In vitro activity of LY127935, a new 1-oxa cephalosporin, against aerobic gram-negative bacilli.

A total of 434 clinical aerobic gram-negative bacillary isolates were tested against LY127935, a new 1-oxa cephalosporin, and compared with other cephalosporins, penicillins, and aminoglycosides by a broth microdilution technique. Cefotaxime (HR756), a new semisynthetic cephalosporin, and LY127935 were more active, and showed lower minimum inhibitory concentrations (ranges, less than or equal to 0.12 to 2.0 micrograms/ml), than cefamandole, cefoxitin, and cefazolin against Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, indole-positive Proteus spp., Serratia marcescens, Providencia spp., and Citrobacter spp. Against P. aeruginosa, pepercillin, azlocillin, and mezlocillin were the most active beta-lactam agents; 64 micrograms/ml inhibited 99, 93, and 87% of the isolates, respectively. LY127935 and cefotaxime at 16 micrograms/ml inhibited 71% of Pseudomonas isolates, whereas the aminoglycosides gentamicin, tobramycin, and amikacin at a concentration of 4 micrograms/ml inhibited 84, 88, and 93%, respectively. Minimum bactericidal concentrations were determined for all isolates and were generally the same as the minimum inhibitory concentrations.     

In vitro activity of FK037, a new parenteral cephalosporin, against anaerobic bacteria.

The activity of FK037, a new parenteral cephalosporin, was compared with those of cefpirome, ceftazidime, and flomoxef against 322 recent clinical isolates of anaerobic bacteria. A fastidious facultative anaerobe, Gardnerella vaginalis, was also studied. FK037 inhibited 90% of isolates of Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Clostridium perfringens, Mobiluncus spp., G. vaginalis, and Porphyromonas gingivalis at < or = 0.78 micrograms/ml. The MICs of FK037 for 50 and 90% of Bacteroides fragilis isolates were 25 and > 200 micrograms/ml, respectively; the activity of FK037 was comparable to those of cefpirome and ceftazidime but lower than that of flomoxef. The activity of FK037 against Fusobacterium nucleatum, Fusobacterium varium, and Bilophila wadsworthia decreased when inoculum size was increased from 10(6) to 10(8) CFU/ml. Little influence of inoculum size on the activity of FK037 was observed for other isolates tested. Medium pH affected the activity of FK037 against F. varium (MICs at pHs 5 and 7, 3.13 and 100 micrograms/ml, respectively) and Bacteroides gracilis (MICs at pHs 5 and 7, 12.5 and 1.56 micrograms/ml, respectively) but not against other organisms tested. FK037 was less resistant than flomoxef to hydrolysis by beta-lactamase group 2e derived from B. fragilis GAI 0558 and GAI 10150.     

Amifloxacin activity against well-defined gentamicin-resistant, gram-negative bacteria.

Amifloxacin (WIN 49375) activity against a well-defined group of gentamicin-resistant gram-negative bacilli was compared with the activity of 11 other antimicrobial agents. For all strains, amifloxacin and norfloxacin were the most active agents, followed by cefotaxime and moxalactam. For Acinetobacter sp. only amifloxacin had an achievable MIC for 90% of the strains. Amifloxacin joins other newly developed DNA gyrase inhibitors as potentially useful agents for infections due to aminoglycoside-resistant gram-negative bacilli.     

