In vitro activities of beta-lactam-beta-lactamase inhibitor combinations against Stenotrophomonas maltophilia: correlation between methods for testing inhibitory activity, time-kill curves, and bactericidal activity.

The activities of ampicillin, ampicillin-sulbactam, amoxicillin, amoxicillin-clavulanic acid, ticarcillin, ticarcillin-clavulanic acid, piperacillin, piperacillin-tazobactam, aztreonam, and aztreonam-clavulanic against Stenotrophomonas maltophilia strains for which the MICs of penicillins and commercially available beta-lactam-beta-lactamase inhibitor combinations were higher than the breakpoints usually recommended for Pseudomonas aeruginosa in commercially available broth microdilution methods were tested by the agar diffusion, agar dilution, and broth microdilution methods. Time-kill curve studies were performed when discrepancies between these methods were observed. The MICs obtained by the commercially available broth microdilution method, the agar dilution method, and the broth microdilution method were almost identical. Twenty-five percent of the strains tested showed inhibition diameters of > or =15 mm for ticarcillin-clavulanic acid, and 43.7% of the strains tested showed inhibition diameters of > or =18 mm for piperacillin-tazobactam by the agar diffusion method. The time-kill curves for these strains confirmed the results obtained by dilution methods. Aztreonam-clavulanic acid (2:1) at concentrations of < or =16 microg/ml inhibited all of these strains (MIC range, 1 to 16 microg/ml). The time-kill curves confirmed this activity. The addition of piperacillin to this combination did not modify the MICs. The combination aztreonam-clavulanic acid-ticarcillin was two- to fourfold more active than aztreonam-clavulanic acid alone. We studied the inhibitory and bactericidal activities of the two most active combinations (aztreonam-clavulanic acid and aztreonam-clavulanic acid-ticarcillin) against the standard inoculum and 10 and 50 times the standard inoculum. Inoculum modifications did not modify the MICs. Both combinations showed good bactericidal activity against the standard inoculum. With 10 times the standard inoculum, minimum bactericidal concentration (MBC) results were heterogeneous (for 55% of the strains, MBCs were between the MIC and 4-fold the MIC, and for 45% of the strains MBCs were between 8- and >32-fold the MIC). With 50 times the standard inoculum, MBCs were at least 32-fold the MICs for all the strains tested.     

Rapid selection of organisms with increasing resistance on subinhibitory concentrations of norfloxacin in agar.

Serial passage of Pseudomonas aeruginosa ATCC 27853 or Escherichia coli ATCC 25922 on agar with subinhibitory concentrations of norfloxacin rapidly produced isolates with minimal inhibitory concentrations (MICs) of norfloxacin up to 512-fold higher than that for the original strain. Although MICs of seven unrelated antibiotics were unchanged, increasing MICs occurred in parallel with norfloxacin, cinoxacin, and nalidixic acid regardless of which of these three organic acids was used to select for increased resistance. P. aeruginosa with a norfloxacin MIC of greater than 256 micrograms/ml could be selected; however, E. coli with MICs greater than the clinically achievable level of 16 micrograms/ml could not be produced.     

Susceptibility of Bordetella pertussis to doxycycline, cinoxacin, nalidixic acid, norfloxacin, imipenem, mecillinam and rifampicin

The susceptibility of Bordetella pertussis to doxycycline, cinoxacin, nalidixic acid, norfloxacin, imipenem (N-formimidoyl-thienamycin), mecillinam and rifampicin was studied by agar and broth dilution. There were discrepancies between MICs registered on solid medium and in fluid medium. There seems to be a need for methodological studies on the antibiotic susceptibility of Bord. pertussis using different techniques. None of the compounds tested seemed to be realistic alternatives to the well documented erythromycin.     

In vitro activity of CI-934, a new quinolone, compared with that of other quinolones and other antimicrobial agents.

The in vitro activity of CI-934, a new 4-quinolone, was determined against gram-positive and gram-negative bacteria. The MICs for 90% of the isolates tested were 0.25 microgram/ml for Streptococcus pneumoniae, 0.5 microgram/ml for Streptococcus faecalis, 0.25 microgram/ml for staphylococci, including methicillin-resistant strains, and less than or equal to 1.0 microgram/ml for Escherichia coli, Salmonella and Shigella spp., Klebsiella spp., Proteus spp., and Citrobacter spp. CI-934 had activity superior to that of other quinolones against streptococci by four- to eightfold. Against members of the family Enterobacteriaceae, ciprofloxacin was 2- to 18-fold more active; ofloxacin and norfloxacin were twofold more active or similar to CI-934. CI-934 inhibited ampicillin-cephalothin-resistant urinary isolates of E. coli, Klebsiella pneumoniae, and Proteus mirabilis and cefoxatime-resistant Acinetobacter spp., Citrobacter freundii, Enterobacter cloacae, Proteus vulgaris, and Morganella morganii. The medium, inoculum size, and oxygen concentration, as well as the addition of serum, had not major effect on the activity of CI-934. Magnesium at a concentration of 9 mM increased MICs and MBCs four- to eightfold, and testing at pH 6 increased MICs as much as 32- to 64-fold for some organisms in comparison with MICs at pH 7. The frequency of spontaneous mutation to resistance was comparable to that for other new quinolones, but resistant isolates could be selected by repeated subculture.     

In-vitro activity of ofloxacin, a quinolone carboxylic acid compared to other quinolones and other antimicrobial agents

Ofloxacin is a new quinolone carboxylic acid compound. Its activity against 900 bacterial isolates was determined. It inhibited 90% of Escherichia coli, Klebsiella sp., Aeromonas hydrophila, Salmonella spp., Shigella spp., Citrobacter spp., Enterobacter spp., Morganella morganii, Proteus mirabilis, Yersinia enterocolitica at less than or equal to 0.8 mg/l. Branhamella catarrhalis, Haemophilus sp., Neisseria sp. were inhibited by less than or equal to 0.1 mg/l. Pseudomonas aeruginosa and other Pseudomonas species were inhibited by less than or equal to 6.3 mg/l. Although most staphylococcal species, including methicillin-resistant staphylococci were inhibited by 3.1 mg/l, many streptococcal species had higher MIC values, and most Bacteroides species were inhibited at less than or equal to 6.3 mg/l. The overall activity of ofloxacin was similar to enoxacin and norfloxacin. Ofloxacin inhibited organisms resistant to nalidixic acid, ampicillin, cephalexin, piperacillin, and gentamicin including Enterobacter spp., Citrobacter freundii and Serratia marcescens resistant to cefotaxime. The activity of ofloxacin was lower at an acid pH and in urine, but serum had no effect on MICs or MBCs. Increase in ofloxacin MICs for various bacteria could be achieved by repeated subculture in the presence of ofloxacin.     

Cefazaflur, a New Parenteral Cephalosporin: In Vitro Studies

Cefazaflur was tested in vitro against 262 strains of bacteria. Inhibitory and bactericidal concentrations were determined with two inoculum sizes of bacterial cells in Mueller-Hinton broth and nutrient broth. Agar dilution studies also were performed. When tested in agar, 5.0 mug or less of cefazaflur per ml inhibited almost all strains of Staphylococcus aureus, Escherichia coli, Klebsiella, and Proteus mirabilis. The drug was less active against Enterobacter and indole-positive Proteus, and 7.5 mug of antibiotic per ml inhibited approximately two-thirds to one-fourth of the strains. A concentration of 50 mug of cefazaflur per ml was required for inhibition of the enterococci. There was negligible activity against Pseudomonas. The drug demonstrated less activity in broth than in agar, and a major inoculum effect was seen with some strains. For example, with a lower inoculum, 2.5 mug of cefazaflur per ml killed all strains of E. coli, whereas with the higher inoculum, 7.5 mug of cefazaflur per ml, inhibited 64% and killed only 8% of strains. The activity of the drug for some strains was greater in Mueller-Hinton broth; for others, it was greater in nutrient broth. There were considerable differences in the results of the broth and agar studies for some species when the same medium was employed. Because of differences in activity found with different media, inocula, and method of testing, an evaluation of the eventual usefulness of cefazaflur must await the results of in vivo studies.     

In Vitro Activity of Netilmicin, Gentamicin, and Amikacin

The in vitro activity of netilmicin (Sch 20569), a new semisynthetic derivative of gentamicin, was compared with that of gentamicin and amikacin. One hundred and ninety-two clinical isolates of Enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus were tested using both agar and broth dilution techniques. Netilmicin was comparable to gentamicin, with the following exceptions: (i) for Serratia marcescens and P. aeruginosa, gentamicin was more active than netilmicin; (ii) all strains of Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis, and Citrobacter freundii, which were resistant to gentamicin, were susceptible to netilmicin; (iii) some strains of S. marcescens, indole-positive Proteus, and Providencia, which were resistant to gentamicin, were susceptible to netilmicin. Netilmicin was more active than amikacin for all Enterobacteriaceae and S. aureus and equal to amikacin in activity against gentamicin-susceptible strains of P. aeruginosa. All strains of P. aeruginosa, resistant to gentamicin, were also resistant to netilmicin but were susceptible to amikacin. Minimal inhibitory concentrations (MICs) obtained with broth and agar showed no significant differences except for P. mirabilis, where broth MICs were twofold greater than agar MICs, and for P. aeruginosa, where agar MICs were twofold higher than broth MICs. The minimal bactericidal concentration (MBC) was either identical to or within one twofold dilution of the MIC for the strains tested. A 100-fold increase in inoculum size produced less increase in MIC and MBC with netilmicin than with gentamicin or amikacin.     

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.     

Effect of inoculum, pH, and medium on the activity of ciprofloxacin against anaerobic bacteria

The in vitro activity of ciprofloxacin against 30 Bacteroides fragilis group, 30 Clostridium, and 30 Peptococcaceae strains was determined by the agar dilution method in two different culture media at three pH and in three inoculum densities. In Wilkins-Chalgren agar the MICs for 90% of the strains were 0.12 micrograms/ml for B. fragilis, 0.5 micrograms/ml for Clostridium spp., and 2 micrograms/ml for Peptococcaceae. The pH and medium composition affected the MICs of ciprofloxacin.     

In vitro and in vivo activity of DL-8280, a new oxazine derivative.

DL-8280, 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H- pyrido-(1,2,3-de)1,4-benzoxazine-6-carboxylic acid, is a new nalidixic acid analog with a broad spectrum of antibacterial activity against gram-negative and gram-positive bacteria, including obligate anaerobes. The activity of DL-8280 against Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus influenzae, Neisseria gonorrhoeae, and Clostridium perfringens was roughly comparable to that of norfloxacin and far exceeded that of pipemidic acid and nalidixic acid. DL-8280 had greater activity against Staphylococcus spp., Streptococcus spp., Pseudomonas maltophilia, Acinetobacter spp., and Bacteroides fragilis than did norfloxacin, pipemidic acid, and nalidixic acid. Nalidixic acid-resistant Enterobacteriaceae, ampicillin-resistant gonococci, and clindamycin-resistant obligate anaerobes were also susceptible to DL-8280. The activity of DL-8280 was affected very little by inoculum size, and its action was bactericidal at two times the minimal inhibitory concentrations at most. Administered orally to mice experimentally infected with Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Proteus mirabilis, Serratia marcescens, or P. aeruginosa, DL-8280 was 2 to 7 times more effective than norfloxacin and 7 to more than 50 times more active than pipemidic acid.     

In vitro activities of PD 117,596 and reference antibiotics against 448 clinical bacterial strains.

The in vitro activity of PD 117,596, a new fluoroquinolone antibiotic, was tested against 448 bacterial isolates (15 genera) by agar dilution (inoculum, 10(4) CFU per spot). The activity of PD 117,596 was compared with that of 15 antibiotics against 327 gram-negative strains and with that of 8 other antibiotics against 121 gram-positive strains. PD 117,596 demonstrated the best activity against Klebsiella spp., Enterobacter spp., Acinetobacter spp., Serratia marcescens, and Branhamella catarrhalis (MICs for 90% of the isolates [MIC90S], 0.008 to 0.25 microgram/ml). PD 117,596 (MIC90, 0.25 microgram/ml) was at least twofold more active than ciprofloxacin against Pseudomonas aeruginosa and Pseudomonas spp. PD 117,596 and ciprofloxacin were similar in activity against Escherichia coli, Proteus mirabilis, Haemophilus influenzae, H. parainfluenzae, Neisseria gonorrhoeae, Legionella pneumophila, and Campylobacter jejuni (MIC90, 0.002 to 0.125 microgram/ml). PD 117,596 was more active than ciprofloxacin against streptococcal groups A, B, C, and G, S. pneumoniae, and enterococci (MIC90S, 0.06 to 0.125 microgram/ml). Against Staphylococcus aureus, including methicillin-resistant isolates, PD 117,596 (MIC90S, 0.03 to 0.06 microgram/ml) was 4- to 16-fold more active than ciprofloxacin and was most active against Corynebacterium spp. PD 117,596 appears to be the most active fluoroquinolone to date, with excellent activity against gram-positive bacteria and enhanced activity against gram-negative aerobic-facultative bacteria.     

Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila.

The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml). The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin, 1 to 3 tubes higher than the broth dilution MICs for ofloxacin, 1 to 3 tubes higher than the broth dilution MICs for erythromycin, and the same as the broth dilution MICs for rifampin. In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin. At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L. pneumophila. In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin. Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h. In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy. Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L. pneumophila when it was studied alone or in a combination with rifampin.     

Comparison of in vitro activity of quinolone antibiotics and vancomycin against gentamicin- and methicillin-resistant Staphylococcus aureus by time-kill kinetic studies.

Quinolone antibiotics have been proposed as possible alternatives to vancomycin for methicillin-resistant Staphylococcus aureus infections. We investigated the activities of amifloxacin, ciprofloxacin, norfloxacin, and vancomycin by time-kill kinetic studies. Antibiotic concentrations of 0, 1.0, and 4.0 times the MIC were used against four strains of gentamicin- and methicillin-resistant S. aureus. Staphylococci were plated onto ciprofloxacin-containing agar at all time points, in repeat time-kill kinetic studies. Macrobroth dilution MICs and MBCs were determined. Ciprofloxacin levels were measured by bioassay. Replica plating was performed from the original susceptible inoculum (MIC, 0.125 micrograms/ml) onto ciprofloxacin-supplemented agar. At 4.0 times the MIC, only with ciprofloxacin was there regrowth at 24 and 48 h. All four strains of staphylococci grew on agar supplemented with 1 microgram of ciprofloxacin per ml; three of four grew on agar supplemented with 2 micrograms of ciprofloxacin per ml. MICs and MBCs for these resistant clones ranged from 8 to 32 micrograms/ml. No degradation in activity or amount of ciprofloxacin could be detected in the bioassay. Replica-plated staphylococci grew on agar containing 1 microgram/ml but not higher concentrations of ciprofloxacin at 48 h. Amifloxacin and norfloxacin sustained bactericidal activity comparable to that of vancomycin. We conclude that heteroresistant subpopulations of gentamicin- and methicillin-resistant S. aureus can emerge under antibiotic selection pressure. Such resistant clones may then mutate in the presence of subinhibitory concentrations of antibiotic to higher levels of ciprofloxacin resistance.     

In-vitro activity of pefloxacin compared to enoxacin, norfloxacin, gentamicin and new beta-lactams

The in-vitro activity of pefloxacin was compared with that of norfloxacin, enoxacin, nalidixic acid, gentamicin, cefotaxime, ceftazidime and, where appropriate, other beta-lactams against a total of 363 recent clinical isolates. An agar dilution procedure was used to determine MICs and two inocula (10(4) and 10(6) cfu) were used throughout. Pefloxacin inhibited 90% of isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, indole-positive Proteus spp., Enterobacter spp., Shigella sonnei, Salmonella typhi, Campylobacter jejuni, Staphylococcus aureus and Haemophilus influenzae at less than or equal to 0.5 mg/l. Serratia marcescens and Providencia stuartii were somewhat more resistant, 2 mg/l of pefloxacin being required to inhibit 90% of isolates of these species. Pefloxacin inhibited 90% of isolates of Pseudomonas aeruginosa at 4 mg/l and 90% of isolates of the Bacteroides fragilis group at 16 mg/l. The activity of enoxacin was similar to that of pefloxacin, with enoxacin being four-fold less active against Staph. aureus, two-fold less active against the Bacteroides fragilis group and most species of the Enterobacteriaceae, and two-fold more active against Ps. aeruginosa. Pefloxacin showed good activity against gentamicin-resistant Ps. aeruginosa and Enterobacteriaceae and against methicillin-resistant Staph. aureus. Strains with decreased susceptibility to norfloxacin tended to be less susceptible to both pefloxacin and enoxacin.     

In-vitro activity of enoxacin (CL-919), a new quinoline derivative, compared with that of other antimicrobial agents

The in-vitro activity of enoxacin (CI-919), a new synthetic quinoline derivative was compared with that of three other quinolines ofloxacin, norfloxacin and nalidixic acid. In addition beta-lactams and gentamicin were also included when appropriate. The MICs of enoxacin for 90% of Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus spp., Providencia stuartii, Pseudomonas aeruginosa and Staphylococcus aureus were less than 4 mg/l, for Haemophilus influenzae less than 0.25 mg/l and Neisseria gonorrhoeae less than 0.03 mg/l. Bacteroides fragilis and streptococci (including Streptococcus pneumoniae) were less susceptible, MIC90 16 mg/l. Against many of the common Enterobacteriaceae enoxacin displayed a similar degree of activity as gentamicin. Gentamicin-resistant strains of common bacterial pathogens were susceptible to enoxacin as were methicillin-resistant Staph. aureus. The protein binding of enoxacin (concentration 5 mg/l) was 18%.     

In vitro activity of norfloxacin, a quinolinecarboxylic acid, compared with that of beta-lactams, aminoglycosides, and trimethoprim.

Norfloxacin is a quinolinecarboxylic acid compound. We examined the in vitro activity of this compound against gram-positive and -negative species, including anaerobic species. It inhibited 90% (MIC90) of strains of Escherichia coli at 0.05 microgram/ml, Klebsiella sp. at 0.4 microgram/ml, Salmonella and Shigella spp. at 0.1 microgram/ml, Citrobacter sp. at 0.4 microgram/ml, Enterobacter cloacae at 0.2 microgram/ml, Enterobacter aerogenes at 0.4 microgram/ml, and Enterobacter agglomerans at 0.2 microgram/ml. The MICs of Proteus mirabilis, Morganella sp., Proteus vulgaris, Proteus rettgeri, and Providencia sp. were 0.1, 0.2, 0.8, 0.3, and 1.6 micrograms/ml, respectively. The MIC90 of Serratia sp. was 1.6 micrograms/ml, and that of Acinetobacter sp. was 6.3 micrograms/ml. For Pseudomonas aeruginosa the MIC50, the MIC75, and the MIC90 were 0.8, 1.6, and 3.1 micrograms/ml, respectively. The MIC50 of Pseudomonas maltophilia was 3.1 micrograms/ml, and the MIC90 was 12.5 micrograms/ml. Yersinia, Arizona, and Aeromonas all were inhibited at concentrations below 1 microgram/ml, as was Campylobacter. The activity of the compound against gram-positive species was less impressive: the MIC90s of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, and Streptococcus faecalis were 1.6, 6.3, 3.1, and 12.5 micrograms/ml, respectively. All Listeria strains were inhibited by 3.1 micrograms/ml. The activity of norfloxacine was not affected by the type of medium, pH, or inoculum size. There was no major difference between MIC and minimum bactericidal concentration values. Norfloxacin inhibited bacteria in every species which was resistant to ampicillin, carbenicillin, cephalexin, gentamicin, and trimethoprim at concentrations lower than those of aminothiazolyl cephalosporins, moxalactam, and aminoglycosides.     

Tigemonam, an oral monobactam.

Tigemonam is an orally administered monobactam. At less than or equal to 1 microgram/ml it inhibited the majority of strains of Escherichia coli, Klebsiella spp., Enterobacter aerogenes, Citrobacter diversus, Proteus spp., Providencia spp., Aeromonas hydrophila, Salmonella spp., Shigella spp., Serratia marcescens, and Yersinia enterocolitica. At less than or equal to 0.25 microgram/ml it inhibited Haemophilus spp., Neisseria spp., and Branhamella catarrhalis. It did not inhibit Pseudomonas spp. or Acinetobacter spp. Tigemonam was more active than cephalexin and amoxicillin-clavulanate and inhibited many members of the family Enterobacteriaceae resistant to trimethoprim-sulfamethoxazole and gentamicin. Some Enterobacter cloacae and Citrobacter freundii strains resistant to aminothiazole iminomethoxy cephalosporins and aztreonam were resistant to tigemonam. The MIC for 90% of hemolytic streptococci of groups A, B, and C and for Streptococcus pneumoniae was 16 micrograms/ml, but the MIC for 90% of enterococci, Listeria spp., Bacteroides spp., and viridans group streptococci was greater than 64 micrograms/ml. Tigemonam was not hydrolyzed by the common plasmid beta-lactamases such as TEM-1 and SHV-1 or by the chromosomal beta-lactamases of Enterobacter, Morganella, Pseudomonas, and Bacteroides spp. Tigemonam inhibited beta-lactamases of E. cloacae and Pseudomonas aeruginosa but did not induce beta-lactamases. The growth medium had a minimal effect on the in vitro activity of tigemonam, and there was a close agreement between the MICs and MBCs.     

In vitro and in vivo antibacterial activity of AT-2266.

AT-2266 [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carbo xylic acid] showed a broad spectrum of antibacterial activity against gram-positive and gram-negative microorganisms, including Pseudomonas aeruginosa. The in vitro antibacterial activity of AT-2266 was in general comparable to that of norfloxacin, but much higher than that of pipemidic or nalidixic acid. The 90% minimal inhibitory concentrations (MIC90s) of AT-2266 for P. aeruginosa resistant to gentamicin (MIC range, 25 to greater than 200 microgram/ml) and Enterobacteriaceae resistant to nalidixic acid (25 to greater than 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The to nalidixic acid (25 to 1,600 micrograms/ml) were 3.13 and 12.5 micrograms/ml, respectively. The MICs of AT-2266 were only slightly affected by the addition of horse serum or sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was sodium cholate, by the pH of the medium, and by inoculum size. AT-2266 was bactericidal at concentrations near its MIC value. The 50% effective doses of AT-2266 after oral administration against systemic infections in mice were about 1/2 those of norfloxacin, about 1/10 those of pipemidic acid, and between 1/20 and 1/40 those of nalidixic acid.     

In vitro activity of DJ-6783 (a keto carboxylic acid) compared with six other orally administered antimicrobial agents

DJ-6783 is a new keto carboxylic acid having an expanded antimicrobial activity when compared with nalidixic acid or cinoxacin. Its usable activity includes the following: Enterobacteriaceae (MIC90, less than or equal to 0.06-4.0 micrograms/ml), Acinetobacter species (MIC90, 0.25-1.0 microgram/ml), Pseudomonas species (MIC90, 1.0-2.0 micrograms/ml), P. aeruginosa (MIC90, 16 micrograms/ml), Staphylococcus species (MIC90, 1.0-32 micrograms/ml), Haemophilus influenzae (MIC900, less than or equal to 0.06 microgram/ml), and Neisseria species (MIC90 less than or equal to 0.06 microgram/ml). The Streptococcus species were resistant to DL-6783 with MIC50 ranging from 16 to greater than 32 micrograms/ml. The drug appears to be bactericidal, minimally influenced by increasing inocula, but resistant mutants can be selected by serial subinhibitory concentration passages of strains in DJ-6783. The resulting resistant organisms also have higher MICs to related drugs such as norfloxacin, cinoxacin, and nalidixic acid. DJ-6783 was the most active organic acid not having structural characteristics of the fluorinated 4-quinolones.     

In-vitro activity of lomefloxacin in comparison with pefloxacin and ofloxacin

The in-vitro activity of lomefloxacin (SC 47111, NY-198) was investigated by the determination of MICs in agar and in broth, of MBCs in broth, of killing curves and of the duration of the post-antibiotic effect. MICs measured in broth and in agar were almost identical. Lomefloxacin was two- to eight-fold less active against Gram-positive bacteria than ofloxacin. Its activity against Staphylococcus aureus was independent of resistance to penicillin and oxacillin. The activity of lomefloxacin, ofloxacin and pefloxacin was poor against JK corynebacteria. Enterobacteriaceae, Aeromonas spp., Haemophilus, influenzae, Neisseriaceae and Campylobacter jejuni were highly susceptible to the three quinolones investigated. Non-fermenting Gram-negative bacilli were less susceptible. MBCs were within one dilution of the corresponding MICs. The killing rate was very high against Gram-negative bacilli (2.5-4.0 log cfu/ml reduction in 2 h) whereas it was low against Gram-positive bacteria (0.5-1.0 log cfu/ml reduction in 2 h). Emergence of resistance was not observed. The duration of the post-antibiotic effect with Gram-negative bacilli depended on the strain and species (median: 0.9-1.5 h). The post-antibiotic effect was insignificant with Staph. aureus.