Emergence of Resistance to Ceftazidime During Therapy for Enterobacter cloacae Infections

Abstract

The mechanism of resistance to ceftazidime in two clinical isolates of Enterobacter cloacae that emerged during therapy with broad-spectrum β-lactam antibiotics was studied. Both isolates acquired broad resistance to advanced-spectrum β-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 β-lactamase constitutively. Slow but definite hydrolysis of ceftazidime was demonstrated by using purified β-lactamase in a spectrophotometric assay, Further evidence that β-lactamase is responsible for resistance in these organisms was provided by the demonstration that cefoxitin, a potent inducer of β-lactamase, antagonized the activity of ceftazidime against these isolates. This antagonism could be prevented by inhibition of derepression of β-lactamase with clindamycin. Clindamycin also prevented regrowth of ceftazidime-treated cells in time-kill studies and markedly reduced production of β-lactamase in induced cultures at concentrations as low as 2 μg/ml.