Page 813 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 799

Peptidoglycan Amino acid peptide
G = N-acetylglucos-amine
(N-Ag)
G M G M G M G M
Bacterial cell wall M = N-acetylmuramic acid
(N-Am)
Periplasmic space M G M G M G M G

Cytoplasmic membrane
G M G M G M G M
Cytoplasm

Schematic of normal bacterial cell wall peptidoglycan
synthesis transpeptidation reaction.

G M + M G G M G M
Transpeptidase

M G M G

Beta-lactams bind the transpeptidase
at the Penicillin Binding Protein site,
resulting in inhibition of transpeptidation,
thus halting peptidoglycan synthesis. No transpeptidation reaction

Transpeptidase β-lactam
G M + M G G M + M G

FIGURE 43–5 Schematic of a bacterial cell wall and normal synthesis of cell wall peptidoglycan via transpeptidation; M, N-acetylmuramic
acid; Glc, glucose; NAcGlc or G, N-acetylglucosamine. Beta-lactams work by binding the transpeptidase at the penicillin-binding protein site,
resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis.

Benzathine and procaine penicillins are formulated to delay Penicillin is rapidly excreted by the kidneys; small amounts
absorption, resulting in prolonged blood and tissue concentra- are excreted by other routes. Tubular secretion accounts
tions. A single intramuscular injection of 1.2 million units of for about 90% of renal excretion, and glomerular filtration
benzathine penicillin maintains serum levels above 0.02 mcg/mL accounts for the remainder. The normal half-life of penicillin
for 10 days, sufficient to treat β-hemolytic streptococcal infec- G is approximately 30 minutes but, in renal failure, may be
tions. After 3 weeks, levels still exceed 0.003 mcg/mL, which is as long as 10 hours. Ampicillin and the extended-spectrum
enough to prevent most β-hemolytic streptococcal infections. A penicillins are secreted more slowly than penicillin G and
600,000-unit dose of procaine penicillin yields peak concentra- have half-lives of 1 hour. For penicillins that are cleared by the
tions of 1–2 mcg/mL and clinically useful concentrations for kidney, the dose must be adjusted according to renal function,
12–24 hours after a single intramuscular injection. with approximately one-fourth to one-third the normal dose
Penicillin concentrations in most tissues are equal to those in being administered if creatinine clearance is 10 mL/min or less
serum. Penicillin is also excreted into sputum and breast milk to (Table 43–1).
levels 3–15% of those in the serum. Penetration into the eye, the Nafcillin is primarily cleared by biliary excretion. Oxacillin,
prostate, and the central nervous system is poor. However, with dicloxacillin, and cloxacillin are eliminated by both the kidney
active inflammation of the meninges, as in bacterial meningitis, and biliary excretion, and no dosage adjustment is required for
penicillin concentrations of 1–5 mcg/mL can be achieved with these drugs in patients in renal failure. Because clearance of peni-
a daily parenteral dose of 18–24 million units. These concentra- cillins is less efficient in the newborn, doses adjusted for weight
tions are sufficient to kill susceptible strains of pneumococci and alone result in higher systemic concentrations for longer periods
meningococci. than in the adult.