The in-vitro activity of BMY 28142, an iminomethoxy, aminothiazolyl cephalosporin containing a methyl pyrrolidinio C-3 was compared with that of cefotaxime, ceftazidime, aztreonam, imipenem and tobramycin against various bacteria. BMY 28142 was the most active agent tested against the Enterobacteriaceae inhibiting 90% at less than or equal to 1 mg/l. The in-vitro activity of BMY 28142 was equal to or superior to cefotaxime against the highly susceptible members of the Enterobacteriaceae and several-fold superior to ceftazidime and aztreonam. BMY 28142 inhibited many Enterobacter cloacae, Citrobacter freundii and Serratia marcescens resistant to cefotaxime, ceftazidime and aztreonam. BMY 28142 was more active than imipenem against Proteus, Providencia and Morganella species. Ceftazidime and imipenem were more active than BMY 28142 against Pseudomonas aeruginosa, but it inhibited piperacillin and tobramycin-resistant isolates. BMY 28142 inhibited beta-lactamase producing Haemophilus influenzae and Neisseria gonorrhoeae. BMY 28142 was more active than ceftazidime against streptococcal and staphylococcal species, but it did not inhibit or kill most methicillin-resistant Staphylococcus aureus. BMY 28142 did not inhibit most Bacteroides species. BMY 28142 was not hydrolyzed by common plasmid and chromosomal beta-lactamases, but it bound poorly to Enterobacter beta-lactamase, was a poor inhibitor of the TEM plasmid beta-lactamase and was a poor inducer of beta-lactamases.

Temocillin, a 6-a-methoxy penicillin, inhibited 90% of strains of Escherichia coli, Klebsiella pneumoniae, Citrobacter, Proteus, Providencia, Salmonella, and Shigella at a concentration of <16 ,ug/ml. Haemophilus influenzae and Neisseria gonorrhoeae were inhibited by s1 pug/ml. Changing the medium or pH of the cultures did not alter the minimal inhibitory concentrations, which were similar in broth and human serum, as were the minimal bactericidal concentrations. An increase in inoculum size from 105 to 107 colony-forming units increased concentration required for inhibition. Temocillin inhibited strains resistant to ampicillin, ticarcillin, cefazolin, cefamandole, and cefoxitin. Most Pseudomonas aeruginosa strains and other Pseudomonas spp. and Acinetobacter spp. were resistant, as were gram-positive organisms. Temocillin was not hydrolyzed by the common plasmid and chromosomal P-lactamases but inhibited them. The resistance of certain gram-negative bacilli to temocillin seemed to be a result of failure of the molecule to enter through the cell wall, since combination of temocillin with EDTA made Pseudomonas, Acinetobacter, and Enterobacter strains susceptible to low concentrations of the compound.

Combinations of ciprofloxacin with azlocillin, piperacillin and ticarcillin were tested in vitro against clinical isolates. Azlocillin plus ciprofloxacin showed synergy against 30% of Pseudomonas aeruginosa isolates; it was either synergistic or additive against 78% of all isolates tested even those resistant to the beta-lactam. Synergism was rarely noted for Klebsiella pneumoniae, Escherichia coli, Enterobacter spp. or Branhamella spp. isolates. Minimum inhibitory concentrations of ciprofloxacin plus azlocillin, plus piperacillin and plus ticarcillin against Pseudomonas spp. were reduced 4 or 2 fold, respectively. However, the combination azlocillin plus ciprofloxacin showed primarily indifference against gram-positive strains. Neutropenic mice infected with a lethal challenge of Pseudomonas spp. were protected by a combination of azlocillin and ciprofloxacin. Its additive and/or synergistic effects and expanded spectrum of activity against streptococci, methicillin-resistant staphylococci and JK corynebacteria may provide an alternative to traditional therapy.

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Cefodizime, an iminomethoxy aminothiazolyl cephalosporin similar to moxalactam and ceftazidime, was less active (minimal inhibitory concentration, 1.6 to 12 p.g) than cefazolin or cefotaxime against Staphylococcus aureus and Staphylococcus epidermidis. It inhibited Haemophilus and Neisseria spp. at <0.5 ,ug/ml. It did not inhibit methicillin-resistant staphylococci, enterococci, or Listeria spp. and was 8-to 32-fold less active than cefotaxime, moxalactam, or ceftazidime against Escherichia coli, Citrobacter spp., Klebsiella pneumoniae, Providencia spp., and Serratia spp. Cefotaxime-resistant Enterobacter cloacae, Citrobacter freundii, and Proteus vulgaris were resistant to cefodizime. Cefodizime was less active than cefoxitin or moxalactam against Bacteroides fragilis. Cefodizime was not hydrolyzed by common plasmid or chromosomal ,-lactamases, and it inhibited type I ,-lactamases.The introduction of the iminomethoxy group on the acyl side chain of the dihydrothiazime ring of the cephalosporine nucleus and the presence of the aminothiazolyl group have provided increased activity against Enterobacteriaceae while retaining much of the gram-positive activity of the earlier cephalosporins (3). Cefodizime is structurally similar to cefotaxime but has a 1-mercapto-1,3-thiazole chain substituted for the acetoxy group at position 3 of the dihydrothiazine ring (J. Bacterial isolates were obtained from patients recently hospitalized at the Columbia-Presbyterian Medical Center, New York, N.Y. In addition, organisms which were known to be multiply resistant to antibiotics and to contain previously characterized ,B-lactamases were used in some experiments. These isolates had been stored frozen for a number of years.Antimicrobial activity was measured by an agar dilution method with Mueller-Hinton agar unless specified otherwise. Fresh dilutions of the compounds were prepared daily in sterile medium or distilled water. A final inoculum of 105 CFU prepared by dilution of a fresh overnight broth culture was applied as a spot to the agar with a replicating device. Broth dilutions were performed in 1-mi (volume) tubes with a final inoculum of 105 CFU. Plates or tubes were incubated at 350C for 18 h. The minimal inhibitory concentration (MIC) was defined as the lowest concentration of antibiotic that inhibited visible growth on agar or in broth. The minimal bactericidal concentration (MBC) was determined by plating 0.1-ml amounts from clear 1-mi broth tubes onto blood agar plates. The MBC was defined as the concentration at which there was no growth after 24 h of incubation at 35C. The susceptibility of streptococci was determined by using Muelier-Hinton agar supplemented with 5% sheep blood. The susceptibility of Neisseria and Haemophilus spp. was determined on chocolate MuellerHinton agar incubated in the presence of 5% CO2.