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.
The antibacterial activity and pharmacokinetics of the P-lactamase-stable cephalosporin cefuroxime and the gram-negative 3-lactamase-susceptible cephalosporin cefazolin were compared in two contrasting infection models in which Proteus morganii 82, which produces chromosomally mediated 3-lactamase, was the pathogen. In the rat paw model, characterized by high numbers of localized bacteria, cefazolin was destroyed at the site of infection and consequently did not produce a therapeutic response. In the mouse intraperitoneal model cefazolin was also inactive, despite peritoneal concentrations being unaffected by high counts of the 3-lactamase-producing P. morganii in the body cavity. In contrast the pharmacokinetics of cefuroxime was unaffected by the presence of the Ilactamase-producing P. morganii, and good therapeutic responses were seen in both models.During the past few years numerous cephalosporins have been introduced which have a broader antibacterial spectrum than earlier cephalosporins and greater stability in the presence of bacterial P-lactamases. The latter characteristic is important because of the increasing incidence of 3-lactamase-producing clinical isolates. It is therefore useful to have suitable experimental models for the correct evaluation of this characteristic. In vitro techniques, e.g., stability of a new P-lactam antibiotic in the presence of partially purified bacterial ,B-lactamases or the effects of bacterial inoculum size on the minimal inhibitory concentration, give some indication of the P-lactamase stability of a new antibiotic. However, in vitro conditions which are optimal for antibiotic-bacteria interactions do not necessarily extrapolate to patients where factors such as the number of bacterial cells at a site of infection and the tissue distribution of the antibiotic have an important bearing on the outcome of therapy.In this study we have evaluated, in two experimental animal models, the influence of Plactamase on the tissue distribution and the rate of bacterial killing by the P-lactamase-stable cephalosporin cefuroxime (3) and the gram-negative, 3-lactamase-sensitive cephalosporin cefazolin. MATERIALS AND METHODSAntibiotics. Cefuroxime sodium salt was prepared by Glaxo; cefazolin (Totacef; Bristol Laboratories) was purchased.Bacterial strain. The strain of Proteus morganii 82 used in the experiments was characterized by high minimal inhibitory concentrations of both cefuroxime (62 pg/ml) and cefazolin (>125 .g/ml). P. morganii 82 produced a chromosomally mediated P-lactamase with an isoelectric point of 7.6 as determined by isoelectric focusing on polyacrylamide gel (2). This enzyme, in the experimental conditions of the iodometric method used, hydrolyzed cefazolin (216 pmol/h), but no hydrolysis of cefuroxime was detectable (4). Paw infection model. Twenty-four Charles River CD (Cobs) male rats weighing 200 g were used. Three groups of four animals were infected by inoculating into the plantar dermis of the right hind paw 0.1 ml of a 10-fold-concentrated overnight culture o...
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