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1.  Paradoxical antibacterial activity of cefmenoxime against Proteus vulgaris. 
The growth-inhibitory effect of cefmenoxime against Proteus vulgaris was studied by using the broth dilution and paper disk diffusion methods. Cefmenoxime showed growth-inhibitory activity against Proteus vulgaris at low concentrations but not at high concentrations up to a certain limit. This paradoxical antibacterial activity was not observed with cefoperazone and cefbuperazone. The induction of beta-lactamase by cefmenoxime and the rate of hydrolysis of cefmenoxime in the culture broth were proportional to the initial concentration of this antibiotic. At high initial concentrations, cefmenoxime was rapidly inactivated. On the other hand, neither cefoperazone nor cefbuperazone was inactivated irrespective of concentration. We conclude that cefmenoxime induces beta-lactamase in P. vulgaris, perhaps accounting for its paradoxical antibacterial effect.
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PMCID: PMC284201  PMID: 3304155
2.  Antimicrobial Activity of Cefmenoxime (SCE-1365) 
The in vitro activity of cefmenoxime (SCE-1365 or A-50912), a new semisynthetic cephalosporin antibiotic, was compared with those of cefazolin, cefoxitin, and cefamandole against a broad spectrum of 486 organisms and with that of cefotaxime against 114 organisms. Cefmenoxime and cefotaxime exhibited nearly equivalent activities against those organisms tested and were the most active of these cephalosporins against all aerobic and facultative organisms except Staphylococcus aureus. The minimum inhibitory concentration (MIC) of cefmenoxime required to inhibit at least 90% of strains tested (MIC90) ranged from 0.06 to 8 μg/ml for the Enterobacteriaceae. The MIC90s for gram-positive cocci were 0.015 and ≤0.008 μg/ml for Streptococcus pneumoniae and Streptococcus pyogenes, respectively, and 2 μg/ml for S. aureus. Group D streptococci were less susceptible. Cefmenoxime was very active against Haemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidis with MIC90s ranging from ≤0.008 to 0.25 μg/ml. Cefmenoxime, at a concentration of 16 μg/ml, inhibited 78% and 73% of Pseudomonas aeruginosa and Acinetobacter spp., respectively. MICs for anaerobes ranged from 0.5 to >128 μg/ml with good activity against the gram-positive organisms. In addition, cefmenoxime activity was bactericidal and only slightly affected by differences in inoculum size. The combination of cefmenoxime and gentamicin was synergistic against 80% of the Enterobacteriaceae and 100% of P. aeruginosa strains tested. Development of resistance to cefmenoxime was slow or absent for organisms with low initial MICs but more rapid for those with higher initial MICs. Cefmenoxime exhibited good protective activity in mice infected with Escherichia coli, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, or S. aureus but was less effective against P. aeruginosa.
PMCID: PMC181453  PMID: 6264846
3.  Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect. 
Fifteen beta-lactam antibiotics were divided into four classes based on their antibacterial actions and beta-lactamase-inducing activities in Proteus vulgaris. One of these groups, which included cefmenoxime, ceftriaxone, cefuzonam, and cefotaxime, showed a clear paradoxical antibacterial activity against P. vulgaris. This group showed growth-inhibitory activity at relatively low concentrations, up to certain limits. These cephalosporins have, as a common moiety, an aminothiazolyl-oxyimino group in the 7-acyl side chain and have high beta-lactamase-inducing activities and low stabilities against the beta-lactamase. In a mutant strain incapable of inducing beta-lactamase, however, the paradoxical antibacterial activity was not observed. These findings suggest that beta-lactamase plays an essential role in the paradoxical antibacterial effect in P. vulgaris. We conclude that the induction of a large amount of beta-lactamase and the low stability against beta-lactamase may account for the paradoxical antibacterial activity in P. vulgaris.
