The optimal aminoglycoside and its dosage for the treatment of severe Enterococcus faecalis infection. An experimental study in the rabbit endocarditis model.

Aminoglycosides are recommended for the treatment of Enterococcus faecalis infections, especially in severe and bacteremic infection. However, the optimal aminoglycoside or the optimal dosage remains uncertain. This study aimed to compare the activity of four aminoglycosides against E. faecalis (gentamicin, netilmicin, tobramycin, and amikacin) and two dosages of gentamicin. One clinical strain of E. faecalis was used to induce aortic endocarditis in the study rabbits. Each aminoglycoside was infused daily over 3 days with a computer-regulated flow simulating human pharmacokinetics of 15 mg/kg/day for amikacin, 6 mg/kg/day for netilmicin, and 3 mg/kg/day for gentamicin and tobramycin. Additionally, two dosages of gentamicin (simulating 3 or 6 mg/kg/day) were compared over 1 or 3 days of treatment. The in vivo efficacy was assessed according to the bacterial count in vegetations, in comparison with a control group. Of the four aminoglycosides tested, only gentamicin and netilmicin showed significant antibacterial efficacy after 3 days of treatment. After only 1 day of treatment, the high dosage of gentamicin (6 mg/kg/day) was more effective than the standard dosage (3 mg/kg/day). Among the tested aminoglycosides, gentamicin showed the best efficacy, with the best results after 24 h of treatment for the highest dosage.

Is there a rationale for the continuous infusion of cefepime? A multidisciplinary approach.

This review is the fruit of multidisciplinary discussions concerning the continuous administration of beta-lactams, with a special focus on cefepime. Pooling of the analyses and viewpoints of all members of the group, based on a review of the literature on this subject, has made it possible to test the hypothesis concerning the applicability of this method of administering cefepime. Cefepime is a cephalosporin for injection which exhibits a broader spectrum of activity than that of older, third-generation cephalosporins for injection (cefotaxime, ceftriaxone, ceftazidime). The specific activity of cefepime is based on its more rapid penetration (probably due to its zwitterionic structure, this molecule being both positively and negatively charged) through the outer membrane of Gram-negative bacteria, its greater affinity for penicillin-binding proteins, its weak affinity for beta-lactamases, and its stability versus certain beta-lactamases, particularly derepressed cephalosporinases. The stability of cefepime in various solutions intended for parenteral administration has been studied, and the results obtained demonstrated the good compatibility of cefepime with these different solutions. These results thus permit the administration of cefepime in a continuous infusion over a 24-h period, using two consecutive syringes.

Different aminoglycoside-resistant phenotypes in a rabbit Staphylococcus aureus endocarditis infection model.

The impact of different types of enzymatic resistance on the in vivo antibacterial activity of aminoglycosides (amikacin, gentamicin, and netilmicin) was studied in the rabbit endocarditis model with four strains of Staphylococcus aureus. Animals were treated in a manner simulating the administration of a single daily human dose. Amikacin had no effect on the three kanamycin-resistant strains despite apparent susceptibility in the disk diffusion test. Gentamicin appears to be the preferable aminoglycoside for treatment of staphylococcal infections.

In vivo efficacy of continuous infusion versus intermittent dosing of ceftazidime alone or in combination with amikacin relative to human kinetic profiles in a Pseudomonas aeruginosa rabbit endocarditis model.

