Emergence of resistance in gram-negative bacilli during beta-lactam therapy: a challenge for the future.

The means by which gram-negative bacilli can resist newer beta-lactam antibiotics are reviewed. A first situation is generated by mutants which produce great amounts of a chromosomal cephalosporinase. These cells are present (frequency: 10(-4) to 10(-7] within bacterial populations such as Enterobacter cloacae, and multiply after selection during therapy by third-generation cephalosporins or monobactams. A second problem arose by 1985, with the sudden development of plasmid-mediated beta-lactamases markedly active against third-generation cephalosporins. Some recent molecules, such as penems, are not affected by the two mechanisms mentioned above but remain exposed to other resistance problems. Notably Pseudomonas aeruginosa strains can develop resistance during therapy by imipenem thanks to specific alterations of the bacterial outer membrane. As a consequence of these resistance difficulties, new interpretations for susceptibility testing and new therapeutic approaches should be considered.