PMCID: PMC172346  PMID: 3056246
4.  Cefmenoxime (SCE-1365), a novel broad-spectrum cephalosporin: in vitro and in vivo antibacterial activities. 
The activity of cefmenoxime (SCE-1365), 7 beta-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid, was compared with that of other cephalosporins. Cefmenoxime exhibited high activity against a wide variety of gram-positive and gram-negative bacteria. The in vitro activity of cefmenoxime against Streptococcus pyogenes, Haemophilus influenzae, and Enterobacteriaceae, including indole-positive Proteus, Serratia marcescens, Enterobacter cloacae, and Citrobacter freundii, was 10 to 1,000 times greater than that of several other cephalosporins. Against Pseudomonas aeruginosa, cefmenoxime showed activity two to four times that of sulbenicillin and carbenicillin but less than that of cefsulodin. Variation in pH, addition of horse serum, and type of growth medium had definite effects on the activity of cefmenoxime, and the inoculum size affected the activity against bacterial species. In Escherichia coli cefmenoxime showed marked affinity for penicillin-binding protein 3 (PBP-3), followed by PBP-1 (1A and 1B). This affinity profile was well correlated with its filamentous cell-forming activity under extremely low drug concentrations and with its bactericidal activity against microorganisms. The high in vitro activity of cefmenoxime was reflected in the degree of protection observed in mice infected intraperitoneally with a wide variety of gram-positive and gram-negative bacteria. Furthermore, cefmenoxime showed good therapeutic activity against infection models in mice such as respiratory tract infection caused by Klebsiella pneumoniae and urinary tract infection caused by Proteus mirabilis.
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PMCID: PMC181357  PMID: 6941742
5.  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
6.  Comparative efficacy of cefotiam, cefmenoxime, and ceftriaxone in experimental endocarditis and correlation with pharmacokinetics and in vitro efficacy. 
To determine the influence of in vitro activity, pharmacokinetic properties, and therapeutic regimen on the antibacterial effect in vivo, we compared three cephalosporins, cefotiam, cefmenoxime, and ceftriaxone, in a rabbit model of experimental Escherichia coli endocarditis after 4 days of treatment. The MBCs of cefotiam, cefmenoxime, and ceftriaxone for the E. coli strain were 0.5, 0.125, and 0.06 microgram/ml, respectively. Killing curves at 10 times the MBC were similar for the three cephalosporins. In serum, the elimination half-life of ceftriaxone was twice as much as the elimination half-life of cefotiam or cefmenoxime (2.8 +/- 0.45 versus 1.4 +/- 0.25 or 1.3 +/- 0.4 h, respectively). Ceftriaxone was much more effective than cefotiam. The bacterial titer in the vegetations (log10 CFU per gram of vegetation) was 7.56 +/- 1 with cefotiam and 2.41 +/- 2.6 with ceftriaxone, as their concentrations were 18 and 466 times higher, respectively, than their MBCs. Although ceftriaxone and cefmenoxime exhibited a similar rate of killing and percentage of protein binding, ceftriaxone was more effective than cefmenoxime at the same regimen of 15 mg/kg twice a day (3.08 +/- 1.1 versus 4.82 +/- 3.2 log10 CFU/g of vegetation). When antibiotic was given as a single daily injection of 30 mg/kg, the antibacterial effect persisted for ceftriaxone, but not for cefmenoxime. The longer elimination half-life and the higher local concentration/MBC ratio of ceftriaxone explained these results. The bacterial titer measured 24 h after the fourth injection of 30 mg of ceftriaxone per kg confirmed that this regimen prevented regrowth of bacteria. These results suggest that the local antibiotic level/MBC ratio roughly correlated with the antibacterial effect and could represent an adequate basis to explain the differences observed between the drugs in vivo. They also demonstrate that, provided that the dose is sufficient, a long-acting broad-spectrum cephalosporin may be effective in severe gram-negative infections, even when given at relatively long dosing intervals, in contrast with a rapidly cleared drug with the same intrinsic activity.
PMCID: PMC174769  PMID: 3300530
7.  In vitro activity and beta-lactamase stability of cefmenoxime. 
The activity of cefmenoxime, an aminothiazolyl cephalosporin, was studied against 650 bacteria. It was slightly less active than cefotaxime and more active than moxalactam against staphylococci. It had activity similar to that of cefotaxime and ceftizoxime against group A and B streptococci and Streptococcus pneumoniae. It did not inhibit Streptococcus faecalis or Listeria spp. Cefmenoxime had activity similar to that of cefotaxime, ceftizoxime, ceftazidime, and moxalactam against Escherichia coli, Citrobacter diversus, Klebsiella, Proteus mirabilis, Salmonella, and Shigella. It inhibited beta-lactamase-positive and -negative isolates at less than or equal to 0.4 microgram/ml. Cefmenoxime was somewhat less active than moxalactam or ceftizoxime against Enterobacter cloacae, Enterobacter aerogenes, and Enterobacter agglomerans, but was more active than cefotaxime, ceftizoxime, or ceftazidime against Morganella (minimum inhibitory concentration for 90% of isolates, 0.1 microgram/ml.), Proteus vulgaris and Providencia spp. It was as active as ceftizoxime was against Serratia. Pseudomonas spp. and Bacteroides spp. were relatively resistant (minimum inhibitory concentration for 90% of isolates, greater than 100 micrograms/ml). The compound was stable to the common plasmid beta-lactamases, such as that of TEM. It was stable to most chromosomally mediated beta-lactamases, which act primarily as cephalosporinases, but was hydrolyzed by Bacteroides and Acinetobacter.
