.

The addition of new side chains created a socalled

second generation of cephalosporins with greater
potency, especially against Gram-negative anaerobes. The
third- and fourth-generation cephalosporins, synthesized
with further modifi cations of the side chains, have a
somewhat expanded spectrum of activity (see Fig. 5-5).
Cephalosporins in this class have two important advantages:
First, they extend the spectrum of activity to
organisms that were resistant to most of the previous
cephalosporins, including Pseudomonas, an opportunistic
pathogen, and Haemophilus infl uenzae, an important
pathogen in pulmonary infections and meningitis. Second,
unlike the previous cephalosporins, they penetrate well
into the central nervous system. This ability has made
them especially useful in the treatment of Gram-negative
meningitis. Like third- and fourth-generation cephalosporins,
carbapenems typically have a very broad spectrum
of activity, including most Gram-positive, Gram-negative,
and anaerobic bacteria.
The bactericidal action of the -lactam antibiotics
requires the following steps:
1. Association with the bacteria
2. Penetration through the outer membrane and the periplasmic
space (only in Gram-negatives)
3. Interaction with penicillin-binding proteins (PBPs) on
the cytoplasmic membrane
4. Activation of an autolysin that degrades the cell wall
murein
The principal mechanism of resistance to the -lactams
is the elaboration of inactivating enzymes, the b-lactamases.
So far, more than 300 -lactamases have been identifi ed, a
small number of which account for most of the clinically
encountered resistance. They can be divided into major
categories, including the penicillinase, cephalosporinases,
extended-spectrum beta-lactamases or ESBLs (which confer