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Faropenem is a new oral beta-lactam antibiotic unique from carbapenems and other available beta-lactams. Determinants of the in vitro activity of beta-lactam antibiotics include affinity to penicillin-binding proteins (PBPs) and beta-lactamase stability. In this study, the binding affinity of faropenem to various PBPs and its impact on the morphology of Staphylococcus aureus and Escherichia coli were evaluated. In general, faropenem demonstrated high binding affinity to high-molecular-weight PBPs but low affinity to low-molecular-weight PBPs. In S. aureus and Streptococcus pneumoniae, faropenem exhibited high binding affinity to PBP1, followed by PBP3 and PBP2. In E. coli, faropenem showed the highest affinity for PBP2, followed by PBP1A, PBP1B, PBP3 and PBP4. In Proteus vulgaris, binding was highest to PBP4, followed by PBP1A, PBP2 and PBP3. In Serratia marcescens, faropenem bound preferentially to PBP2 and PBP4. Exposure of S. aureus to faropenem at minimum inhibitory concentrations (MICs) of 1/8 or 1/4 resulted in irregular septum formation. At 1x MIC or higher, a larger number of lysed cells were observed. Exposure of E. coli to 1/8x MIC or 1/4x MIC also induced changes in cellular shape; the normal rod-shaped form changed to a spherical form in a time-dependent manner. After exposure of E. coli to 1x MIC for 2 h, bulging-shaped E. coli cells were observed and after 4 h of exposure cell lysis was demonstrated. In the presence of 4x MIC, spheroplast-like forms and cell lysis were observed. The morphological changes triggered by faropenem are in agreement with the PBP binding affinities reported. Thus, the high binding affinities of faropenem to PBPs from gram-negative and gram-positive bacteria are mirrored by its pronounced and concentration-dependent bactericidal effect., (Copyright 2003 S. Karger AG, Basel)

Although many complications may arise with the use of central venous catheters, catheter-related bacteremia is considered to be the most serious complication. Microflora on the patient's skin (coagulase-negative staphylococci, Staphylococcus aureus) is thought to represent the major source of microorganisms causing catheter-related infections. Gram-negative rods are increasingly observed as causative agents. We therefore performed an in vitro study to elucidate the pathogenesis of polymer-associated infections caused by enterobacteriaceae and nonfermenters and to study the resistance of polymer surface-grown gram-negative rods against antibiotics. Using a modification of the semiquantitative method for culturing vascular cannulas on solid media described by Maki et al., we studied the adherence of various gram-negative rods to 1-cm segments of silastic catheters, a material used for Port-A-Cath-systems. Organisms were obtained from the American Type Culture Collection (Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Pseudomonas aeruginosa, Enterobacter cloacae). All organisms but Klebsiella showed extensive irreversible adherence. Production of an extracellular slime substance was observed only with antimicrobially treated Pseudomonas. After 'infection', the silastic catheter segments were treated with various antimicrobial agents. The following antibiotics were used either individually or in combination: cefotaxime, ciprofloxacin, imipenem, fosfomycin and gentamicin. Despite the fact that the antibiotic concentrations used were many times greater than the respective MICs of the various antibiotics, none of the antibiotics tested succeeded in eliminating the organisms. E. coli was found to be the most susceptible organism. These in vitro data substantiate our clinical impression that it is hardly possible to successfully eliminate the colonization of central venous catheters with gram-negative rods by using the antimicrobial agents employed here.

Upon exposure of Enterobacter cloacae silver sulfadiazine, a number of ultrastructural changes involving the cell envelope take place. Foremost among these is a modification of the cell wall from an undulating structure to one which is smooth and has become enlarged. Strains of E. cloacae resistant to silver sulfadiazine do not exhibit these changes.