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.

Importance of inoculum growth phase when using an in vitro pharmacokinetic model to evaluate beta-lactam antibiotics.

The bactericidal activity of cefuroxime, cephaloridine and cephalexin is evaluated in an in vitro model. The inocula are derived from an overnight static culture, or after a pre-incubation period of 1 or 2 hours to allow cell re-growth. The early bactericidal effect of the antibiotics is more evident using pre-incubated cells, especially for Staphylococcus aureus 663. At hour 8, with Escherichia coli 851/E, there is re-growth using the static inoculum, while the antibiotic effect is still evident using the pre-incubated one. The importance arises therefore for considering the phase of growth of the inoculum as a critical parameter when using in vitro models with varying concentrations of beta-lactam antibiotics.

Ofloxacin: bactericidal effect in an in vitro pharmacokinetic model.

Ofloxacin has been evaluated in an in vitro model where microorganisms were exposed to the varying concentrations met in human serum after the oral administration of a 200 mg dose. The recently isolated strains were selected with minimum inhibitory concentrations (MICs) representative of the MICs 90% of ofloxacin against the species considered. Results showed that ofloxacin sterilized the bacterial cultures of S. aureus, P. morganii and E. coli, with 99.99% of killing still evident for P. aeruginosa after 12 hours of exposure. All the reference compounds (amoxicillin 1 g b.i.d., cefaclor 500 mg t.i.d., rifampicin 450 mg b.i.d.) showed, in the same test, worse results than ofloxacin.

Study on the antibacterial activity of ceftazidime in an in vitro pharmacokinetic model.

A kinetic model was used to evaluate the activity of ceftazidime against recently isolated bacterial strains. The microorganisms were subjected in vitro to drug concentrations simulating the serum kinetics of ceftazidime after i.v. administration of 1 g of the drug. In these conditions ceftazidime showed a bactericidal effect lasting up to 12 h, even at concentrations below the MICs for some strains. In no case did resistant populations develop after exposure to the drug.

In vitro evaluation of ceftazidime (GR 20263), amikacin and sisomicin, in a model simulating serum pharmacokinetics of therapeutic doses.

The activity of ceftazidime, amikacin and sisomicin was investigated in an in vitro model using varying concentrations of antibiotic which mimic the serum levels of patients after the intramuscular administration of a 500, 250 and 70 mg dose respectively. Using this test, during the time of the agar MIC value correlation, ceftazidime, amikacin and sisomicin proved to be active against strains sensitive to 16 micrograms/ml, 8 micrograms/ml and 4 micrograms/ml respectively. Using the above concentrations as the cut-off points in defining the sensitivity of the strains, ceftazidime revealed the same level of activity as amikacin (6 and 5 resistant strains respectively out of the 185 tested) and proved much more active than sisomicin (48 resistant strains).

Experimental infections for the evaluation of beta-lactamase resistance.

The antibacterial activity and pharmacokinetics of the beta-lactamase-stable cephalosporin cefuroxime and the gram-negative beta-lactamase-susceptible cephalosporin cefazolin were compared in two contrasting infection models in which Proteus morganii 82, which produces chromosomally mediated beta-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 beta-lactamase-producing P. morganii in the body cavity. In contrast the pharmacokinetics of cefuroxime was unaffected by the presence of the beta-lactamase-producing P. morganii, and good therapeutic responses were seen in both models.