Evaluation of the in vitro activity of BMY-28142, a new broad-spectrum cephalosporin.

The in vitro activity of BMY-28142, a new cephalosporin, was tested by a broth microdilution system and compared with those of cefotaxime, ceftazidime, cefoperazone, moxalactam, and HR 810 against 747 bacterial isolates, one-third of which were resistant to one or more third-generation cephalosporins. BMY-28142 was the most active drug tested against 326 Enterobacteriaceae with an MIC for 90% of the organisms tested (MIC90) of 1.0 micrograms/ml. Against these Enterobacteriaceae the relative activities were: BMY-28142 greater than HR 810 greater than moxalactam and ceftazidime greater than cefotaxime greater than cefoperazone. For cefotaxime- and cefoperazone-resistant strains, the MIC90 of BMY-28142 was 4.0 micrograms/ml (compared with 0.13 micrograms/ml for susceptible strains). BMY-28142, with an MIC90 of 8.0 micrograms/ml for Pseudomonas aeruginosa, was about half as active as ceftazidime. The relative activities against P. aeruginosa were: ceftazidime greater than BMY-28142 greater than HR 810 greater than cefoperazone greater than moxalactam and cefotaxime. The MIC90 of BMY-28142 against staphylococci was 2.0 micrograms/ml, which was fourfold less active than HR 810, slightly less active than cefotaxime and cefoperazone, and fourfold more active than ceftazidime and moxalactam. BMY-28142 was very active against beta-lactamase-positive and -negative Haemophilus influenzae (MIC90, 0.06 micrograms/ml), Neisseria gonorrhoeae (MIC90, 0.015 micrograms/ml),aand nonenterococcal streptococci. Its activity against Streptococcus faecalis was poor (MIC90, 64 micrograms/ml). BMY-28142 was stable against the several beta-lactamases tested but exhibited little beta-lactamase inhibitory effect.     

In vitro evaluation of HR810, a new wide-spectrum aminothiazolyl alpha-methoxyimino cephalosporin

HR810 (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.) is a new, cyclical-pyridinium cephalosporin that appeared superior to numerous comparison drugs against 658 strains of aerobic and facultative anaerobic bacteria. Seventeen Enterobacteriaceae spp. were tested by broth microdilution methods, and the 50% MICs (MIC50S) and 90% MICs (MIC90s) were 0.03 to 0.12 and 0.03 to 2.0 micrograms/ml, respectively. Only one strain had an MIC greater than 8.0 micrograms/ml (99.6% is considered susceptible). HR810 inhibited 98% of Pseudomonas aeruginosa isolates at less than or equal to 16 micrograms/ml, and the MIC90 for Acinetobacter spp. was 4.0 micrograms/ml. It was also very active against Pseudomonas spp. and Staphylococcus aureus (MIC90, 0.5 micrograms/ml) but marginally active against methicillin-resistant staphylococcal strains (MIC90, 16 micrograms/ml) and enterococcus (MIC90, 32 micrograms/ml). Non-enterococcal streptococci had MIC50s ranging from 0.008 micrograms/ml for Streptococcus pyogenes to 0.12 micrograms/ml for pneumococci. All MICs of HR810 against Haemophilus and Neisseria spp. were less than or equal to 0.03 micrograms/ml (MIC50, 0.002 to 0.008 micrograms/ml). HR810 poorly inhibited beta-lactamases and was very stable against 11 tested beta-lactamases of plasmid (TEM, OXA, SHV-1, and PSE) and chromosomal (K1, K14, P99) types.     

In vitro activity of RU 29246, the active compound of the cephalosporin prodrug ester HR 916.