In vivo antibacterial activity of RWJ-54428, a new cephalosporin with activity against gram-positive bacteria

RWJ-54428 (MC-02,479) is a new cephalosporin with activity against resistant gram-positive organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. The in vivo efficacy of RWJ-54428 was evaluated against gram-positive bacteria in four mouse models of infection. RWJ-54428 was effective in vivo against methicillin-susceptible and -resistant S. aureus in a mouse model of sepsis, with 50% effective doses being similar to those of vancomycin. In a single-dose neutropenic mouse thigh model of infection, RWJ-54428 at 30 mg/kg of body weight showed activity similar to that of vancomycin at 30 mg/kg against a strain of methicillin-resistant S. aureus. RWJ-54428 also showed a prolonged in vivo postantibiotic effect in this model. In a mouse model of pneumonia due to a penicillin-susceptible strain of Streptococcus pneumoniae, RWJ-54428 displayed efficacy and potency superior to those of penicillin G and cefotaxime. In a mouse model of pyelonephritis due to Enterococcus faecalis, RWJ-54428 had bactericidal effects similar to those of vancomycin and ampicillin, but at two- to threefold lower total daily doses. These studies show that RWJ-54428 is active in experimental mouse models of infection against gram-positive organisms, including strains resistant to earlier cephalosporins and penicillin G.     

Studies with cefuroxime: a new beta-lactamase resistant cephalosporin.

28 patients suffering from a variety of bacterial infections have been treated with cefuroxime. 18 were cured and 6 improved during treatment. Side effects were minimal and intramuscular injection was well tolerated. Serum and urine levels well in excess of the MICs of sensitive organisms were obtained using dosages of 750 mg 8 hourly. Biliary excretion was impaired in the presence of obstruction, but adequate bile levels of cefuroxime were observed following relief of the obstruction. Cefuroxime was widely active against gram-negative bacilli and against Streptococcus faecalis, but less active against Bacteroides spp.     

Antibacterial activity of ceftizoxime (FK 749), a new cephalosporin, against cephalosporin-resistant bacteria, and its stability to beta-lactamase.

Antibacterial activity of FK 749 against ampicillin-resistant clinical isolates of Escherichia coli was compared with those of other newly developed cephalosporins. FK 749 was the most active against strains possessing R-plasmids specifying ampicillin resistance and those whose resistance was chromosomally determined. The susceptibility of ampicillin-susceptible E. coli to FK 749 was not decreased by transduction of ampicillin resistance-specifying plasmids. However, most of the transconjugants acquired a high level of resistance to cefoperazone and cefamandole and a moderate level of resistance to cefoperazone and cefamandole and a moderate level to cefotiam. FK 749 was highly stable to both penicillinase- and cephalosporinase-type beta-lactamases, including R-plasmid-mediated beta-lactamase. Its level of resistance to beta-lactamases was comparable to those of cefoxitin, cefmetazole, and cefotaxime, slightly superior to that of cefuroxime, and much superior to those of cefotiam, cefamandole, and cefoperazone.     

In vitro activity of ciprofloxacin against aerobic gram-negative bacteria

For 177 gram-negative isolates, the MICs for ciprofloxacin ranged from 0.02 microgram/ml (Escherichia coli) to 0.31 microgram/ml (Pseudomonas aeruginosa). In time-kill curves, ciprofloxacin at 8 X the MIC almost completely killed 10(6) CFU of P. aeruginosa by 24 h. Ciprofloxacin at 4 X the MIC allowed bacterial regrowth by 24 h, with development of partial resistance to ciprofloxacin.     

In vitro activity of cefquinome, a new cephalosporin, compared with other cephalosporin antibiotics.