PMCID: PMC183732  PMID: 6100427
8.  Cefmenoxime (SCE-1365), a new Cephalosporin: In Vitro Activity, Comparison with Other Antimicrobial Agents, Beta-Lactamase Stability, and Disk Diffusion Testing with Tentative Interpretive Criteria 
The in vitro activity of cefmenoxime (SCE-1365) was evaluated in a multiphased collaborative investigation. Over 7,500 consecutive clinical isolates were tested in five laboratories, and greater than 90% of the following organisms were inhibited by cefmenoxime at the following concentrations: Enterobacteriaceae and non-enterococcal streptococci, ≤0.125 μg/ml; Staphylococcus aureus, ≤2.0 μg/ml; and nonfermenting gram-negative bacilli and Bacteroides fragilis group, ≤32 μg/ml. Both beta-lactamase-producing and -nonproducing Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by cefmenoxime at ≤0.03 μg/ml. The spectrum of cefmenoxime was similar to that of other, newer cephalosporins, particularly cefotaxime. A pronounced inoculum effect was found with some species upon increasing inocula from 105 to 107 colony-forming units per ml, resulting in an approximate eightfold increase in minimum inhibitory concentrations. Cefmenoxime was bactericidal when tested with inocula of 105 colonyforming units per ml, and mean differences between the minimum inhibitory concentration and the minimum lethal concentration were less than one log2 dilution. No significant hydrolysis of cefmenoxime by five different beta-lactamases was detectable, and cefmenoxime exhibited marked inhibition of type I beta-lactamases. Regression and error rate-bounded analyses of results of disk diffusion and reference broth microdilution susceptibility tests were performed on 421 bacterial isolates, and the following tentative zone size breakpoints are proposed: ≥22 mm, susceptible; ≤14 mm, resistant; and 15 to 21 mm, moderately susceptible (indeterminate). These data and cross-resistance studies with other newer cephalosporins indicate marked similarity of in vitro activity within this group of drugs, particularly between cefmenoxime, moxalactam, and cefotaxime. Any one of these could serve as the representative for the disk diffusion testing of this group of drugs if comparable minimum inhibitory concentration breakpoints were used for each drug.
PMCID: PMC181794  PMID: 6275784
9.  Levels of cefmenoxime in sera and peritoneal tissues of patients undergoing gastrointestinal surgery. 
It is not known whether a prophylactic antibiotic administered prior to surgery reaches adequate levels in the peritoneum, where peritonitis may take place. This study determined levels of cefmenoxime in sera and peritoneal tissues of patients undergoing gastrointestinal surgery. Fifteen patients who underwent elective gastrointestinal surgery received an intravenous drip infusion of cefmenoxime (2 g) over 1 h prior to surgery. In patients who underwent gastrectomy, the level of cefmenoxime in serum was 130.8 +/- 6.9 micrograms/ml at laparatomy and decreased to 5.0 +/- 0.7 micrograms/ml at 4 h. Levels in parietal peritoneal and omental tissues at laparotomy were 35.3 +/- 5.2 and 19.2 +/- 3.5 micrograms, respectively, and decreased time dependently. In patients who underwent cholecystectomy, the level of cefmenoxime in serum was 137.9 +/- 7.3 micrograms/ml at laparotomy and decreased to 5.0 +/- 1.2 micrograms/ml at 4 h. Levels in parietal peritoneal and omental tissues were 31.0 +/- 8.4 and 13.7 +/- 3.3 micrograms/g, respectively, and decreased time dependently. The level of cefmenoxime in serum correlated with the levels of cefmenoxime in parietal peritoneum (r = 0.64, P less than 0.01) and in omentum (r = 0.47, P less than 0.02). In patients with appendicitis who received a bolus injection of 2 g of cefmenoxime, the level of drug in inflammatory omental tissue correlated with the level in serum. The levels in peritoneal tissue during surgery lasting up to 2 h were significantly greater than in MIC of cefmenoxime against almost all bacteria reported. A preoperative single dose of 2 g of cefmenoxime probably is effective as a prophylactic for intraoperative contamination.
