title: Efficacy of cefepime and imipenem in experimental murine pneumonia caused by porin-deficient Klebsiella pneumoniae producing CMY-2 beta-Lactamase.
abstract: Previous studies have shown decreased in vitro activity of zwitterionic cephalosporins and carbapenems against porin-deficient Klebsiella pneumoniae expressing a plasmid-mediated AmpC-type beta-lactamase (PACBL). The in vitro and in vivo activities of cefepime and imipenem were evaluated against the porin-deficient strain K. pneumoniae C2 and its CMY-2-producing derivative [K. pneumoniae C2(pMG248)]. The MICs (in micrograms/milliliter) of cefepime and imipenem against K. pneumoniae C2 were 0.125 and 0.25, respectively, while the corresponding values against K. pneumoniae C2(pMG248) were 8 and 16. Cefepime showed a greater inoculum effect than imipenem against both strains. Imipenem showed a significant postantibiotic effect (>2 h) against K. pneumoniae C2(pMG248) at 1x, 2x, 4x, 6x, and 8x MIC. The maximum concentrations of drug in serum of cefepime and imipenem in a pneumonia model using mice were 124.1 and 16.9 mug/ml, respectively. DeltaT/MIC for K. pneumoniae C2 and C2(pMG248) were 1.29 h and 0.34 h for imipenem and 2.96 h and 1.27 h for cefepime. Both imipenem (30 mg/kg of body weight every 3 h) and cefepime (60 mg/kg every 4 h), administered for 72 h, increased the survival rate (86.6% and 100%) compared with untreated control animals (26.6%, P < 0.003) infected with K. pneumoniae C2. For the CMY-2-producing strain, imipenem, but not cefepime, increased the survival rate compared to the controls (86.6% and 40% versus 40%, P < 0.01). Bacterial concentration of the lungs was significantly decreased by both antimicrobials. In conclusion, imipenem was more active in terms of survival than cefepime for the treatment of murine pneumonia caused by a porin-deficient K. pneumoniae expressing PACBL CMY-2.
authors.affiliation: Department of Microbiology, School of Medicine, University of Seville, Apdo. 914, 41080 Seville, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pichardo
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Rodríguez-Martínez
authors.forename: María E
authors.initials: ME
authors.lastname: Pachón-Ibañez
authors.forename: Carmen
authors.initials: C
authors.lastname: Conejo
authors.forename: José
authors.initials: J
authors.lastname: Ibáñez-Martínez
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Martínez
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Pachón
authors.forename: Alvaro
authors.initials: A
authors.lastname: Pascual
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000077723:Cefepime; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015378:Imipenem / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology; D018272:Porins / Q000172:deficiency / Q000235:genetics; D016896:Treatment Outcome; D001618:beta-Lactamases / Q000096:biosynthesis*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D018272:Porins; D015378:Imipenem; D000077723:Cefepime; C103022:beta-lactamase CMY-2; D001618:beta-Lactamases