In vitro activity and beta-lactamase stability of FK-037, a parenteral cephalosporin

Abstract

The in vitro activity of FK-037, 5-amino-2-[[(6R, 7R)-7-[[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetyl] aminol-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yllmethyl1-1-(2-hydroxyethyl)-lH-pyrazolium hydroxide, inner salt, sulfate (1:1), a new parenteral cephem, was compared with those of cefepime, ceftazidime, imipenem, and ciprofloxacin. FK-037 inhibited methicillin-susceptible staphylococci at c4 jig/ml. Of 98 isolates of homogenous methicillin-resistant Staphylococcus aureus, 55 (56.1%) were inhibited by 8 jig of FK-037 per ml, compared to 3.1% for cefepime. Imipenem was the most active 13-lactam tested against staphylococci. The MIC of FK-037 for 90o of the strains tested (MIC90) was 0.06 ,ug/ml for hemolytic streptococci, Streptococcus pneumoniae, viridans group streptococci, and Streptococcus bovis. The MIC90 for many of the members of the family Enterobacteriaceae was 1 ji.g/ml, similar to that of cefepime and lower than those of ceftazidime and imipenem. The MIC,0 for KiebsieUla pneumonwiae and Enterobacter cloacae was 8 jug/ml, similar to that for cefepime, but all isolates were inhibited by 2 ,ig of imipenem per ml. K. pneumoniae isolates with cefotaxime and ceftazidime MICs of >32 jig/ml with Bush type 2b' 13-lactamases were inhibited by 4 jig of FK-037 per ml. E. cloacae, Citrobacterfreundii, and S. aureus stably resistant to FK-037 could be selected by repeated transfer in the presence of FK-037. The FK-037 MIC90 for Pseudomonas aeruginosa was 4 ,Ig/ml, compared to 32 jug/ml for cefepime and ceftazidime and 8 pg/ml for imipenem. Xanthomonas maltophilia, Pseudomonas cepacia, Acinetobacter anitratus, and Bacteroides species were resistant to FK-037 (MIC, >32 ,ig/ml). MBCs were identical to or within twofold of the MICs except for a 32-fold greater MBC for P. aeruginosa. Inoculum size and acid environment did not lower the activity of FK-037. FK-037 was not appreciably hydrolyzed by Bush group 1, 2a, 2b, and 2e 1-lactamases but was hydrolyzed by 2b' and 2d enzymes at rates comparable to that of ceftazidime. Nonetheless, FK-037 inhibited bacteria possessing TEM-3, -5, and -7 and SHV-5 at <8 ,ug/ml. Overall, FK-037 has lower MICs against staphylococci and P. aeruginosa than the currently available iminomethoxy aminothiazolyl cephalosporins and has activity against members of the family Enterobacteriaceae comparable to that of cefepime.Although a number of parenteral cephalosporins have been synthesized during the past 2 decades, there has been continued interest in finding new cephalosporins with improved activity against gram-positive bacteria, particularly for methicillin-resistant staphylococci, and which retain the excellent activity of the aminothiazolyl cephalosporins against gram-negative organisms. FK-037, an oxime-type cephem, contains a 1-hydroxyethyl-5-amino pyra-zoliomethyl moiety at position 3 of the cephem ring. Preliminary studies showed FK-037 to have a broad spectrum of antibacterial activity against gram-negative and gram-positive bacteria, including methicillin-resistan...

In vitro activities of various beta-lactam antimicrobial agents against clinical isolates of Escherichia coli and Klebsiella spp. resistant to oxyimino cephalosporins

“…While recent animal model studies suggest that piperacillin-tazobactam may have an effective role in the treatment of infections caused by such strains, further investigations regarding the optimum dosing level of this agent are (17,31). Although previous reports of the activity of cefepime against ESBL producers have been contradictory (3,13,20,23,34,37), we found cefepime activity to be comparable to that of cefotaxime and aztreonam. On the basis of the level of activity and inoculum effect data, cefepime appears to have limited potential against such resistant strains.…”

Pulsed-field gel electrophoresis of restriction-digested genomic DNA and antimicrobial susceptibility of Xanthomonas maltophilia strains from Brazil, Switzerland and the USA

“…The agents tested were: ciprofloxacin (Miles Pharmaceuticals, West Haven, USA); levofloxacin, ofloxacin and FK-037 (Neu, Chin & Huang, 1993) RFLP of chrDNA was determined using the procedure previously used for Pseudomonas aeruginosa (Sader et al, 1993). After growing the cells in trypticase soy broth to the exponential phase, they were pelleted by centrifugation, washed and mixed with 2% agarose (SeaPlaque GTG, FMC, Rockland, USA) to a final 1% agarose concentration.…”

Multicenter comparison of in vitro activities of FK-037, cefepime, ceftriaxone, ceftazidime, and cefuroxime

“…FK-037 has also been reported to have a broad spectrum of activity against gram-negative bacilli, including members of the family Enterobacteriaceae and Pseudomonas aeruginosa, and to be active against many ceftazidime-resistant isolates of Citrobacter spp., Enterobacter spp., and P. aeruginosa (2, 4-7, 11, 13, 16). Fu et al (2), Neu et al (14), and Nishino et al (15) have also demonstrated the activity of this compound against isolates of streptococci, including beta-hemolytic groups and Streptococcus pneumoniae, and Haemophilus influenzae. FK-037 has also been shown to be active against a variety of anaerobic bacteria other than the Bacteroides fragilis group (9).…”

“…Data presented in abstracts in 1991 and 1992 suggested that FK-037 was more active than currently available extended-spectrum cephalosporins against staphylococci, including methicillin-resistant strains (5,12,15); however, at four times its MIC, FK-037 reduced the number of CFU of methicillin-resistant Staphylococcus aureus by only 1 order of magnitude while vancomycin reduced the number of CFU by over 3 orders of magnitude in killing curve studies (1). In studies by Neu et al (14), 16 ,ug of FK-037 per ml inhibited 50% of the S. aureus isolates tested with oxacillin MICs of >16 ,ug/ml. FK-037 has also been reported to have a broad spectrum of activity against gram-negative bacilli, including members of the family Enterobacteriaceae and Pseudomonas aeruginosa, and to be active against many ceftazidime-resistant isolates of Citrobacter spp., Enterobacter spp., and P. aeruginosa (2, 4-7, 11, 13, 16).…”