title: Impact of various conditions on the efficacy of dual carbapenem therapy against KPC-producing Klebsiella pneumoniae.
abstract: The efficacy of dual carbapenem therapy under various conditions, including increased MIC, different immune status and treatment duration and use of a higher ertapenem dose, was evaluated in a murine thigh model. Three KPC-producing Klebsiella pneumoniae isolates with different phenotypic profiles were used. Human-simulated doripenem and ertapenem doses were given alone or in combination. Three isolates were tested over 24 h in immunocompetent and immunocompromised ICR mice. Two of the isolates were also evaluated over 72 h in neutropenic mice. High-dose ertapenem regimens were also evaluated. The efficacy of combination therapy was enhanced in the immunocompetent model over the neutropenic model (P<0.05 for all three isolates). In the immunocompetent model, bacterial density was further reduced with use of combination therapy over doripenem monotherapy for two isolates with doripenem MICs≤16 mg/L (statistically greater for one isolate; P<0.05). Whilst not statistically different at 24 h in neutropenic mice, combination therapy demonstrated significantly greater efficacy over doripenem alone for one of two isolates at 72 h (P<0.05). Use of ertapenem 2g did not enhance efficacy over ertapenem 1 g (P>0.05). The beneficial effects of dual carbapenem therapy and potential difference in efficacy based on doripenem MICs are evident at 24 h in an immunocompetent setting. Within a neutropenic setting, enhanced efficacy with combination therapy may only be evident with continued therapy. Dual carbapenem regimens may represent a promising option for infections caused by KPC-producing isolates, particularly when the MIC is low.
authors.affiliation: University of Saint Joseph, School of Pharmacy, Hartford, CT, USA.
authors.forename: Dora E
authors.initials: DE
authors.lastname: Wiskirchen
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000378:metabolism*; D015780:Carbapenems / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D016867:Immunocompromised Host; D007710:Klebsiella Infections / Q000188:drug therapy* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008813:Mice, Inbred ICR; D009503:Neutropenia / Q000150:complications; D016896:Treatment Outcome; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D001618:beta-Lactamases; C063912:carbapenemase