The in vitro activity of cefquinome, a new aminothiazolyl cephalosporin with a C-3 bicyclic pyridinium group, was compared with ceftazidime, cefpirome, and cefepime. Cefquinome inhibited members of the Enterobacteriaceae at less than or equal to 0.5 microgram/ml for Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Citrobacter diversus, Salmonella Shigella, Proteus mirabilis, Morganella, and Providencia. Although most Citrobacter freundii and Enterobacter cloacae were inhibited by less than 2 micrograms/ml, some strains resistant to ceftazidime were resistant, [minimum inhibitory concentration (MIC) greater than 16 micrograms/ml]. Serratia marcescens were inhibited by less than 1 microgram/ml and Pseudomonas aeruginosa by 8 micrograms/ml similar to the activity of cefepime. The majority of Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by less than 0.25 microgram/ml. Most enterococci had cefquinome MICs of 4-8 micrograms/ml. Cefquinome was extremely active against group-A streptococci and Streptococcus pneumoniae with MICs less than 0.12 microgram/ml. 90% of methicillin-susceptible Staphylococcus aureus 90% were inhibited by 2 micrograms/ml. Overall, the in vitro activity of cefquinome was comparable with aminothiazolyl cephalosporins. It inhibited some Enterobacter and Citrobacter freundii resistant to ceftazidime as did cefpirome and cefepime. Cefquinome was not destroyed by the common plasmid beta-lactamases TEM-1, TEM-2, SHV-1, or by the chromosomal beta-lactamases of Klebsiella, Branhamella, and Pseudomonas, but it was hydrolyzed by TEM-3, TEM-5, and TEM-9. Its activity was not adversely decreased in different medium or protein, and minimum bactericidal concentrations (MBCs) for most species except for Enterobacter were within a dilution of MICs.     

In vitro activity of HR 810, a new cephalosporin.

The in vitro susceptibility of 409 clinical isolates to HR 810, a new cephalosporin, was evaluated and compared with their susceptibility to aztreonam, cefazolin, ceftazidime, imipenem, moxalactam, piperacillin, and gentamicin. On a weight basis, the activity of HR 810 against gram-negative bacilli was equivalent or superior to that of the other beta-lactam agents except imipenem.     

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.     

In vitro activity of Ro 15-8074, a new oral cephalosporin, against Neisseria gonorrhoeae.

Ro 15-8074, a new cephalosporin the pivaloyloxymethylester of which (Ro 15-8075) is orally absorbable, showed greater in vitro activity than cefaclor against 48 Neisseria gonorrhoeae strains, including 25 penicillinase-producing strains. Unlike cefaclor, Ro 15-8074 was unaffected by increase in inoculum size, and it exhibited a remarkable stability against gonococcal beta-lactamase hydrolysis.     

In vitro antimicrobial activity of cefotaxime, a new cephalosporin.

Cefotaxime, a new semisynthetic cephalosporin derivative, showed a broad spectrum of antibacterial activity against clinically isolated strains of gram-positive 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 minimal inhibitory concentrations against Escherichia coli and P. aeruginosa and four times higher against S. marcescens. A reduction of inoculum size decreased greatly the minimal 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.     

Biological activity of BO-1236, a new antipseudomonal cephalosporin.

BO-1236, a new cephalosporin having an N-methyl-5,6-dihydroxyisoindolinium moiety on the 3-methylene of the cephem, showed potent activity against gram-negative organisms, including Pseudomonas aeruginosa. The in vitro activity of BO-1236 was superior or comparable to that of ceftazidime, cefotaxime, and cefoperazone in susceptibility tests with clinical isolates. BO-1236 was significantly more active than ceftazidime against P. aeruginosa strains susceptible or resistant to ceftazidime or gentamicin or both. MBCs were usually close to MICs, both of which were influenced by inoculum size to about the same degree as those of the other beta-lactams. BO-1236 was stable to all types of beta-lactamases except type I oxyiminocephalosporin-hydrolyzing enzyme, by which BO-1236 was slightly hydrolyzed. BO-1236 showed protective activity superior to that of ceftazidime and cefotaxime in experimental infections in mice caused by two strains of P. aeruginosa and showed activity comparable to that of ceftazidime and cefotaxime against other gram-negative bacterial infections.     

