Penicillins (and cephalosporins) act by inhibiting transpeptidases, which are also referred to as penicillin-binding proteins (PBPs). These enzymes catalyze the final cross-linking step in the synthesis of peptidoglycan. For example, in S. aureus, transpeptidation occurs between the amino group on the end of the pentaglycine cross-link and the terminal carboxyl group of the D-alanine on the tetrapeptide side chain. Because the stereochemistry of penicillin is similar to that of a dipeptide, D-alanyl-D-alanine, penicillin can bind to the active site of the transpeptidase and inhibit its activity. Autolytic enzymes called murein hydrolases (murein is a synonym for peptidoglycan) are activated in penicillin-treated cells and degrade the peptidoglycan. Some bacteria (e.g., strains of S. aureus) are tolerant to the action of penicillin because these autolytic enzymes are not activated. A tolerant organism is one that is inhibited but not killed by a drug that is usually bactericidal, such as penicillin. Penicillin-treated cells die by rupture as a result of the influx of water into the high osmotic-pressure interior of the bacterial cell.
Penicillin is bactericidal, but it kills cells only when the bacteria are actively growing. As cells grow, new peptidoglycan is synthesized, and transpeptidation occurs. However, in non growing cells, no new cross-linkages are required, and penicillin is inactive. Penicillins are therefore more active during the log phase of bacterial cell growth than during the stationary phase.
Penicillins (and cephalosporins) are called β-lactam drugs because of the importance of the β-lactam ring (Figure 1). An intact ring structure is essential for antibacterial activity; cleavage of the ring by penicillinases (β-lactamases) inactivates the drug. The most important naturally occurring compound is benzylpenicillin (penicillin G), which is composed of the 6-aminopenicillanic acid nucleus that all penicillins have, plus a benzyl side chain (see Figure 1). Penicillin G is available in three main forms:
(1) Aqueous penicillin G, which is metabolized most rapidly.
(2) Procaine penicillin G, in which penicillin G is conjugated to procaine. This form is metabolized more slowly and is less painful when injected intramuscularly because the procaine acts as an anesthetic.
(3) Benzathine penicillin G, in which penicillin G is conjugated to benzathine. This form is metabolized very slowly and is often called a “depot” preparation.
Fig1. Penicillins. A: The 6-aminopenicillanic acid nucleus is composed of a thiazolidine ring (a), a β-lactam ring (b), and an amino group (c). The sites of inactivation by stomach acid and by penicillinase are indicated. B: The benzyl group, which forms benzylpenicillin (penicillin G) when attached at R. C: The large aromatic ring substituent that forms nafcillin, a β-lactamase–resistant penicillin, when attached at R. The large ring blocks the access of β-lactamase to the β-lactam ring.
Benzylpenicillin is one of the most widely used and effective antibiotics. However, it has four disadvantages, the first three of which have been successfully overcome by chemical modification of the side chain. The four disadvantages are
(1) limited effectiveness against many gram-negative rods due to the inability of the drug to penetrate the outer membrane of the organism.
(2) hydrolysis by gastric acids, so that it cannot be taken orally.
(3) inactivation by β-lactamases.
(4) hypersensitivity reactions, especially anaphylaxis, in some recipients of the drug. This disadvantage has not been overcome by chemical modification.
The effectiveness of penicillins against gram-negative rods has been increased by a series of chemical changes in the side chain (Table 1). Ampicillin and amoxicillin have activity against several gram-negative rods that earlier penicillins lack. However, these drugs are not useful against Pseudomonas aeruginosa and K. pneumoniae. Hence, other penicillins were introduced. Generally speaking, as the activity against gram-negative bacteria increases, the activity against gram-positive bacteria decreases.
Table1. Activity of Selected Penicillins
Acid hydrolysis in the stomach has been addressed by modification of the side chain. The site of acid hydrolysis is the amide bond between the side chain and penicillanic acid nucleus (see Figure 1). Minor modifications of the side chain in that region, such as addition of an oxygen (to produce penicillin V) or an amino group (to produce ampicillin), prevent hydrolysis and allow the drug to be taken orally.
Inactivation of penicillin G by β-lactamases is another important disadvantage, especially in S. aureus infections. Access of the enzyme to the β-lactam ring is blocked by modification of the side chain with the addition of large aromatic rings containing bulky methyl or ethyl groups (methicillin, oxacillin, nafcillin, etc.; see Figure 1). β-Lactamase inhibitors, such as clavulanic acid, tazobactam, sulbactam, and avibactam, are structural analogues of penicillin that have little antibacterial activity but bind strongly to β-lactamases. Thus, prescribing these in combination protects the penicillin. Combinations, such as amoxicillin and clavulanic acid (Augmentin) and piperacillin plus tazobactam (Zosyn), are in clinical use.
Penicillins are usually nontoxic at clinically effective levels. The major disadvantage of these compounds is hypersensitivity, with a reported prevalence of 1% to 10% of patients. The most serious of the hypersensitivity reactions is IgE–mediated, which can give rise to bronchospasm, urticarial rash, and anaphylactic shock. Fortunately, this occurs in only 0.5% of patients. Death as a result of anaphylaxis occurs in 0.002% of patients (1 in 50,000 patients). IgG and cell-mediated hypersensitivity reactions are more common and can include nonurticarial skin rashes, hemolytic anemia, nephritis, and drug fever. A maculopapular drug-induced rash is quite common. While these manifestations are not considered to be “true” allergy and are not life-threatening, they are adverse reactions, and an alternative antibiotic should be considered for patients with a history of these symptoms.
To determine whether the patient’s allergy is clinically significant, a skin test using penicilloyl-polylysine as the test reagent can be performed. A wheal and flare reaction occurs at the site of injection in allergic individuals. If the patient’s disease requires penicillin treatment, the patient can be desensitized under the supervision of a trained allergist.
