In vitro and in vivo antibacterial activities of carumonam (AMA-1080), a new N-sulfonated monocyclic beta-lactam antibiotic.

The in vitro and in vivo antibacterial activities of carumonam (AMA-1080), a synthetic sulfazecin derivative, were compared with those of aztreonam, cefoperazone, ceftazidime, and cefsulodin. Carumonam was highly active in vitro against members of the family Enterobacteriaceae, Pseudomonas aeruginosa, and Haemophilus influenzae and weakly active against Streptococcus pneumoniae, but it was not active against Staphylococcus aureus. The MICs of carumonam for 90% of 1,156 clinical Enterobacteriaceae isolates were between 0.013 and 25 micrograms/ml, which were the lowest MICs of the antibiotics tested. The MIC of carumonam for 90% of Klebsiella oxytoca was 0.2 micrograms/ml, whereas that of aztreonam was 50 micrograms/ml. The superiority of carumonam to aztreonam and the reference cephalosporins was also demonstrated by their activities against Klebsiella pneumoniae and Enterobacter cloacae. The MIC of carumonam for 90% of P. aeruginosa was 12.5 micrograms/ml, which was comparable to the MICs of aztreonam and ceftazidime. Carumonam showed a high affinity for the penicillin-binding protein 3 of gram-negative bacteria, but not for the penicillin-binding proteins of S. aureus and Bacteroides fragilis. Carumonam was resistant to hydrolysis by 12 plasmid-mediated beta-lactamases and 7 chromosomal beta-lactamases. It was more stable than aztreonam to hydrolysis by the beta-lactamase of K. oxytoca; this stability is related to the superiority of the in vitro and in vivo activities of carumonam to those of aztreonam against this species. In general, the protective activities (50% effective dose) of carumonam and reference antibiotics in mice with experimental intraperitoneal infections correlated with the in vitro activities (MIC); carumonam showed excellent protective activity against most aerobic gram-negative bacteria.     

Antibacterial activity of RU44790, a new N-tetrazolyl monocyclic beta-lactam.

RU44790 belongs to a new class of synthetic monocyclic beta-lactam antibiotics which feature a bioisosteric tetrazole moiety instead of the more classical acidic functions at the N-1 position of the beta-lactam ring. Its antibacterial activity was evaluated against some 900 strains and was compared with those of other recent beta-lactam derivatives, especially aztreonam. RU44790 is endowed with potent activity against gram-negative bacteria. At less than or equal to 0.6 micrograms/ml, RU44790 inhibited 90% of all strains of the family Enterobacteriaceae with the exception of Citrobacter spp. (MIC for 90% of strains tested, 1.2 micrograms/ml). The activity was similar to that of aztreonam against strains that are normally susceptible to expanded-spectrum cephalosporins. On the other hand, the new compound was 10 to 100 times more potent than aztreonam and most of the other antibiotics tested against enterobacteria that produce chromosome-encoded or plasmid-mediated extended-spectrum beta-lactamases. Pseudomonas aeruginosa isolates were equally susceptible to both monobactams. RU44790 was inactive against staphylococci and had only marginal activity against streptococci (MIC for 50% of strains tested, 2.5 micrograms/ml). RU44790 was highly resistant to hydrolysis by various beta-lactamases, particularly cephalosporinases such as P99. The latter enzyme was also inhibited by the compound. RU44790 showed a high affinity for penicillin-binding protein 3 of Escherichia coli. The results suggest that RU44790 has good potential in the treatment of infections caused by gram-negative microorganisms.     

Antibacterial properties of carumonam (Ro 17-2301, AMA-1080), a new sulfonated monocyclic beta-lactam antibiotic

The in vitro and in vivo activity of carumonam was tested in comparison with that of aztreonam and other beta-lactam antibiotics. With the exception of a few isolates that were overproducers of cephalosporinase, Enterobacteriaceae were highly susceptible to carumonam, 90% of the isolates being inhibited at 0.5 micrograms/ml. Aztreonam, ceftriaxone and ceftazidime were overall slightly less active than carumonam against Enterobacteriaceae. Carumonam was intermediate between ceftazidime and aztreonam as to the activity against Pseudomonas aeruginosa. Staphylococci were resistant to the monocyclic beta-lactams. In accordance with the in vitro data, carumonam was effective against experimental septicemias and infections of the thigh and the kidney that were caused by gram-negative pathogens.     

Disposition of carumonam (AMA-1080/Ro 17-2301), a new N-sulfonated monocyclic beta-lactam, in rats and dogs.

Rats and dogs were given a single 20-mg/kg dose of [14C]carumonam intramuscularly or intravenously. In rats, the level in plasma of [14C]carumonam administered intramuscularly peaked (29.1 micrograms/ml) 15 min after dosing and then declined with an apparent elimination half-life of 16.2 min. Intramuscular injection of [14C]carumonam to dogs gave a peak level (36.8 micrograms/ml) in plasma at 20 min and an apparent elimination half-life of 51.7 min. After administration of the intravenous dose, apparent elimination half-lives were 13.1 and 52.7 min in rats and dogs, respectively. In both animals, the radioactivity in plasma was made up largely (greater than 80%) of unchanged carumonam, which was protein bound to only a small extent. In rats given [14C]carumonam intramuscularly, radioactivity was distributed widely in tissues, with relatively high concentrations in the kidney and liver. The radioactivity concentration in the rat fetus was relatively low, as was that in milk. In both rats and dogs carumonam did not undergo extensive metabolism; the most prominent metabolite was AMA-1294, the compound resulting from beta-lactam ring hydrolysis. [14C]carumonam and metabolites were mostly eliminated from the bodies within 72 h in rats and 120 h in dogs. In both animals, a large amount of the dosed radioactivity was excreted in the urine largely as unchanged antibiotic. The remainder was eliminated in the feces via bile. AMA-1294 was eliminated from the bodies of rats and dogs at a considerably slower rate than was unchanged carumonam. In rats, [14C]carumonam was eliminated by both glomerular filtration (67%) and tubular secretion (33%); the renal elimination of [14C]AMA-1294 was only by glomerular filtration.     

Comparative in vitro activity of SM7338, a new carbapenem antimicrobial agent.

The comparative in vitro activity of SM7338 was tested against 670 routine clinical isolates and 130 cefoperazone-resistant isolates of bacteria by agar dilution methods. SM7338 was at least as active as imipenem against gram-negative organisms but was slightly less active against gram-positive organisms. SM7338 was particularly active against members of the family Enterobacteriaceae, with MICs for 90% of strains of less than or equal to 0.125 micrograms/ml for all species tested. Differences in activity between SM7338 and imipenem were particularly striking against Proteus vulgaris, Proteus mirabilis, and Morganella morganii, against which MICs of SM7338 and imipenem for 90% of strains were 0.125 and 4 micrograms/ml, respectively. The presence of unique plasmid-mediated beta-lactamases in Pseudomonas aeruginosa PU21 transconjugants did not affect activity substantially, except in the case of OXA-2 (eightfold-increased MIC) and OXA-3 (fourfold-increased MIC). SM7338 was also active against a laboratory-derived strain of P. aeruginosa which hyperproduced chromosomal beta-lactamase, inhibiting both the wild type and the mutant at a concentration of 1.0 micrograms/ml.     

Comparative in vitro activity of WIN 57273, a new fluoroquinolone antimicrobial agent.

The in vitro activity of WIN 57273, a new fluoroquinolone antimicrobial agent, was evaluated against approximately 600 bacterial isolates. The new drug was 4- to 128-fold more active than ciprofloxacin against a broad range of gram-positive organisms, with the new drug inhibiting 90% of strains of each species except Enterococcus faecium at concentrations of less than or equal to 0.25 microgram/ml. WIN 57273 was four- to eightfold less active than ciprofloxacin against many members of the family Enterobacteriaceae, but the MICs of the new drug for 90% of strains tested (MIC90s) were less than or equal to 8 micrograms/ml (range, 0.25 to 8 micrograms/ml) for all species. Branhamella catarrhalis, Haemophilus influenzae, Neisseria gonorrhoeae, and Legionella spp. were highly susceptible (MIC90s, less than or equal to 0.06 microgram/ml). WIN 57273 demonstrated excellent activity against anaerobes (MIC90s, less than or equal to 0.25 microgram/ml), and the drug was also more active than ciprofloxacin against 30 strains of Mycobacterium avium-M. intracellulare (MIC, 0.1 to 1.0 microgram/ml). The activity of WIN 57273 against gram-positive organisms was minimally affected by pH and increased at low pH (5.4) against gram-negative organisms. The bactericidal activity of WIN 57273 was demonstrated by time-kill techniques against selected organisms. The frequencies of spontaneous resistance to the new agent were low, but resistant colonies could be selected after serial passage of initially susceptible organisms through incremental concentrations of the drug.     

Comparative in vitro synergistic activity of new beta-lactam antimicrobial agents and amikacin against Pseudomonas aeruginosa and Serratia marcescens.

The in vitro synergistic activities of moxalactam, cefoperazone, or cefotaxime in combination with amikacin or piperacillin were compared against aminoglycoside-susceptible and aminoglycoside-resistant isolates of Pseudomonas aeruginosa and Serratia marcescens by the checkerboard agar dilution method. All antimicrobial combinations demonstrated some synergy, and no antagonism was observed. Moxalactam plus amikacin and piperacillin plus amikacin were most frequently synergistic (two-thirds of the isolates inhibited synergistically by each combination), whereas combinations of moxalactam, cefotaxime, or cefoperazone with piperacillin were synergistic against only 18 to 25% of the isolates. Moxalactam plus amikacin was the combination most often synergistic for amikacin-susceptible P. aeruginosa, and piperacillin plus amikacin was the combination most frequently synergistic for amikacin-resistant P. aeruginosa and amikacin-susceptible S. marcescens. These results demonstrate frequent in vitro synergistic activity between the new beta-lactam agents and amikacin (especially moxalactam or piperacillin with amikacin), but comparative clinical trials are needed to establish the relative efficacy and toxicity of these combinations.     

In vitro activity of carumonam.

The in vitro activities of carumonam and eight comparative antimicrobial agents were studied. MICs of carumonam were less than or equal to 0.5 microgram/ml for 91% of members of the family Enterobacteriaceae and less than or equal to 16 micrograms/ml for 88% of nonfermenters; gram-positive cocci and anaerobic bacteria were resistant. Combinations of carumonam with piperacillin, nafcillin, or clindamycin were usually indifferent, although synergy between carumonam and piperacillin was observed with 20 (13%) of 155 strains.     

In vitro antimicrobial activity of eight new beta-lactam antibiotics against penicillin-resistant Neisseria gonorrhoeae.

Increasing numbers of cases of penicillin-resistant gonorrhea necessitate the evaluation of new antibiotics for treatment of this disease. We tested the susceptibility of 92 penicillinase-producing (PP) Neisseria gonorrhoeae isolates and 88 penicillin-susceptible (PS) isolates to eight new beta-lactam antibiotics. The minimal inhibitory concentrations of these antibiotics were determined by the agar plate method. PP and PS N. gonorrhoeae isolates were susceptible to clinically achievable levels of all antibiotics tested. There were, however, marked differences among the drugs with regard to the concentration required to inhibit growth. The PP N. gonorrhoeae isolates were extremely susceptible to ceftriaxone, ceftizoxime, and cefotaxime, highly susceptible to moxalactam and cefoperazone, and less susceptible to cefoxitin, ceforanide, and cefonicid (geometric mean minimal inhibitory concentrations were 0.002, 0.003, 0.007, 0.03, 0.07, 0.6, 2.4, and 3.1 micrograms/ml, respectively). Although this in vitro study showed PP N. gonorrhoeae isolates to be comparatively more susceptible to ceftriaxone, ceftizoxime, and cefotaxime than to the other antibiotics, these results may not correlate with clinical efficacy.     

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.     

Comparative in vitro antimicrobial activity of carumonam (Ro 17-2301) and its influence on the activity of other antibiotics

The antimicrobial activity of carumonam (Ro 17-2301) was compared with that of 20 antibiotics against 338 clinical isolates. Carumonam did not possess activity against gram-positive cocci, MIC90 of carumonam were less than or equal to 0.5 mg/l for Enterobacteriaceae, except for Citrobacter (less than or equal to 8 mg/l) and less than or equal to 32 mg/l for nonfermenters. It was slightly more active than aztreonam against gentamicin-resistant bacilli (MIC90 less than or equal to 64 vs greater than or equal to 256). Combinations of carumonam with antibiotics with activity against gram-positive microorganisms were indifferent.     

In vitro activity, efficacy, and pharmacology of moxalactam, a new beta-lactam antibiotic.

Moxalactam, a potent new beta-lactam antibiotic with a relatively wide spectrum of activity against facultative and anaerobic gram-negative bacilli, was evaluated in vitro and in 28 patients with a variety of severe infections with moxalactam-susceptible organisms (minimum inhibitory concentration less than or equal to 31 microgram/ml). Although therapy was successful in most of these patients, caution is suggested because of the development of resistance on therapy in one patient, persistence of Bacteroides fragilis endocarditis in another, and for certain organisms, a significant inoculum effect on the minimum inhibitory concentration and minimum bactericidal concentration of moxalactam.     

Comparative in vitro activities of several new fluoroquinolones and beta-lactam antimicrobial agents against community isolates of Streptococcus pneumoniae.

The in vitro susceptibilities of 551 community isolates of Streptococcus pneumoniae from the Canadian province of Ontario to several new fluoroquinolones and beta-lactam antimicrobial agents were determined by a broth microdilution technique. Eight (1.5%) of these isolates were moderately susceptible (MICs, greater than or equal to 0.12 and less than or equal to 1.0 microgram/ml) to penicillin; none was resistant. Temafloxacin, ciprofloxacin, and ofloxacin (MICs for 90% of strains tested, between 1 and 2 micrograms/ml) were the most active fluoroquinolones tested, and BMY-28100 (MIC for 90% of strains tested, 0.25 microgram/ml) was the most active of the new beta-lactams tested.     

In vitro activity of ciprofloxacin, a new carboxyquinoline antimicrobial agent.

The in vitro activity of ciprofloxacin (Bay o 9867), a new carboxyquinoline antimicrobial agent, was compared with those of norfloxacin, nalidixic acid, and several other oral and parenteral antimicrobial agents. Ciprofloxacin was substantially more active than nalidixic acid or cinoxacin against all gram-negative bacteria tested. Virtually all strains of Enterobacteriaceae were inhibited by the new drug at concentrations of less than or equal to 0.125 micrograms/ml. Ciprofloxacin was more active than norfloxacin against Klebsiella sp., Enterobacter sp., and Serratia marcescens, and it was the most active agent against Pseudomonas aeruginosa (MIC90, 0.5 micrograms/ml). The new drug also demonstrated significant activity against gram-positive cocci, inhibiting all strains of staphylococci at concentrations of less than or equal to 1.0 microgram/ml. Ciprofloxacin was bactericidal at concentrations near the MIC against most isolates tested. Although stepwise increases in resistance were seen with Escherichia coli and P. aeruginosa during serial passage on plates containing incremental concentrations of the drug, significant resistance did not emerge during incubation of strains in broth containing concentrations of ciprofloxacin above the MBC.     

Comparative in vitro activity of a new quinolone, AM-1091.

The in vitro activity of a new quinolone, AM-1091 [7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro- 4-oxo- 3-quinoline carboxylic acid hydrochloride], was compared with those of ciprofloxacin, ofloxacin, beta-lactams, and gentamicin. AM-1091 inhibited 90% of the isolates of the family Enterobacteriaceae at less than or equal to 0.12 micrograms/ml. For many species AM-1091 was 2-fold more active than ciprofloxacin and 2- to 32-fold more active than ofloxacin. It inhibited Enterobacter, Citrobacter, and Klebsiella species resistant to ceftazidime and gentamicin. Ninety percent of Pseudomonas aeruginosa isolates were inhibited by 0.5 micrograms/ml, so for this species AM-1091 was twofold less active than ciprofloxacin. AM-1091 was more active against Pseudomonas cepacia and Xanthomonas maltophilia, inhibiting isolates resistant to imipenem and gentamicin. Most Haemophilus influenzae, Neisseria gonorrhoeae, Neisseria meningitidis, and Branhamella catarrhalis isolates were inhibited by less than or equal to 0.06 micrograms/ml. The MICs for 90% of Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis isolates were 0.06, 0.06, and 2 micrograms/ml, respectively. AM-1091 inhibited hemolytic streptococci and Streptococcus pneumoniae at 0.25 micrograms/ml and was more active than ciprofloxacin or ofloxacin against gram-positive species. AM-1091 inhibited 90% of the Bacteroides species at 0.5 micrograms/ml. The frequency of spontaneous resistance was less than 10(-10) for most organisms, but resistant strains could be selected by repeated subculturing. Although AM-1091 had lower in vitro activity at pH 5.5 and in the presence of high concentrations of Mg2+, it still inhibited most organisms at 相似文献   

In vitro antimicrobial activity of doripenem, a new carbapenem

The doripenem MICs at which 90% of the tested strains were inhibited ranged from 0.03 to 1 microg/ml for 10 species of Enterobacteriaceae (n = 351), from 0.03 to 0.12 microg/ml for oxacillin-susceptible staphylococci (n = 119), from 4 to 32 microg/ml for oxacillin-resistant staphylococci (n = 64), from < or =0.008 to 0.06 microg/ml for penicillin-susceptible streptococci (n = 132), and from 1 to 4 microg/ml for penicillin-resistant streptococci (n = 51). Overall, doripenem demonstrated in vitro activity similar to that of meropenem against gram-negative pathogens and to that of imipenem against gram-positive pathogens.     

Comparative in vitro antimicrobial activity of a new carbapenem, E1010, and tentative disc diffusion test interpretative criteria.

