The in-vitro activity of faropenem, a novel oral penem, was studied in comparison with other beta-lactam antimicrobials against 711 recent clinical isolates including Gram-negative, Gram-positive and anaerobic bacteria. MIC data showed that faropenem was active against most members of the Enterobacteriaceae (MICs < or = 4 mg/L), with reduced activity against Serratia spp. (MIC90 = 32 mg/L). In common with its comparators, faropenem had weak activity against Pseudomonas aeruginosa and Stenotrophomonas maltophilia (MIC > 128 mg/L). Faropenem was active against staphylococci, although for MRSA MICs were raised (MIC90 = 2 mg/L) compared with those for MSSA (MIC90 = 0.12 mg/L). Faropenem was also found to be active against streptococci, Neisseria spp., Enterococcus faecalis and beta-lactamase-producing and non-producing strains of Haemophilus influenzae and Moraxella catarrhalis. Of the anaerobic bacteria studied, faropenem was most active against peptostreptococci and Clostridium perfringens (MIC90 < or = 1 mg/L) and Bacteroides fragilis (MIC90 = 4 mg/L). An increase in inoculum from 10(4) to 10(6) cfu raised faropenem MICs for Morganella morganii from 0.06-1 mg/L to 2-4 mg/L and for MRSA from 0.25-2 mg/L to 8 mg/L (a similar increase was not observed for MSSA). The MICs of faropenem were not affected by the presence of either 20% or 70% (v/v) serum. MICs for faropenem to 11 well characterized beta-lactamase producers were similar to those of non-producers. In hydrolysis studies, faropenem was shown to be highly stable to a number of beta-lactamases, including TEM-1, SHV-1, the extended spectrum beta-lactamases, TEM-3 and TEM-9, and the beta-lactamase produced by Staphylococcus aureus (NCTC 11561).

The in-vitro activity of sparfloxacin (AT-4140), a new difluorinated quinolone, was compared with those of ciprofloxacin, temafloxacin and selected members of other groups of antimicrobial agents, against 651 recent distinct clinical isolates and strains with known mechanisms of resistance. Three strains of Chlamydia trachomatis were also studied. The MICs for 90% of the Enterobacteriaceae were between 0.06 and 1 mg/l; for Pseudomonas aeruginosa the MIC90 was 2 mg/l. Sparfloxacin was 16-fold more active against Acinetobacter spp. than ciprofloxacin. For Staphylococcus spp., Streptococcus, spp. and Enterococcus faecalis the MIC90 was between 0.25 and 1 mg/l; sparfloxacin was four-fold more active against Str. pneumoniae than ciprofloxacin. Ninety percent of strains of Haemophilus influenzae, Branhamella catarrhalis and Neisseria spp. were inhibited by less than 0.03 mg/l; for Bacteroides fragilis the MIC90 was 1 mg/l. The three strains of Chl. trachomatis were susceptible to 0.06-0.12 mg/l sparfloxacin, which was 16-fold more active than ciprofloxacin. There was cross resistance among the quinolones, but not between the quinolones and other groups of antimicrobials. The protein binding of sparfloxacin was 40% and serum had little effect on its activity.

Prostaglandin H synthase (PHS) and horseradish peroxidase catalyze the oxidation of benzidine to the same free radical species. No radical was observed if either benzidine, H2O2 or enzyme was omitted. The similarity of the fine structure of this radical to a computer-simulated model suggests the presence of a free cation radical of benzidine. Neither superoxide nor hydroxyl radicals appear to be involved in the co-oxidation of benzidine or 2-amino-4-(5-nitro-2-furyl)-thiazole (ANFT) by PHS. Production of the benzidine radical by PHS was inhibited by ANFT, acetaminophen, cyanide and ascorbate. ANFT was metabolized by PHS but not by horseradish peroxidase. ANFT had no effect on either radical production or 14C-metabolism of benzidine by horseradish peroxidase. These results indicate that different peroxidases may exhibit specificity with respect to the carcinogens they activate. The free radical cation of benzidine may be the electrophilic intermediate responsible for PHS-catalyzed binding of benzidine to protein and nucleic acids.

Prostaglandin H synthase oxidized the carcinogens benzidine and o-dianisidine to their respective quinonediimines. Analysis of the reaction media by u.v./visible spectroscopy and liquid chromatography with electrochemical and radiochemical detection revealed that these quinonediimines can be both conjugated and reduced by glutathione, cysteine and N-acetylcysteine. Analysis of the purified conjugate formed between synthetic benzidinediimine and glutathione by proton magnetic resonance spectroscopy demonstrated the product to be 3-(glutathion-S-yl)-benzidine. This metabolite was also formed during peroxidation of benzidine by prostaglandin H synthase in the presence of excess glutathione. These conjugates may be useful markers of peroxidatic activation of aromatic amines in vivo.