The fourth generation penicillins are semisynthetic modifications of natural penicillin that have the advantage of an extended spectrum of activity particularly against gram negative bacteria including Pseudomonas, Enterobacter, Proteus and Klebsiella species. The first generation penicillins are bactericidal antibiotics naturally derived from the mold, Penicillium chrysogenum. Their basic structure includes a thiazolidine ring connected to a beta-lactam ring with a variable side chain. Penicillins bind to bacterial proteins and inhibit synthesis of the bacterial cell wall, causing cell lysis particularly in rapidly growing organisms. Bacterial resistance to penicillin is usually mediated by beta-lactamase, an enzyme which destroys the beta-lactam ring of penicillin, rendering it inactive.
The fourth generation penicillins (sometimes referred to as penicillins with extended spectrum of action) like natural penicillin are susceptible to beta-lactamase. The extended spectrum penicillins are used for therapy of moderate to severe urinary, respiratory, gastrointestinal tract, skin, bone and joint infections. They have activity against Escherichia coli, Hemophilus influenzae, Listeria monocytogenesis, Neisseria gonorrhoeae, Proteus mirabilis, Salmonella, Shigella, Staphylococcus aureus (non-penicillinase producing), Staphylococcus epidermidis, and Streptococcus pneumoniae.
Only one fourth generation penicillin is currently available in the United States: piperacillin (pi" per a sil' in). Several others were used in the United States or Europe, but were abandoned or have been withdrawn (ticarcillin, carbenicillin, mezlocillin and azlocillin). Piperacillin is also available in combination with the beta-lactamase inhibitor tazobactam (taz" oh bak' tam), which provides coverage against penicillinase-resistant bacteria. Piperacillin is a rare cause of acute liver injury and appears to share a common pattern of associated liver injury with other penicillins. Carbenicillin (kar" ben i sil' in), mezlocillin (mez" loe sil' in), and ticarcillin (tye” car sil’ in) fourth generation penicillins that have been withdrawn from use, have also been linked to penicillin-like hepatotoxicity. The combination of ticarcillin with clavulanic acid has been associated with injury that resembles the cholestatic hepatitis that follows therapy with amoxicillin-clavulanate.