In vitro and in vivo antibacterial activities of GV129606, a new broad-spectrum trinem.

GV129606 is a new parenteral trinem antibiotic belonging to the beta-lactam class. It combines broad-spectrum activity (against gram-negative and -positive bacteria, aerobes and anaerobes), with high potency and resistance to beta-lactamases. Comparative in vitro and in vivo antibacterial activities were determined for GV129606 against more than 400 recent clinical isolates (aerobes, including beta-lactamase producers, and anaerobes), using representative antibacterial agents (meropenem, piperacillin, ceftazidime, cefpirome, ciprofloxacin, and gentamicin for aerobes and metronidazole, cefoxitin, piperacillin, and clindamycin for anaerobes). Against methicillin-susceptible staphylococci and streptococci, GV129606 and meropenem were the most active of the drugs tested. GV129606 showed an MIC for 90% of strains tested (MIC90) ranging from < or =0.015 to 0.06 microg/ml against methicillin-susceptible staphylococci and Streptococcus sanguis, Streptococcus pyogenes, and Streptococcus agalactiae. Against penicillin-susceptible and -resistant Streptococcus pneumoniae isolates, GV129606, meropenem, and cefpirome showed MIC90s of < or =0.015 and 1 microg/ml, respectively. Meropenem was the most active compound against members of the family Enterobacteriaceae with MIC90s of < or =0.5 microg/ml. Against these species, GV129606 possessed activity superior to those of piperacillin, ceftazidime, cefpirome, and gentamicin, with MIC90s of < or =8 microg/ml, but its activity was two- to sixfold less than that of ciprofloxacin (with the exception of Proteus rettgeri and Providencia stuartii). Haemophilus spp., Moraxella catarrhalis, Neisseria gonorrhoeae, and Pseudomonas aeruginosa were also included in the spectrum of GV129606. GV129606 showed good antianaerobe activity, similar to metronidazole. It was stable against all clinically relevant beta-lactamases (similar to meropenem). The in vitro activity was confirmed in vivo against septicemia infections induced in mice by selected gram-positive and -negative bacteria with 50% effective doses (ED50s) of < or =0.05 and < or =0.5 mg/kg of body weight/dose, respectively. GV129606 was as effective as meropenem against septicemia in mice caused by ceftazidime-resistant Pseudomonas aeruginosa, exhibiting an ED50 of 0.33 mg/kg/dose.

In vitro activity of the tribactam GV104326 against gram-positive, gram-negative, and anaerobic bacteria.

GV104326 is the first member of a new class of antibiotics (tribactams) selected for development. It combines a particularly broad spectrum (including gram-negative and gram-positive aerobes and anaerobes) with high potency, resistance to beta-lactamases, and complete stability to dehydropeptidases. Comparative MICs were determined for GV104326 against 415 recent clinical isolates (including beta-lactamase producers), using representative antibacterial agents (imipenem, amoxicillin-clavulanic acid, cefpirome, ciprofloxacin, gentamicin, and erythromycin). GV104326 was particularly active against gram-positive bacteria; in general, its in vitro activity was equivalent to that of imipenem, equivalent to or better than that of amoxicillin-clavulanic acid, and superior to that of cefpirome, ciprofloxacin, and erythromycin. Against gram-negative bacteria, GV104326 possessed activity similar to that of imipenem and cefpirome against enterobacteria and Haemophilus spp. but its activity was superior to that of amoxicillin-clavulanic acid. GV104326 showed excellent antianaerobe activity. GV104326 was stable to all clinically relevant beta-lactamases and was rapidly lethal to susceptible bacteria. In Escherichia coli, GV104326 bound predominantly to PBPs 1a and 2 and at low concentrations osmotically stable round forms were observed. GV104326 showed an affinity for PBPs 2 and 4 of Staphylococcus aureus.

Synthesis of prostaglandin E2 in rat liver.

We have investigated whether rat liver microsomes can release prostaglandins and determined the 'optimal conditions' for the in vitro synthesis of PGE2. We also studied the effect of the oral administration of indomethacin, piroxicam and ibuprofen on PGE2 release ex vivo. The drugs were administered to animals at high doses for one or three consecutive days and the animals were killed 24 h after the first or the third administration. The increased PGE2 synthesis observed for indomethacin and piroxicam (animals treated for three consecutive days) could be explained by the depression of cytochrome P-450 observed in the same animals. Cytochrome P-450 could modulate the activity of eicosanoids derived from cyclooxygenase. Moreover the different inhibition of PG synthesis exhibited by these drugs could lead to a different rise in concentration of arachidonic acid in microsome membranes and contribute to an increased PGE2 synthesis.

Anti-ulcer activity of carbenoxolone and ISF 3401 on PGE2 release in rat gastric mucosa.

We have investigated the ability of carbenoxolone and ISF 3041, a new carbenoxolone derivative, to protect the rat gastric and intestinal mucosa against lesions induced by acetylsalicyclic acid (ASA) and indomethacin. Moreover, we determined the capacity of the rat gastric mucosa to release PGE2 both in vitro and ex vivo, in the presence or absence of carbenoxolone or its analogs. These compounds are effective against lesions induced by ASA and intestinal damage induced by indomethacin. The amount of PGE2 obtained from incubated rat gastric mucosal pieces by in vitro and ex vivo indicate that carbenoxolone and ISF 3401 cause a concentration related increase of PGE2 with exception of the highest concentration. Increased prostaglandin content of gastric mucosa can partly explain the gastric and intestinal protection of these compounds and additional mechanisms could be involved in this action.