Antimicrobial activity against Staphylococcus aureus of semisynthetic injectable streptogramins: RP 59500 and related compounds.

Pristinamycin displays unique antibacterial properties due to the synergy between its two components, pristinamycin I and pristinamycin II. Because this antibiotic is not water-soluble, its administration is restricted to the oral route, and its therapeutic potential is thereby limited. Novel water-soluble derivatives of the naturally-occurring antibiotic pristinamycin were obtained by modifications of its two major components. The modifications included regioselective and stereoselective substitution alpha to the carbonyl group in the 4-oxo-pipecolic acid residue of pristinamycin IA (PIA) and stereoselective conjugate addition to the double bond of the dehydroproline ring in pristinamycin IIA (PIIA). We report here the in-vitro and in-vivo activities of some representative water-soluble derivatives of pristinamycin IA and pristinamycin IIA against Staphylococcus aureus reference strains, sensitive or resistant to methicillin and/or macrolides.

[Relationship between virulence and resistance to antibiotics in pneumococci. Contribution of experimental data obtained in an animal model]. / Relation entre virulence et résistance aux antibiotiques des pneumocoques. Apport des donnée expérimentales sur un modèle animal.

Epidemiologic data show that the organ affinity of Streptococcus pneumoniae varies across serotypes. As a result of this heterogeneous distribution, exposure to antimicrobials is greater for serotypes 6, 14, 19 and 23. Most strains with resistance to antimicrobials are found among these four serotypes. Virulence of the various serotypes of pneumococci varies with adhesion, enzyme secretion, and resistance to phagocytosis. In a mouse model of experimental septicemia, neither the origin of strains nor the acquisition of a resistant phenotype modified virulence, which appeared as an intrinsic feature specific to each phenotype. Strains belonging to serotypes 6, 14, 19 and 23 with or without resistance to antimicrobials were only very rarely virulent in the experimental model used. As an indirect result, resistance to antimicrobials and virulence were inversely related among the strains of S. pneumoniae tested.

[In vitro comparative bactericidal effect of cefotaxime and cefixime in a kinetic model]. / Activité bactéricide comparée du céfotaxime et du céfixime dans un modèle cinétique in vitro.

The bactericidal activity of cefotaxime against Escherichia coli, Klebsiella pneumoniae and Serratia marcescens, was compared with that of cefixime in an in vitro model simulating the human pharmacokinetics of these antibiotics. Kinetic parameters in this model were T1/2 = 1.3 h and Cmax = 45 mg/l for cefotaxime; T1/2 = 3.5 h and Cmax = 5 or 3.5 mg/l for cefixime. These parameters mimicked those obtained after a 1 g intravenous infusion of cefotaxime and an oral uptake of 0.4 or 0.2 g of cefixime, respectively. Both antibiotics demonstrated a strong bactericidal activity. Against Escherichia coli, the bactericidal effect of cefotaxime was slightly more rapid and more prolonged than that of cefixime: -5 log10 CFU/ml over 4 h vs -3 log10 CFU/ml over 8 h respectively. Against Klebsiella pneumoniae and Serratia marcescens, both drugs exhibited similar bactericidal activity despite different dosages and routes of administration: -2 to -3 log10 CFU/ml over 4 h.

[Comparison of the in vitro post-antibiotic effect of C14 macrolides (erythromycin and roxithromycin) and C16 macrolides (josamycin and spiramycin) against Staphylococcus aureus]. / Comparaison de l'effet post-antibiotique in vitro de macrolides en C14 (érythromycine et roxithromycine) et en C16 (josamycine et spiramycine) vis-a-vis de Staphylococcus aureus.

In vitro post-antibiotic effect (PAE) induced by erythromycin, roxithromycin, josamycin and spiramycin has been compared on Staphylococcus aureus. Three MLSB sensitive and three MLSB inducible resistant S. aureus strains have been used. delta t was the time required for culture to increase by 1 log10 after drug removal in comparison with controls. For erythromycin and roxithromycin delta t ranged from 6 minutes at 1 x MIC to 48 minutes at 4 x MIC (average of the six strains at 4 x MIC: 33 minutes). For josamycin and spiramycin, delta t ranged from 36 at 1/2 x MIC to 138 minutes at 4 x MIC (average at 4 x MIC: 101 minutes). No difference was observed between MLSB sensitive and MLSB inducible resistant S. aureus strains. In our experimental conditions, PAEs observed with josamycin and spiramycin (16-membered-ring macrolides) were 2.5 to 3 times longer than those observed with erythromycin and roxithromycin (14-membered-ring macrolides). These results added to biological differences previously observed between 14-membered-ring and 16-membered-ring macrolides.

[Antipneumococcal activity of erythromycin and spiramycin in 2 experimental models in mice]. / Activité antipneumococcique de l'érythromycine et de la spiramycine dans deux modèles expérimentaux chez la souris.

Macrolides often remain the first intention treatment in many chest infections caused by S. pneumoniae. Antipneumococcal activities of spiramycin and erythromycin have then been tested in a septicaemia model and in a pulmonary infection model in mice. In the septicaemia model, spiramycin has been found 5 to 15 times more active than erythromycin by subcutaneous route and 1.5 to 6 times by oral route. In the pneumonia model, spiramycin has been found as active (one strain) to 5 times more active than erythromycin (three strains) by both subcutaneous and oral route. These data might indicate that better tissular penetration of spiramycin is responsible for better in vivo activity. These facts also support the statement that MIC should not be the only choice standard of infectious chemotherapy.

[Curative activity of spiramycin adipate by parenteral route in experimental septicemia in mice. Comparison with orally administered basic spiramycin]. / Activité curative de l'adipate de spiramycine utilisé par voie parentérale dans la septicémie expérimentale de la souris. Comparaison avec la spiramycine base administrée par voie orale.

Experimental septicemia was induced in mice by intraperitoneal injection of 10 to 100 lethal doses of Staphylococcus aureus and Streptococcus pneumoniae. Animals were treated by a mixture of adipic acid and spiramycin (subcutaneous route) or by spiramycin base (oral route), 1 and 6 hours after infection. To determine the effective dose 50% that achieves survival of half the mice after 7 days, each drug was used in 6 dosages (mg/kg) and each dosage was given to 12 mice. In 21 independent experiments, ED50S of spiramycin adipate by the subcutaneous route were found to be 5 to 50 times lower than those of spiramycin base per os. These results are consistent with the high serum peak concentrations of spiramycin adipate observed following subcutaneous administration.

Comparative efficacy of pefloxacin and six other antimicrobial agents on Staphylococcus aureus experimental abscesses.

Pefloxacin (Pef) is a new quinolone which has been shown to have good in-vitro activity against Staphylococcus aureus, and to reach high tissue concentrations. Its efficacy was compared to that of 2 quinolone derivatives, norfloxacin (Nor) and ciprofloxacin (Cip) and to that of methicillin (Meth), cephalothin (Cep), pristinamycin (Pri) and vancomycin (Van), in an experimental model of S. aureus abscesses. Mice challenged with an intramuscular thigh injection of a calibrated inoculum developed local abscesses. Three S. aureus strains (with different antibiotic resistance profiles (Pase-, Pase+, MethR)) were used. In this model, the antibiotics showing the best ED50 following oral administration, against all three strains were Pef greater than Cip greater than Pri greater than Nor, by subcutaneous administration for the Pase- strain Pef = Cip greater than Cep greater than Van; for the Pase+ strain Pef = Cip greater than Van greater than Meth and for the Pase+ MethR strain: Pef = Cip greater than Van greater than Cep. These data indicate that pefloxacin and ciprofloxacin are highly active in vivo against various strains of S. aureus, and appear to be more potent than norfloxacin, vancomycin, cephalothin and methicillin.

[A simple in vitro system for comparing the bactericidal activity of antibiotics at variable concentrations]. / Mise au point d'un système simple, in vitro, permettant de comparer l'activité bactéricide d'antibiotiques à concentrations variables.

An in vitro device is described that allows the study of bactericidal activity of decreasing antibiotic concentrations. This simple and easily set up device was found to be accurate and reliable. The bactericidal kinetics of three antibacterial compounds (cephalothin, norfloxacin and pristinamycin) on Staphylococcus aureus were compared in a system simulating serum concentration and half-life of each antibacterial compound. The results show the importance of pharmacokinetic parameters on antibacterial activity and their usefulness in new antibiotics evaluation.

Protective activity of habekacin and four other aminoglycosides in mouse septicaemia caused by Enterobacteriaceae.

The in vivo efficacy of habekacin, an aminoglycoside antibiotic obtained by chemical derivation from dibekacin, was compared to that of gentamicin (GEN), tobramycin (TOB), kanamycin (KAN) and amikacin (AMI) in a protection test in mice. The 50% effective dose (ED50) was determined in groups of animals challenged with bacterial suspensions injected intraperitoneally together with mucin, and treated subcutaneously 1 h and 6 h later. The bacterial strains used were: Escherichia coli (three GEN sensitive strains and one GEN-KAN-TOB resistant strain), Enterobacter cloacae (one GEN-KAN resistant strain), Serratia marcescens and Klebsiella pneumoniae (one GEN sensitive strain and one GEN resistant strain). In this model, habekacin was found to be as active as GEN against GEN sensitive strains and more active than AMI on GEN, GEN-KAN and GEN-KAN-TOB resistant strains.

[Structure-activity relationship of semi-synthetic derivatives of the PIA component of pristinamycin]. / Relations structure-activité de dérivés semi-synthétiques du constituant PIA de la pristinamycine.

Pristinamycin is a naturally occurring streptogramin made up of 2 groups of synergistic components (PI and PII). Because these components are not water soluble, use of pristinamycin has up till now been confined to the oral route. Water soluble semisynthetic derivatives of the PIA component, appropriate for parenteral use, have lately been developed. PIA is a peptidic macrolactone. As opening of the lactone results in total loss of biologic activity, semisynthesis must spare this function and preserve the macrocycle. Reactions at 5 gamma and 5 delta yielded 4 families of derivatives. Antimicrobial activity has been studied for more than 80 compounds. Several derivatives are promising as they are water soluble and have in vitro and in vivo (mice) activities similar to those of the original PIA component.

[Influence of ranitidine during a 24-hour period on the level of nitrites, nitrates, nitrosamines and bacterial flora in the gastric juice of healthy subjects]. / Influence de la ranitidine durant une période de 24 heures sur la teneur en nitrites, nitrates, nitrosamines et sur la flore bactérienne du suc gastrique du suject sain.

The aim of this study was to determine the influence of 24 h of ranitidine treatment on gastric bacterial flora and N-nitroso compound formation. Nitrate, nitrite levels, N-nitroso compound concentration were measured and bacterial flora was studied in the fasting and postprandial gastric juice of four healthy men under placebo and ranitidine treatment (150 mg. bid). The pH of seventy-five per cent of the gastric juice samples was over 4 when the patients received their ranitidine treatment. While the mean intragastric concentrations of nitrate, nitrite, N-nitroso compounds and counts of nitrate-reducing organisms were not significantly altered by ranitidine, there was a statistically significant rise in the number of total bacteria. During ranitidine treatment, the nitrite/nitrate ratio was positively correlated with intragastric pH and with the nitrate-reducing organism count of the placebo period. These results suggest that the reduction of nitrate to nitrite required the combination of two factors: a high count of nitrate-reducing organisms before treatment and a high intragastric pH.

[Comparative effects of 4 cephalosporins on the incorporation of tritiated diaminopimelic acid during bacterial growth]. / Effects comparés de quatre céphalosporines sur l'incorporation d'acide diaminopimélique tritié au cours de la croissance bactérienne.

When comparing antibiotic activities, it might be of interest to study parameters other than minimal inhibitory concentrations (MIC's). Specific activity of beta-lactams on bacterial cell wall makes it possible to determine radiolabelled diaminopimelic acid (DAP) incorporation in growing cultures. We have studied the effects of various concentrations of cefalotin , cefotaxime, latamoxef (moxalactam) and ceftiolene (42 980 RP) on DAP incorporation in 6 strains of E. coli, E. cloacae and S. aureus. Drug concentration which inhibits 90 % of radioactivity incorporation (CII 90) was found to vary from 0.1 X MIC to 3 X MIC. This fact suggests that beta-lactam action on cell wall synthesis and/or structure and MIC's are not always strictly correlated.