The in vitro activity of RU 29246 was compared with those of other agents against 536 recent clinical isolates. The MICs of RU 29246 for 90% of members of the family Enterobacteriaceae tested (MIC90s) were less than 2 micrograms/ml except those for Morganella spp. (16 micrograms/ml) and Proteus spp. (8 micrograms/ml). RU 29246 was active against Staphylococcus aureus (MIC90, < or = 8 micrograms/ml) and against Staphylococcus saprophyticus and coagulase-negative staphylococci (MIC90s, < or = 2 micrograms/ml). Streptococci and Neisseria gonorrhoeae were highly susceptible to RU 29246, and the activity of the agent against isolates of Streptococcus pneumoniae (MIC90, < or = 0.5 micrograms/ml), Haemophilus influenzae (MIC90, < or = 2 micrograms/ml), and Moraxella catarrhalis (MIC90, < or = 2 micrograms/ml) was comparable to those of the other cephalosporins tested. RU 29246 was insusceptible to hydrolysis by the common plasmid-mediated beta-lactamases (TEM-1 and SHV-1). However, hydrolysis by the new extended-spectrum beta-lactamases (TEM-3, TEM-5, and TEM-9) was detected. Results of the study suggested that RU 29246 should be investigated clinically for use in the treatment of a wide range of infections.     

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.     

Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms

The macrolide antibiotic azithromycin (CP-62,993; 9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A; also designated XZ-450 [Pliva Pharmaceuticals, Zagreb, Yugoslavia]) showed a significant improvement in potency against gram-negative organisms compared with erythromycin while retaining the classic erythromycin spectrum. It was up to four times more potent than erythromycin against Haemophilus influenzae and Neisseria gonorrhoeae and twofold more potent against Branhamella catarrhalis, Campylobacter species, and Legionella species. It had activity similar to that of erythromycin against Chlamydia spp. Azithromycin was significantly more potent versus many genera of the family Enterobacteriaceae; its MIC for 90% of strains of Escherichia, Salmonella, Shigella, and Yersinia was less than or equal to 4 micrograms/ml, compared with 16 to 128 micrograms/ml for erythromycin. Azithromycin inhibited the majority of gram-positive organisms at less than or equal to 1 micrograms/ml. It displayed cross-resistance to erythromycin-resistant Staphylococcus and Streptococcus isolates. It had moderate activity against Bacteroides fragilis and was comparable to erythromycin against other anaerobic species. Azithromycin also demonstrated improved bactericidal activity in comparison with erythromycin. The mechanism of action of azithromycin was similar to that of erythromycin since azithromycin competed effectively for [14C]erythromycin ribosomebinding sites.     

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 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.     

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.     

In vitro and in vivo evaluations of A-80556, a new fluoroquinolone.

A-80556 is a novel fluoroquinolone with potent antibacterial activity against gram-positive, gram-negative, and anaerobic organisms. A-80556 was more active than ciprofloxacin, ofloxacin, lomefloxacin, and sparfloxacin against gram-positive bacteria. A-80556 was particularly active against Staphylococcus aureus (MIC for 90% of isolates [MIC90], 0.12 microgram/ml, relative to fluoroquinolone-susceptible strains) and Streptococcus pneumoniae (MIC90, 0.12 microgram/ml). A-80556 was also the most active of the quinolones tested against ciprofloxacin-resistant S. aureus, with an MIC90 of 4.0 micrograms/ml; that of ciprofloxacin was > 128 micrograms/ml. However, the significance of this activity is not known. A-80556 was slightly less active against Escherichia coli (MIC90, 0.06 microgram/ml) and other enteric organisms than ciprofloxacin (MIC90 for E. coli, < or = 0.03 microgram/ml). A-80556 was slightly less active against Pseudomonas aeruginosa (MIC90, 4.0 micrograms/ml) than ciprofloxacin (MIC90, 2.0 micrograms/ml) and more active against Acinetobacter spp. (respective MIC90s, 0.12 and 0.5 microgram/ml). A-80556 was also the most active compound against anaerobes. Against Bacteroides fragilis, the MIC90 of A-80556 was 2.0 micrograms/ml; that of ciprofloxacin was 16 micrograms/ml. The in vivo efficacy of A-80556 in experimental models with both gram-positive and gram-negative infections was consistent with the in vitro activity and pharmacokinetics and oral absorption in mice.     

