Single- and combination-antibiotic therapy for experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.

The efficacy of fosfomycin in combination with vancomycin or gentamicin was evaluated in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. After 5 days of therapy, both combinations proved to be highly effective since all rabbits had sterile vegetations.

Penetration of N-formimidoyl thienamycin into extravascular fluids in rabbits.

The penetration of N-formimidoyl thienamycin into extravascular fluids was studied in rabbits. Two different models were used: subcutaneously implanted tissue chambers and fibrin clots. The antibiotic was given intramuscularly as a single dose of 10 mg/kg. The degree of penetration into these compartments was determined by comparing the area under the curve for the specific fluid with the area under the curve for plasma expressed in percent. The percentage of penetration of N-formimidoyl thienamycin into tissue chamber fluid (76.24%) was similar to that into fibrin clots (75.15%).

Experimental endocarditis and fosfomycin.

The effectiveness of fosfomycin in combination with other antibiotics was studied in vitro and in the treatment of left-sided endocarditis in rabbits caused by S. sanguis, S. faecalis, S. aureus or P. aeruginosa. In vitro combinations of fosfomycin plus penicillin, fosfomycin plus cloxacillin, and fosfomycin plus amikacin were synergistic against the strains tested. In vivo synergism was also demonstrated since fosfomycin combinations produced a greater reduction in the number of CFU/g of vegetations than the administration of one antibiotic alone.

International collaborative study on standardization of bacterial sensitivity to fosfomycin.

An international collaborative study was undertaken involving 6 working groups to correlate the zone sizes obtained with 50 micrograms fosfomycin + 25 micrograms glucose-6-micrograms glucose-6-phosphate (G6P) and 50 micrograms fosfomycin + 50 micrograms G6P/disc with the MICs in the presence of 25 mg G6P/litre. The recommendations of the ICS for the MIC and disc diffusion methods were followed and Oxoid Mueller-Hinton agar was used. The regression lines obtained with the method of least squares show that the best correlation coefficient (r = 0.8227) corresponds to the disc with 50 micrograms fosfomycin + 50 micrograms G6P. Considering both the pharmacokinetics of fosfomycin after intravenous administration of 2 or 4 g and the distribution of sensitive bacterial populations, two breakpoints were established at MIC values of 16 and 64 mg/l corresponding to zone sizes and 18 and 22 mm, respectively.

Experimental endocarditis caused by Streptococcus sanguis: single and combined antibiotic therapy.

The effectiveness of penicillin G, fosfomycin, and cefoxitin alone and in combination was studied in vitro and in the treatment of left-sided Streptococcus sanguis endocarditis in rabbits. In vitro, the combinations penicillin G plus fosfomycin, penicillin G plus cefoxitin, and fosfomycin plus cefoxitin were synergistic or partially synergistic for S sanguis. Therapy with the combinations was more effective in eradicating the species from cardiac vegetations that was that with each antibiotic used alone.

Diffusion of beta-lactam antibiotics and fosfomycin to interstitial tissue fluid in rabbits.

The ability of seven antibiotics (carbenicillin, cloxacillin, ampicillin, cephalothin, cephaloridine, cefoxitin and fosfomycin) to enter interstitial tissue fluid was evaluated. Using rabbits with implanted subcutaneous chambers, antibiotics were given intramuscularly as a single dose of 15 mg/kg, and antibiotic levels in serum and interstitial fluid of the chambers were determined at variously scheduled times after injection. The results indicated that antibiotic concentrations in the two compartments did not run parallel. The pharmacokinetic analysis showed that, in general, antibiotic diffusion from blood to interstitial fluid increased with the concentration gradient and the serum half-life, and there was an inverse relationship to pKa, protein binding and molecular weight of the antibiotic.

Pharmacokinetic study of fosfomycin and its bioavailability.

The pharmacokinetics of fosfomycin in humans was studied in six young healthy volunteers after intravenous administration of 500 mg fosfomycin and after the same dose in oral administration in three different formulations. It was proven that fosfomycin follows a bicompartmental pattern, for which the disposition constants, the biological half-lives for the fast and slow phases, and the distribution constants were calculated. The renal excretion constant was evaluated making determinations of fosfomycin in the urine, and this constant together with the elimination constant allowed us to determine the extrarenal elimination. The concentration and quantity of the drug in the central and peripheral compartments were calculated and tabulated for different periods of time. An analogous behavior was obtained with the three formulations that were orally administered, with an average bioavailability of 37% in relation to the intravenous bioavailability, as evaluated by means of the accumulative renal excretion.

The passage of fosfomycin into the cerebrospinal fluid in children's meningitis.

