Chapter 53

### INTRODUCTION

The β-lactam antibiotics are useful and frequently prescribed antimicrobial agents that share a common structure and mechanism of action: inhibition of synthesis of the bacterial peptidoglycan cell wall. The group includes penicillins, cephalosporins, and carbapenems.

The penicillins consist of penicillins G and V, which are highly active against susceptible gram-positive cocci; penicillinase-resistant penicillins such as nafcillin, which are active against penicillinase-producing Staphylococcus aureus; ampicillin and other agents with an improved gram-negative spectrum, especially when combined with a β-lactamase inhibitor; and extended-spectrum penicillins with activity against Pseudomonas aeruginosa, such as piperacillin.

The β-lactams also include the cephalosporin antibiotics, which are classified by generation: First-generation agents have excellent gram-positive and modest gram-negative activity; second-generation agents have somewhat better activity against gram-negative organisms and include some agents with antianaerobe activity; third-generation agents have activity against gram-positive organisms and much more activity against the Enterobacteriaceae, with a subset active against P. aeruginosa; and fourth-generation agents encompass the antimicrobial spectrum of all the third-generation agents and have increased stability to hydrolysis by inducible chromosomal β-lactamases.

Carbapenems, including imipenem, doripenem, ertapenem and meropenem, have the broadest antimicrobial spectrum of any antibiotic, whereas the monobactam aztreonam has a gram-negative spectrum resembling that of the aminoglycosides.

β-Lactamase inhibitors such as clavulanate are used to extend the spectrum of penicillins against β-lactamase-producing organisms. Bacterial resistance against the β-lactam antibiotics continues to increase at a dramatic rate. Mechanisms of resistance include not only production of β-lactamases that in some cases destroy all β-lactam antibiotics, but also alterations in or acquisition of novel penicillin-binding proteins PBPs and decreased entry and/or active efflux of the antibiotic. It is not an exaggeration to state that we are re-entering the pre-antibiotic era, with many nosocomially acquired gram-negative bacterial infections resistant to all available antibiotics.

### THE PENICILLINS

Despite the existence of microbial resistance, the penicillins constitute one of the most important groups of antibiotics. Many of these have unique advantages such that members of this group of antibiotics are currently the drugs of choice for a large number of infectious diseases.

History. The history of the brilliant research that led to the discovery and development of penicillin is well chronicled. In 1928, while studying Staphylococcus variants in the laboratory at St. Mary's Hospital in London, Alexander Fleming observed that a mold contaminating one of his cultures caused the bacteria in its vicinity to undergo lysis. Broth in which the fungus was grown was markedly inhibitory for many microorganisms. Because the mold belonged to the genus Penicillium, Fleming named the antibacterial substance penicillin.

A decade later, penicillin was developed as a systemic therapeutic agent by the concerted research of a group of investigators at Oxford University headed by Florey, Chain, and Abraham. By May 1940, a crude preparation was found to produce dramatic therapeutic effects when ...

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