The in-vitro activity of ceftibuten against 475 clinical isolates of gram-negative bacilli, compared with cefuroxime and cefadroxil

The in-vitro activity of ceftibuten was compared with cefuroxime and cefadroxil against 475 clinically-significant, epidemiologically-distinct isolates of Gram-negative bacilli: 170 from blood, 212 from urine and 93 from a supplementary collection of multiply-resistant strains known to have resistance plasmids, to have caused sporadic or epidemic nosocomial infection, or both. Ceftibuten MICs ranged from 0.003 to greater than 32 mg/l, with a modal MIC of 0.01 mg/l: 95% of all isolates had ceftibuten MIC values of less than or equal to 8 mg/l, the sensitivity breakpoint suggested by the manufacturer. Ninety per cent of isolates had MICs of less than or equal to 1 mg/l and 49% had MICs of less than or equal to 0.03 mg/l. All isolates of Klebsiella, Serratia, Proteus and Providencia spp., and Morganella morganii had MIC values of 8 mg/l or less. Only two of 124 isolates of Escherichia coli tested, and only one of 23 Citrobacter spp., had MICs of greater than 8 mg/l (16, 16 and greater than 32 mg/l respectively). Resistance MIC greater than 16 mg/l) was more frequent among Enterobacter and Acinetobacter spp. Thirteen of 52 Enterobacter spp., and seven of 18 Acinetobacter calcoaceticus had MICs of at least 32 mg/l. MIC ranges, modal MICs and MIC90s indicated that ceftibuten was, with the exception of only two strains, consistently more active in-vitro than cefuroxime, which was in turn more active than cefadroxil.     

GR 20263, a new broad-spectrum cephalosporin with anti-pseudomonal activity.

GR 20263 is a new broad-spectrum injectable cephalosporin which is stable to most beta-lactamases. Its in vitro activities were of the same order as those of cefotaxime against most gram-negative bacteria, were clearly inferior to cefotaxime against Staphylococcus aureus, but were significantly more active against Pseudomonas aeruginosa. Against the 25 strains used, GR 20263 was significantly more active than any of the other agents tested: piperacillin, azlocillin, gentamicin, amikacin, and carbenicillin. GR 20263 protected mice against experimental infections with P. aeruginosa more effectively than other beta-lactam antibiotics; its general effectiveness in this test was comparable with gentamicin. Studies on human volunteers showed that it produces high, long-lasting blood levels, with much of the antibiotic being recovered in the urine. Intramuscular and intravenous injections were well tolerated by the volunteers, and there were no untoward side effects.     

In vitro activity of U-63196E, a new cephalosporin, against clinical bacterial isolates

The in vitro activity of U-63196E, a new cephalosporin, was compared with those of other extended-spectrum cephalosporins and penicillins against clinical bacterial isolates. Against Pseudomonas aeruginosa, the activity of U-63196E was comparable to those of cefoperazone and piperacillin, each of which inhibited 90% of strains at concentrations of less than or equal to 16 micrograms/ml. The new drug also demonstrated activity against a variety of other bacterial species, but it was generally less active than cefotaxime, moxalactam, and cefoperazone against members of the family Enterobacteriaceae and staphylococci. The presence of any 1 of 10 plasmid-mediated beta-lactamases in a series of otherwise isogenic laboratory strains of P. aeruginosa resulted in a significant reduction in the activity of U-63196E in comparison with its activity against the parent strain, which lacks these enzymes. Combinations of U-63196E with tobramycin demonstrated bacteriostatic synergism against 11 of 20 clinical isolates of P. aeruginosa.     

Mechanism of action of BAY v 3522, a new cephalosporin with unusually good activity against enterococci.

The in vitro activity of BAY v 3522, a new cephalosporin with unusually good activity against enterococci, was tested on 100 clinical isolates of Enterococcus faecalis. The MIC for 86.3% of the strains was 4 micrograms/ml, whereas the MIC for 13.7% ranged from 8 to 16 micrograms/ml. No differences were found between MICs determined with low- or high-density inocula. The bactericidal activity of BAY v 3522 was tested on eight clinical strains; most strains showed a ca. 3-log decrease of the original inoculum at two to eight times the MIC. The interaction of BAY v 3522 and of other beta-lactams with penicillin-binding proteins (PBPs) was studied with a laboratory strain, E. hirae ATCC 9790, producing a discernible amount of PBP 5, a protein belonging to the family of low-affinity PBPs, responsible for the low susceptibility of enterococci to beta-lactams. PBPs 3 and 5 of ATCC 9790 showed the highest affinity for the new cephalosporin. Bay V 3522 at the MIC (8 micrograms/ml) saturated these two PBPs without any significant binding to the other PBPs. This result may explain the good antienterococcal activity of BAY v 3522.     