Antimicrobial activity, spectrum, and recommendations for disk diffusion susceptibility testing of ceftibuten (7432-S; SCH 39720), a new orally administered cephalosporin.

The antimicrobial activity and spectrum of ceftibuten (7432-S; SCH 39720) was determined on a wide variety of bacterial species selected for resistance to oral and parenteral beta-lactam antimicrobial agents. Ceftibuten was found to be the most active beta-lactam tested against members of the family Enterobacteriaceae, inhibiting 81.6% of strains at less than or equal to 8.0 micrograms/ml compared with 75.0 and 54.8% of strains inhibited by cefixime and cefuroxime, respectively. All strains of Haemophilus influenzae (MIC for 90% of strains [MIC90], less than or equal to 0.06 microgram/ml), Branhamella catarrhalis (MIC90, 3.0 micrograms/ml), and pathogenic Neisseria spp. (MIC90, less than or equal to 0.06 and 0.019 microgram/ml) were susceptible to ceftibuten. Beta-hemolytic Streptococcus spp. (serogroups A, B, C, and G) were also inhibited by ceftibuten, but penicillin-resistant pneumococci were generally resistant to cefixime and ceftibuten. The activity and spectrum of ceftibuten seem most applicable to infections of the respiratory and urinary tract plus those infections caused by pathogenic Neisseria spp. Ceftibuten disks (30 micrograms) were evaluated and found to have an acceptable correlation (r = 0.88) with ceftibuten MICs. Preliminary zone size interpretive criteria for MIC breakpoints of less than or equal to 4.0 and less than or equal to 8.0 micrograms/ml were calculated.     

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.     

In vitro and in vivo activities of a new quinolone, WIN 57273, possessing potent activity against gram-positive bacteria.

The antibacterial activity of a new 7-dimethylpyridinyl quinolone, WIN 57273, was assessed by using in vitro and in vivo models. Agar inclusion and broth dilution in vitro tests revealed broad-spectrum activity against gram-positive and selected gram-negative organisms, with the greatest potency observed against the staphylococci. The MIC for 90% of coagulase-positive strains tested (MIC90) was less than or equal to 0.002 micrograms/ml; for the coagulase-negative strains the MIC90 was 0.008 micrograms/ml. Against enterococci the MIC90 was 0.06 micrograms/ml, with comparable activity observed against group A and group B streptococci as well as against the pneumococci. In general, the MIC90s for the gram-negative bacteria were less than or equal to 1 micrograms/ml. Exceptions were Serratia marcescens (MIC90, 16 micrograms/ml), Citrobacter freundii (MIC90, 4 micrograms/ml), and Pseudomonas aeruginosa (MIC90, 8 micrograms/ml). The greatest potency was observed against Haemophilus spp. and Neisseria spp., with MIC90s of 0.06 and 0.016 micrograms/ml, respectively. Broad-spectrum activity was also observed against anaerobes, with MIC90s ranging from 0.125 to 0.5 micrograms/ml among the species tested. The in vivo efficacy was determined by using a murine model by calculating the 50% protective doses against a lethal bacterial infection caused by strains of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The staphylocci were most susceptible, with 50% protective doses for all strains ranging from 0.1 to 0.7 mg/kg. With the exception of the Pseudomonas infection, which was refractory to treatment, animals that were part of the other infection models responded to less than 10 mg/kg. Equivalent activity was seen with the subcutaneous or the oral route of drug administration. WIN 57273 was significantly more potent than ciprofloxacin in treating gram-positive bacterial infections (2- to 20-fold) but was significantly less effective at treating gram-negative bacterial infections (30- to 300-fold).     

Lomefloxacin, a new fluoroquinolone. Studies on in vitro antimicrobial spectrum, potency, and development of resistance

Lomefloxacin (NY-198; SC-47111), a potent new difluoroquinolone, was studied to compare its in vitro activity with that of other antimicrobials against 2194 clinical isolates. Lomefloxacin showed excellent inhibitory and bactericidal activity against strains of Enterobacteriaceae and inhibited greater than 99% of the isolates at a concentration of 4 micrograms/ml or less. Lomefloxacin exhibited good-to-moderate activity against strains of Acinetobacter (MIC90 4 micrograms/ml) and Pseudomonas aeruginosa (MIC90 8 micrograms/ml), but poor activity for Pseudomonas cepacia (MIC90 greater than 16 micrograms/ml). Staphylococcus aureus, and Staphylococcus epidermidis isolates, both oxacillin-susceptible and -resistant strains, were susceptible (MIC90 1 micrograms/ml) to lomefloxacin and the other fluoroquinolones. Strains of Haemophilus influenzae, (MIC90 less than or equal to 0.13 micrograms/ml) Neisseria gonorrhoeae (MIC90 less than or equal to 0.03 micrograms/ml), and Branhamella catarrhalis (MIC90 less than or equal to 0.03 micrograms/ml) were highly susceptible to lomefloxacin. Streptococcal isolates, especially viridans streptococci, were considerably less susceptible to the fluoroquinolones. Overall, lomefloxacin had comparable activity to norfloxacin, fleroxacin, and ofloxacin, and against many facultative anaerobes lomefloxacin was more active than imipenem, cefotaxime, ceftazidime, ticarcillin/clavulanic acid, aztreonam, trimethoprim/sulfamethoxazole and gentamicin. Development of resistance to lomefloxacin by spontaneous mutation was low and comparable to that of other fluoroquinolones. Growth in subinhibitory concentrations resulted in increased resistance to fluoroquinolones for selected test strains.     

Activity of WY-49605 compared with those of amoxicillin, amoxicillin-clavulanate, imipenem, ciprofloxacin, cefaclor, cefpodoxime, cefuroxime, clindamycin, and metronidazole against 384 anaerobic bacteria.

The National Committee for Clinical Laboratory Standards agar dilution method was used to compare the in vitro activity of WY-49605 (also called SUN/SY 5555 and ALP-201), a new broad-spectrum oral penem, to those of amoxicillin, amoxicillin-clavulanate, imipenem, ciprofloxacin, cefaclor, cefpodoxime, cefuroxime, clindamycin, and metronidazole against 384 clinically isolated anaerobes. These anaerobic organisms included 90 strains from the Bacteroides fragilis group, 87 Prevotella and Porphyromonas strains, non-B. fragilis group Bacteroides strains, 56 fusobacteria, 55 peptostreptococci, 49 gram-positive non-spore-forming rods, and 47 clostridia. Overall, WY-49605 had an MIC range of 0.015 to 8.0 micrograms/ml, an MIC at which 50% of the isolates are inhibited (MIC50) of 0.25 microgram/ml, and an MIC at which 90% of the isolates are inhibited (MIC90) of 2.0 micrograms/ml. Good activity against all anaerobe groups was observed, except for Clostridium difficile and lactobacilli (MIC50s of 4.0 and 2.0 micrograms/ml, respectively, and MIC90s of 8.0 and 2.0 micrograms/ml, respectively). Imipenem had an MIC50 of 0.03 microgram/ml and an MIC90 of 0.25 microgram/ml. Ciprofloxacin was much less active (MIC50 of 2.0 micrograms/ml and MIC90 of 16.0 micrograms/ml). By comparison, all oral beta-lactams were less active than WY-49605, with susceptibilities as follows: amoxicillin MIC50 of 8.0 micrograms/ml and MIC90 of > 256.0 micrograms/ml), amoxicillin-clavulanate MIC50 of 1.0 microgram/ml and MIC90 of 8.0 micrograms/ml, cefaclor MIC50 of 8.0 micrograms/ml and MIC90 of > 32.0 micrograms/ml, cefpodoxime MIC50 of 4.0 micrograms/ml and MIC90 of > 32.0 micrograms/ml, and cefuroxime MIC50 of 4.0 micrograms/ml and MIC90 of > 32.0 micrograms/ml. Clindamycin was active against all groups except some members of the B. fragilis group, Fusobacterium varium, and some clostridia ( overall MIC50 of 0.5 micrograms/ml and overall MIC90 of 8.0 micrograms/ml). Metronidazole was active (MIC of less than or equal to 4.0 micrograms/ml) against all gram-negative anaerobic rods, but most gram-positive non-spore-forming rods, some peptostreptococci, and some clostridia were less susceptible. To date, WY-49605 is the most active oral beta-lactam against anaerobes: these results suggest clinical evaluation for clinical indications suitable for oral therapy.     

In vitro activity of BAY 12-8039, a new fluoroquinolone.

The in vitro activity of BAY 12-8039, a new fluoroquinolone, was studied in comparison with those of ciprofloxacin, trovafloxacin (CP 99,219), cefpodoxime, and amoxicillin-clavulanate against gram-negative, gram-positive, and anaerobic bacteria. Its activity against mycobacteria and chlamydia was also investigated. BAY 12-8039 was active against members of the family Enterobacteriaceae (MIC at which 90% of strains tested were inhibited [MIC90S] < or = 1 microgram/ml, except for Serratia spp. MIC90 2 microgram/ml), Neisseria spp. (MIC90S, 0.015 microgram/ml), Haemophilus influenzae (MIC90, 0.03 microgram/ml), and Moraxella catarrhalis (MIC90, 0.12 micrgram/ml), and these results were comparable to those obtained for ciprofloxacin and trovafloxacin. Against Pseudomonas aeruginosa, the quinolones were more active than the beta-lactam agents but BAY 12-8039 was less active than ciprofloxacin. Strains of Stenotrophomonas maltophilia were fourfold more susceptible to BAY 12-8039 and trovafloxacin (MIC90S, 2 micrograms/ml) than to ciprofloxacin. BAY 12-8039 was as active as trovafloxacin but more active than ciprofloxacin against Streptococcus pneumoniae (MIC90, 0.25 microgram/ml) and methicillin-susceptible Staphylococcus auerus (MIC90S, 0.12 micrograms/ml). The activity of BAY 12-8039 against methicillin-resistant S. aureus (MIC90, 2 micrograms/ml) was lower than that against methicillin-susceptible strains. BAY 12-8039 was active against anaerobes (MIC90S < or = 2 micrograms/ml), being three- to fourfold more active against Bacteroides fragilis, Prevotella spp., and Clostridium difficile than was ciprofloxacin. Against Mycobacterium tuberculosis, BAY 12-8039 exhibited activity comparable to that of rifampin (MICs < or = 0.5 micrograms/ml). Against Chlamydia trachomatis and Chlamydia pneumoniae BAY 12-8039 was more active (MICs < or = 0.12 microgram/ml) than either ciprofloxacin or erythromycin and exhibited a greater lethal effect than either to these two agents. The protein binding of BAY 12-8039 was determined at 1 and 5 micrograms/ml as 30 and 26.4%, respectively. The presence of human serum (at 20 or 70%) had no marked effect on the in vitro activity of BAY 12-8039.     

Antimicrobial activity of CS-940, a new trifluorinated quinolone.

The antimicrobial activity of CS-940, a new trifluorinated quinolone drug, was tested against 761 clinical isolates. CS-940 activity against members of the family Enterobacteriaceae was most similar to that of ciprofloxacin and ofloxacin, with a large range of MICs inhibiting 90% of isolates tested (MIC90S) of 0.015 to 16 micrograms/ml (median MIC90, 0.06 micrograms/ml). CS-940 had greater activity than ciprofloxacin or ofloxacin when they were tested against Acinetobacter spp. (MIC90S, 0.03 micrograms/ml) and Stenotrophomonas (Xanthomonas) maltophilia (MIC90S, 2 micrograms/ml). CS-940 demonstrated a high degree of potency against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. (MIC90S, < or = 0.06 micrograms/ml). CS-940 was two- to eightfold more active than ciprofloxacin or ofloxacin against oxacillin-susceptible Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, and coagulase-negative Staphylococcus spp. CS-940 was also very active against Streptococcus spp. and enterococci, for which MIC90S were < or = 2 micrograms/ml; for Enterococcus faecium, however, the MIC90 was 4 micrograms/ml. CS-940 was generally less active than a comparison investigational fluoroquinolone, clinafloxacin. This compound appears promising by in vitro test analysis and warrants further in vivo trials.     

In vitro activity and beta-lactamase stability of a new penem, CGP 31608.

The in vitro activity of CGP 31608, a new penem, against aerobic and anaerobic organisms was evaluated and compared with those of other beta-lactams. CGP 31608 inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Citrobacter diversus, and Salmonella, Shigella, Aeromonas, and Yersinia spp. with MICs for 50% of the strains (MIC50s) of 2 to 4 micrograms/ml and MIC90s of 4 micrograms/ml, compared with cefotaxime, ceftazidime, aztreonam, and imipenem MICs of less than 0.25 microgram/ml. MIC90s were 8 micrograms/ml for Enterobacter species and C. freundii, for which other agents had MICs of 32 micrograms/ml, except imipenem, which had equal activity. The MIC90 for Proteus vulgaris, Morganella morganii, Providencia stuartii, and Providencia rettgeri was 8 micrograms/ml, compared with less than 2 micrograms/ml shown by the other agents. Acinetobacter species resistant to other agents except imipenem were inhibited by 4 micrograms/ml, as were Pseudomonas aeruginosa, including piperacillin-, ceftazidime-, and gentamicin-resistant isolates. The MIC for P. cepacia, P. fluorescens, and P. acidovorans was less than or equal to 8 micrograms/ml, but that for P. maltophilia was greater than or equal to 128 micrograms/ml. Hemolytic streptococci A, B, C, G, and F were inhibited by less than 1 micrograms/ml, but the MIC for Streptococcus faecalis was greater than or equal to 32 micrograms/ml. MICs for Staphylococcus aureus methicillin-susceptible and -resistant strains were less than or equal to 1 microgram/ml, as were those for methicillin-susceptible and -resistant S. epidermidis. Bacteroides fragilis and Clostridium species and Fusobacterium spp. were inhibited by less than or equal to 4 micrograms/ml. CGP 31608 was not hydrolyzed by plasmid beta-lactamases TEM-1, TEM-2, SHV-1, PSE-1, OXA-2, PSE-4, or by S. aureus. Chromosomal beta-lactamases of type Ia in Enterobacter cloacae P99 and Morganella morganii, Ic in P. vulgaris, K-1 in K. oxytoca, and Id in P. aeruginosa also did not hydrolyze CGP 31608. It inhibited TEM-1, but the 50% inhibitory concentration was 14.2 micrograms/ml compared with 0.15 micrograms/ml for the P99 enzyme. CGP 31608 induced beta-lactamases in P. aeruginosa, E. cloacae, C. freundii and Providencia rettgeri, but there was no increase in MICs for the isolates and it did not select strains derepressed for beta-lactamase production. Synergy of CGP 31608 and gentamicin was found against 90% P. aeruginosa, 60% Enterobacter cloacae, and 50% Serratia marcescens strains. No synergy was found with rifampin. A postantibiotic effect was found against E. coli.     

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.     

