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1.  Activity of beta-lactamase produced by Bacteroides fragilis against newly introduced cephalosporins. 
The purified beta-lactamase from Bacteroides fragilis hydrolyzed newly introduced cephalosporins including cefuroxime and HR 756, and was inhibited by 7 alpha-methoxylated cephalosporins such as 6059-S and YM09330.
PMCID: PMC283862  PMID: 6967295
2.  Identification of R plasmids mediating gentamicin resistance from Escherichia coli strains in Japan. 
Eight gentamicin-resistant Escherichia coli were identified from among 630 E. coli strans isolated from parenteral infections. All eight strains were multiply resistant and harbored R plasmids mediating gentamicin resistance. The R plasmids specified the formation of two types of aminoglycoside-inactivating enzymes AAD (2") and APH (3').
PMCID: PMC181610  PMID: 7023382
3.  In vitro and in vivo antibacterial activities of ME1207, a new oral cephalosporin. 
ME1207 (pivaloyloxymethyl ester of ME1206) is a new oral cephalosporin. ME1206 is (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)- acetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)-ethyl]-cephem-4-carboxy lic acid. The susceptibilities of about 1,600 clinical isolates to ME1206 were determined by the agar dilution method. ME1206 showed a broad spectrum of activity against gram-positive and gram-negative bacteria. ME1206 was more active than cefaclor, T-2525, and cefixime against Staphylococcus aureus and Staphylococcus epidermidis. Against gram-negative bacteria, the activity of ME1206 was comparable with that of T-2525, but ME1206 was less active than cefixime. Against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae, ME1206 had high activity (MIC, less than or equal to 0.05 microgram/ml). ME1206 was stable against various beta-lactamases, except beta-lactamases from Providencia rettgeri, Pseudomonas cepacia, and Escherichia coli W3630 (Rms213). The 50% effective doses of ME1207 after oral administration against systemic infections in mice were comparable with those of T-2588 against gram-negative bacteria and about one-fourth that of T-2588 against Staphylococcus aureus Smith.
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PMCID: PMC175880  PMID: 3264132
4.  In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin. 
CS-807 is a new oral prodrug of R-3746, a cephalosporin derivative, with potent in vitro and in vivo antibacterial activity against both gram-positive and gram-negative bacteria. The susceptibility of about 1,200 clinical isolates to R-3746 was determined by the agar dilution method. Ninety percent or more of pathogens such as Staphylococcus aureus, streptococci, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, indole-positive and indole-negative Proteus spp., Providencia rettgeri, and Haemophilus influenzae were inhibited at concentrations ranging less than or equal to 0.01 to 1.56 micrograms/ml. Furthermore, at a concentration of 3.13 micrograms/ml, 50% or more of Staphylococcus epidermidis, Morganella morganii, Citrobacter freundii, and Serratia marcescens strains were also inhibited. Pseudomonas aeruginosa and Xanthomonas maltophilia were resistant to R-3746. The activity of R-3746 was scarcely influenced by several growth conditions. R-3746 was highly resistant to hydrolysis by beta-lactamases derived from various species of bacteria. Killing-curve studies demonstrated bactericidal activity of R-3746 at concentrations above the MIC. R-3746 showed high affinity for penicillin-binding proteins 1, 3, and 4 of Staphylococcus aureus and 1A, 1Bs, and 3 of Escherichia coli. Systemic infections in mice caused by various pathogens, including beta-lactamase-producing strains, responded well to therapy with oral doses of CS-807.
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PMCID: PMC174876  PMID: 3310868
5.  Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli. 
The mechanism of penetration of quinolones through the bacterial outer membrane was studied with lipopolysaccharide-deficient and porin-deficient mutants. The data indicated that the lipopolysaccharide layer might form a permeability barrier for hydrophobic quinolones such as nalidixic acid but not for hydrophilic quinolones such as norfloxacin and ciprofloxacin. The results also showed that quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a low relative hydrophobicity appeared to permeate through OmpF porin, whereas quinolones with a high relative hydrophobicity appeared to permeate through both OmpF porin and phospholipid bilayers.
PMCID: PMC180431  PMID: 3521490
6.  Beta-lactamase stability and antibacterial activity of cefmenoxime (SCE-1365), a novel cephalosporin. 
Cefmenoxime, a new cephalosporin antibiotic, has been shown to be stable to a Staphylococcus aureus penicillinase and R plasmid-mediated type I and type IV penicillinases. It was also resistant to hydrolysis by most cephalosporinases, but was susceptible to hydrolysis by a Proteus vulgaris beta-lactamase. Cefmenoxime was active against cephaloridine-resistant species, except Pseudomonas aeruginosa, which was moderately resistant to cefmenoxime. Cefmenoxime was an inducer of P. vulgaris beta-lactamase biosynthesis, but 1 microgram or more of the drug per ml, which inhibits most of the clinical isolates of P. vulgaris, was required for the production of detectable amounts of the enzyme. Cefmenoxime was a strong competitive inhibitor of beta-lactamases of Enterobacter cloacae, Citrobacter freundii, P. aeruginosa, and Serratia marcescens, but it did not inhibit penicillinases in spite of its resistance to hydrolysis.
PMCID: PMC181659  PMID: 6269488
7.  Purification and biochemical properties of beta-lactamase produced by Proteus rettgeri. 
beta-Lactamase produced by Proteus rettgeri was found to be a typical cephalosporin beta-lactamase on the basis of its substrate hydrolysis profile. The enzyme activity was enhanced by prior treatment with an inducer. The enzyme was purified 166-fold by carboxymethyl-Sephadex column chromatography which indicated that its molecular weight was 42,000 +/- 2,000 and its isoelectric point was 8.7. Cefoperazone, cefoxitin, cefusulodin, cefmetazole, cefotaxime, 6059-S, FK749, YM-09330, carbenicillin, and cloxacillin were stable to this enzyme and possessed the function of competitive inhibition, as shown by their affinity for the beta-lactamase. The enzyme activity was inhibited by iodine, p-chloromerburibenzoate, and HG2+ ion. Clavulanic acid and CP-45899 displayed poor inhibitory activity toward this enzyme. The optimal pH was 8.0, and the optimal temperature was 50 degrees C.
PMCID: PMC284076  PMID: 6969578
8.  Affinity of cefoperazone for penicillin-binding proteins. 
Cefoperazone (T-1551, CFP) a new semisynthetic cephalosporin, has a broad spectrum of antibacterial activity. We investigated the affinity of CFP to penicillin-binding proteins (PBPs) and the inhibition of peptidoglycan synthesis by CFP. CFP had high affinities for Escherichia coli PBP-3, -1Bs, -2, and -1A, in descending order, and low affinities for PBP-4, -5, and -6. Similarly, CFP showed high affinity for Pseudomonas aeruginosa PBP-3, -1A, -1B, -2, and -4, in descending order. It is known that E. coli PBP-3 and P. aeruginosa PBP-3 participate in cell division. These results are in good agreement with the formation of filamentous cells of E. coli and P. aeruginosa treated with CFP. CFP had lower inhibitory activities on D-alanine carboxypeptidase IA and IB of E. coli than that of penicillin G, but its inhibitory activities on the cross-link formation in peptidoglycan synthesis were the same as those of penicillin G and higher than those of ampicillin.
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PMCID: PMC283963  PMID: 6448021
9.  In vitro antibacterial activity of DU-6859a, a new fluoroquinolone. 
Antimicrobial Agents and Chemotherapy  1995;39(12):2822-2826.
The in vitro antibacterial activity of DU-6859a, a new fluoroquinolone, against a wide variety of clinical isolates was evaluated and compared with those of tosufloxacin, ofloxacin, ciprofloxacin, and sparfloxacin. DU-6859a showed potent broad-spectrum activity against gram-positive, gram-negative, and anaerobic bacteria, and its activity was greater than those of the control quinolones. By comparison of MICs at which 90% of strains are inhibited, DU-6859a had potent activity against bacteria resistant to the control quinolones. The time-killing curves of quinolones showed that the number of viable cells decreased rapidly during 2 to 4 of incubation, and regrowth was not seen even after 8 h incubation. At a concentration of four times the MIC, the frequencies of appearance of spontaneous mutants of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa resistant to DU-6859a were < or = 4.0 x 10(-9) to 1.9 x 10(-8). The 50% inhibitory concentrations of DU-6859a were 0.86 and 1.05 micrograms/ml for the supercoiling activities of DNA gyrases isolated from E. coli and P. aeruginosa, respectively. The rank order of the 50% inhibitory concentrations observed for both DNA gyrases roughly paralleled the MICs.
PMCID: PMC163041  PMID: 8593031
10.  In vitro antibacterial activity and beta-lactamase stability of a new carbapenem, BO-2727. 
Antimicrobial Agents and Chemotherapy  1995;39(10):2331-2336.
The in vitro activity of BO-2727, a new carbapenem, was compared with those of meropenem, biapenem, imipenem, and ceftazidime. BO-2727 was four- or eightfold more active than the other carbapenems against methicillin-resistant staphylococci and Pseudomonas aeruginosa strains, including imipenem- and ceftazidime-resistant bacteria. BO-2727 was quite stable to penicillinases, cephalosporinases, and oxyiminocephalosporinases, but not to metallo-beta-lactamase. Time-kill studies against Staphylococcus aureus Smith, Escherichia coli ML4707, and P. aeruginosa GN11189 showed that BO-2727 has potent bactericidal activity at concentrations greater than the MIC.
PMCID: PMC162938  PMID: 8619591
11.  A beta-lactamase from Serratia marcescens hydrolyzing the 2-carboxypenam T-5575. 
A beta-lactamase was purified from Serratia marcescens GN16694; it hydrolyzed T-5575 and oxime-type cephalosporins, i.e., cefuroxime and ceftazidime. Its isoelectric point and molecular weight were 8.6 and 42,000, respectively. This enzyme was not inhibited by EDTA and clavulanic acid. This enzyme is an unusual beta-lactamase and has been classified as a group 1 cephalosporinase.
PMCID: PMC162895  PMID: 8540730
12.  Mechanism of tonB-dependent transport of KP-736, a 1,5-dihydroxy-4-pyridone-substituted cephalosporin, into Escherichia coli K-12 cells. 
The mechanism of transport of KP-736, a novel cephalosporin with a 1,5-dihydroxy-4-pyridone moiety at the C-7 position, into the Escherichia coli K-12 cell was investigated by determining the susceptibilities of iron transport mutants to KP-736. The tonB mutant showed a higher degree of resistance to KP-736, indicating that KP-736 was incorporated into E. coli cells via the tonB-dependent iron transport system. The product of the exbB gene was also necessary for the maximal antibacterial potency of KP-736. Cir-lacking and Fiu-lacking mutants showed a moderate level of resistance to KP-736. However, mutants lacking any one of the proteins FepA, FecA, FhuA, and FhuE did not show any increased resistance to KP-736. Two types of spontaneous mutants (e.g., KT1004 and KT1011) could be isolated from cir and fiu mutants by selection for KP-736 resistance and showed the same level of resistance to KP-736 as a tonB mutant. KT1004 showed tonB phenotypes, resistance to phage phi 80, and loss of FecA, whereas KT1011 did not. KT1011 lost the ability to express both Cir and Fiu proteins. These results indicate that the Cir and Fiu outer membrane proteins are involved specifically in the tonB-dependent transport process of KP-736. Against OmpF- and OmpC-deficient transformants producing various groups of beta-lactamases, KP-736 was more effective than the other cephalosporins tested.
PMCID: PMC162593  PMID: 7793861
13.  In vitro antibacterial activity and beta-lactamase stability of CP-70,429 a new penem antibiotic. 
In in vitro susceptibility tests, the new penem CP-70,429 showed potent antibacterial activity against gram-positive and gram-negative bacteria except Pseudomonas aeruginosa and Xanthomonas maltophilia. CP-70,429 was stable to various types of beta-lactamases except for the enzyme from X. maltophilia and was 16- to 128-fold more active than the other compounds against beta-lactamase-producing strains of Enterobacter cloacae and Citrobacter freundii.
PMCID: PMC188011  PMID: 8363389
14.  In vitro activity of T-3761, a new fluoroquinolone. 
Antimicrobial Agents and Chemotherapy  1992;36(10):2293-2303.
The in vitro activity of T-3761, a new fluoroquinolone antimicrobial agent which has an oxazine ring structure with a cyclopropyl moiety at C-10, was compared with those of other agents against 2,854 clinical isolates. T-3761 had a broad spectrum of activity and had potent activity against gram-positive and -negative bacteria. The MICs of T-3761 against 90% of the methicillin-susceptible Staphylococcus aureus, methicillin-susceptible and -resistant Staphylococcus epidermidis, and Clostridium spp. tested were 0.39 to 6.25 micrograms/ml. Its activity was comparable to those of ciprofloxacin and ofloxacin and four- to eightfold greater than those of norfloxacin and fleroxacin, but its activity was two- to eightfold less than that of tosufloxacin. Some isolates of ciprofloxacin-resistant S. aureus (MIC of ciprofloxacin, greater than or equal to 3.13 micrograms/ml) were still susceptible to T-3761 (MIC of T-3761, less than or equal to 0.78 micrograms/ml). The MICs of T-3761 against 90% of the streptococci and enterococci tested were 3.13 to 100 micrograms/ml. Its activity was equal to or 2- or 4-fold greater than those of norfloxacin and fleroxacin, equal to or 2- or 4-fold less than those of ofloxacin and ciprofloxacin, and 4- to 16-fold less than that of tosufloxacin. The activity of T-3761 against gram-negative bacteria was usually fourfold greater than those of norfloxacin, ofloxacin, and fleroxacin. Many isolates which were resistant to nonfluoroquinolone agents, such as minocycline- or imipenem-resistant S. aureus, ceftazidime-resistant members of the family Enterobacteriaceae, gentamicin- or imipenem-resistant Pseudomonas aeruginosa, and ampicillin-resistant Haemophilus influenzae and Neisseria gonorrhoeae, were susceptible to T-3761. The MBCs of T-3761 were either equal to or twofold greater than the MICs. The number of viable cells decreased rapidly during incubation with T-3761 at one to four times the MIC. At a concentration of four times the MIC, the frequencies of appearance of spontaneous mutants resistant to T-3761 against S. aureus, Escherichia coli, Serratia marcescens, and P. aeruginosa were 2.2 x 10(-8) to less than or equal to 1.2 x 10(-9). The 50% inhibitory concentrations of T-3761 for DNA gyrases isolated from E. coli and P. aeruginosa were 0.88 and 1.9 micrograms/ml, respectively.
PMCID: PMC245492  PMID: 1332594
15.  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.
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PMCID: PMC284285  PMID: 1656852
16.  Transferable imipenem resistance in Pseudomonas aeruginosa. 
We isolated an imipenem-resistant strain, GN17203, of Pseudomonas aeruginosa. The strain produced a beta-lactamase that hydrolyzed imipenem. The beta-lactamase was encoded by a 31-MDa plasmid, pMS350, which belongs to incompatibility group P-9. The plasmic conferred resistance to beta-lactams, gentamicin, and sulfonamide and was transferable by conjugation to P. aeruginosa but not to Escherichia coli. The molecular weight of the purified enzyme was estimated to be 28,000, and the isoelectric point was 9.0. The enzyme showed a broad substrate profile, hydrolyzing imipenem, oxyiminocephalosporins, 7-methoxycephalosporins, and penicillins. The enzyme activity was inhibited by EDTA, iodine, p-chloromercuribenzoate, CuSO4, and HgCl2 but not by clavulanic acid or sulbactam.
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PMCID: PMC244956  PMID: 1901695
17.  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.
PMCID: PMC175974  PMID: 2167038
18.  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.
PMCID: PMC171769  PMID: 2393270
19.  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.
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PMCID: PMC171745  PMID: 2203313
20.  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.
PMCID: PMC171643  PMID: 2344162
21.  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.
PMCID: PMC171545  PMID: 2183709
22.  Interaction of E1040 with cephalosporinase from Citrobacter freundii GN7391. 
Antimicrobial Agents and Chemotherapy  1989;33(12):2157-2159.
The interactions of E1040 with cephalosporinase from Citrobacter freundii, including affinity and hydrolysis, were studied in comparison with those of cefotaxime and ceftazidime. E1040 showed a higher stability at low drug concentrations and a much lower affinity for the enzyme than did cefotaxime or ceftazidime. These enzymological properties explain the high activity of E1040 against cephalosporinase-producing C. freundii.
PMCID: PMC172843  PMID: 2694954
23.  In vitro activity of AT-4140 against clinical bacterial isolates. 
Antimicrobial Agents and Chemotherapy  1989;33(11):1980-1988.
The activity of AT-4140, a new fluoroquinolone, was evaluated against a wide range of clinical bacterial isolates and compared with those of existing analogs. AT-4140 had a broad spectrum and a potent activity against gram-positive and -negative bacteria, including Legionella spp. and Bacteroides fragilis. The activity of AT-4140 against gram-positive and -negative cocci, including Acinetobacter calcoaceticus, was higher than those of ciprofloxacin, ofloxacin, and norfloxacin. Its activity against gram-negative rods was generally comparable to that of ciprofloxacin. Some isolates of methicillin-resistant Staphylococcus aureus (MIC of methicillin, greater than or equal to 12.5 micrograms/ml) were resistant to existing quinolones, but many of them were still susceptible to AT-4140 at concentrations below 0.39 micrograms/ml. The MICs of AT-4140, ciprofloxacin, ofloxacin, and norfloxacin for 90% of clinical isolates of methicillin-resistant S. aureus were 0.2, 12.5, 6.25, and 100 micrograms/ml, respectively. AT-4140 was bactericidal for each of 20 clinical isolates of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, and Pseudomonas aeruginosa at concentrations near the MICs. AT-4140 inhibited the supercoiling activity of DNA gyrase from E. coli.
PMCID: PMC172799  PMID: 2558617
24.  In vitro and in vivo antibacterial activities of KB-5246, a new tetracyclic quinolone. 
Antimicrobial Agents and Chemotherapy  1989;33(11):1896-1900.
The in vitro and in vivo antibacterial activities of KB-5246, a tetracyclic quinolone, were compared with those of ciprofloxacin, ofloxacin, and norfloxacin. KB-5246 demonstrated a broad antibacterial spectrum. The in vitro activity of KB-5246 against gram-negative bacteria was higher than that of ofloxacin or norfloxacin and was comparable to that of ciprofloxacin. KB-5246 demonstrated the greatest activity against gram-positive bacteria of the four agents tested. Among Streptococcus pyogenes strains resistant to 1.56 micrograms of norfloxacin per ml, there were 26 strains susceptible to 0.2 micrograms of KB-5246 per ml. Similarly, among the Staphylococcus aureus and Staphylococcus epidermidis strains resistant to 3.13 micrograms of norfloxacin per ml, there were 23 S. aureus and 11 S. epidermidis strains susceptible to 0.39 micrograms of KB-5246 per ml. Among the Streptococcus pneumoniae and Enterococcus faecalis strains resistant to 12.5 micrograms of norfloxacin per ml, there were 5 S. pneumoniae and 10 E. faecalis strains susceptible to 0.39 micrograms of KB-5246 per ml. KB-5246 had bactericidal activity at the MIC. KB-5246 demonstrated excellent antibacterial activity against various systemic infections in mice. After oral administration, KB-5246 was as active as ofloxacin and about two times more active than norfloxacin.
PMCID: PMC172784  PMID: 2610501
25.  In vitro activity of amifloxacin against outer membrane mutants of the family Enterobacteriaceae and frequency of spontaneous resistance. 
Antimicrobial Agents and Chemotherapy  1989;33(11):1837-1840.
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.
PMCID: PMC172773  PMID: 2558611

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