Page 811 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 43 Beta-Lactam & Other Cell Wall- & Membrane-Active Antibiotics 797

B. Penicillin Units and Formulations polysaccharides and peptides known as peptidoglycan. The poly-
The activity of penicillin G was originally defined in units. Crys- saccharide contains alternating amino sugars, N-acetylglucosamine
talline sodium penicillin G contains approximately 1600 units and N-acetylmuramic acid (Figure 43–4). A five-amino-acid
per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g). peptide is linked to the N-acetylmuramic acid sugar. This peptide
Semisynthetic penicillins are prescribed by weight rather than terminates in d-alanyl-d-alanine. Penicillin-binding protein (PBP,
units. The minimum inhibitory concentration (MIC) of any an enzyme) removes the terminal alanine in the process of forming
penicillin (or other antimicrobial) is usually given in mcg/mL. a cross-link with a nearby peptide. Cross-links give the cell wall its
Most penicillins are formulated as the sodium or potassium salt of rigidity. Beta-lactam antibiotics, structural analogs of the natural
the free acid. Potassium penicillin G contains about 1.7 mEq of d-Ala-d-Ala substrate, covalently bind to the active site of PBPs.
+
K per million units of penicillin (2.8 mEq/g). Nafcillin contains This binding inhibits the transpeptidation reaction (Figure 43–5)
+
Na , 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G and halts peptidoglycan synthesis, and the cell dies. The exact
provide repository forms for intramuscular injection. In dry crys- mechanism of cell death is not completely understood, but auto-
talline form, penicillin salts are stable for years at 4°C. Solutions lysins are involved in addition to the disruption of cross linking of
lose their activity rapidly (eg, within 24 hours at 20°C) and must the cell wall. Beta-lactam antibiotics kill bacterial cells only when
be prepared fresh for administration. they are actively growing and synthesizing cell wall.

Mechanism of Action Resistance

Penicillins, like all β-lactam antibiotics, inhibit bacterial growth Resistance to penicillins and other β-lactams is due to one of four
by interfering with the transpeptidation reaction of bacterial cell general mechanisms: (1) inactivation of antibiotic by β-lactamase,
wall synthesis. The cell wall is a rigid outer layer that completely (2) modification of target PBPs, (3) impaired penetration of drug
surrounds the cytoplasmic membrane (Figure 43–3), maintains to target PBPs, and (4) antibiotic efflux. Beta-lactamase produc-
cell integrity, and prevents cell lysis from high osmotic pressure. tion is the most common mechanism of resistance. Hundreds
The cell wall is composed of a complex, cross-linked polymer of of different β-lactamases have been identified. Some, such as

Porin

Outer
membrane

Cell
wall

Peptidoglycan

β Lactamase
Periplasmic
space

PBP PBP

Cytoplasmic
membrane

FIGURE 43–3 A highly simplified diagram of the cell envelope of a Gram-negative bacterium. The outer membrane, a lipid bilayer, is
present in Gram-negative but not Gram-positive organisms. It is penetrated by porins, proteins that form channels providing hydrophilic
access to the cytoplasmic membrane. The peptidoglycan layer is unique to bacteria and is much thicker in Gram-positive organisms than in
Gram-negative ones. Together, the outer membrane and the peptidoglycan layer constitute the cell wall. Penicillin-binding proteins (PBPs) are
membrane proteins that cross-link peptidoglycan. Beta-lactamases, if present, reside in the periplasmic space or on the outer surface of the
cytoplasmic membrane, where they may destroy β-lactam antibiotics that penetrate the outer membrane.