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PubMed1977

Evolution of sensitivity to fosfomycin in bacteria isolated in 1973, 1974 and 1975 in the Servicio de Microbiologia y Epidemiologia of the 'Clinica Puerta de Hierro', Madrid.

The bacteriostatic activity of fosfomycin was studied in vitro against 1,243 clinical isolations of gram-positive cocci and 4,086 isolations of gram-negative bacilli that were obtained in 1973, 1974 and in the period from January to May of 1975. MIC was determined by the agar diffusion method, quantifying it by means of the standard curve that was worked out with the strain of E. coli NCTC 10,418. A slight increase in resistance was observed in the gram-positive cocci: 64 mug/ml were inhibitory for 63% of the 249 isolations obtained in 1973, 59.1% of the 716 isolations obtained in 1974, and 57.5% of the 278 isolations from 1975. A slight loss of sensitivity was also observed in the gram-negative bacilli: the aforementioned concentration of fosfomycin inhibited 36% of the 742 isolations from 1973, 33.6% of the 2,387 isolations from 1974 and 32.6% of the 957 isolations from 1975. 933 g of this antibiotic were consumed in our hospital in 1973, 4,203 g in 1974 and 957 g in 1975. The consumption rate per patient per year was 0.15, 0.72 and 0.20 g, respectively. In conclusion, although no change was observed in the sensitivity of some bacterial strains to fosfomycin, the overall study indicates a slight decrease in the sensitivity, although it does not apparently have any relationship to the consumption of fosfomycin in our hospital.

Anti-Bacterial Agents↗

PubMed1977

Genetic localization of the resistance to fosfomycin.

The possible existence of a transferable resistance to fosfomycin was studied in 50 strains of enterobacteria that were isolated in our hospital and which showed a resistance to fosfomycin of more than 256 mug/ml. E. coli K12 E711 was used as a receptor strain in the conjugation -- the times of conjugation were 20 min and 18 h. We found a transferable resistance in 28% of the strains. In all but one of the cases, only the resistance to fosfomycin was transferred. The recombinant which received the resistance to fosfomycin together with three other resistances was used as the donor for the transduction with the phage P1Kc to the receptor strain which was E. coli UTH 1038. A study was carried out on the influence of the radiation of the transducing phages with ultraviolet light on the frequency of transduction. The findings demonstrated a linear decrease in the frequency in proportion to the increase in the time of radiation.

Ampicillin↗

PubMed1977

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.

Administration, Oral↗

PubMed1977

Fosfomycin in puerperal infections and its elimination in lochia.

31 patients suffering from puerperal endometritis, 16 of whom with other concomitant infections (sepsis, infection of episiotomy, pyelonephritis) were treated with fosfomycin. 86% of the germs isolated were sensitive to fosfomycin. The results obtained have been excellent in 26 patients (84%) and null in 5 (16%). Fosfomycin showed to be an antibiotic of wide-spectrum, and it acted very rapidly, since apirexia of the patients was achieved after 2-3 days of treatment. The antibiotic had perfect tolerance. No disagreeable secondary effects nor changes in the haematological data were observed. We have also carried out a study on the elimination in lochia of fosfomycin in a group of 21 patients with normal birth and puerperium. The concentrations of the antibiotic in lochia, although variable, are sufficient to achieve the desired bactericide action.

Anti-Bacterial Agents↗

PubMed1977

Surgical suppurating infections and surgical abdominal infections treated with fosfomycin.

Two groups of patients suffering surgical infections were treated with fosfomycin. The first includes 21 suppurating dermic of soft underlying tissue lesions. The second group includes 29 surgical abdominal infections. The bacteriology of the first group was made up of gram-positive and gram-negative germs predominantly S. aureus and E. coli, all the isolated species appeared to be sensitive to fosfomycin. In the second group a gram-negative bacterial flora predominantly E. coli was obtained; with a sensitivity to this antibiotic of 90.5%. Surgical treatment accompanied the treatment with fosfomycin. In the first group, all the patients were cured with the oral administration of 2-6 g/day and in an average time less than that of the similar control group which did not receive the antibiotic. In the second group surgical treatment was necessary in 25 of the 29 patients and in all of them parenteral treatment was done with fosfomycin, preferably intramuscularly and in general the dosage was 4 g daily. All patients were cured except for one who was not operated on and who suffered from a fever of undetermined origin.

Abdomen↗

PubMed1982

The role of culture media on the fosfomycin sensitivity of six Serratia strains and their resistant mutants.

