Biomedical subjects

S Mitsuhashi

Publications and source records attributed to S Mitsuhashi.

At least 91 records · Page 5Linked to original sources

PubMed1991

Preferential hydrolysis of cis configuration compounds at the 3,4 position of monobactams by beta-lactamase from Morganella morganii.

Carumonam and BO-1166 (cis configuration) were inactivated by beta-lactamase of Morganella morganii more rapidly than were aztreonam and BO-1165 (trans configuration), as demonstrated by spectrophotometric analysis and microbiological assay. An active enzyme was recovered more rapidly from the inactivated enzyme-monobactam complex derived from the cis form of monobactams than from the complex derived from the trans form of monobactams. This result suggests that the configuration at the 3,4 position on the azetidinone ring of monobactams, together with the chemical structure of the side chains attached to the azetidinone ring, may play an important role in the stability of monobactams to the beta-lactamase of M. morganii.

Aztreonam↗

PubMed1991

Mechanisms of clinical resistance to fluoroquinolones in Enterococcus faecalis.

About 10% of 100 clinical isolates of Enterococcus faecalis were resistant to greater than or equal to 25 micrograms of norfloxacin, ofloxacin, ciprofloxacin, and temafloxacin per ml. In this study, the DNA gyrase of E. faecalis was purified from a fluoroquinolone-susceptible strain (ATCC 19433) and two resistant isolates, MS16968 and MS16996. Strains MS16968 and MS16996 were 64- to 128-fold and 16- to 32-fold less susceptible, respectively, to fluoroquinolones than was ATCC 19433; MICs of nonquinolone antibacterial agents for these strains were almost equal. The DNA gyrase from ATCC 19433 had two subunits, designated A and B, with properties similar to those of DNA gyrase from other gram-positive bacteria such as Bacillus subtilis and Micrococcus luteus. Inhibition of the supercoiling activity of the enzyme from ATCC 19433 by the fluoroquinolones correlated with their antibacterial activities. In contrast, preparations of DNA gyrase from MS16968 and MS16996 were at least 30-fold less sensitive to inhibition of supercoiling by the fluoroquinolones than the gyrase from ATCC 19433 was. Experiments that combined heterologous gyrase subunits showed that the A subunit from either of the resistant isolates conferred resistance to fluoroquinolones. These findings indicate that an alteration in the gyrase A subunit is the major contributor to fluoroquinolone resistance in E. faecalis clinical isolates. A difference in drug uptake may also contribute to the level of fluoroquinolone resistance in these isolates.

Adenosine Triphosphate↗

PubMed1991

In vitro activity of YM133, a new semisynthesized macrolide.

YM133, the 4"-O-(4-methoxyphenyl)acetyltylosin, is a new macrolide. The in vitro activity of YM133 was compared with those of erythromycin, josamycin, and rokitamycin by an agar dilution method. YM133 inhibited 90% of the tested isolates of Streptococcus pneumoniae, Legionella spp., and anaerobic bacteria at less than or equal to 1.56 micrograms/ml. The drug inhibited 90% of erythromycin-resistant staphylococci and Streptococcus pyogenes at less than or equal to 50 micrograms/ml. YM133 showed activity against erythromycin-, josamycin-, and rokitamycin-resistant (MIC greater than or equal to 100 micrograms/ml) strains of staphylococci, streptococci, Bacteroides spp., and Clostridium spp. Enterococci were less susceptible to other YM133-like macrolides. Unlike other macrolides, YM133 showed killing activity, and the MBC/MIC ratios of YM133 for several strains were 1:32, whereas those of erythromycin were 4:1,024. In a time-kill curve study, the reduction of viable cells started within 2 h after the addition of YM133.

Anti-Bacterial Agents↗

PubMed1991

In vitro and in vivo antibacterial activities of ME1220 and ME1221, novel cephalosporins.

The antibacterial activities and serum pharmacokinetic properties of ME1220 and ME1221, new aminothiazolylalkoxyiminoacetylcephalosporins having an N-alkylpyridiniumthiomethyl side chain at C-3, were compared with those of cefpirome and ceftazidime. ME1220 and ME1221 exhibited broad antibacterial activity against Gram-positive and Gram-negative bacteria. The in vitro and in vivo activities of ME1220 were similar to cefpirome, while ME1221 was superior to ceftazidime against almost all test organisms except pseudomonas. On intravenous injection in rats, ME1220 and ME1221 were excreted mainly in the urine. ME1221 was excreted moderately in the bile and showed higher serum concentration and AUC than those of ME1220.

Animals↗

PubMed1990

Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol on experimental liver tumor in rats.

Anticancer effects and biodistribution of a new lipophilic anticancer agent, estradiol-chlorambucil (KM2210), dissolved in lipiodol (LPD) were investigated as an intra-arterial chemotherapy (IAC) on Walker 256 carcinosarcoma grown in the liver of 136 Wistar rats. All rats treated with KM2210 (10 mg)-LPD survived for 90 days after administration, whereas none of the rats with LPD alone were alive for more than 19 days. Histological examination revealed that there was no viable tumor cell in the encapsulated necrotic tumor at 21 days after administration. There was no significant liver dysfunction or leukopenia due to KM2210. The biodistribution study using [14C, 3H]KM2210-LPD solution showed that KM2210 accumulated selectively in tumor and that the tumor-to-normal-liver and tumor-to-blood ratios were 10 and 1,000, respectively, at 21 days after administration. These results suggest that KM2210 has potential clinical application in the treatment of human liver cancer.

Animals↗

PubMed1990

In vitro antibacterial activity and beta-lactamase stability of the new carbapenem LJC10,627.

In in vitro susceptibility tests the new carbapenem LJC10,627 showed potent antibacterial activity against gram-positive and gram-negative bacteria, except that most methicillin-resistant Staphylococcus aureus strains tested were found to be resistant to LJC10,627. LJC10,627 showed high activity against Pseudomonas aeruginosa and was active against Enterobacter cloacae and Citrobacter freundii strains which were resistant to ceftazidime and cefpirome. The Ki values of LJC10,627 for penicillinase Type I, cephalosporinase and oxyiminocephalosporinase were low, whereas the Ki value for L-1 enzyme from Xanthomonas maltophilia was high.

Bacteria↗

PubMed1990

Inhibition of beta-lactamases by tazobactam and in-vitro antibacterial activity of tazobactam combined with piperacillin.

The in-vitro synergistic activity of tazobactam, a new beta-lactamase inhibitor, combined with piperacillin was tested against various beta-lactamase-producing strains. The beta-lactamase inhibitory activity of tazobactam against various known types of beta-lactamase was also tested in comparison with clavulanic acid or sulbactam. Tazobactam caused a remarkable reduction of the piperacillin MICs for penicillinase- and oxyiminocephalosporinase-producing strains and also showed a moderate synergistic effect against cephalosporinase-producing strains. The bactericidal activity of piperacillin was enhanced in combination with tazobactam. Tazobactam inhibited the penicillinases, and the oxyiminocephalosporinase produced by Proteus vulgaris, at low concentration. In these cases its activity was comparable with that of clavulanic acid and stronger than that of sulbactam. Tazobactam demonstrated a better inhibitory capability than sulbactam against the cephalosporinases tested. Tazobactam was able to inactivate intracellular beta-lactamase in Prot. vulgaris and Morganella morganii, confirming its ability to penetrate the cell membrane of these species.

Bacteria↗

PubMed1990

In-vitro antibacterial activity of DQ-2556 and its stability to various beta-lactamases.

DQ-2556, a new cephalosporin, showed a broad antibacterial spectrum over Gram-positive and -negative organisms. The activity of DQ-2556 against recent clinical isolates of Gram-positive cocci and Enterobacteriaceae was comparable with that of cefpirome, and superior to that of ceftazidime. DQ-2556 was almost as active as cefpirome against Pseudomonas aeruginosa, but was less active than ceftazidime. With the exception of Ps. aeruginosa, DQ-2556 was bactericidal against various organisms at either the MIC or twice the MIC. DQ-2556 bound preferentially to penicillin-binding proteins (PBPs) 2, 1 and 3 of Staphylococcus aureus, PBPs 3, 1A and 1B of Escherichia coli and PBPs 1A, 3 and 4 of Ps. aeruginosa. DQ-2556 was stable to various penicillinases and cephalosporinases, but was unstable to oxyiminocephalosporinases. The Km values of DQ-2556 for the cephalosporinases of Citrobacter freundii and Enterobacter cloacae were only two- or three-fold higher than those of ceftazidime, indicating that DQ-2556 had a relatively high affinity for these enzymes compared with other recently developed cephalosporins. The MIC of DQ-2556 for Esch. coli increased four-fold in an OmpF-deficient mutant, indicating that the OmpF porin was one of the major routes for penetration of DQ-2556 into Esch. coli cells.

Ceftazidime↗

PubMed1990

In vitro emergence of quinolone-resistant mutants of Escherichia coli, Enterobacter cloacae, and Serratia marcescens.

Norfloxacin- and ciprofloxacin-resistant mutants of several Enterobacter cloacae and Serratia marcescens isolates occurred at frequencies of greater than or equal to 10(-7)/CFU, which were higher than those of Escherichia coli isolates, in accordance with the increasing emergence of less-susceptible or resistant strains in clinical isolates of E. cloacae and S. marcescens.

Anti-Infective Agents↗

PubMed1990

Antimicrobial activity and stability to beta-lactamase of BMY-28271, a new oral cephalosporin ester.

BMY-28271, the acetoxyethyl ester of BMY-28232, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3(Z) -propen-1-yl-3- cephem-4-carboxylic acid, is a new oral cephalosporin. BMY-28232 has a widely expanded spectrum with high activity against gram-positive and gram-negative bacteria. BMY-28232 is far more active than cefixime or cefteram against Staphylococcus aureus and Staphylococcus epidermidis. Against gram-negative bacteria, the activity of BMY-28232 was comparable to or somewhat weaker than that of cefixime or cefteram. BMY-28232 was a poor substrate for various beta-lactamases. Orally administered BMY-28271 had a good therapeutic effect on systemic infections with S. aureus and some gram-negative bacteria in mice. Oral BMY-28271 was efficacious against S. aureus Smith infection: the efficacy of BMY-28271 was 80 to 90 times higher than that of cefixime or cefteram.

Administration, Oral↗

PubMed1990

In vitro activity of AT-4140 against quinolone- and methicillin-resistant Staphylococcus aureus.

Eighty-nine clinical isolates of Staphylococcus aureus that were resistant to both ciprofloxacin (MIC, greater than or equal to 3.13 micrograms/ml) and methicillin (MIC, greater than or equal to 12.5 micrograms/ml) were divided into two groups with respect to their susceptibilities to AT-4140. Most isolates that were moderately resistant to ciprofloxacin (MICs, 3.13 to 12.5 micrograms/ml) or ofloxacin (MICs, 0.78 to 6.25 micrograms/ml) were susceptible to AT-4140 (MICs, 0.05 to 0.2 microgram/ml). Most isolates that were highly resistant to ciprofloxacin (MIC, greater than or equal to 25 micrograms/ml) or ofloxacin (MIC, greater than or equal to 12.5 micrograms/ml) were resistant to AT-4140 (MICs, 3.13 to 25 micrograms/ml). The appearance of spontaneous single-step, quinolone-resistant mutants of S. aureus P-20, a methicillin-resistant isolate, was more frequent than was that of S. aureus 209P JC-1, a susceptible laboratory strain. Spontaneous single-step, quinolone-resistant mutants of P-20 were not selected by AT-4140, and those selected by existing fluoroquinolones were susceptible to AT-4140. Spontaneous double-step, quinolone-resistant mutants of P-20 were selected by various fluoroquinolones. All second-step mutants selected by AT-4140 or ofloxacin from P-20-C, a spontaneous single-step mutant of P-20 selected by ciprofloxacin, were resistant to all the quinolones. All second-step mutants selected by nonfloxacin were resistant to all existing fluoroquinolones but were less resistant to AT-4140. There was a close resemblance between the resistance profiles of spontaneous quinolone-resistant mutants and those of clinically isolated quinolone- and methicillin-resistant S. aureus.

4-Quinolones↗

PubMed1990

In vitro activity of LJC10,627, a new carbapenem antibiotic with high stability to dehydropeptidase I.

The in vitro activity of LJC10,627, a new carbapenem, was compared with those of imipenem and ceftazidime. LJC10,627 had broad-spectrum activity against gram-positive and gram-negative clinical isolates. The MICs of this compound for 90% of members of the family Enterobacteriaceae tested (MIC90s), including strains resistant to ceftazidime, ranged from 0.1 to 25 micrograms/ml. LJC10,627 inhibited Pseudomonas aeruginosa at an MIC90 of 3.13 micrograms/ml; it thus was twofold more active than imipenem. This compound inhibited Haemophilus, Neisseria, and Branhamella species at MIC90s of 3.13, 0.1, and 0.1 micrograms/ml, respectively. LJC10,627 was two- to fourfold less active than imipenem against methicillin-susceptible Staphylococcus aureus and Staphylococcus epidermidis at MIC90s of 0.1 and 0.39 microgram/ml. However, the compound was found to be twofold more active than imipenem against Bacteroides fragilis at an MIC90 of 1.56 microgram/ml. LJC10,627 was very stable to various beta-lactamases except for Xanthomonas maltophilia oxyiminocephalosporinase type II. LJC10,627 was minimally hydrolyzed by swine renal dehydropeptidase I; its residual activity was 93.0% after 2 h. Killing kinetics of this compound for Escherichia coli and Pseudomonas aeruginosa showed that bactericidal action occurred at concentrations above the MIC (0.05 and 0.39 microgram/ml, respectively). LJC10,627 had a high affinity for penicillin-binding proteins 2, 4, and 1B(s) of Escherichia coli and Pseudomonas aeruginosa and penicillin-binding proteins 1 and 4 of Staphylococcus aureus.

Animals↗

PubMed1990

Activity of KB-5246 against outer membrane mutants of Escherichia coli and Salmonella typhimurium.

The inhibitory activity of KB-5246 against Escherichia coli DNA gyrase and the antibacterial activity and apparent uptake in E. coli and Salmonella typhimurium outer membrane mutants of KB-5246 were measured. The 50% inhibitory concentrations of KB-5246, ciprofloxacin, oflaxacin, and norfloxacin for E. coli KL-16 DNA gyrase were 0.72, 0.62, 0.84, and 1.16 micrograms/ml, respectively. The activity of KB-5246 was twofold lower against an OmpF-deficient mutant and twofold higher against a mutant which produced OmpF constitutively than against the parent with osmoregulated OmpF production. KB-5246 had twofold-higher activity against a deep rough mutant of S. typhimurium than against the parent. The apparent uptake of KB-5246 in the OmpF-deficient mutant was decreased and its uptake in the deep rough mutant was increased when compared with those in the parents. These results suggest that KB-5246 is taken up by porin and nonporin pathways and has strong inhibitory activity against DNA gyrase, resulting in potent antibacterial activity.

4-Quinolones↗

PubMed1990

Effects of intraarterial chemotherapy using the new lipophilic anticancer agent 'KM2210' (estradiol-chlorambucil) dissolved in lipiodol on Walker 256 carcinosarcoma in Wistar rats--a preliminary report.

The effect of a new oil-soluble anticancer agent 'KM2210' (estradiol-chlorambucil) dissolved in lipiodol (LPD) was investigated as intraarterial chemotherapy, using 40 Wistar rats bearing Walker 256 carcinosarcoma in the extremities. KM2210-LPD significantly inhibited tumor growth and prolonged the survival time, as compared to LPD alone or saline alone, p less than 0.01 and p less than 0.01, respectively. Pathological study revealed that KM2210-LPD made the tumor necrotic. It was revealed that KM2210-LPD injected into the femoral artery was retained in the hind limb tumor. These findings suggest that KM2210 may possibly become a new anticancer agent with potential clinical use in LPD chemoembolization.

Animals↗

PubMed1990

In vitro antibacterial activity of DR-3355, the S-(-)-isomer of ofloxacin.

DR-3355, the S-(-)-isomer of ofloxacin, possessed generally twice higher activity than ofloxacin, and its action was bactericidal. The difference in antibacterial activity of these compounds was attributable to their inhibitory activity against DNA gyrase. DR-3355 was characterized by its higher potency against gram-positive cocci and obligate anaerobes than ofloxacin and ciprofloxacin. DR-3355 was somewhat less potent than ciprofloxacin against Enterobacteriaceae and Pseudomonas aeruginosa, but was active against organisms resistant to cefteram, ceftazidime, and amikacin. The activity of DR-3355 was decreased by gyrA mutation, like that of the other quinolones, although it did not alter significantly by deficiency of outer membrane protein F or lipopolysaccharide. Moderately norfloxacin-resistant isolates of Staphylococcus aureus remained susceptible to DR-3355, but not to ciprofloxacin.

Cephalosporins↗

PubMed1990

In vitro activity of temafloxacin hydrochloride (TA-167 or A-62254), a new fluorinated 4-quinolone.

The in vitro antibacterial activity of temafloxacin hydrochloride (TA-167 or A-62254) was evaluated against a wide variety of clinical isolates and compared with those of other fluoroquinolones. The potency (MIC90) of the compound against gram-positive aerobic bacteria was higher or comparable to those of ciprofloxacin, ofloxacin, and norfloxacin. Against most gram-negative enteric bacteria and Pseudomonas species, temafloxacin was less active than ciprofloxacin, but was generally as active as ofloxacin and norfloxacin, except against Proteus species and Morganella morganii. Against obligate anaerobes, it was more active than the reference quinolones. Temafloxacin was bactericidal for one strain each of Staphylococcus aureus. Escherichia coli, and Pseudomonas aeruginosa. The compound inhibited E. coli DNA gyrase activity at a low concentration.

4-Quinolones↗

PubMed1989

In vitro antibacterial activity and beta-lactamase stability of the new carbapenem SM-7338.

The in vitro activity of the new carbapenem SM-7338 was tested in comparison with imipenem, ceftazidime, cefotaxime, flomoxef, cefuzonam and cefmetazole against 2850 clinical bacterial isolates. SM-7338 showed good activity against a broad spectrum of gram-positive and gram-negative bacteria. SM-7338 was very active against gram-negative bacteria, inhibiting all Enterobacteriaceae, except 25% of Serratia marcescens isolates, at a concentration of 0.78 mg/l. SM-7338 inhibited the majority of Pseudomonas spp. at concentrations of less than or equal to 3.13 mg/l, its activity being twofold higher than that of imipenem. However, the activity of SM-7338 against gram-positive cocci was about one-fourth that of imipenem. Against anaerobes, SM-7338 also had the best activity of the beta-lactams tested. The compound was inactive against methicillin-resistant staphylococci, Enterococcus faecium, Xanthomonas maltophilia and Flavobacterium spp., as were the other beta-lactams. SM-7338 was quite stable in the presence of various types of beta-lactamase, but was hydrolyzed by Xanthomonas maltophilia beta-lactamase, as was imipenem. This high degree of stability was responsible for the potent activity of SM-7388 against beta-lactamase-producing species such as Enterobacter cloacae, Citrobacter freundii and Proteus vulgaris. SM-7338 also showed bactericidal activity against clinical isolates at the MIC or at concentrations slightly above the MIC.

Anti-Bacterial Agents↗

PubMed1989

In vitro activity of amifloxacin against outer membrane mutants of the family Enterobacteriaceae and frequency of spontaneous resistance.

Amifloxacin showed potent inhibitory activity against DNA gyrase of Escherichia coli. The difference in the susceptibilities of lipopolysaccharide-deficient Salmonella typhimurium mutants and their parent strain was less than twofold, and the difference in the susceptibilities of porin-deficient E. coli mutants and their parent strain was less than twofold. There was cross resistance among the quinolone group of agents; however, the decrease in MIC for norB mutants was slightly lower than that of other fluoroquinolones. Cell lysis was induced with combined treatment of amifloxacin and sodium dodecyl sulfate in E. coli. The frequency of mutants spontaneously resistant to amifloxacin was extremely low in all species tested.

Anti-Bacterial Agents↗