This
class of antibiotics has a broader spectrum of activity
than most other β-lactam antibiotics.
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CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS