SCE-963, a New Broad-Spectrum Cephalosporin: In Vitro and In Vivo Antibacterial Activities

The effect of cefotiam and cefazolin on the ultrastructure of Klebsiella pneumoniae DT-S in vitro and in experimental pneumonia in mice was examined by electron microscopy. The action of both cephalosporins against K. pneumoniae DT-S was bactericidal, and a dose response in the action was definite. At the miniimal inhibitory concentration of each cephalosporin, filamentation of the cells was induced and the cytoplasm became sparse during the course of incubation. With elevation of the concentration of the cephalosporins, spheroplasts were formed; they subsequently collapsed. In the lungs of mice, the infecting organisms localized in the alveolar space, and each cell was connected by a threadlike material. A fibrous matrix, located on the cell surface of the infecting organisms, was observed in ultrathin sections. By administration of each cephalosporin to the mice, several morphological changes, similar to those noted in vitro, were observed in the infecting organisms.Cefotiam is a cephalosporin with a potent antibacterial activity against various gram-positive and gram-negative organisms, and its activity, especially against gram-negative organisms, is superior to that of previously available ,Blactam antibiotics (21,22). The excellent in vitro and in vivo antibacterial effects of cefotiam on Klebsiella pneumoniae have also been reported (21,22).Although there are several reports on the experimental pneumonia caused by K. pneumoniae, only observation by light microscopy of the infecting organisms in lungs has been performed (2,3,12,(16)(17)(18). A few studies on the morphological response of K. pneumoniae exposed to /8-lactam antibiotics have been presented (6, 23); however, all of them have been carried out in vitro only.This report describes the effect of cefotiam on the morphology of K. pneumoniae examined in vitro and in experimental pneumonia in mice, with cefazolin used as a control cephalosporin.MATERIALS AND METHODSCephalosporin. Cefotiam was prepared at Takeda Chemical Industries, Ltd., Osaka, Japan. Cefazolin (Cefamezin; Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan) was obtained from a commercial source.Bacteria. K.pneumoniae DT-S (biotype edwardsii, capsular type 1) was maintained on Trypticase soy agar (BBL Microbiology Systems, Cockeysville, Md.).The minimal inhibitory concentrations of cefotiam and cefazolin against this strain were 0.1 and 1.56 ug/ ml, respectively. The other characteristics of this strain have been previously detailed (12).Culture conditions. Organisms were grown overnight at 37°C in brain heart infusion broth (Difco Laboratories, Detroit, Mich.). For in vitro experiments, the overnight culture was diluted in fresh brain heart infusion broth and cultivated at 37°C for 2 h with shaking to about 7 x 107 colony-forming units per ml cell density. For in vivo experiments, the overnight culture was processed as previously described (12).Bactericidal activity. The killing of cefotiam and cefazolin against K. pneumoniae DT-S was determined in brain heart infusion broth containing fou...

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confidence: 99%

In vitro and in vivo morphological response of Klebsiella pneumoniae to cefotiam and cefazolin

Nakao¹,

Nishi²,

Tsuchiya³

1981

“…Much effort has been expended in an attempt to develop broad-spectrum antibiotics with resistance to the enzyme. As a result, recently introduced cephalosporins, such as cefoxitin, cefotiam, and cefuroxime, have possessed some in vitro activity against isolates of Enterobeter and indole-positive Proteus, but not Pseudomonas (13,14,17,26,27 CE.…”

Section: Discussionmentioning

confidence: 99%

“…and Pseudomonas spp. (13,15,17,26,27). Cefotaxime, a new cephalosporin, has been reported to have a broad antimicrobial spectrum (1, 2, 4,6,7,14,23,24,28,29) Table 1 were shown to be standard strains by the Japan Society of Chemotherapy; other strains were isolated from patients in several hospitals in Japan between 1977 and 1978.…”

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confidence: 99%

In vitro antimicrobial activity of cefotaxime, a new cephalosporin

Masuyoshi¹,

Arai²,

Miyamoto³

et al. 1980

Laboratories, Hoechst Japan Limited, Saitama,2 Japan Cefotaxime, a new semisynthetic cephalosporin derivative, showed a broad spectrum of antibacterial activity against clinically isolated strains of grampositive and gram-negative bacteria. This cephalosporin was slightly less active than cefazolin against Staphylococcus aureus but 4 to 300 times as active as carbenicillin against gram-negative organisms, including Pseudomonas aeruginosa, Pseudomonas cepacia, Enterobacter cloacae, and Serratia marcescens. Cefotaxime was the most active compound against members of the Enterobacteriaceae and 20-to 100-fold more active than cefoxitin against the indole-positive Proteus group. The minimal bactericidal concentrations of the compound were identical to, or two times higher than, the minximal inhibitory concentrations against Escherichia coli and P. aeruginosa and four times higher against S. marcescens. A reduction of inoculum size decreased greatly the miniimal inhibitory and bactericidal concentrations of cefotaxime against E. coli, P. aeruginosa, and S. marcescens. The antibiotic was very stable to penicillinase and cephalosporinase produced by gram-negative bacteria, including Proteus vulgaris.Many cephalosporins with broad antibacterial spectra have been in clinical use for the treatment of a wide range of bacterial infections. Recently, however, the effectiveness of the existing cephalosporins has been shown to be limited; there has been a steady increase in clinical infections caused by gram-negative bacteria resistant to 8l-lactam antibiotics, e.g., Pseudomonas spp., Enterobacter spp., Serratia marcescens, and indole-positive Proteus spp., which have been reported to produce ,B-lactamase (11,12,25). Much effort has been expended in developing broad-spectrum antibiotics with resistance to the enzyme. Cefoxitin, cefotiam, and cefuroxime have been semisynthesized, but they are still ineffective against some strains of Enterobacter spp. and Pseudomonas spp. (13,15,17,26,27). Cefotaxime, a new cephalosporin, has been reported to have a broad antimicrobial spectrum (1, 2, 4,6,7,14,23,24,28,29) Table 1 were shown to be standard strains by the Japan Society of Chemotherapy; other strains were isolated from patients in several hospitals in Japan between 1977 and 1978. We selected the strains at random.Media. Heart infusion (HI) agar and brain heart infusion (BHI) agar were used. BHI broth and antibiotic medium 3 (ABM 3) were used. Other media used were medium B, peptone water, and nutrient agar containing bromothymol blue and lactose. Medium B consisted of 2 g of yeast extract, 10 g of polypeptone, 8 g of Na2HPO4 12H20, 2 g of KH2PO4,1.2 g of (NH4)2SO4, 2 g of glucose, 0.4 g of MgSO4.7H20, and 1,000 ml of purified water, and the medium was adjusted to pH 7.4. Peptone water consisted of 10 g of polypeptone, 5 g of NaCl, and 1,000 ml of purified water. For the dilution of cell suspensions, ABM 3 and buffered saline containing gelatin (3)

“…These agents include cefazolin (7), cefmetazole (8), cefamandole (13), and cefotiam (10). Cefotiam, 7- (10). The present report compares the therapeutic activities of cefotiam and cefazolin in experimental pneumonias caused by Klebsiella pneumoniae DT-S.…”

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confidence: 97%

“…Other broadspectrum antimicrobial agents with marked activity against Klebsiella have been introduced recently. These agents include cefazolin (7), cefmetazole (8), cefamandole (13), and cefotiam (10). Cefotiam, 7- (10).…”

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confidence: 99%

Therapeutic effects of cefotiam and cefazolin on experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice

Nishi¹,

Tsuchiya²

1980

The efficacies of several dosage schedules, productive of plasma levels of cefotiam and cefazolin of short and long duration and starting at three different times (3, 18, and 30 h) after infection, were examined in experimental pneumonia caused by Klebsiella pneumoniae DT-S in mice. With each of the multiday regimens there was a large segment of the day when plasma levels fell below assayable concentrations. In all cases, cefotiam proved about eight times as active as cefazolin, indicating that the potent in vitro antibacterial activity of cefotiam was well reflected in the therapeutic effect in this model infection. As judged by the total dose administered, the regimen of cefotiam producing a low but sustained plasma level gave better therapeutic effects than that exhibiting a high but transient plasma level. The cefotiam levels in the plasma of mice that received the regimen effective when initiated at 18 h after infection were less than the expected levels in humans after intravenous infusion of the usual clinical dose.Aminoglycoside antibiotics have been used xwidely as first-line agents in the treatment of Klebsiella pneumonias. These antibiotics, however, have significant side effects. Other broadspectrum antimicrobial agents with marked activity against Klebsiella have been introduced recently. These agents include cefazolin (7), cefmetazole (8), cefamandole (13), and cefotiam (10).]methyl]ceph-3-em-4-carboxylic acid, is a new semisynthetic cephalosporin with potent antibacterial activity. The in vitro activities of cefotiam against susceptible gramnegative bacilli are about ten times those of commercially available cephalosporins. The favorable activity of cefotiam has been confirmed in protection tests in mice infected intraperitoneally with various strains of bacteria (10). The present report compares the therapeutic activities of cefotiam and cefazolin in experimental pneumonias caused by Klebsiella pneumoniae DT-S. The murine model described previously (6) was employed for the evaluation. MATERLALS AND METHODSRespiratory tract infection. Experimental pneumonia was induced in mice as described previously (6). Four-week-old Slc:ICR male mice, weighing 18 to 25 g, were infected with K. pneumoniae DT-S by the aerosol method, resulting in deposition of about 104 colony-forming units per lung.Treatment. Cefotiam was prepared by Takeda Chemical Industries, Ltd., Osaka, Japan. Cefazolin (Cefamezin, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan) was obtained from a commercial source. They were dissolved in 0.85% NaCl and injected subcutaneously (0.1 ml per mouse) following the schedules presented in each experiment (see Tables 1 to 4 and Fig. 1 and 2). The minimum inhibitory concentrations and minimum bactericidal concentrations (10) against K. pneumoniae DT-S were 0.1 and 0.2 ug/ml for cefotiam and 1.56 and 3.13 ,tg/ml for cefazolin, respectively. Evaluation of efficacy. Deaths of mice were recorded daily for 7 or 8 days. In the therapeutic tests, surviving animals were sacrificed 8 days after infection fo...