PMCID: PMC191608  PMID: 1510444
10.  Comparative antibacterial activities of 7 alpha-methoxy cephalosporins and 7 beta-methoxyiminoacetamido cephalosporins against Bacteroides fragilis. 
The in vitro antibacterial activities of the newly developed 7 alpha-methoxy cephalosporins and 7 beta-methoxyiminoacetamido cephalosporins against 67 clinical isolates of Bacteroides fragilis and their resistance to the hydrolytic action of a beta-lactamase produced by B. fragilis were simultaneously compared. The minimal inhibitory concentrations that inhibited 90% of the 7 alpha-methoxy cephalosporins, cefoxitin, cefmetazole, moxalactam, and cefotetan, against the isolates were 4, 8, 8, and 16 micrograms/ml, respectively, and these antibiotics were entirely resistant to hydrolysis by beta-lactamases (0.10 mumol/h per mg of protein) of the isolates. By contrast, 7 beta-methoxyiminoacetamido cephalosporins represented by cefotaxime, ceftizoxime, and cefmenoxime were not effective, as indicated by the minimal inhibitory concentrations that inhibited 90%, 64, 32, and 128 micrograms/ml, respectively. Their antibacterial activities clearly corresponded to their resistance to the hydrolytic action of the beta-lactamase: namely, the correlation coefficients in regression curves of cefotaxime, ceftizoxime, and cefmenoxime, which were expressed by the antibacterial activity (x axis) and the beta-lactamase activity (y axis) were 0.098, 0.034, and 0.163, respectively.
PMCID: PMC185451  PMID: 6322676
11.  In vivo activity of ceftriaxone (Ro 13-9904), a new broad-spectrum semisynthetic cephalosporin. 
Ceftriaxone (Ro 13-9904) was compared with other newer beta-lactam antibiotics for activity in experimental infections of mice with Enterobacteriaceae, Haemophilus influenzae, Pseudomonas aeruginosa, and gram-positive bacteria. Overall, ceftriaxone was equal or superior to cefotaxime and cefoperazone against systemic infections. All three drugs were highly potent against most organisms but were considerably less active against P. aeruginosa. However, ceftriaxone tended to be more active than the other two agents against 8 of the 10 P. aeruginosa strains tested. Ceftriaxone, cefmenoxime (SCE 1365), and moxalactam were all highly active against systemic infections with 16 strains of Enterobacteriaceae, whereas ceftriaxone was more active against infections with two strains of streptococci. When the drugs were administered at various time intervals before infection, ceftriaxone was superior to cefotaxime, cefmenoxime, and moxalactam. This suggested that ceftriaxone might be eliminated from mice more slowly than the other drugs. In the case of cefotaxime, this was directly confirmed by microbiological assays of plasma samples. In a murine meningitis model induced by Klebsiella pneumoniae or Streptococcus pneumoniae, ceftriaxone was more active than ampicillin or cefotaxime. Ceftriaxone was more active than ampicillin, cefotaxime, piperacillin, cefamandole, or carbenicillin in a pneumococcal, pneumonia model in mice. These studies indicate that ceftriaxone is a potent, broad-spectrum cephalosporin with unusual pharmacokinetic properties.
PMCID: PMC181657  PMID: 6269487
12.  Pharmacokinetics of cephem antibiotics in exudate of pelvic retroperitoneal space after radical hysterectomy and pelvic lymphadenectomy. 
Many cephalosporin antibiotics have recently been invented and attempts have been made to use them clinically. The choice of which of these drugs should be used has been difficult in gynecology. The efficacies of these drugs depend on their antibacterial spectra, potencies, and concentrations in tissues. This study was designed to investigate the pharmacokinetics of various cephem antibiotics in the exudate of the retroperitoneal space that is formed after radical hysterectomy and pelvic lymphadenectomy. These cephem antibiotics were cefoxitin, cefotiam, cefotetan, cefpiramide, cefminox, cefotaxime, ceftizoxime, cefoperazone, cefmenoxime, cefbuperazone, ceftazidime, cefpimizole, flomoxef, and cefuzonam. The maximum concentrations after administration of a 1-g dose in the exudate of the pelvic retroperitoneal space were 37.9 micrograms/ml with cefminox, 30.3 micrograms/ml with cefpimizole, 21.6 micrograms/ml with flomoxef, 21.5 micrograms/ml with ceftazidime, and 17.6 micrograms/ml with cefbuperazone, which were relatively high. When selecting antibiotics for prophylactic use against infections in the retroperitoneal space after radical hysterectomy and pelvic lymphadenectomy, on the basis of drug transfer, flomoxef, cefminox, cefbuperazone, ceftazidime, and cefpimizole were considered to be the drugs of first choice at a dose of 1 g.
PMCID: PMC171777  PMID: 2393276
13.  In vitro evaluation of E1040, a new cephalosporin with potent antipseudomonal activity. 
E1040 is a new parenteral cephalosporin with a broad antibacterial spectrum and potent antipseudomonal activity. The compound was four- to eightfold more active than ceftazidime and cefsulodin against Pseudomonas aeruginosa (MIC of E1040 for 90% of strains tested [MIC90], 3.13 micrograms/ml). E1040 also showed a potent activity against other glucose-nonfermentative rods, including Acinetobacter species. The activities of E1040 against most species of the family Enterobacteriaceae were roughly comparable to the activities of ceftazidime and cefmenoxime and exceeded that of cefotiam. Against Citrobacter freundii (MIC90, 0.78 micrograms/ml), Enterobacter cloacae (MIC90, 3.13 micrograms/ml), and Enterobacter aerogenes (MIC90, 0.2 micrograms/ml), E1040 was 16- to 256-fold more active than ceftazidime and cefmenoxime. The activities of E1040 against gram-positive cocci and anaerobes were comparable to those of ceftazidime, but the compound was less active than cefmenoxime. E1040 was at least as resistant as ceftazidime and cefmenoxime to hydrolysis by various beta-lactamases and showed high affinities for penicillin-binding protein 3 of both Escherichia coli and P. aeruginosa.
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PMCID: PMC172254  PMID: 3134847
14.  Comparative efficacy of cefmenoxime versus penicillin in the treatment of gonorrhea. 
A total of 121 men with complicated infections caused by beta-lactamase-negative Neisseria gonorrhoeae were included in this study. They were randomly assigned to regimens of either cefmenoxime (1.0 g) or procaine penicillin G (4.8 X 10(6) U) intramuscularly. Only the penicillin group also took 1.0 g of probenecid orally. A total of 99 patients completed the study, providing data from 108 infected sites. In the cefmenoxime group, there were 49 urethral, 1 rectal, and 2 pharyngeal infections; in the penicillin group, there were 49 urethral, 4 rectal, and 3 pharyngeal infections. In the cefmenoxime group, all except one urethral infection were eradicated. This patient admitted having had sexual intercourse during the follow-up period and was considered to be reinfected. In the penicillin group, all except one pharyngeal infection were cured. No adverse reactions were noted in either group. In this study, cefmenoxime was as effective as penicillin in the treatment of gonococcal urethritis in men.
PMCID: PMC184649  PMID: 6303209
15.  In vitro activity of cefbuperazone, a new cephamycin, against anaerobic bacteria. 
The 90% MIC of cefbuperazone (BMY 25182) was 32 micrograms/ml for Bacteroides fragilis and Bacteroides spp., 128 micrograms/ml for Fusobacterium and Clostridium spp., 64 micrograms/ml for Eubacterium and Peptococcus spp., 8 micrograms/ml for Actinomyces spp., and 32 micrograms/ml for Peptostreptococcus spp. The level of activity of cefbuperazone was higher against B. fragilis and lower against anaerobic cocci than those of related cephalosporins, i.e., cefoxitin, cefoperazone, cefotaxime, ceftizoxime, and cefmenoxime. However, the activity of cefbuperazone was comparable to that of moxalactam against all groups tested. Size of inoculum and type of media used did not alter the MICs of cefbuperazone for B. fragilis. Cefbuperazone showed synergistic activity when combined with cefoxitin against resistant strains of B. fragilis.
PMCID: PMC180111  PMID: 4004195
16.  Efficacy of cefmenoxime in experimental Escherichia coli bacteremia and meningitis. 
Cefmenoxime, a new semisynthetic cephalosporin structurally similar to cefotaxime, was evaluated for its activities in vitro and in vivo against a K1 Escherichia coli strain in comparison with activities of cefotaxime and ampicillin. In vitro the MICs and MBCs of both cefmenoxime and cefotaxime were the same, 1/16th and 1/32nd those of ampicillin, respectively. The efficacies of cefmenoxime and cefotaxime against experimentally induced E. coli bacteremia and meningitis in newborn rats were similar and significantly better than that of ampicillin as judged by bactericidal titers of blood and cerebrospinal fluid, rapidity of clearance of bacteria from blood and cerebrospinal fluid, and incidence of meningitis in animals with bacteremias. The efficacy of cefmenoxime or cefotaxime measured by impact on mortality was influenced by the size of bacterial populations. The mortality was significantly greater in rats with bacterial counts before therapy of greater than or equal to 10(6) CFU/ml of blood than in animals with lower counts. Overall, the in vivo efficacy of cefmenoxime was similar to that of cefotaxime; thus it could be useful in the therapy of neonatal E. coli infection.
PMCID: PMC180259  PMID: 3907491
17.  Comparative in vitro activity of cefmenoxime, cefotaxime, cefuroxime, cefoxitin, and penicillin against Neisseria gonorrhoeae. 
The in vitro activity of a new beta-lactam antibiotic, cefmenoxime, was compared with those of cefotaxime, cofuroxime, cefoxitin, and penicillin against 72 beta-lactamase-negative and 26 beta-lactamase-positive Neisseria gonorrhoeae. Cefmenoxime was as active as cefotaxime and more active than the other three antimicrobial agents. It inhibited all isolates, regardless of beta-lactamase activity, at a concentration of less than or equal to 0.015 microgram/ml.
PMCID: PMC181772  PMID: 6275781
18.  Antimicrobial activities of BMY-28142, cefbuperazone, and cefpiramide compared with those of other cephalosporins. 
The antimicrobial activities of BMY-28142, cefbuperazone (BMY-25182; formerly T-1982), and cefpiramide (WY-44635; formerly SM-1652) were compared with those of cefmenoxime, cefoperazone, cefotaxime, ceftizoxime, and moxalactam. BMY-28142 was the most active cephalosporin against the majority of aerobic and facultatively anaerobic microorganisms studied. Its spectrum of activity was very similar to that of cefotaxime. However, BMY-28142, cefbuperazone, cefmenoxime, cefotaxime, ceftizoxime, and moxalactam were equivalent in activity and rate of killing against members of the family Enterobacteriaceae. Cefpiramide was considerably less active than the other cephalosporins against the Enterobacteriaceae.
PMCID: PMC179970  PMID: 6549120
19.  Influence of inoculum size on comparative susceptibilities of penicillinase-positive and -negative Neisseria gonorrhoeae to 31 antimicrobial agents. 
The effects of two inoculum sizes (10(4) and 10(6) CFU) on the MICs of 20 beta-lactam antibiotics, 4 aminoglycosides, and 7 other antimicrobial agents were compared for 102 unselected strains of Neisseria gonorrhoeae (26 penicillinase positive and 76 penicillinase negative), with three replicates for each test. The method was agar plate dilution on Mueller-Hinton agar supplemented with 1% hemoglobin and 1% IsoVitaleX. For penicillinase-positive strains, a large inoculum (10(6) CFU) increased the MIC greater than or equal to 16-fold for benzylpenicillin, piperacillin, azlocillin, and mezlocillin and increased the MIC greater than or equal to 8-fold for ampicillin, cefoperazone, ceftazidime, cefonicid, and cefamandole. The inoculum size had little or no influence on MICs of any antimicrobial agent for penicillinase-negative strains. For penicillinase-positive strains, the most active antibiotics (MIC, less than or equal to 0.001 microgram/ml) were the new cephalosporins: cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, and cefmenoxime. For penicillinase-negative strains, the most active antibiotics were piperacillin, ceftriaxone, ceftizoxime, and cefmenoxime (MIC, less than or equal to 0.001 microgram/ml), closely followed by ceftazidime, moxalactam, azlocillin, mezlocillin, and cefuroxime.
PMCID: PMC284117  PMID: 6435514
20.  Activities of beta-lactam antibiotics against Escherichia coli strains producing extended-spectrum beta-lactamases. 
Seven extended-spectrum beta-lactamases related to TEM and four enzymes derived from SHV-1 were transferred to a common Escherichia coli host so that the activity of a variety of beta-lactams could be tested in a uniform genetic environment. For most derivatives, penicillinase activity was 10% or less than that of strains making TEM-1, TEM-2, or SHV-1 beta-lactamase, suggesting that reduced catalytic efficiency accompanied the broader substrate spectrum. Despite this deficit, resistance to aztreonam, carumonam, cefdinir, cefepime, cefixime, cefmenoxime, cefotaxime, cefotiam, cefpirome, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, and E1040 was enhanced. For strains producing TEM-type enzymes, however, MICs of carumonam, cefepime, cefmenoxime, cefotiam, cefpirome, and ceftibuten were 8 micrograms/ml or less. Susceptibilities of cefmetazole, cefotetan, cefoxitin, flomoxef, imipenem, meropenem, moxalactam, temocillin, FCE 22101, and Sch 34343 were unaffected. FCE 22101, imipenem, meropenem, and Sch 34343 were inhibitory for all strains at 1 microgram/ml or less. In E. coli an OmpF- porin mutation in combination with an extended-spectrum beta-lactamase enhanced resistance to many of these agents, but generally by only fourfold. Hyperproduction of chromosomal AmpC beta-lactamase increased resistance to 7-alpha-methoxy beta-lactams but not that to temocillin. When tested at 8 micrograms/ml, clavulanate was more potent than sulbactam or tazobactam in overcoming resistance to ampicillin, while cefoperazone-sulbactam was more active than ticarcillin-clavulanate or piperacillin-tazobactam, especially against TEM-type extended-spectrum beta-lactamases.
PMCID: PMC171706  PMID: 2193623
21.  In vitro evaluation of E1077, a new cephalosporin with a broad antibacterial spectrum. 
E1077 is a novel parenteral cephalosporin with a wide spectrum of potent antibacterial activity against aerobic and anaerobic gram-positive and gram-negative bacteria. Against methicillin-susceptible Staphylococcus aureus, E1077 was twice as active as cefpirome, with an MIC for 90% of strains tested (MIC90) of 0.78 micrograms/ml. Methicillin-resistant S. aureus was moderately to highly resistant to E1077, but E1077 was at least twice as active as other beta-lactams tested. Against Enterococcus faecalis, E1077 was the most active of the cephalosporins tested (MIC90, 12.5 micrograms/ml) and was at least fourfold more active than cefpirome and ceftazidime. At concentrations of less than or equal to 0.78 micrograms/ml, E1077 inhibited 90% of streptococci and most of the members of the family Enterobacteriaceae tested, with the exceptions of Serratia marcescens and Proteus vulgaris, for which the MIC90s of E1077 were both 3.13 micrograms/ml. Against Pseudomonas aeruginosa, E1077 was two- to fourfold more active than cefpirome and ceftazidime. For the anaerobes, E1077 was as active against Bacteroides fragilis as was cefuzonam, and its activity was fourfold higher than those of cefpirome and ceftazidime. E1077 was at least as resistant as cefpirome to hydrolysis by various beta-lactamases, and these enzymes had a low affinity for E1077.
PMCID: PMC190561  PMID: 1622167
22.  In vitro activity of cefbuperazone compared with that of other new beta-lactam agents against anaerobic gram-negative bacilli and contribution of beta-lactamase to resistance. 
Cefbuperazone was compared with other currently available and investigational antibiotics against 278 clinical isolates of anaerobic gram-negative bacilli by an agar dilution method. Cefbuperazone and cefotetan were equally active against Bacteroides fragilis, with 8% of the organisms tested found to be resistant to 32 micrograms of either drug per ml. Cefoperazone, cefotaxime, ceftriaxone, and cefmetazole were less active against these strains; cefoxitin, moxalactam, piperacillin, clindamycin, and metronidazole were more active. None of the agents were consistently active against any of the other anaerobic gram-negative bacilli except imipenem, for which the minimum concentration required to inhibit 90% of all strains tested was 4 micrograms/ml. A 10,000-fold increase in inoculum size caused an increase in the MIC of ceftriaxone, cefotaxime, and cefoperazone but not of cefbuperazone, cefotetan, or cefoxitin. Investigation of the mechanism of resistance to cephalosporin-like agents demonstrated a correlation between the level of resistance and beta-lactamase activity. Cefbuperazone, cefotetan, and cefoxitin were not hydrolyzed, had lower MICs, and were less affected by changes in inoculum size than were cefotaxime, ceftriaxone, and cefoperazone.
PMCID: PMC180158  PMID: 3874597
23.  Chromosomal beta-lactamase expression and resistance to beta-lactam antibiotics in Proteus vulgaris and Morganella morganii. 
Indole-positive members of the Proteeae usually have inducible expression of chromosomal beta-lactamases. Mutants with stably derepressed beta-lactamase expression occur in inducible populations at frequencies in the range of 10(-6) to 10(-8). The contribution of these beta-lactamases to drug resistance was examined in Morganella morganii and Proteus vulgaris. The M. morganii enzyme was a high-molecular-weight (49,000) class I cephalosporinase with low Vmax rates for ampicillin, carbenicillin, and and broad-spectrum cephalosporins. The P. vulgaris enzyme had a lower molecular weight (32,000) and high Vmax rates for ampicillin, cephaloridine, cefotaxime, and ceftriaxone. Imipenem and cefoxitin inactivated the P. vulgaris enzyme but were low-Vmax, low-Km substrates for that of M. morganii. Despite these differences, the two beta-lactamases caused similar resistance profiles. Ampicillin and cephaloridine were strong inducers for both species, and beta-lactamase-inducible strains and their stably derepressed mutants were resistant, whereas basal mutants (those with low-level uninducible beta-lactamase) were susceptible to these two compounds. Mezlocillin, cefotaxime, ceftriaxone, and (usually) carbenicillin were almost equally active against beta-lactamase-inducible organisms and their basal mutants, but were less active against stably derepressed mutants. This behavior reflected the beta-lactamase lability of these drugs, coupled with their weak inducer activity below the MIC. Carbenicillin was a labile strong inducer for a single P. vulgaris strain, and inducible enzyme was protective against the drug in this atypical organism. Cefoxitin and imipenem, both strong inducers below the MIC, were almost equally active against beta-lactamase-inducible organisms and their basal and stably derepressed mutants.
PMCID: PMC175873  PMID: 3058021
24.  In vitro and in vivo antibacterial activities of E1077, a novel parenteral cephalosporin with a broad antibacterial spectrum. 
E1077 is a new injectable cephalosporin with a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria, including staphylococci and Pseudomonas aeruginosa. The in vitro activities of E1077 against clinical isolates of methicillin-susceptible Staphylococcus aureus (MIC of E1077 for 90% of the strains tested [MIC90], 0.78 microgram/ml) and methicillin-resistant S. aureus (MIC90, 50 micrograms/ml) were similar to those of cefpirome and flomoxef. Against Enterococcus faecalis (MIC90, 6.25 micrograms/ml), E1077 was the most active of the drugs tested and four times more active than cefpirome. The MIC90S of E1077 for streptococci, Haemophilus influenzae, and Neisseria gonorrhoeae ranged from 0.05 to 0.78 microgram/ml; E1077 was similar in activity to cefpirome. E1077 inhibited 90% of most species of the family Enterobacteriaceae at concentrations of less than or equal to 1.56 micrograms/ml, with the exception of Serratia marcescens and Proteus vulgaris (12.5 micrograms/ml). The activity of E1077 against P. aeruginosa (MIC90, 6.25 micrograms/ml) was comparable to that of ceftazidime. In vivo activity was evaluated with systemic infections in mice. E1077 showed a protective effect against systemic infections by gram-positive or gram-negative bacteria, as reflected by its in vitro activity. The protective effects of E1077 were higher than those of cefpirome against S. aureus and P. aeruginosa infections and similar to those of cefpirome against other bacterial infections. Morphological studies using differential interference and phase-contrast microscopy showed that low concentrations of E1077 caused swelling of S. aureus and spheroplast and bulge formation in P. aeruginosa. In general, the antibacterial profile of E1077 is similar to that of cefpirome.
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PMCID: PMC192206  PMID: 1416879
25.  Effects of beta-lactamases and omp mutation on susceptibility to beta-lactam antibiotics in Escherichia coli. 
Four types of beta-lactamases consisting of a penicillinase type I (TEM-1), a penicillinase type II (OXA-1), a cephalosporinase of Citrobacter freundii, and a cephalosporinase of Proteus vulgaris were introduced into Escherichia coli MC4100 and its omp mutants, MH1160 (MC4100 ompR1) and MH760 (MC4100 ompR2), by transformation. Effects of the combination of the omp mutations and these beta-lactamases on the susceptibility of E. coli strains were studied with 15 beta-lactam antibiotics including cephalosporins, cephamycins, penicillins, imipenem, and aztreonam. The ompR1 mutant, MH1160, lacks OmpF and OmpC, and it showed reduced susceptibility to 11 of the 15 beta-lactam agents. The reduction in susceptibility to cefoxitin, moxalactam, and flomoxef was much greater than reduction in susceptibility to the other agents. When the ompR1 mutant produced the cephalosporinase of C. freundii, the susceptibility of the mutant to 12 of the 15 beta-lactam antibiotics decreased. The reduction in susceptibility of MH1160 to 10 of the 12 agents affected by the enzyme was two- to fourfold greater than that observed in MC4100. Such a synergistic effect was also observed with the cephalosporinase of P. vulgaris and ompR1 mutation against six cephalosporins, moxalactam, and aztreonam.
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PMCID: PMC171497  PMID: 2658786

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