The penicillins share a common chemical nucleus (6-aminopenicillanic acid) that contains a beta-lactam ring essential to their biologic activity.
Antimicrobial Action & Resistance
The initial step in penicillin action is the binding receptors, ie, penicillin-binding proteins. After attaching to receptors, penicillins inhibit peptidoglycan synthesis by blocking transpeptidation. The final bactericidal action is to remove an autolytic enzyme inhibitor in the cell wall, which results in cell lysis. Organisms that produce beta-lactamases (penicillinases) are resistant to some penicillins because the beta-lactam ring is broken. Only organisms actively synthesizing peptidoglycan (in the process of multiplication) are susceptible to penicillins and other beta-lactam antibiotics. Nonmultiplying organisms or those lacking cell walls are not susceptible.
Microbial resistance to penicillins is associated with five mechanisms: (1) production of beta-lactamases, (eg, by staphylococci, gonococci, Haemophilus species, and coliform organisms, including extended-spectrum beta-lactamase [ESBL]–producing bacteria); (2) lack of penicillin-binding proteins or decreased affinity of penicillin-binding protein for beta-lactam antibiotic receptors (eg, resistant pneumococci, methicillin-resistant staphylococci, enterococci); (3) impermeability of the cell envelope (eg, by Pseudomonas species); (4) failure to activate autolytic enzymes in the cell wall—“tolerance” (eg, in staphylococci, group B streptococci); and (5) cell wall-deficient (L) forms or mycoplasmas, which do not synthesize peptidoglycans.
The natural penicillins include penicillin G for parenteral administration (aqueous crystalline for intravenous or benzathine penicillin G for intramuscular administration) or for oral administration (penicillin G and phenoxymethyl penicillin [penicillin V]). They are most active against gram-positive organisms and are susceptible to hydrolysis by beta-lactamases. They are used (1) for infections caused by susceptible and moderately susceptible pneumococci, depending at the site of infection; (2) other streptococci, such as Streptococcus pyogenes, (including anaerobic streptococci); (3) meningococci; (4) non–beta-lactamase-producing staphylococci; (5) Treponema pallidum and other spirochetes; (6) Cutibacterium (formerly Propionibacterium) acnes and other gram-positive anaerobic bacilli; (7) non-difficile clostridia; and (8) Actinomyces. See Table 30–4.
Pharmacokinetics & Administration
Penicillin has wide extracellular distribution with decreased levels in the eye, prostate, and cerebrospinal fluid. However, with inflamed meninges and appropriate dosing, sufficient penetration into the cerebrospinal fluid can be achieved.
Because intramuscular administration of benzathine penicillin allows for extended release of penicillin, continuous therapeutic blood and tissue levels allow for the treatment of syphilis.
Phenoxymethyl penicillin (penicillin V) is the oral penicillin of choice because of its superior bioavailability compared to penicillin G. Penicillin is primarily eliminated by the kidney through both glomerular filtration and active tubular secretion.
Most infections due to susceptible organisms respond to aqueous penicillin G in daily doses of 1–2 million units administered intravenously every 4–6 hours. For more serious infections (meningitis, endocarditis), increased doses (3–4 million units intravenously every 4–6 hours with normal kidney function) are required.