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

This is their valid clinical use. Dicloxacillin is the most active, and
many strains of S. aureus are inhibited by concentrations of 0.05-
0.8 μg/mL. Comparable values for cloxacillin (not currently marketed
in the U.S.) and oxacillin are 0.1-3 and 0.4-6 μg/mL,
respectively. These differences may have little practical significance,
however, because dosages are adjusted accordingly. These agents
are, in general, less effective against microorganisms susceptible to
penicillin G, and they are not useful against gram-negative bacteria.
These agents are absorbed rapidly but incompletely (30-80%)
from the GI tract. Absorption of the drugs is more efficient when
they are taken on an empty stomach; preferably they are administered
1 hour before or 2 hours after meals to ensure better absorption. Peak
concentrations in plasma are attained by 1 hour and ~5-10 μg/mL
after the ingestion of 1 g oxacillin. Slightly higher concentrations
are achieved after the administration of 1 g cloxacillin, whereas the
same oral dose of dicloxacillin yields peak plasma concentrations
of 15 μg/mL. There is little evidence that these differences are of
clinical significance. All these congeners are bound to plasma albumin
to a great extent (~90-95%); none is removed from the circulation
to a significant degree by hemodialysis.
The isoxazolyl penicillins are excreted rapidly by the kidney.
Normally, ~50% of a dose of these drugs is excreted in the urine in
the first 6 hours after oral administration. There also is significant
hepatic elimination of these agents in the bile. The half-lives for all
are between 30 and 60 minutes. Intervals between doses of oxacillin,
cloxacillin, and dicloxacillin do not have to be altered for patients
with renal failure. The differences just noted in plasma concentrations
produced by the isoxazolyl penicillins are related mainly to
differences in rate of urinary excretion and degree of resistance to
degradation in the liver.
Nafcillin. This semisynthetic penicillin is highly resistant
to penicillinase and has proven effective against infections
caused by penicillinase-producing strains of S. aureus.
Its structural formula is shown in Table 53–1.
Pharmacological Properties. Nafcillin is slightly more active than
oxacillin against penicillin G–resistant S. aureus (most strains are
inhibited by 0.06–2 μg/mL). Although it is the most active of the
penicillinase-resistant penicillins against other microorganisms, it is
not as potent as penicillin G. The peak plasma concentration is
~8 μg/mL 60 minutes after a 1-g intramuscular dose. Nafcillin is ~90%
bound to plasma protein. Peak concentrations of nafcillin in bile are
well above those found in plasma. Concentrations of the drug in CSF
appear to be adequate for therapy of staphylococcal meningitis.
The Aminopenicillins: Ampicillin,
Amoxicillin, and Their Congeners
These agents have similar antibacterial activity and a
spectrum that is broader than the antibiotics already
discussed. They all are destroyed by β-lactamase (from
both gram-positive and gram-negative bacteria).
Antimicrobial Activity. Ampicillin and the related
aminopenicillins are bactericidal for both gram-positive
and gram-negative bacteria. The meningococci and
L. monocytogenes are sensitive to this class of drugs.
Many pneumococcal isolates have varying levels of resistance
to ampicillin. Penicillin-resistant strains should be
considered ampicillin/amoxicillin-resistant. H. influenzae
and the viridans group of streptococci exhibit varying
degrees of resistance. Enterococci are about twice as sensitive
to ampicillin on a weight basis as they are to
penicillin G (MIC for ampicillin averages 1.5 μg/mL).
Although most strains of N. gonorrhoeae, E. coli, P.
mirabilis, Salmonella, and Shigella were highly susceptible
when ampicillin was first used in the early 1960s, an
increasing percentage of these species now is resistant.
From 30% to 50% of E. coli, a significant number of
P. mirabilis, and practically all species of Enterobacter
presently are insensitive. Resistant strains of Salmonella
(plasmid mediated) have been recovered with increasing
frequency in various parts of the world. Most strains of
Shigella now are resistant. Most strains of Pseudomonas,
Klebsiella, Serratia, Acinetobacter, and indole-positive
Proteus also are resistant to this group of penicillins;
these antibiotics are less active against B. fragilis than
penicillin G. However, concurrent administration of a
β-lactamase inhibitor such as clavulanate or sulbactam
markedly expands the spectrum of activity of these drugs.
Ampicillin. This drug is the prototype of the group. Its
structural formula is shown in Table 53–1.
Pharmacological Properties. Ampicillin (PRINCIPEN, others) is stable
in acid and is well absorbed after oral administration. An oral dose
of 0.5 g produces peak concentrations in plasma of ~3 μg/mL at
2 hours. Intake of food prior to ingestion of ampicillin diminishes
absorption. Intramuscular injection of 0.5 or 1 g sodium ampicillin
yields peak plasma concentrations of ~7 or 10 μg/mL, respectively,
at 1 hour; these decline exponentially, with a t 1/2
of ~80 minutes.
Severe renal impairment markedly prolongs the persistence of ampicillin
in the plasma. Peritoneal dialysis is ineffective in removing the
drug from the blood, but hemodialysis removes ~40% of the body
store in ~7 hours. Adjustment of the dose of ampicillin is required in
the presence of renal dysfunction. Ampicillin appears in the bile,
undergoes enterohepatic circulation, and is excreted in appreciable
quantities in the feces.
Amoxicillin. This drug, a penicillinase-susceptible
semi-synthetic penicillin, is a close chemical and pharmacological
relative of ampicillin (Table 53–1). The
drug is stable in acid and designed for oral use. It is
absorbed more rapidly and completely from the GI tract
than ampicillin, which is the major difference between
the two. The antimicrobial spectrum of amoxicillin is
essentially identical to that of ampicillin, with the
important exception that amoxicillin appears to be less
effective than ampicillin for shigellosis.
Peak plasma concentrations of amoxicillin (AMOXIL, others)
are 2-2.5 times greater for amoxicillin than for ampicillin after oral
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CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS