In vitro and in vivo antibacterial activities of FK037, a novel parenteral broad-spectrum cephalosporin

Abstract

FK037, a new parenteral cephalosporin, is an oxime-type cephem antibiotic with a 1-hydroxyethyl-5-aminopyrazole moiety at the 3 position. FK037 was evaluated for antimicrobial activity in vitro and in vivo. In vitro, FK037 was twofold or more active than ceftazidime, cefoperazone, cefotaxime, and ceftriaxone against Pseudomonas aeruginosa (MIC for 90%o of the strains [MIC.] = 32 ,ug/ml), members of the family Enterobacteriaceae (MIC90 5 2 ,ug/ml), group A streptococci (MIC9 0.015 ,g/ml), and methicillin-sensitive or -resistant coagulase-negative staphylococci (MIC90 = 2 and 16 ,ug/ml, respectively). In addition, the activity of FK037 was equal to or greater than that of ceftazidime, cefotaxime, or ceftriaxone against Streptococcus pneumoniae (MIC90 = 0.12 .g/ml) and methicillin-sensitive or -resistant Staphylococcus aureus (MIC90 = 2 and 16 ug/ml, respectively). FK037 was more active in vitro than cefepime (two-to fourfold) and cefpirome (twofold) against S. aureus. In murine systemic infection models, FK037 showed potent activity against P. aeruginosa, Escherichia coli, and methicillin-sensitive and methicillin-resistant S. aureus. FK037 was also efficacious in a mouse model of pyelonephritis caused by S. aureus or KlebsieUla pneumoniae and in a mouse model of pneumococcal pneumonia caused by S. pneumoniae. Additional studies on this compound to assess its potential clinical utility are warranted.Cephalosporins are very important in the treatment of bacterial infections because they exhibit broad antibacterial activities, have little toxicity, and are generally well tolerated (1). Structural modifications of the cephem nucleus have produced a variety of antimicrobial agents with improved, broad spectra of activity and ,-lactamase stability (8, 14). FK037 (Fig. 1) is a new parenteral cephalosporin (10) with the chemical formula erboard agar dilution method was used to evaluate the interaction of combined drugs. Synergy was determined by using the fractional inhibitory concentration index (9).Bactericidal activity. The MBCs of FK037 and ceftazidime were determined by a broth microdilution method (12). Compounds were serially diluted in Mueller-Hinton broth (MHB) cation supplemented as described by NCCLS. After incubation, negative broths were subcultured onto blood agar to determine the MBC. The lowest concentration of FK037 that exhibited 99.9% reduction of the numbers of colonies compared with the CFU in the initial inoculum was considered the MBC.Time-kill study. FK037 at two-and fourfold the MICs against Staphylococcus aureus OC2069 and Pseudomonas aeruginosa OC43 was tested in a time-kill study. Test organisms were grown overnight, diluted to 1 x 106 to 3 x 106 CFU/ml. One milliliter of this was added to MHB with and without FK037, resulting in a final inoculum of 3.5 x 105 CFU/ml. At 2, 4, 6, 8, and 24 h of incubation, 1-ml aliquots were removed, and viable cell counts were determined with Mueller-Hinton agar (MHA).Development of resistance. Two strains each of methicillinresistant and -sensitive S. aureus ...

Synthesis, Spectral Characterization and Thermal Behaviour of New Metal(ii) Complexes With Schiff Base Derived From Amoxicillin

“…The mechanism that makes bacteria resistant to β-lactams is due to the synthesis of β-lactamase enzymes which break the β-lactam ring and the antibiotic cannot bind to peptidoglycan layer 9 . Amoxicillin is sometimes combined with clavulanic acid, a β-lactamase inhibitor, to increase the spectrum of action against Gram-negative organisms, and to overcome bacterial antibiotic resistance mediated through β-lactamase production.…”

Susceptibilities of 177 penicillin-susceptible and -resistant pneumococci to FK 037, cefpirome, cefepime, ceftriaxone, cefotaxime, ceftazidime, imipenem, biapenem, meropenem, and vancomycin

“…FK 037, cefpirome, and cefepime are all new extended-spectrum cephalosporins with broad-spectrum antimicrobial activity against gram-positive and gram-negative organisms equal or superior to that of existing broad-spectrum cephalosporins (2,3,6,10,11,(14)(15)(16)21). Geslin and coworkers (6) and Lifiares and coworkers (16) have documented good in vitro activity of cefpirome against S, I, and R pneumococci (MICs for 90% of the strains tested of s0.03, 0.5, and 1.0 ,ug/ml, respectively).…”

Laboratory assessment of antibacterial activity of zwitterionic 7-methoxyimino cephalosporins

“…The newer compounds have not yet been compared in the same study. Overall, cefpirome, cefepime and cefclidin seem to display similar activities against Enterobacteriacea which produce Class 1 /Mactamase, while FK037 and DQ2556 appear to be slightly less active than cefpirome or cefepime (Fujimoto etal., 1990;Jones et al, 1991 b;Tanaka et al, 1992;Fu et al, 1993;Washington et al, 1993).…”

“…A majority of Burkholderia cepacia isolates should be considered as being resistant (MIC > 8 mg/L) to the zwitterionic 7-methoxyimino cephalosporins (and to ceftazidime), despite the existence of some susceptible strains (Watanabe et al, 1988;Fujimoto et al, 1990;Fu et al, 1993). Most S. maltophilia isolates are also resistant to the new compounds but several isolates are susceptible to ceftazidime (Watanabe et al, 1988;Fujimoto et al, 1990;Jones et al, 1991a;Fu et al, 1993;Reeves et al, 1993;Verbist & International Study Group, 1993;Washington et al, 1993).…”

“…Ceftazidime and the zwitterionic 7-methoxyimino cephalosporins are equally active against Acinetobacter spp. (Watanabe et al, 1988;Fujimoto et al, 1990;Jones et al, 1991a, b;Tanaka et al, 1992;Fu et al, 1993;Washington et al, 1993).…”