The susceptibility of 705 bacterial isolates representing 46 different species to E1010 (ER-35786), imipenem, meropenem and cefepime was determined by the NCCLS broth microdilution test. The MIC(90)s for E1010 were < or =1.0 mg/L for Enterobacteriaceae, fastidious Gram-negative bacteria, streptococci and anaerobes. E1010 was two- to four-fold more active than imipenem and meropenem against Pseudomonas aeruginosa, and four-fold more active than the other carbapenems against methicillin-resistant Staphylococcus aureus. Vancomycin-resistant enterococci and most Enterococcus faecium were resistant to all four drugs tested. The NCCLS disc diffusion test was performed simultaneously on the non-fastidious organisms. Assuming the MIC breakpoints for E1010 will be the same as for the other carbapenems, the disc diffusion zone diameter breakpoints of imipenem and meropenem would also be applicable to E1010.     

In vitro antimicrobial activity of tigemonam, a new orally administered monobactam.

At five geographically separate medical centers, over 6,000 clinical bacterial isolates were tested for their susceptibility to tigemonam by the broth microdilution method. The antimicrobial spectrum of tigemonam was similar to that of aztreonam, but with two differences. Aztreonam was more active against Pseudomonas spp., and tigemonam was more active against some streptococci. Tigemonam was highly resistant to hydrolysis by the eight beta-lactamase enzymes tested. A significant (greater than a fourfold increase in the MICs of tigemonam) inoculum effect occurred when 3 of 13 isolates were tested with inocula of 5 X 10(5) and 1 X 10(7) CFU/ml. Tigemonam was bactericidal for all but 1 of the 13 isolates. Of the four quality-control strains recommended by the National Committee for Clinical Laboratory Standards, only Escherichia coli ATCC 25922 provided on-scale results. The proposed MIC quality-control range of tigemonam for E. coli ATCC 25922 is 0.13 to 0.5 micrograms/ml.     

Comparative in vitro activity of CGP 31608, a new penem antibiotic.

The in vitro activity of a new penem antimicrobial agent, CGP 31608, was compared with those of imipenem, SCH 34343, and several other antimicrobial agents against approximately 600 bacterial isolates. CGP 31608 was active against gram-positive organisms, including methicillin-susceptible Staphylococcus aureus (MIC for 90% of the isolates [MIC90], 0.25 microgram/ml) and penicillin-susceptible streptococci (MIC90s, less than or equal to 2 micrograms/ml). Penicillin-resistant streptococci (including enterococci) and methicillin-resistant S. aureus were more resistant to the penem. Activities of CGP 31608 against members of the family Enterobacteriaceae were remarkably uniform, with MIC90s of 8 to 16 micrograms/ml. CGP 31608 was at least as active as imipenem and ceftazidime and more active than piperacillin against Pseudomonas aeruginosa. Drug activity was not influenced by the presence of any of 10 plasmid-mediated beta-lactamases. Against strains of Serratia marcescens, Enterobacter cloacae, and P. aeruginosa with derepressible chromosomally mediated beta-lactamases, the presence of cefoxitin did not induce increased resistance to CGP 31608. The new drug was also active against anaerobes (MIC90s, 0.25 to 8 micrograms/ml), Haemophilus influenzae (MIC90s, 0.5 to 1.0 micrograms/ml), and Legionella spp. (MIC90, 2 micrograms/ml). CGP 31608 showed an antibacterial spectrum similar to those of imipenem and SCH 34343 (except that the latter is not active against P. aeruginosa) but was generally less potent than these drugs. However, CGP 31608 demonstrated more activity (MIC90) than imipenem against P. aeruginosa, Pseudomonas cepacia, and methicillin-resistant Staphylococcus epidermidis and S. aureus.     

In vitro activity of BMY-28142 in comparison with those of other beta-lactam antimicrobial agents.

The in vitro susceptibility of 406 clinical isolates to BMY-28142, a new semisynthetic cephem, was evaluated and compared with cefpimizole, HR 810, ceftazidime, cefotaxime, moxalactam, and cefoperazone in a broth microdilution assay. On a weight basis, the activity of BMY-28142 against Escherichia coli, Proteus species, and Klebsiella-Enterobacter-Serratia was superior to the other cephems. Against gentamicin-susceptible and -resistant Pseudomonas aeruginosa, BMY-28142 was more active than the other cephems, except ceftazidime and HR 810. A total of 74% of gram-negative and 56% of gram-positive isolates resistant to third-generation cephalosporins were susceptible to less than or equal to 8 micrograms of BMY-28142 per ml. Finally, for 83% of tested isolates, the bactericidal concentration of BMY-28142 was within one dilution of the inhibitory concentration.