This report deals with the results of a study that was made on the passage of fosfomycin into the CSF in 22 children with meningitis (11 parotideal meningitis and 11 meningococcal meningitis). The plasma and liquor levels of fosfomycin were determined in the acute phase of the illness and after the normalization of the CSF, with the object of studying the passage of the antibiotic through the blood-brain barrier in the presence and absence of meningeal inflammation. A greater permeability of the meninges was found to exist when they were in an inflammatory state and there seems to be a certain accumulative effect in the CSF when the fosfomycin is administered by intravenous perfusion. The concentrations that were obtained in the CSF were not high enough to justify the exclusive use of fosfomycin in the treatment of meningitis. Nevertheless, considering its wide antibacterial spectrum, its MIC against different microbial species and its lack of toxicity, we believe that fosfomycin can be of use when associated with other antibiotics in the treatment of meningitis caused by S. aureus, D. pneumoniae, H. influenzae, E. coli, P. mirabilis and S. marcescens.

Fosfomycin in patients subjected to periodic hemodialysis.

The sensitivity to fosfomycin which is found in organisms that are frequently found in urinary infections and the lack of toxicity of this antibiotic were the reasons for which we tested fosfomycin on patients who were subjected to periodic hemodialysis. We were interested in studying (1) if fosfomycin was dialyzable, and (2) its therapeutic pattern in these patients. We selected a group of 27 patients from our programme of periodic hemodialysis who spend 18 h each week in three sessions with an RSP Travenol artificial kidney, using Ultra Flo II as the dialytic unit. They were all free of infection and had not received any antibiotics for 40 days before the test was carried out. They were administered 1 or 2 g of fosfomycin by the intravenous route at the time of beginning the dialysis. Blood samples and samples from the dialytic bath were taken before administering the fosfomycin, and 1/2, 3 and 6 hours after administering it. Our results show that fosfomycin is 70-80% dialyzed by the membranes of the artificial kidney and that during the hemodialysis, given the clearance which the dialyzing membrane makes of the antibiotic, the usual doses of fosfomycin should not be altered. No side effects were observed in any of the patients.

Pharmacodynamic data on fosfomycin in underweight infants during the neonatal period.

A study was made of the blood levels, half-life and elimination of fosfomycin in two groups of underweight infants during the 1st to 3rd days of life and after 3-4 weeks. The test dose was 50 mg/kg i.v., administered in a single dose. The times at which the blood was controlled were 5 min, 1, 3, 6, 9 and 24 h; and 0-24 h for the urine. All samples were evaluated by the microbiological method of diffusion in plate. The results obtained indicate that the elimination of fosfomycin after 24 h is slower and occurs in smaller quantities in the group of infants 1-3 days old than in the group of 3- to 4-week-old infants, the half-life of the antibiotic being 7 and 4.9 h, respectively.

Bacteriological evaluation of fosfomycin in clinical studies.

Since fosfomycin has behaved in vitro as a broad-spectrum antibiotic, an attempt has been made to evaluate this behaviour in controlled clinical study carried out at different Spanish hospitals. A total of 959 patients were treated for some of the following infectious clinical processes: gonococcal urethritis, typhoid fever, enterocolitis, acute and chronic urinary tract infections, osteomyelitis, chronic otorrhoea, septicaemia, meningitis, peritonitis, surgical and suppurative infections, bronchitis, pneumonia, pharyngoamygdalitis, burns, endometritis, ocular infection, whooping cough and nasal carriers of S. aureus. The results obtained as a function of the microorganism isolated in these clinical processes in percentage of clinical and bacteriological success have been 96% of the S. aureus infections, 95% of the Streptococcus sp. including S. pneumoniae, 90% of the N. gonorrhoeae infections, 94% of the E. coli infections including enteropathogenic E. coli, 90% of the S. marcescens infections, 76% of the Proteus sp. infections, 72% of the Klebsiella-Enterobacter infections, 66% of P. aeruginosa infections and 78% of the S. typhi infections.

Acute infantile pneumonopathies treated with fosfomycin.

Reference is made to the results obtained in 24 children, from 11 months to 12 years, affected with acute pneumopathies and treated with fosfomycin with a dosage of 200 mg/kg/day. In all cases a clinical, radiological, biological and bacteriological study was carried out. At the same time, levels of fosfomycin in plasma and sputum were checked every 5 days during the course of treatment. In the 4 cases of pleurisy the level of antibiotic in the pleural liquid was also checked. The concentration of fosfomycin in the sputum gives very variable results with average values oscillating between 16.5 and 23.4% of the plasmatic level respectively at the beginning and end of treatment, a cumulative effect of the antibiotic being observed. Concentration in pleural liquid oscillates between 39 and 50%. The clinical, radiological and biological evolution has been favourable iin 21 cases, unfavourable in two cases and in one case treatment had to be suspended because of the apparition of a cutaneous necrosis. Apart from this case no notable toxic effects were observed. Children do not support intramuscular injections very well and intravenous injections often cause phlebitis.

Fosfomycin in Osteomyelitis.

Fosfomycin was exclusively used as antibiotic treatment in 37 patients suffering from osteomyelitis, out ot which 23 were operated for sequestrectomy or fistulectomy, whereas the remaining 14 did not undergo any surgery during fosfomycin treatment. Fosfomycin was adminsitered parenterally, alone or combined with oral administration, and in some cases only orally. The dosage varied from 4 to 8 g/day for an average period of 3 weeks. After one or two treatments the results were 29 definitive cures (78%), 2 failures and 6 relapses (22%).