Cefuroxime Treatment Failure of Nontypable Haemophilus influenme Meningitis Associated with Alteration of Penicillin-Binding Proteins

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Abstract
A 10-year-old boy presented with nuchal rigidity and cerebrospinal fluid (CSF) leukocytosis initially and again on day 6 of intravenous cefuroxime therapy (200 mg/kg/day). Both CSF specimens yielded nontypable β-lactamase-negative Haemophilus influenzae that were susceptible by disk tests but relatively resistant to cefuroxime (MIC, 8- to 16-fold greater than that of control isolates). To define the mechanism of resistance, the cefuroxime resistance marker was transformed to a susceptible H. influenzae recipient; inactivation and permeability of β-lactam substrate were tested and the penicillin-binding protein (PBP) profiles were examined. Inactivation of β-lactam substrate was not detected and reduced permeability was not found. However, reduced β-lactam binding to PBPs 4 and 5 was observed; 18- to 27-fold more penicillin and 2.5 to 4-fold more cefuroxime was required to saturate or block 50% of the binding sites of these PBPs, respectively. Thus, reduced affinity of PBPs 4 and 5 for β-lactam substrate appears to be the mechanism of cefuroxime resistance in this strain. The reduced affinity of these targets appears to have contributed to the bacteriologic and clinical failure in this patient.