The influence of glucose-6-phosphate (G6P) on the fosfomycin minimum inhibitory concentration (MIC) of six Serratia marcescens strains was determined using two standard media (Müller-Hinton and nutrient agar) and three synthetic media. G6P did not affect fosfomycin MIC when S. marcescens was grown on standard media, but on synthetic media the presence of 5-100 mg/l G6P lowered the MIC by 1-7 log2. Five fosfomycin-resistant mutants were grown on synthetic media. In the presence of G6P, four of five mutant strains became more sensitive (MICs were 128 mg/l or less). The fifth mutant strain remained resistant under all culture conditions. The implications of these results are discussed with regard to the mechanism of action of fosfomycin, and the practical determination of the MIC in the clinic.

Anti-Bacterial Agents↗

PubMedDate not supplied

Pharmacokinetic profile of fosfomycin trometamol.

The pharmacokinetics of fosfomycin trometamol has been assessed in 12 healthy volunteers given oral doses of 2, 3, and 4 g of fosfomycin and 3 g intravenously of fosfomycin as fosfomycin sodium, all in the fasting state. The assay was microbiological (Proteus mirabilis ATCC 21100). There was a gradual rise in both peak serum concentrations and total area under the curve by rising oral doses, from 16.0 mg/l and 106.7 mg x h/l, after 2 g to 30.9 mg/l and 189.7 mg x h/l after 4 g respectively. The serum half-life was 4 h after the oral doses and 2.1 h after the intravenous dose. After the oral doses, the amounts excreted in urine in the active form ranged from 36 to 40% compared to 93% after the intravenous dose. The bioavailability was slightly below 40%. Concentrations in urine covers the usual urinary tract pathogens after oral doses of 2, 3, and 4 g.

Administration, Oral↗

PubMed1985

Reduction of cisplatin ototoxicity by fosfomycin in animal model.

The protective effect of fosfomycin against cisplatin-induced ototoxicity was studied in rats. Sixty-four Fischer rats were injected intravenously with daily doses of 1, 2, 5, and 10 mg/kg of cisplatin with or without 300 mg/kg of fosfomycin for a varying period from 1 to 10 days. The total dose of 10 mg/kg of cisplatin was given equally in all animals. Inner ear damage appeared to be more reduced histopathologically in animals given both cisplatin and fosfomycin than in animals given cisplatin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of cisplatin and fosfomycin.

Animals↗

PubMed2005

Second-line treatment of limb-threatening diabetic foot infections with intravenous fosfomycin.

Diabetic foot infections (DFI) expanding to bones and joints are associated with a poor prognosis of limb salvage. The bactericidal epoxide fosfomycin accumulates in inflamed soft and bone tissue, and may represent a potential treatment option for targeting severe DFI. Fifty-two patients (35 men, 17 women, mean age 62.9 +/- SD 9.2 years) with limb-threatening DFI (that is, Wagner grade 3 and higher) were enrolled in a multi-center compassionate use program of fosfomycin. Twenty-two patients (42.4%) had unsuccessfully been pretreated with other antimicrobials. Besides standard treatment (topical wound care and surgical debridement), eligible subjects received a combination of 8 to 24 g fosfomycin daily, and a conventional antibiotic agent, usually a beta-lactam compound. Treatment duration averaged 14.4 +/- 8.3 days. Limb-sparing surgery was possible in 48 patients (92.3%, 95% confidence interval 81.5-97.9%). Only four participants faced mild drug-related side effects (nausea, rash). Logistic regression analysis showed a trend towards better results with prolonged treatment, whereas a dose increase above 12 g daily did not affect outcomes. In DFI being resistant to conventional antibiotic agents, intravenous fosfomycin offers an effective treatment choice that may increase the likelihood of limb preservation. The present data warrant a larger comparative trial to stabilize effect estimates.

Aged↗

PubMed1985

Chronic granulomatous disease: uptake and intracellular activity of fosfomycin in granulocytes.

In chronic granulomatous disease (CGD) polymorphonuclear leukocytes (PMN) are unable to kill phagocytized catalase-positive bacteria. Therefore, patients with CGD are prone to infections and dependent on antimicrobial agents able to penetrate PMN membranes and to act intracellularly. Owing to their good lipid solubility, trimethoprim/sulfamethoxazole and rifampicin passively diffuse the membrane. In contrast, fosfomycin is transported actively into the cell. In normal PMN, it reaches cellular-to-extracellular ratios of 1.83 after 15 min, in CGD-PMN 2.18 after 30 min. At concentrations between 16 and 200 mg/liter, fosfomycin was able to kill staphylococci surviving within CGD-PMN, thus compensating for the bactericidal deficiency in CGD. A combination of low concentrations of fosfomycin (8 mg/liter) plus rifampicin (0.06 mg/liter) was more effective at the intracellular level than either agent alone. Apart from a stimulation of PMN-chemiluminescence of yet unknown significance, the agent did not interfere with other neutrophil functions. Clinical investigations are indicated to study whether fosfomycin can be added to the small number of antibiotics useful in CGD.

Adolescent↗

PubMed1999

Effects of fosfomycin and imipenem-cilastatin on the nephrotoxicity of vancomycin and cisplatin in rats.

The nephrotoxicity of vancomycin and cisplatin and the protective effects of fosfomycin and imipenem-cilastatin on renal function have been studied in rats. The renal clearance of vancomycin after the induction of renal dysfunction was also evaluated by calculating the glomerular filtration rate (GFR) and its secretory clearance. Plasma concentrations of creatinine and urea nitrogen increased dose-dependently after vancomycin injection. No such increases were observed after co-treatment with fosfomycin or imipenem-cilastatin. Changes of N-acetyl-beta-D-glucosaminidase activity in the urine of vancomycin-treated rats were not remarkable compared with those in cisplatin-treated animals. The reduced renal clearance of vancomycin in rats with acute renal failure induced by vancomycin was because of a decrease in both GFR and secretory clearance. However, the changes in GFR and secretory clearance were not proportional-the change in GFR was more pronounced than that of secretory clearance in the experimental groups. In addition, the renal clearance of vancomycin was maintained at the control level after co-administration of fosfomycin or imipenem-cilastatin with vancomycin. These results suggest that vancomycin impairs glomerular filtration more markedly than renal tubular function as compared with cisplatin. Co-administration with fosfomycin or imipenem-cilastatin confers significant protection against the nephrotoxic effects of vancomycin.

Acetylglucosaminidase↗

PubMed1999

Cloning and expression in Escherichia coli of 2-hydroxypropylphosphonic acid epoxidase from the fosfomycin-producing organism, Pseudomonas syringae PB-5123.

The fosfomycin resistance gene, fosC, has been cloned from the fosfomycin-producing organism, Pseudomonas syringae PB-5123. Sequence analysis upstream of this gene found a new ORF showing significant homology to 2-hydroxypropylphosphonic acid epoxidase from fosfomycin-producing Streptomyces wedmorensis. The purified recombinant protein of this ORF converted 2-hydroxypropylphosphonic acid to fosfomycin. This result clearly showed the ORF to encode 2-hydroxypropylphosphonic acid epoxidase in PB-5123.

Amino Acid Sequence↗

PubMedDate not supplied

Fosfomycin does not reduce cytostatic activity of cis-platinum against human osteosarcoma cell lines in vitro.

Fosfomycin has been shown to ameliorate the dose-limiting ototoxicity and nephrotoxicity associated with the antineoplastic agent cis-platinum. Clinical use of fosfomycin in cis-platinum-treated tumor patients critically depends on retaining therapeutic efficacy of cis-platinum while designing modalities to reduce side effects. This study uses two independent assay systems for cell viability and proliferation; we demonstrate that cytocidal activity of cis-platinum against human osteosarcoma cell lines is not affected by various concentrations of fosfomycin up to 0.1 mg/ml in vitro. This suggests that in these cells there is no direct pharmacodynamic interaction of cis-platinum and fosfomycin with respect to mechanisms crucial for tumor kill.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

[Effects of erythromycin and fosfomycin on Pseudomonas aeruginosa biofilm in vitro].

OBJECTIVE: To observe the effects on Pseudomonas aeruginosa biofilm of non-antipseudomonal drugs such as erythromycin and fosfomycin. METHODS: Clinical isolates of Pseudomonas aeruginosa in respiratory infection and ATCC27853 were cultivated in TSB-Teflon and NS-Teflon system respectively for biolfilm formation. Biofilm was observed under scanning electronic microscope (SEM). MICs were determined by broth micro-dilution. RESULTS: SEM showed that biofilm of clinical isolate in TSB-Teflon system and ATCC27853 in NS-Teflon system increased as being cultivated for longer in 1, 3 and 7 days. And biofilm formation in the process of cultivating was inhibited by SubMIC of erythromycin and fosfomycin. MICs evaluation suggested that there were synergetic effects against biofilm Pseudomonas aeruginosa when SubMIC of erythromycin and fosfomycin were combined with ceftazidime or levofloxacin in vitro. CONCLUSION: SubMIC of erythromycin and fosfomycin could inhibit Pseudomonas aeruginosa biofilm in vitro.

Anti-Bacterial Agents↗

PubMed1999

[Study on high performance liquid chromatography/indirect photometric detection of fosfomycin with acridine as detection reagent].

Fosfomycin is a broad-spectrum antibacterial agent which has strong polarity and weak UV absorption. In this work, a method using standard ODS column and conventional UV detector set at 254 nm to analyse fosfomycin was investigated. Firstly, several UV detection reagents were tested and acridine(A) was found to give the highest indirect detection response and proper modification on retention of fosfomycin. With acridine as the UV detection reagent, the mobile phase parameters which affect retention and detection response of solute are discussed, e.g. pH, concentration of organic solvent and concentration of acridine. The mechanism is interpreted for each case. After optimization, we adopted mobile phase as V(CH3OH):V(H2O) = 50:50, pH 3.18, [HAc] = 2 mmol/L, [A] = 1 x 10(-5) mol/L. A new chromatographic system monitored by indirect photometry for detection of fosfomycin was established. This method was used for quantitative analysis, the minimum detectable level was 10 mumol/L, the relative deviation was 4.51%.

