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

1482 Classification of the Penicillins and
Summary of Their Pharmacological
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Properties
It is useful to classify the penicillins according to
their spectra of antimicrobial activity (Table 53–1)
(Chambers, 2005).
• Penicillin G and its close congener penicillin V are
highly active against sensitive strains of gram-positive
cocci, but they are readily hydrolyzed by penicillinase.
Thus they are ineffective against most strains
of S. aureus.
• The penicillinase-resistant penicillins (methicillin,
discontinued in U.S.), nafcillin, oxacillin, cloxacillin
(not currently marketed in the United States), and
dicloxacillin have less potent antimicrobial activity
against microorganisms that are sensitive to penicillin
G, but they are the agents of first choice for treatment
of penicillinase-producing S. aureus and S. epidermidis
that are not methicillin resistant.
• Ampicillin, amoxicillin, and others make up a group
of penicillins whose antimicrobial activity is
extended to include such gram-negative microorganisms
as Haemophilus influenzae, E. coli, and
Proteus mirabilis. Frequently these drugs are
administered with a β-lactamase inhibitor such as
clavulanate or sulbactam to prevent hydrolysis by
class A β-lactamases.
• The antimicrobial activity of carbenicillin (discontinued
in the U.S.), its indanyl ester (carbenicillin indanyl),
and ticarcillin (marketed only in combination with
clavulanate in the U.S.) is extended to include
Pseudomonas, Enterobacter, and Proteus spp.
These agents are inferior to ampicillin against grampositive
cocci and Listeria monocytogenes and are less
active than piperacillin against Pseudomonas.
• Mezlocillin, azlocillin (both discontinued in the
U.S.), and piperacillin have excellent antimicrobial
activity against many isolates of Pseudomonas,
Klebsiella, and certain other gram-negative microorganisms.
However, the emergence of broad-spectrum
beta-lactamases is threatening the utility of
these agents (Jacoby and Munoz-Price, 2005; Walsh,
2008). Piperacillin retains the activity of ampicillin
against gram-positive cocci and L. monocytogenes.
Although the pharmacological properties of the
individual drugs are discussed in detail later in this
chapter, certain generalizations are useful. Following
absorption of orally administered penicillins, these
agents are distributed widely throughout the body.
Therapeutic concentrations of penicillins are achieved
readily in tissues and in secretions such as joint fluid,
pleural fluid, pericardial fluid, and bile. Penicillins do
not penetrate living phagocytic cells to a significant
extent, and only low concentrations of these drugs are
found in prostatic secretions, brain tissue, and intraocular
fluid. Concentrations of penicillins in cerebrospinal
fluid (CSF) are variable but are <1% of
those in plasma when the meninges are normal. When
there is inflammation, concentrations in CSF may
increase to as much as 5% of the plasma value.
Penicillins are eliminated rapidly, particularly by
glomerular filtration and renal tubular secretion, such
that their half-lives in the body are short, typically
30-90 minutes. As a consequence, concentrations of
these drugs in urine are high.
Penicillin G and Penicillin V
Antimicrobial Activity. The antimicrobial spectra of
penicillin G (benzylpenicillin) and penicillin V (the
phenoxymethyl derivative) are very similar for aerobic
gram-positive microorganisms. However, penicillin G
is 5-10 times more active than penicillin V against
Neisseria spp. that are sensitive to penicillins and
against certain anaerobes.
Penicillin G has activity against a variety of
species of gram-positive and gram-negative cocci,
although many bacteria previously sensitive to the agent
are now resistant. Most streptococci (but not enterococci)
are very susceptible to the drug; concentrations
of <0.01 μg/mL usually are effective. However, penicillin-resistant
viridans streptococci (Carratalá et al.,
1995) and S. pneumoniae are becoming more common.
Penicillin-resistant pneumococci are especially common
in pediatric populations, such as children attending daycare
centers. Many penicillin-resistant pneumococci
also are resistant to third-generation cephalosporins.
Whereas most strains of S. aureus were highly sensitive to
penicillin G when this agent was first employed therapeutically,
>90% of strains of staphylococci isolated from individuals inside or
outside of hospitals are now resistant to penicillin G (and nearly half
are methicillin-resistant). Most strains of S. epidermidis also are
resistant to penicillin. Unfortunately, penicillinase-producing strains
of gonococci that are highly resistant to penicillin G have become
widespread. With rare exceptions, meningococci are quite sensitive
to penicillin G.
Although the vast majority of strains of Corynebacterium diphtheriae
are sensitive to penicillin G, some are highly resistant. The
presence of chromosomally encoded β-lactamase in Bacillus anthracis
is the reason that penicillin was not used for prophylaxis of anthrax
exposure, although most isolates are susceptible. Most anaerobic