Comparative Activities of Doripenem versus Isolates, Mutants, and Transconjugants of Enterobacteriaceae and Acinetobacter spp. with Characterized β-Lactamases

Abstract

ABSTRACT Doripenem (S-4661), a new parenteral carbapenem, was tested against over 250 clinical isolates, mutants, and transconjugants of Enterobacteriaceae and Acinetobacter spp., selected or derived for their β-lactamase expression characteristics. Imipenem, meropenem, and ertapenem were tested as comparators, along with cephalosporins and piperacillin-tazobactam, by using National Committee for Clinical Laboratory Standards agar dilution methodology. Doripenem MICs were from 0.03 to 0.25 μg/ml for Klebsiella isolates, irrespective of the presence of extended-spectrum β-lactamases (ESBLs) or plasmid-mediated AmpC or hyperproduced K1 β-lactamase. Similarly, MICs of doripenem for both AmpC-inducible and -derepressed Enterobacter isolates were 0.06 to 0.5 μg/ml. ESBL production did not raise the MICs of doripenem for Escherichia coli transconjugants, and studies with known expression mutants confirmed that neither inducible nor depressed AmpC β-lactamase expression was protective in Enterobacter cloacae , Citrobacter freundii , Serratia marcescens , or Morganella morganii . In all of these respects, doripenem resembled meropenem and imipenem, whereas the MICs of ertapenem were raised (but still ≤1 μg/ml) for many ESBL-producing klebsiellas and AmpC-derepressed E. cloacae and C. freundii strains. Resistance to all carbapenems, including doripenem (MICs of mostly 16 to 64 μg/ml, compared with 0.25 to 1 μg/ml for typical strains), was seen in Acinetobacter isolates with metallo-β-lactamases or OXA-carbapenemases. Isolates of Klebsiella and Serratia spp. with IMP, KPC, and SME β-lactamases also were resistant to doripenem (MICs, 8 to >64 μg/ml) and to other carbapenems, although the continued apparent susceptibility (MICs, ≤0.5 μg/ml) of E. coli derivatives with cloned IMP-1 and NMC-A β-lactamases suggested that carbapenem resistance might require other factors besides the enzymes.