Page 812 - Basic _ Clinical Pharmacology ( PDFDrive )

798 SECTION VIII Chemotherapeutic Drugs

those produced by Staphylococcus aureus, Haemophilus influenzae,
and Escherichia coli, are relatively narrow in substrate specificity,
preferring penicillins to cephalosporins. Other β-lactamases, eg,
M AmpC β-lactamase produced by Pseudomonas aeruginosa and
L-Ala Enterobacter sp and extended-spectrum β-lactamases (ESBLs) in
M
Enterobacteriaceae, hydrolyze both cephalosporins and penicil-
L-Ala R lins. Carbapenems are highly resistant to hydrolysis by peni-
G
R cillinases and cephalosporinases, but they are hydrolyzed by
G metallo-β-lactamases and carbapenemases.
Altered target PBPs are the basis of methicillin resistance in
M staphylococci and of penicillin resistance in pneumococci and
most resistant enterococci. These resistant organisms produce
M L-Ala
PBPs that have low affinity for binding β-lactam antibiotics, and
L-Ala + D-Glu they are not inhibited except at relatively high, often clinically
G
unachievable, drug concentrations.
G D-Glu L-Lys [Gly] 5 Resistance due to impaired penetration of antibiotic occurs
only in Gram-negative species because of the impermeable outer
L-Lys [Gly] 5* D-Ala* membrane of their cell wall, which is absent in Gram-positive bac-
R teria. Beta-lactam antibiotics cross the outer membrane and enter
D-Ala D-Ala Gram-negative organisms via outer membrane protein channels
called porins. Absence of the proper channel or down-regulation
D-Ala of its production can greatly impair drug entry into the cell. Poor
penetration alone is usually not sufficient to confer resistance
Transpeptidase
because enough antibiotic eventually enters the cell to inhibit
growth. However, this barrier can become important in the pres-
ence of a β-lactamase, even a relatively inefficient one, as long as
M
it can hydrolyze drug faster than it enters the cell. Gram-negative
M L-Ala organisms also may produce an efflux pump, which consists of
cytoplasmic and periplasmic protein components that efficiently
L-Ala R
G transport some β-lactam antibiotics from the periplasm back
R across the cell wall outer membrane.
G
Pharmacokinetics
M

M L-Ala Absorption of orally administered drug differs greatly for indi-
vidual penicillins, depending in part on their acid stability and
L-Ala protein binding. Gastrointestinal absorption of nafcillin is erratic,
G
D-Glu so it is not suitable for oral administration. Dicloxacillin, ampicil-
D-Glu
G lin, and amoxicillin are acid-stable and relatively well absorbed,
producing serum concentrations in the range of 4–8 mcg/mL after
L-Lys [Gly] 5 D-Ala L-Lys [Gly] 5
a 500-mg oral dose. Absorption of most oral penicillins (amoxicil-
lin being an exception) is impaired by food, and the drugs should
D-Ala
be administered at least 1–2 hours before or after a meal.
Intravenous administration of penicillin G is preferred to
D-Ala + D-Ala the intramuscular route because of irritation and local pain
from intramuscular injection of large doses. Serum concen-
FIGURE 43–4 The transpeptidation reaction in Staphylococcus trations 30 minutes after an intravenous injection of 1 g of
aureus that is inhibited by β-lactam antibiotics. The cell wall of Gram- penicillin G (equivalent to approximately 1.6 million units) are
positive bacteria is made up of long peptidoglycan polymer chains 20–50 mcg/mL. Only a fraction of the total drug in serum is
consisting of the alternating aminohexoses N-acetylglucosamine (G) present as free drug, the concentration of which is determined by
and N-acetylmuramic acid (M) with pentapeptide side chains linked (in protein binding. Highly protein-bound penicillins (eg, nafcillin)
S aureus) by pentaglycine bridges. The exact composition of the side generally achieve lower free-drug concentrations in serum than
chains varies among species. The diagram illustrates small segments of less protein-bound penicillins (eg, penicillin G or ampicillin).
two such polymer chains and their amino acid side chains. These linear Penicillins are widely distributed in body fluids and tissues with a
polymers must be cross-linked by transpeptidation of the side chains at
the points indicated by the asterisk to achieve the strength necessary for few exceptions. They are polar molecules, so intracellular concen-
cell viability. trations are well below those found in extracellular fluids.