Efficacy of Cefepime and Imipenem in Experimental Murine Pneumonia Caused by Porin-Deficient Klebsiella pneumoniae Producing CMY-2 β-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 ␤-lactamase (PACBL). The in vitro and in vivo activities of cefepime and imipenem were evaluated against the porindeficient 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 1؋, 2؋, 4؋, 6؋, and 8؋ MIC. The maximum concentrations of drug in serum of cefepime and imipenem in a pneumonia model using mice were 124.1 and 16.9 g/ml, respectively. ⌬T/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.

Broad-spectrum -lactams for treating experimental peritonitis in mice due to Escherichia coli producing plasmid-encoded cephalosporinases

“…In vivo, our experiments showed that cefepime and imipenem were efficient for treating high inoculum infections with E. coli strains producing plasmid-mediated AmpC-type b-lactamases. These results correlate with data reporting the in vivo efficacy of these b-lactams for treating experimental respiratory infections with K. pneumoniae expressing plasmid-mediated cephalosporinases (ACT-1, 25 CMY-2 26 and FOX-5 27 ). Despite relatively low MIC values determined by a plate dilution method, piperacillin/tazobactam failed to treat experimental infections, indicating that in vitro susceptibility testing was not a good predictive factor of its in vivo efficacy.…”

AmpC β-Lactamases

“…Also, in a rat pneumonia model with a K. pneumoniae strain producing ACT-1, ␤-lactam therapy with imipenem, meropenem, ertapenem, or cefepime gave equivalent results, even if the test strain was porin deficient (243). However, in a mouse pneumonia model with a porindeficient strain of K. pneumoniae producing CMY-2 ␤-lactamase, survival with cefepime therapy was no better than that without antibiotic and significantly inferior to that with imipenem treatment (256). Nonetheless, cefepime has cured infections due to multiply resistant Enterobacter spp.…”

“…Cefepime is a poor inducer of AmpC ␤-lactamase, rapidly penetrates through the outer cell membrane, and is little hydrolyzed by the enzyme (232,283), so many AmpC-producing organisms test cefepime susceptible with a conventional inoculum (see Table 6 for examples). If a 100-fold-higher inoculum is used, however, cefepime MICs increase dramatically for some AmpC producers, suggesting caution in its use (154,256), and some strains are frankly resistant (238). In a pneumonia model using guinea pigs, cefepime, imipenem, and meropenem were equally effective against a porin-deficient K. pneumoniae strain producing FOX-5 ␤-lactamase (255).…”

Clinical management of infections caused by multidrug-resistant Enterobacteriaceae

“…It has been shown to be effective in animal models [Vimont et al 2007], even for porin-deficient, plasmid-mediated AmpC-producing K. pneumoniae [Pichardo et al 2005]. Development of cefepime resistance in vivo has been described during cefepime therapy in infections caused by AmpCexpressing Enterobacter aerogenes [Barnaud et al 2004;Rodriguez-Martinez et al 2012].…”