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

toxic concentrations of procaine. It has been reported to occur in 1
of 200 patients receiving 4.8 million units of penicillin G procaine
to treat venereal disease.
Reactions Unrelated to Hypersensitivity or Toxicity. Regardless
of the route by which the drug is administered, but most strikingly
when it is given by mouth, penicillin changes the composition of
the microflora in the GI tract by eliminating sensitive microorganisms.
This phenomenon is usually of no clinical significance, and
normal microflora are typically reestablished shortly after therapy
is stopped. In some persons, however, superinfection results from
pathological changes to the flora. Pseudomembranous colitis,
related to overgrowth and production of a toxin by Clostridium difficile,
has followed oral and, less commonly, parenteral administration
of penicillins.
THE CEPHALOSPORINS
Cephalosporium acremonium, the first source of the
cephalosporins, was isolated in 1948 by Brotzu from
the sea near a sewer outlet off the Sardinian coast.
Crude filtrates from cultures of this fungus were found
to inhibit the in vitro growth of S. aureus and to cure
staphylococcal infections and typhoid fever in humans.
Culture fluids in which the Sardinian fungus was cultivated
were found to contain three distinct antibiotics,
which were named cephalosporin P, N, and C. With
isolation of the active nucleus of cephalosporin C,
7-aminocephalosporanic acid, and with the addition of
side chains, it became possible to produce semisynthetic
compounds with antibacterial activity very much
greater than that of the parent substance.
Chemistry. Cephalosporin C contains a side chain derived from D-
α-aminoadipic acid, which is condensed with a dihydrothiazine β-
lactam ring system (7-aminocephalosporanic acid). Compounds
containing 7-aminocephalosporanic acid are relatively stable in
dilute acid and highly resistant to penicillinase regardless of the
nature of their side chains and their affinity for the enzyme.
Cephalosporin C can be hydrolyzed by acid to 7-
aminocephalospo ranic acid. This compound subsequently has been
modified by the addition of different side chains to create a whole
family of cephalosporin antibiotics. It appears that modifications at
position 7 of the β-lactam ring are associated with alteration in antibacterial
activity and that substitutions at position 3 of the dihydrothiazine
ring are associated with changes in the metabolism and
pharmacokinetic properties of the drugs.
The cephamycins are similar to the cephalosporins but
have a methoxy group at position 7 of the β-lactam ring of the
7-aminocephalosporanic acid nucleus. The structural formulas of
representative cephalosporins and cephamycins are shown in
Table 53–2, along with dosages schedules and half-lives.
Mechanism of Action. Cephalosporins and cephamycins inhibit
bacterial cell wall synthesis in a manner similar to that of penicillin.
Classification. The large number of cephalosporins makes a system
of classification most desirable. Although cephalosporins may be
classified by their chemical structure, clinical pharmacology, resistance
to β-lactamase, or antimicrobial spectrum, the well-accepted
system of classification by “generations” is very useful, although
admittedly somewhat arbitrary (Table 53–3). It is important to
remember that none of the cephalosporins has activity against
MRSA, listeria, or enterococci.
Classification by generations is based on general features of
antimicrobial activity (Andes and Craig, 2005). The first-generation
cephalosporins, epitomized by cephalothin (discontinued in the U.S.)
and cefazolin, have good activity against gram-positive bacteria and
relatively modest activity against gram-negative microorganisms.
Most gram-positive cocci (with the exception of enterococci, methicillin-resistant
S. aureus, and S. epidermidis) are susceptible. Most
oral cavity anaerobes are sensitive, but the B. fragilis group is resistant.
Activity against Moraxella catarrhalis, E. coli, K. pneumoniae,
and P. mirabilis is good. The second-generation cephalosporins have
somewhat increased activity against gram-negative microorganisms
but are much less active than the third-generation agents. A subset of
second-generation agents (cefoxitin, cefotetan, and cefmetazole,
which have been discontinued in the U.S.) also is active against the B.
fragilis group. Third-generation cephalosporins generally are less
active than first-generation agents against gram-positive cocci; these
agents are much more active against the Enterobacteriaceae, although
resistance is dramatically increasing due to β-lactamase-producing
strains. A subset of third-generation agents (ceftazidime and cefoperazone,
which are discontinued in the U.S.) also is active against P.
aeruginosa but less active than other third-generation agents against
gram-positive cocci. Fourth-generation cephalosporins, such as
cefepime, have an extended spectrum of activity compared with the
third generation and have increased stability from hydrolysis by plasmid
and chromosomally mediated β-lactamases (but not the KPC
class A β-lactamases). Fourth-generation agents are useful in the
empirical treatment of serious infections in hospitalized patients when
gram-positive microorganisms, Enterobacteriaceae, and Pseudomonas
all are potential etiologies. It is important to remember that none of the
cephalosporins has reliable activity against the following bacteria:
penicillin-resistant S. pneumoniae, MRSA, methicillin-resistant S. epidermidis
and other coagulase-negative staphylococci, Enterococcus,
L. monocytogenes, Legionella pneumophila, L. micdadei, C. difficile,
Xanthomonas maltophilia, Campylobacter jejuni, KPC-producing
Enterobacteriaceae, and Acinetobacter spp.
Mechanisms of Bacterial Resistance to the Cephalosporins.
Resistance to the cephalosporins may be related to the
inability of the antibiotic to reach its sites of action or to
alterations in the penicillin-binding proteins (PBPs) that
are targets of the cephalosporins such that the antibiotics
bind to bacterial enzymes (β-lactamases) that can
hydrolyze the β-lactam ring and inactivate the
cephalosporin. Alterations in two PBPs (1A and 2X)
that decrease their affinity for cephalosporins render
pneumococci resistant to third-generation cephalosporins
because the other three high-molecular-weight PBPs
have inherently low affinity (Spratt, 1994).
The most prevalent mechanism of resistance to cephalosporins
is destruction of the cephalosporins by hydrolysis of the β-lactam ring.
1493
CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS