Emergence of resistance to ceftazidime during therapy for Enterobacter cloacae infections.

The mechanism of resistance to ceftazidime in two clinical isolates of Enterobacter cloacae that emerged during therapy with broad-spectrum beta-lactam antibiotics was studied. Both isolates acquired broad resistance to advanced-spectrum beta-lactam drugs other than imipenem. Biotyping confirmed strain identity in both cases, and no new plasmids were detected in the resistant isolates. Both resistant isolates produced beta-lactamase constitutively. Slow but definite hydrolysis of ceftazidime was demonstrated by using purified beta-lactamase in a spectrophotometric assay. Further evidence that beta-lactamase is responsible for resistance in these organisms was provided by the demonstration that cefoxitin, a potent inducer of beta-lactamase, antagonized the activity of ceftazidime against these isolates. This antagonism could be prevented by inhibition of derepression of beta-lactamase with clindamycin. Clindamycin also prevented regrowth of ceftazidime-treated cells in time-kill studies and markedly reduced production of beta-lactamase in induced cultures at concentrations as low as 2 micrograms/ml.