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

Penicillins, Cephalosporins, and
Other β-Lactam Antibiotics
William A. Petri, Jr.
The β-lactam antibiotics are useful and frequently prescribed
antimicrobial agents that share a common structure
and mechanism of action: inhibition of synthesis
of the bacterial peptidoglycan cell wall. The group
includes penicillins, cephalosporins, and carbapenems.
The penicillins consist of penicillins G and V,
which are highly active against susceptible gram-positive
cocci; penicillinase-resistant penicillins such as
nafcillin, which are active against penicillinase-producing
Staphylococcus aureus; ampicillin and other agents
with an improved gram-negative spectrum, especially
when combined with a β-lactamase inhibitor; and
extended-spectrum penicillins with activity against
Pseudomonas aeruginosa, such as piperacillin.
The β-lactams also include the cephalosporin
antibiotics, which are classified by generation: Firstgeneration
agents have excellent gram-positive and
modest gram-negative activity; second-generation agents
have somewhat better activity against gram-negative
organisms and include some agents with antianaerobe
activity; third-generation agents have activity against
gram-positive organisms and much more activity against
the Enterobacteriaceae, with a subset active against P.
aeruginosa; and fourth-generation agents encompass the
antimicrobial spectrum of all the third-generation agents
and have increased stability to hydrolysis by inducible
chromosomal β-lactamases.
Carbapenems, including imipenem, doripenem,
ertapenem and meropenem, have the broadest antimicrobial
spectrum of any antibiotic, whereas the monobactam
aztreonam has a gram-negative spectrum resembling
that of the aminoglycosides.
β-Lactamase inhibitors such as clavulanate are
used to extend the spectrum of penicillins against β-lactamase-producing
organisms. Bacterial resistance
against the β-lactam antibiotics continues to increase at
a dramatic rate. Mechanisms of resistance include not
only production of β-lactamases that in some cases
destroy all β-lactam antibiotics, but also alterations in
or acquisition of novel penicillin-binding proteins
PBPs and decreased entry and/or active efflux of the
antibiotic. It is not an exaggeration to state that we are
re-entering the pre-antibiotic era, with many nosocomially
acquired gram-negative bacterial infections resistant
to all available antibiotics.
THE PENICILLINS
Despite the existence of microbial resistance, the penicillins
constitute one of the most important groups of
antibiotics. Many of these have unique advantages
such that members of this group of antibiotics are currently
the drugs of choice for a large number of infectious
diseases.
History. The history of the brilliant research that led to the discovery
and development of penicillin is well chronicled. In 1928, while
studying Staphylococcus variants in the laboratory at St. Mary’s
Hospital in London, Alexander Fleming observed that a mold contaminating
one of his cultures caused the bacteria in its vicinity to
undergo lysis. Broth in which the fungus was grown was markedly
inhibitory for many microorganisms. Because the mold belonged to
the genus Penicillium, Fleming named the antibacterial substance
penicillin.
A decade later, penicillin was developed as a systemic therapeutic
agent by the concerted research of a group of investigators at
Oxford University headed by Florey, Chain, and Abraham. By May
1940, a crude preparation was found to produce dramatic therapeutic
effects when administered parenterally to mice with streptococcal
infections. Sufficient penicillin was accumulated by 1941 to conduct
therapeutic trials in several patients desperately ill with staphylococcal
and streptococcal infections refractory to all other therapy. At this
stage, the crude, amorphous penicillin was only ~10% pure, and it
required nearly 100 L of the broth in which the mold had been grown
to obtain enough of the antibiotic to treat one patient for 24 hours.
Bedpans actually were used by the Oxford group for growing cultures
of Penicillium notatum. Case 1 in the 1941 report from Oxford