Substituents of the 6-aminopenicillanic acid moiety determine the essential pharmacologic and antibacterial properties of the resulting molecules. Penicillins can be assigned to one of three groups (below). Within each of these groups are compounds that are relatively stable to gastric acid and suitable for oral administration, eg, penicillin V, dicloxacillin, and amoxicillin. The side chains of some representatives of each group are shown in Figure 43–2.
1. Penicillins (eg, penicillin G)—These have greatest activity against Gram-positive organisms, Gram-negative cocci, and non-β-lactamase-producing anaerobes. However, they have little activity against Gram-negative rods, and they are susceptible to * The authors thank Dr. Henry F. Chambers and Dr. Daniel Deck for their contributions to this chapter in previous editions. hydrolysis by β-lactamases.
R: CH2 CH2 NH CH
FIGURE 43–1 Core structures of four β-lactam antibiotic families. The ring marked B in each structure is the β-lactam ring. The penicillins are susceptible to inactivation by amidases and lactamases at the points shown. Note that the carbapenems have a different stereochemical configuration in the lactam ring that imparts resistance to most common β-lactamases. Substituents for the penicillin and cephalosporin families are shown in Figures 43–2 and 43–6, respectively.
2.
Antistaphylococcal penicillins (eg, nafcillin)—These penicillins are resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and Gram-negative cocci and rods.
3.
Extended-spectrum penicillins (aminopenicillins and antipseudomonal penicillins)—These drugs retain the antibacterial spectrum of penicillin and have improved activity against Gram-negative rods. Like penicillin, however, they are relatively susceptible to hydrolysis by β-lactamases.
The following structures can each be substituted at the R to produce a new penicillin.
FIGURE 43–2 Side chains of some penicillins (R groups).
B. Penicillin Units and Formulations
The activity of penicillin G was originally defined in units. Crystalline sodium penicillin G contains approximately 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g). Semisynthetic penicillins are prescribed by weight rather than units. The minimum inhibitory concentration (MIC) of any penicillin (or other antimicrobial) is usually given in mcg/mL. Most penicillins are formulated as the sodium or potassium salt of the free acid. Potassium penicillin G contains about 1.7 mEq of K+ per million units of penicillin (2.8 mEq/g). Nafcillin contains Na+, 2.8 mEq/g. Procaine salts and benzathine salts of penicillin G provide repository forms for intramuscular injection. In dry crystalline form, penicillin salts are stable for years at 4°C. Solutions lose their activity rapidly (eg, within 24 hours at 20°C) and must be prepared fresh for administration.
Mechanism of Action