In vitro activities of BAL9141, a novel broad-spectrum pyrrolidinone cephalosporin, against gram-negative nonfermenters

The activities of BAL9141 (formerly Ro 63-9141), a novel pyrrolidinone-3-ylidenemethyl cephalosporin, against 244 strains of gram-negative nonfermenters were evaluated. The overall MIC at which 50% of isolates are inhibited (MIC50) and the overall MIC90 were 2 and 64 microg/ml, respectively, which are similar to those of imipenem, lower than those of the other cephalosporins tested, amoxicillin, and the ticarcillin-clavulanic acid combination, and much higher than those of ciprofloxacin. BAL9141 shows species-dependent activity in vitro against a variety of gram-negative nonfermentative pathogens.     

Antianaerobe activity of ceftobiprole, a new broad-spectrum cephalosporin

Agar dilution testing of 463 anaerobes showed most Gram-positive beta-lactamase-negative strains (other than some Clostridium difficile and Peptostreptococcus anaerobius), as well as both beta-lactamase-positive and beta-lactamase-negative strains of Fusobacterium nucleatum, to have ceftobiprole MIC values of < or =0.016 to 4 microg/mL. Ceftobiprole was less active against beta-lactamase-positive Gram-negative bacilli, especially the members of the Bacteroides fragilis group. Like ceftobiprole, piperacillin was active mainly against beta-lactamase-negative strains, though MIC values for piperacillin were often 1 to 2 dilutions higher than for ceftobiprole. Carbapenems had MIC values < or =4 microg/L against all except some C. difficile and 2 strains of B. fragilis. All strains were susceptible to metronidazole, and all bacteria, except C. difficile and a single Bacteroides distasonis strain, were susceptible to chloramphenicol. Clindamycin resistance was seen in most anaerobe groups, whereas high moxifloxacin MICs were found mainly among the B. fragilis and Prevotella groups, and a few C. difficile and F. nucleatum strains.     

In vitro activity of ME1228, a new parenteral cephalosporin.

ME1228 is a new cephalosporin with an iminocarboxymethyl moiety on the acyl side chain and a novel pyridiniumthiomethyl group at position 3 of the bicyclic ring. Its activity was compared with those of ceftazidime, imipenem, piperacillin, and gentamicin. ME1228 inhibited most members of the family Enterobacteriaceae, except for some Enterobacter spp. and Citrobacter freundii, at less than or equal to 0.25 micrograms/ml, and it inhibited gentamicin- and piperacillin-resistant isolates. It had MICs for Pseudomonas aeruginosa between 1 and 32 micrograms/ml, comparable to those of ceftazidime, and it inhibited piperacillin- and gentamicin-resistant isolates. Most group A, B, C, and G streptococci and Streptococcus pneumoniae were inhibited by less than or equal to 0.25 micrograms/ml. Enterococci and listeriae were resistant (MICs, 64 to 128 micrograms/ml). The MICs for staphylococci were 4 to 8 micrograms/ml, and methicillin-resistant Staphylococcus aureus was resistant. There was a minimal inoculum effect and no effect of the medium. ME1228 was not hydrolyzed by TEM-1, TEM-2, SHV-1, and S. aureus plasmid beta-lactamases and was stable against hydrolysis by Richmond-Sykes type 1a, 1c, 1d, and IV chromosomal beta-lactamases. It was hydrolyzed by TEM-3 and Xanthomonas maltophilia beta-lactamases. Overall, ME1228 had activity comparable or superior to that of ceftazidime.