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Sir, The most relevant single mechanism of resistance of Enterobacteriaceae to cephalosporins is the production of -lactamases. For Klebsiella pneumoniae, these enzymes are usually plasmid-mediated extended-spectrum -lactamases (ESBLs) or, less commonly, plasmid-mediated AmpC-type enzymes. K. pneumoniae produces two major porins, outer membrane proteins (Omps) K35 and K36, which are homologous to Escherichia coli porins OmpF and OmpC, respectively. In klebsiellae, simultaneous loss of both OmpK35 and OmpK36 causes increased resistance to cephalosporins and other -lactams when ESBL or AmpCtype -lactamase is also produced. ESBLs do not confer resistance to cephamycins and carbapenems. Cephamycins, however, are able to select for mutants that are deficient in porins, resulting in subsequent resistance to these agents. Cefepime and cefpirome are poorly hydrolysed by AmpCtype -lactamases but have less activity against ESBLproducing strains, particularly in porin-deficient organisms. ESBL-producing K. pneumoniae are more frequently resistant to aminoglycosides and fluoroquinolones than K. pneumoniae strains not producing these -lactamases. The purpose of this study was to evaluate the activity of cefepime, cefpirome, third-generation cephalosporins, carbapenems, amikacin and ciprofloxacin against clinical isolates of ESBL-producing K. pneumoniae with different porin profiles. Sixty-five non-consecutive clinical isolates of ceftazidime-resistant K. pneumoniae isolated at the Microbiology Laboratory of the University Hospital V. Macarena (Seville, Spain) in the period 1994–1997 were studied. Strains were selected to include 15 isolates deficient in porins (see below). E. coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and K. pneumoniae LB4 (producing SHV-5) were also included as controls for antimicrobial susceptibility testing. K. pneumoniae C3 (producing OmpK35 and OmpK36) and E. coli K-12 mutants deficient in OmpA, OmpF or OmpC were used as reference strains in the determination of porin profiles. The activities of cefepime, cefpirome, cefotaxime, ceftazidime, cefoxitin, imipenem, meropenem, ciprofloxacin and amikacin were evaluated by a microdilution assay according to NCCLS guidelines. A 8-fold decrease in the activities of either ceftazidime or cefotaxime with clavulanic acid (2 mg/L) compared with ceftazidime or cefotaxime alone was taken as an indication of ESBL production. Omps were obtained after sonication of bacteria and sarkosyl treatment of cell membranes. Omps were separated by sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE) using 11% polyacrylamide in the running gel. Bacteria were categorized as porin producers (P ) if at least one protein band corresponding to either OmpK35 or OmpK36 was detected, and as porin-deficient (P ) if no major bands in the region of porins were observed. Fifty of the 65 clinical isolates of ESBL-producing K. pneumoniae produced at least one porin (mostly OmpK36). The remaining 15 strains were deficient in both OmpK35 and OmpK36. The proportion of isolates expressing or not expressing porins does not reflect their actual frequency of isolation among clinical isolates, as K. pneumoniae strains deficient in both porins are much less common than would be predicted from these figures. The activities of nine antimicrobial agents against P and P strains are presented in the Table. The activity of cefepime and cefpirome against both P and P strains is higher than that of cefotaxime and ceftazidime. Nevertheless, and according to the NCCLS recommendations, ESBL-producing K. pneumoniae are considered resistant to all cephalosporins, independently of the in vitro activity of the different compounds within this group. The MIC50s and MIC90s of cefoxitin against P and P strains indicate that loss of porins is critical for resistance to this cephamycin in ESBL-producing K. pneumoniae. Porin loss contributes to increasing the level of resistance to the other cephalosporins in ESBL-producing strains. Both imipenem and meropenem were the most active

the journal of antimicrobial chemotherapy/journal of antimicrobial chemotherapy

Activity of nine antimicrobial agents against clinical isolates of Klebsiella pneumoniae producing extended-spectrum beta-lactamases and deficient or not in porins