Bacterial cell wall Periplasmic space Cytoplasmic membrane Cytoplasm Beta-lactams bind the transpeptidase at the Penicillin Binding Protein site, resulting in inhibition of transpeptidation, thus halting peptidoglycan synthesis. Schematic of normal bacterial cell wall peptidoglycan synthesis transpeptidation reaction. G = N-acetylglucos-amine (N-Ag) M = N-acetylmuramic acid (N-Am) G M M M MG G G G MG M G M G M M M M G M G M G M G G G M M M MG G G G +Transpeptidase No transpeptidation reaction
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 absorption, resulting in prolonged blood and tissue concentrations. A single intramuscular injection of 1.2 million units of benzathine penicillin maintains serum levels above 0.02 mcg/mL for 10 days, sufficient to treat β-hemolytic streptococcal infections. After 3 weeks, levels still exceed 0.003 mcg/mL, which is enough to prevent most β-hemolytic streptococcal infections. A 600,000-unit dose of procaine penicillin yields peak concentrations of 1–2 mcg/mL and clinically useful concentrations for 12–24 hours after a single intramuscular injection.
Penicillin concentrations in most tissues are equal to those in serum. Penicillin is also excreted into sputum and breast milk to levels 3–15% of those in the serum. Penetration into the eye, the prostate, and the central nervous system is poor. However, with active inflammation of the meninges, as in bacterial meningitis, penicillin concentrations of 1–5 mcg/mL can be achieved with a daily parenteral dose of 18–24 million units. These concentrations are sufficient to kill susceptible strains of pneumococci and meningococci.
Penicillin is rapidly excreted by the kidneys; small amounts are excreted by other routes. Tubular secretion accounts for about 90% of renal excretion, and glomerular filtration accounts for the remainder. The normal half-life of penicillin G is approximately 30 minutes but, in renal failure, may be as long as 10 hours. Ampicillin and the extended-spectrum penicillins are secreted more slowly than penicillin G and have half-lives of 1 hour. For penicillins that are cleared by the kidney, the dose must be adjusted according to renal function, with approximately one-fourth to one-third the normal dose being administered if creatinine clearance is 10 mL/min or less (Table 43–1).
Nafcillin is primarily cleared by biliary excretion. Oxacillin, dicloxacillin, and cloxacillin are eliminated by both the kidney and biliary excretion, and no dosage adjustment is required for these drugs in patients in renal failure. Because clearance of penicillins is less efficient in the newborn, doses adjusted for weight alone result in higher systemic concentrations for longer periods than in the adult.
TABLE 43–1 Guidelines for dosing of some commonly used penicillins.
1The total dose should not exceed the adult dose.