Ceftazidime and amikacin were administered in a Pseudomonas aeruginosa rabbit endocarditis model using computer-controlled intravenous (iv) infusion pumps to simulate human serum concentrations for the following regimens: continuous (constant rate) infusion of 4, 6 or 8 g of ceftazidime over 24 h or intermittent dosing of 2 g every 8 h either alone or in combination with amikacin (15 mg/kg once daily). The in vivo activities of these regimens were tested on four Pseudomonas aeruginosa strains. Animals were killed 24 h after the beginning of treatment. Efficacy was assessed by comparing the effects of the different groups on bacterial counts in vegetations for each strain tested. For a susceptible reference strain (ATCC 27853; MICs of ceftazidime and amikacin 1 and 2 mg/L, respectively), continuous infusion of 4 g alone or with amikacin was as effective as intermittent dosing with amikacin. For a clinical isolate producing an oxacillinase (MICs of ceftazidime and amikacin 8 and 32 mg/L, respectively), continuous infusion of 6 g was equivalent to intermittent dosing. For a clinical isolate producing a TEM-2 penicillinase (MIC of ceftazidime and amikacin 4 mg/L), continuous infusion of 6 g, but not intermittent dosing, had a significant in vivo effect. For a clinical isolate producing an inducible, chromosomally encoded cephalosporinase (MIC of ceftazidime and amikacin 8 and 4 mg/L, respectively), neither continuous infusion nor intermittent dosing proved effective. Determination of ceftazidime concentrations in vegetations showed that continuous infusion produced tissue concentrations at the infection site far greater than the MIC throughout the treatment. It is concluded that continuous infusion of the same total daily dose provides significant activity as compared with fractionated infusion. This study confirms that a concentration of 4-5 x MIC is a reasonable therapeutic target in most clinical settings of severe P. aeruginosa infection.

[Critical serum concentration of antibiotics. A therapeutic tool and means of comparative evaluation]. / La concentration sérique critique des antibiotiques. Outil thérapeutique et moyen d'évaluation comparative.

It is difficult to predict the clinical activity of antibiotics solely on the basis of in vitro data. Experimental models measuring the relationship between serum concentration and in vivo activity are essential for comparing the activity of different compounds currently available. The critical serum concentration can be used to compare the intrinsic activity of antibiotics on a given bacterial strain. When compared with the minimal inhibiting concentration measured in vitro, "activity loss" can be determined for each antibiotic placed in contact with bacteria in an infected tissue. The relevance of this therapeutic tool in comparison with other methods is discussed.

Comparative efficacies of ciprofloxacin and pefloxacin alone or in combination with fosfomycin in experimental endocarditis induced by multidrug-susceptible and -resistant Pseudomonas aeruginosa.

The in vivo efficacy of ciprofloxacin or pefloxacin alone or in combination with fosfomycin was evaluated in experimental aortic valve endocarditis induced in 133 rabbits by a multidrug-susceptible or multidrug-resistant strain of Pseudomonas aeruginosa. Therapy was initiated early (12 h after infection), when bacterial counts in aortic valve vegetations were relatively low, or late (48 h after infection), when vegetations contained a larger inoculum. Antibodies were administered as a continuous 24-h intravenous infusion. Mean steady-state levels of ciprofloxacin (64 mg/kg), pefloxacin (64 mg/kg), and fosfomycin (300 mg/kg) in serum were 2.5, 4.2, and 63.9 mg/liter, respectively. For the multidrug-susceptible strain, all regimens except pefloxacin alone significantly reduced the number of CFU per gram of vegetation versus controls, whether treatment was performed early or late. For the multidrug-resistant strain, none of the regimens showed differences from untreated controls, except ciprofloxacin-fosfomycin, which significantly reduced bacterial counts in vegetations compared with controls when therapy was begun early (4.1 +/- 1.1 log10 CFU/g of vegetation; P < 0.001 versus the control). These data suggest that combination of fosfomycin with ciprofloxacin or pefloxacin is more effective than ciprofloxacin or pefloxacin alone for the therapy of severe infections caused by multidrug-susceptible P. aeruginosa.

In vivo bactericidal activities of ciprofloxacin and pefloxacin in an experimental model of Serratia marcescens endocarditis.

The critical concentrations of pefloxacin and ciprofloxacin in serum, corresponding to the lowest concentration in serum able to achieve a 2-log-unit reduction in the CFU in vegetations after a 24-h exposure at a steady-state concentration obtained by a continuous intravenous infusion, were determined in an experimental model of Serratia marcescens endocarditis in rabbits. In vitro data showed that the MICs of ciprofloxacin and pefloxacin were 0.06 and 0.25 mg/liter, respectively. The killing curves indicated a maximum killing rate at a concentration four times that of the MICs. In vivo, the critical concentrations of pefloxacin and ciprofloxacin in serum were 0.4 and 0.24 mg/liter, respectively, corresponding to a concentration of four times the MICs.

Activity of sulbactam in combination with ceftriaxone in vitro and in experimental endocarditis caused by Escherichia coli producing SHV-2-like beta-lactamase.

We studied the efficacy of sulbactam, a beta-lactamase inhibitor, in combination with ceftriaxone in vitro and in experimental endocarditis due to an Escherichia coli strain producing an extended-spectrum beta-lactamase most similar to SHV-2, a new mechanism of resistance to broad-spectrum cephalosporins among members of the family Enterobacteriaceae. In vitro, ceftriaxone demonstrated an important inoculum effect (MICs were 2 and 256 micrograms/ml with 5 X 10(5) and 5 X 10(7) CFU of inoculum per ml, respectively). Sulbactam inhibited the beta-lactamase degradation of ceftriaxone and enhanced the killing by ceftriaxone with both inocula tested. In vivo, sulbactam (100 mg/kg every 8 h) or ceftriaxone (15 or 30 mg/kg every 24 h) alone were ineffective after a 4-day therapy. The addition of sulbactam to ceftriaxone (15 mg/kg) or to the ceftriaxone (15 mg/kg)-netilmicin (6 mg/kg every 24 h) combination produced a reduction of 2 log10 CFU/g of vegetation greater than that produced by therapy without sulbactam. The sulbactam-ceftriaxone (30 mg/kg) combination produced a reduction of almost 5 log10 CFU/g of vegetation greater than that produced by single-drug therapy (P less than 0.01), sterilized five of eight vegetations (versus none of seven for ceftriaxone [30 mg/kg] alone; P less than 0.05), and was as effective as the ceftriaxone (15 mg/kg)-sulbactam-netilmicin combination. We concluded that (i) SHV-2 production was responsible for ceftriaxone failure in vivo, probably because of the high inoculum present in vegetations; (ii) sulbactam used in a regimen which provided levels in serum constantly above 4 micrograms/ml and a vegetation/serum peak ratio of approximately 1:3 enhanced the activity of a broad-spectrum cephalosporin in a severe experimental infection; and (iii) the highest dose of ceftriaxone in combination with sulbactam was as effective as the lowest dose of ceftriaxone plus sulbactam plus an aminoglycoside.

[Efficacy of teicoplanin in 25 cases of severe infections caused by gram-positive cocci]. / Efficacité de la téicoplanine dans vingt-cinq infections sévères a cocci Gram positif.

Teicoplanin was evaluated in 25 severe infections caused by Gram-positive bacteria alone [13], in combination [9], alone then in combination [3], in an open study. Of 22 infections that could be evaluated, there were 18 cures and improvements (81.8%), 2 recurrence and 2 failures. Serum concentrations are unpredictable and steady after 5 days i.v. teicoplanin. Trough and peak concentrations are respectively less than 5 mg/l and less than 20 mg/l in 13 infections and higher in 9, unrelated with success or failure. A trough concentration greater than CMI and kind of infection seem deciding. The choice of the antibiotic combined with teicoplanin warrant more data.

[Experimental Enterobacter cloacae endocarditis treated with gentamicin. Predictive value of the in vitro bactericidal rate]. / Endocardite expérimentale à Enterobacter cloacae traitée par la gentamicine. Valeur prédictive de la vitesse de bactéricidie in vitro.

The predictive value of in vitro time-kill curve was tested on an Enterobacter cloacae endocarditis experimental model. The antibiotic studied was gentamicin. Despite a similar MIC, 2 Enterobacter cloacae strains exhibited very different time-kill curves in vitro. This difference was found being predictive of efficacy on the in vivo model, 24 hours after a single injection of gentamicin.