The comparative activity of fleroxacin, three other quinolones and eight unrelated antimicrobial agents.

The in vitro activity of fleroxacin, a new trifluorinated quinolone was evaluated against 432 bacterial isolates. Fleroxacin was 1- to 2-fold less active than ciprofloxacin and at least as active as ofloxacin and lomefloxacin against most members of the family Enterobacteriaceae. The MICs of fleroxacin for 90% of strains tested (MIC90) were < or = 0.25 micrograms/ml against all isolates of Enterobacteriaceae except Citrobacter freundii (MIC90, 4 micrograms/ml) and Serratia marcescens (MIC90, 2 micrograms/ml). Fleroxacin was as active as ciprofloxacin, ofloxacin and lomefloxacin against Pseudomonas spp, (MIC90 for all quinolones tested were > 8 micrograms/ml). Acinetobacter and Haemophilus influenzae were very susceptible to fleroxacin; however fleroxacin was 1-fold less active than lomefloxacin against Acinetobacter and at least 1-fold less active than ciprofloxacin or ofloxacin against H. influenzae. Methicillin-susceptible and -resistant strains of Staphylococcus epidermidis and methicillin-susceptible strains of S. aureus were very susceptible to fleroxacin, with an MIC90 < or = 1 microgram/ml (range 0.5-1 microgram/ml). Methicillin-resistant S. aureus and Staphylococcus spp. other than aureus and epidermidis were not susceptible to fleroxacin (MIC90 > 8 micrograms/ml). In addition, fleroxacin as well as ciprofloxacin, ofloxacin and lomefloxacin were inactive against Enterococcus spp. (MIC90 > 8 micrograms/ml). Streptococcus pneumoniae and S. pyogenes were resistant to both fleroxacin and lomefloxacin but were very susceptible to ciprofloxacin and ofloxacin. These results suggest that fleroxacin represents a valid therapeutic option in the treatment of infections caused by most Enterobacteriaceae and some species of staphylococcus.     

A-61827 (A-60969), a new fluoronaphthyridine with activity against both aerobic and anaerobic bacteria.

A-61827 (A-60969 is the hydrochloric salt of A-61827) is a new aryl-fluoronaphthyridine which is active against aerobic and anaerobic bacteria. The MICs of A-61827 for 90% of strains (MIC90) of staphylococci and streptococci were less than or equal to 1 microgram/ml and were generally 1 to 4 twofold dilutions less than those of ciprofloxacin for these bacteria. The MIC90S of A-61827 for members of the family Enterobacteriaceae and Pseudomonas aeruginosa were also less than or equal to 1 microgram/ml. Ciprofloxacin was 1 to 3 twofold dilutions more active than A-61827 against these gram-negative bacteria. Neisseria gonorrhoeae, Campylobacter jejuni, and Haemophilus influenzae were susceptible to less than 0.06 microgram of A-61827 per ml. The MIC90 of A-61827 for Legionella pneumophila was 0.25 microgram/ml. A-61827 was as potent or 1 to 2 twofold dilutions more potent than ciprofloxacin against these organisms. The MIC90 of A-61827 for all anaerobic bacteria was less than or equal to 4 micrograms/ml compared with less than or equal to 32 micrograms/ml for ciprofloxacin. In mouse protection tests, A-61827 was as active as ciprofloxacin against Escherichia coli, P. aeruginosa, and Salmonella typhimurium and 5 to 10 times more active than ciprofloxacin against Staphylococcus aureus and Streptococcus pyogenes. A-61827 was as active as ciprofloxacin against P. aeruginosa in a mouse pyelonephritis model and more active than ciprofloxacin and metronidazole in a mouse Bacteroides fragilis abscess model. After oral administration of 100 mg/kg to mice, the peak concentrations of A-61827 and ciprofloxacin in serum were 2.3 and 2.4 micrograms/ml and the half-lives in serum were 3.9 and 1.2 h, respectively.