fosfomycin and Salmonella-Infections--Animal

Therapeutic effects of fosfomycin (FOF) and imipenem (IPM) were investigated in a novel model for endotoxin shock that was caused by intraperitoneal (i.p.) infection with 10(8) colony forming units of attenuated Salmonella typhimurium. Acute lethal shock was observed in BALB/c and ddY but not in lipopolysaccharide (LPS)-nonresponder BALB/lps(d) mice. Effects of FOF, but not its enantiomer, and IPM were dose- and time-dependent, since therapeutic efficacy was demonstrated in mice injected i.p. or orally at doses of more than 20 mg/kg 15 min before or 1 h after infection. Treatment with FOF 1 h postinfection (p.i.) resulted in significant decreases in bacterial numbers in spleen and liver, suggesting that the antimicrobial activity of FOF seems to closely correlate to suppression of infection-induced lethal shock. Regarding coagulation systems, FOF inhibited increase in the prothrombin time but upregulated fibrinogen concentration. Plasma levels of LPS released from bacilli were significantly higher in FOF- than IPM-treated mice and infection controls, but both antibiotics showed similar efficacy in protection.

Topics: Animals; Dose-Response Relationship, Drug; Female; Fosfomycin; Mice; Mice, Inbred BALB C; Salmonella Infections, Animal; Salmonella typhimurium; Shock, Septic; Time Factors

One hundred and twenty 1-day-old broiler chickens were divided into four groups: group I unmedicated and orally challenged with 1.5 x 10(8) cfu of Salmonella enteritidis phage type 4; group F infected and treated with 300 ppm of fosfomycin in their drinking water; group CF uninfected and treated, and group C maintained as a control group. Their performance, clinical signs, S. enteritidis PT4 reisolation and biochemistry variables were compared. Group F showed fewer symptoms and gross lesions than those from group 1. Fosfomycin treatment at 300 ppm improved body weight at 7 days of age by 42.3%. S. enteritidis PT4 reisolation in group I was higher than in the treated group, but total decontamination of challenged birds was not achieved. There was an increase in the levels of total protein and globulins in group I but not in the treated group. Fosfomycin caused no adverse effects on chickens from group CF, assessed by performance and biochemical variables. The results indicate that fosfomycin could be used in the treatment of S. enteritidis PT4 experimental infection.

Topics: Animals; Anti-Bacterial Agents; Bacteriophage Typing; Body Weight; Cecum; Chickens; Colony Count, Microbial; Fosfomycin; Liver; Poultry Diseases; Salmonella enteritidis; Salmonella Infections, Animal; Salmonella Phages; Spleen; Time Factors

Six clinical isolates and 1 reference strain of Salmonella typhimurium were sensitive to conventional antibiotics (ampicillin, chloramphenicol, cotrimoxazole), cefotaxime (CTX), and fosfomycin ( FOSFO ). All 7 strains carried a 55 megadalton plasmid ( Birnboim - Doly agarose gel electrophoresis technique) and were of comparable virulence for outbred NMRI mice (LD50 values = range of 1.7 X 10(5)-1.0 X 10(6) CFU; intraperitoneal route). CTX (5 mg/25 g mouse/day, divided into 2 doses; duration = 7 days) proved efficacious against 3 selected strains (No. H 8800, 14, and 20) of S. typhimurium (p less than 0.01). FOSFO (same therapeutic regimen) failed in this regard; following transitory improvement of diseased animals (days 2-4), the mortality of treated animals eventually approached that of untreated control animals. Administration of 15 mg FOSFO /mouse/day likewise failed to enhance murine survival. Reisolated S. typhimurium bacteria of these 3 assay strains still were susceptible to FOSFO . In vitro, CTX likewise surpassed FOSFO in bactericidal activity against the same 3 S. typhimurium strains on a weight-for-weight basis in various biological fluids (human midstream urine; human defibrinated blood; murine thioglycolate-induced macrophage-rich peritoneal exudate).

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Drug Resistance, Microbial; Female; Fosfomycin; Male; Mice; Microbial Sensitivity Tests; Salmonella Infections, Animal; Salmonella typhimurium

The increase of antimicrobial activity of Fosfomycin by glucose-6-phosphate (G-6-P) has often been demonstrated by in vitro studies. However, this effect was never sufficiently established in vivo. Our study was carried out in order to investigate the effects of the addition of G-6-P to Fosfomycin in white mice (strain G.P. of N.I.H.), which were intraperitoneally infected with a strain of S. typhimurium (10(3) c.f.u/0.5 ml i.p.). One and six hours after the infection, 0.1 ml consisting of increasing doses of G-6-P (0, 5, 25, 50, 250 and 500 micrograms/g) and decreasing doses of Fosfomycin (15.6, 7.8, 3.9, 1.95, 0.98 and 0.49 micrograms/g) were applied i.m., using 10 animals for each combination. Tables 1 and 2 show the results of this therapy with regard to the reduction of the ED50 of Fosfomycin. It can be seen that the addition of 25 micrograms G-6-P/g body-weight significantly reduces the ED50 within the first days (Tab. 1), while doses of 50 and more micrograms G-6-P/g significantly reduce the ED50 during the whole investigation period (Tab. 2). These results justify the proposal to use a combination of Fosfomycin and G-6-P in clinical studies for the treatment of human infections.

Topics: Animals; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Glucosephosphates; Mice; Salmonella Infections, Animal; Salmonella typhimurium

We have examined the antibacterial activity of the new antibiotic, fosfomycin (FOM) in vitro and in vivo. The following results were obtained. 1. FOM showed a broad antibacterial spectrum. 2. The antibacterial activity of FOM was enhanced in the medium at pH 6 and pH 7, and was also influenced by the addition of rabbit serum, calf serum, glucose-6-phosphate or defibrilated sheep blood to the growth medium, and by the size of inoculum. 3 FOM showed especially strong bactericidal action upon the bacteria at the logarithmic phase. 4. FOM showed remarkable therapeutic effect against most strains of gram-positive and gram-negative bacteria tested in experimental infections of mice. 5. The therapeutic effect of FOM was especially remarkable for infection with Salmonella. 6. The therapeutic effect of FOM was more potent than the other drugs tested against infection of Pseudomonas aeruginosa. 7. It seems that FOM is more active in vivo than in vitro with respect to antibacterial activity.

Topics: Animals; Anti-Bacterial Agents; Drug Evaluation, Preclinical; Escherichia coli; Escherichia coli Infections; Fosfomycin; Haemophilus influenzae; Klebsiella Infections; Male; Mice; Microbial Sensitivity Tests; Proteus; Proteus Infections; Pseudomonas aeruginosa; Pseudomonas Infections; Salmonella; Salmonella Infections, Animal; Serratia marcescens; Staphylococcal Infections; Staphylococcus