Acridines↗

PubMedDate not supplied

[Antibiotic prophylaxis using a combination of pefloxacin and fosfomycin in heart surgery with CEC (extracorporeal circulation) in patients allergic to beta-lactams].

This study conducted for 15 months, was carried out in 34 patients with beta-lactam allergy scheduled for open heart surgery. In the study, pefloxacin was given orally an hour before the induction of anaesthesia and then as a short infusion following induction. When the bypass was stopped, pefloxacin (400 mg) and fosfomycin (60 mg.kg-1) were given in association by two separate slow intravenous infusions just before sternal closure and repeated in intensive care unit postoperatively. The antibiotic kinetics was observed in blood and cellular concentrations (atria, sternum and mediastinal part of pleura). The antibiotic level analysis showed a good diffusion during the surgical procedure, particularly during the bypass. The pefloxacin given orally was found to achieve satisfactory plasma levels of 5.4 to 6.9 mg.l-1 during sternotomy and always higher than 3 mg.l-1 during bypass. At the sternal closure, the residual plasma level was about 2.8 mg.l-1 before the reinfusion. The kinetic evaluation of fosfomycin has also shown same effective levels. Hence, the clinical potency of these antibiotics was confirmed as predicted by their excellent tissue diffusion. Thus, clinical evaluation was in favour of this antibiotic-association in most cases, except the two following ones. The first case had a lethal bronchiolar and lung reinfection with Pseudomonas aeruginosa and Candida albicans germs which appeared at the 6th postoperative day. The second patient is a case of antibiotic prophylaxis failure. He had developed an acute suppurating mediastinal infection at the seventh postoperative day with a methicillin resistant Staphylococcus aureus which had become pefloxacin fosfomycin resistant. However, the evolution was ultimately good after surgical disinfection of sternotomy and 30 days of drainage and irrigation with antiseptic solution associated with well adapted antibiotic treatment: vancomycin, pristinamycin and rifamycin. In fact, the choice of pefloxacin and fosfomycin for prophylaxis against staphylococcus in cardiac surgery is the right choice for patients having beta-lactam allergy. Their spectral activity and pharmacokinetics give us satisfactory results. But it is not the absolute solution as the bacteria responsible for nosocomial infection (hospital borne infection) may be found resistant to this association.

Adult↗

PubMed1989

[Use of an antibioprophylaxis with pefloxacin and fosfomycin in cardiac surgery in patients with beta-lactam hypersensitivity].

An association of pefloxacin plus fosfomycin was used as antibioprophylaxis in beta lactam allergic patients who underwent cardiac surgery with cardiovascular-bypass. Pefloxacin (800 mg), was administered orally, one hour before anesthetic induction and fosfomycin (60 mg/kg) was injected at the time of induction. The whole course of prophylaxis wat 24 hours. Antibiotic concentrations were measured in serum before (P1, P2) during (C1, C2, C3, C4) and after cardiovascular-bypass (P3) and in bone, endocardiac and pleural tissues. The efficacy was evaluated on clinical and biological data. Antibiotic levels of pefloxacin were measured by HPLC and those of fosfomycin by bacteriological method. Antibiotic concentrations are high in blood and tissues, without evidence of cardiovascular-bypass influence. The tissue penetration of both drugs is excellent. Two patients have presented serious post-operative infections. The pharmacokinetic of pefloxacin associated with fosfomycin is appropriate during cardiovascular-bypass and the local antibiotic concentrations are above the MIC of the strains commonly responsible of post operative infections in cardiovascular surgery. The clinical efficacy of this prophylaxis must be studied in a large population of patients.

Aged↗

PubMed1988

[Pharmacokinetics of trometamol-fosfomycin in patients with renal insufficiency].

Trometamol fosfomycin is a new form of fosfomycin used orally. We have studied pharmacokinetics of this antibiotic in 23 uraemic patients with various degrees of renal insufficiency. The control group was 5 young adult males with a creatinine clearance of 127 +/- 20 ml/mn. All subjects received a single oral dose of 25 mg/kg trometamol fosfomycin. Serum and urine concentrations of fosfomycin were assayed by a microbiological method. Cmax, tmax, AUC were significantly higher in uraemic patients than in normal subjects. t 1/2 beta were prolonged in uraemic patients. Thus it is necessary to modify usual dose regimen when creatinine clearance is below 50 ml/mn.

Administration, Oral↗