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

Aztreonam generally is well tolerated. Interestingly, patients
who are allergic to penicillins or cephalosporins appear not to react
to aztreonam, with the exception of ceftazidime.
The usual dose of aztreonam for severe infections is 2 g every
6-8 hours. This should be reduced in patients with renal insufficiency.
Aztreonam has been used successfully for the therapy of a
variety of infections. One of its notable features is little allergic
cross-reactivity with β-lactam antibiotics, with the possible exception
of ceftazidime (Perez Pimiento et al., 1998), with which it has
considerable structural similarity. Aztreonam is therefore quite useful
for treating gram-negative infections that normally would be
treated with a β-lactam antibiotic were it not for the history of a prior
allergic reaction.
β-LACTAMASE INHIBITORS
Certain molecules can inactivate β-lactamases, thereby
preventing the destruction of β-lactam antibiotics
that are substrates for these enzymes. β-Lactamase
inhibitors are most active against plasmid-encoded
β-lactamases (including the enzymes that hydrolyze
ceftazidime and cefotaxime), but they are inactive at
clinically achievable concentrations against the type I
chromosomal β-lactamases induced in gram-negative
bacilli (such as Enterobacter, Acinetobacter, and
Citrobacter) by treatment with second- and thirdgeneration
cephalosporins.
Clavulanic acid is produced by Streptomyces
clavuligerus; its structural formula is:
It has poor intrinsic antimicrobial activity, but it is
a “suicide” inhibitor that irreversibly binds β-lactamases
produced by a wide range of gram-positive and
gram-negative microorganisms. Clavulanic acid is well
absorbed by mouth and also can be given parenterally.
It has been combined with amoxicillin as an oral preparation
(AUGMENTIN, others) and with ticarcillin as a parenteral
preparation (TIMENTIN).
Amoxicillin plus clavulanate is effective in vitro and in vivo
for β-lactamase-producing strains of staphylococci, H. influenzae,
gonococci, and E. coli. Amoxicillin-clavulanate plus ciprofloxacin
has been shown to be an effective oral treatment for low-risk febrile
patients with neutropenia from cancer chemotherapy (Freifeld et al.,
1999; Kern et al., 1999). It also is effective in the treatment of acute
otitis media in children, sinusitis, animal or human bite wounds, cellulitis,
and diabetic foot infections. The addition of clavulanate to
ticarcillin (timentin) extends its spectrum such that it resembles
imipenem to include aerobic gram-negative bacilli, S. aureus, and
Bacteroides spp. There is no increased activity against Pseudomonas
spp. The dosage should be adjusted for patients with renal insufficiency.
The combination is especially useful for mixed nosocomial
infections and is used often with an aminoglycoside.
Sulbactam is another β-lactamase inhibitor similar in structure
to clavulanic acid. It may be given orally or parenterally along
with a β-lactam antibiotic. It is available for intravenous or intramuscular
use combined with ampicillin (UNASYN, others). Dosage
must be adjusted for patients with impaired renal function. The combination
has good activity against gram-positive cocci, including β-
lactamase-producing strains of S. aureus, gram-negative aerobes (but
not resistant strains of E. coli or Pseudomonas), and anaerobes; it
also has been used effectively for the treatment of mixed intraabdominal
and pelvic infections.
O
H
N
HO
SULBACTAM
Tazobactam is a penicillanic acid sulfone β-lactamase inhibitor.
In comparison with the other available inhibitors, it has poor activity
against the inducible chromosomal β-lactamases of Enterobacteriaceae
but has good activity against many of the plasmid β-lactamases, including
some of the extended-spectrum class. It has been combined with
piperacillin as a parenteral preparation (ZOSYN).
The combination of piperacillin and tazobactam does not
increase the activity of piperacillin against P. aeruginosa because
resistance is due to either chromosomal β-lactamases or decreased
permeability of piperacillin into the periplasmic space. Because the
currently recommended dose (3 g piperacillin per 375 mg tazobactam
every 4-8 hours) is less than the recommended dose of
piperacillin when used alone for serious infections (3-4 g every
4-6 hours), concern has been raised that piperacillin-tazobactam may
prove ineffective in the treatment of some P. aeruginosa infections
that would have responded to piperacillin. The combination of
piperacillin plus tazobactam should be equivalent in antimicrobial
spectrum to ticarcillin plus clavulanate.
BIBLIOGRAPHY
O O
H O O
S
S
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Andes DR, Craig WA. Cephalosporins. In: Mandell, Douglas,
and Bennett’s Principles and Practice of Infectious Diseases,
6th ed. (Mandell GL, Bennett JE, Dolin R, eds.), Churchill
Livingstone, Philadelphia, 2005, pp. 294–307.
Bayles KW. The bactericidal action of penicillin: New clues to
an unsolved mystery. Trends Microbiol, 2000, 8:81274–81278.
Berrios X, del Campo E, Guzman B, Bisno AL. Discontinuing
rheumatic fever prophylaxis in selected adolescents and young
adults: A prospective study. Ann Intern Med, 1993, 118:401–406.
Bisno AL, Stevens DL. Streptococcal infections of skin and soft
tissues. N Engl J Med, 1996, 334:240–245.
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TAZOBACTAM
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CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS