Synthesis and antibacterial activity of 6315-S, a new member of the oxacephem antibiotic.

TOC-39, a new parenteral cephalosporin, is a hydroxyimino-type cephem antibiotic with vinylthio-pyridyl moiety at the 3 position. TOC-39 was evaluated for antibacterial activity against various clinically isolated strains. TOC-39 had excellent activity, stronger than that of methicillin, oxacillin, the cephalosporins tested, imipenem, gentamicin, minocycline, tobramycin, ofloxacin, and ciprofloxacin against methicillin-resistant Staphylococcus aureus (MRSA) and had an MIC comparable to that of vancomycin (the MICs of TOC-39 and vancomycin for 90% of the strains tested were 3.13 and 1.56 g/ml, respectively). Against Enterococcus faecalis strains, which are resistant to cephalosporins, TOC-39 was twice as active as ampicillin. Against methicillinsusceptible S. aureus, coagulase-negative Staphylococcus spp., and Streptococcus pneumoniae, TOC-39 was twice as active as or more active than cefotiam, ceftazidime, flomoxef, and cefpirome. Against Streptococcus pyogenes, TOC-39 was superior to cefotiam, ceftazidime, and flomoxef and was similar to cefpirome. In addition, the activity of TOC-39 was equal to or greater than that of cefotiam, ceftazidime, flomoxef, and cefpirome against Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Morganella morganii. In terms of bactericidal effect against MRSA, TOC-39 was superior to vancomycin. No mutant resistant to TOC-39 or vancomycin was obtained from susceptible MRSA strains. In murine systemic infection models, TOC-39 showed potent activity against S. aureus and E. coli. Against highly MRSA, the activity of TOC-39 was comparable to that of vancomycin.

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confidence: 99%

TOC-39, a novel parenteral broad-spectrum cephalosporin with excellent activity against methicillin-resistant Staphylococcus aureus

Hanaki

Akagi

Masaru

et al. 1995

“…Flomoxef (6315-S) is an oxacephem antibiotic with considerable activity against methicillin-resistant strains (22). On the basis of bacterial susceptibility to this antibiotic, we classified methicillin-resistant S. aureus into high-resistance and low-resistance groups (K. Murakami, M. Doi, Y. Kameda, T. Yoshida, and K. Shimada, Program Abstr.…”

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confidence: 99%

Production of low-affinity penicillin-binding protein by low- and high-resistance groups of methicillin-resistant Staphylococcus aureus

Murakami

Nomura

Doi

et al. 1987

Methicillin-and cephem-resistant Staphylococcus aureus (137 strains) for which the cefazolin MICs are at least 25 ,ug/ml could be classified into low-resistance (83% of strains) and high-resistance (the remaining 17%) groups by the MIC of flomoxef (6315-S), a 1-oxacephalosporin. The MICs were less than 6.3 jig/ml and more than 12.5 ,ug/ml in the low-and high-resistance groups, respectively. All strains produced penicillin-binding protein 2' (PBP 2'), which has been associated with methicillin resistance and which has very low affinity for

“…The ,B-lactams examined were cefpirome (20) and flomoxef (21), which have strong antimicrobial activities against S. aureus as well as gram-negative bacteria; five other cephalosporins (cefotaxime, moxalactam, cefmetazole, cefotiam, and cefazolin); and two penicillins (penicillin G and methicillin). Interestingly, we found that the activities of some ,-lactamase-stable cephalosporins and methicillin were markedly improved when these drugs were combined with sulbactam but that no such synergy occurred when they were combined with clavulanic acid.…”

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confidence: 99%

In vitro effects of beta-lactams combined with beta-lactamase inhibitors against methicillin-resistant Staphylococcus aureus

Kobayashi¹,

Arai²,

Hayashi³

et al. 1989

The effects of combinations of 13-lactams with two P-lactamase inhibitors, sulbactam and clavulanic acid, were determined in vitro against 22 clinical isolates of methicillin-resistant Staphylococcus aureus. Combinations of cefpirome, cefotaxime, and cefazolin with sulbactam (10 ,ug/ml) showed synergistic effects against more than 70% of the strains. Combinations of methicillin and penicillin G with sulbactam also showed synergistic effects against 50 and 68% of the strains, respectively, while cefotiam, moxalactam, flomoxef, and cefmetazole in combination with sulbactam showed such effects against only 40% or fewer. Clavulanic acid was synergistic only when combined with penicillin G, the effect probably being due to the 1-lactamase inhibition by the inhibitor. Sulbactam did not improve the antimicrobial activities of the 1-lactams against methicillinsusceptible S. aureus strains. At 42°C the MICs of cefotaxime, methicillin, and flomoxef alone were markedly decreased from the values at 35°C, and no synergy between these P-lactams and sulbactam appeared. The resistance to penicillin G was not inhibited by incubation at 42°C, and combinations of penicillin G with sulbactam and clavulanic acid showed synergy. The amounts of 13-lactamase produced were not related to the decreases in the MICs of the I-lactams, except for penicillin G combined with sulbactam. Clavulanic acid showed slightly stronger ,3-lactamase-inhibiting activity than sulbactam did. These results suggest that the synergy between sulbactam and the 13-lactams, except for penicillin G, may not be due to 13-lactamase inhibition but to suppression of the methicillin-resistant S. aureus-specific resistance based on other factors.Recently, reports have been made on the isolation of and infections with methicillin-resistant Staphylococcus aureus (MRSA) (1,5,9,25,26). The resistance of these strains is associated with the presence of a low-affinity penicillinbinding protein, PBP 2' (23) or PBP 2a (10), and the protein has been suggested to be inducible by ,-lactams (7, 18, 22). The role of ,B-lactamase in the resistance has also been examined with the ,B-lactamase inhibitors clavulanic acid (17, 18) and sulbactam (3,8), and it has been reported that staphylococcal P-lactamase may be the cause of decreased antimicrobial activities of drugs such as penicillin G and cefazolin, which are relatively susceptible to 1-lactamase hydrolysis (4, 15). There has also been a report that drug inactivation by penicillinase is the main possible mechanism of resistance to cefazolin, cephaloridine, and cephalothin in S. aureus (14).To determine the role of ,-lactamase in the resistance to more antimicrobial agents, we determined the effects of combinations of nine 3-lactams with the two 3-lactamase inhibitors in vitro against clinically isolated MRSA strains. The ,B-lactams examined were cefpirome (20) and flomoxef (21), which have strong antimicrobial activities against S. aureus as well as gram-negative bacteria; five other cephalosporins (cefotaxime, moxalactam, cefmetazo...