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PubMed1984

[In vitro study of the cefamandole-fosfomycin combination against methicillin-resistant staphylococci].

In vitro antibacterial activity of cefamandole-fosfomycin (CFM-FOS) combination was studied on 50 methicillin-resistant staphylococci strains. Anti-bacterial effects were evaluated with a bactericidal microtiter checkerboard method. CFM-FOS was compared with other combinations known to be potent against staphylococci. Synergy was consistently recorded with CFM-FOS. Mean MBC of CFM combined with FOS was 1 microgram/ml. Vancomycin-fosfomycin combination was infrequently synergistic (20%). Rifampin-fosfomycin, cefamandole-fusidic acid, and cloxacillin-fusidic acid combinations were usually antagonistic at bactericidal levels. Rifampicin-fusidic acid combination usually yielded additive effects. CFM-FOS killed most methicillin-resistant staphylococci studied at therapeutic concentrations.

Anti-Bacterial Agents↗
PubMed1984

[Reduction of cisplatin toxicity by fosfomycin in animal models].

The protective effect of fosfomycin against cisplatin-induced toxicities was studied in rats. A total of 64 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 period varying from 1 to 10 days. The same total dose of 10 mg/kg of cisplatin was given to all animals. Cisplatin-induced toxic side-effects of body weight loss, nephrotoxicity and ototoxicity were significantly reduced functionally or histopathologically by the combined administration of cisplatin and fosfomycin. A comparison of different dosage schedules with a total dose of 10 mg/kg of cisplatin showed that a higher daily dose for a shorter time period produced more marked toxicities.

Alanine Transaminase↗
PubMed1984

Efficacy of metronidazole and fosfomycin alone and in combination in the treatment of experimentally induced intra-abdominal infections.

A reproducible experimental model of intra-abdominal infection in rats has been worked out in order to simulate intra-abdominal sepsis seen in humans and to test different antimicrobials in the treatment of intra-abdominal infections. This experimental model was used to evaluate the efficacy of metronidazole and fosfomycin alone and in combination in the treatment of intra-abdominal sepsis. Seventy per cent of the untreated animals died within two days. Within seven days, 33% of the animals receiving metronidazole alone, and 40% receiving fosfomycin alone died. Animals treated with metronidazole plus fosfomycin showed a significantly decreased mortality and increased cure rates during the experimental period.

Abdomen↗
PubMed1983

[Fosfomycin--a new antibiotic in rhinootolaryngology].

Fosfomycin is a relatively new antibiotic drug, deriving from streptomyces species. Its special chemical structure and small molecular size provide a very good diffusion into tissues like bone, fascia and wound exudates as well. In a clinical study Fosfomycin was given to 26 patients with infections mainly of the middle ear and mastoid as well as other ENT-infections. Clinical success, laboratory investigations and bacteriology are described in detail. The drug proved to be of special value in the treatment of chronic purulent otitis, purulent or chronic secreting tympanoplasties or other postoperative middle-ear affections when caused by penicillin-resistant staphylococci, proteus-species and pseudomonas aeruginosa. In the other cases treatment results were good corresponding to the bactericidal spectrum of Fosfomycin. There was one treatment failure in our series, but no reverse reaction at all.

Adolescent↗
PubMed1980

In vitro investigations on the action fosfomycin alone and in combination with other antibiotics on Pseudomonas aeruginosa and Serratia marcescens.

86.4% of the Pseudomonas aeruginosa and 91% of the Serratia marcescens strains were sensitive to fosfomycin. In combination with mezlocillin, cefoxitin, gentamicin and nalidixic acid a synergistic action was detected against these bacterial strains. It was most marked in the combination fosfomycin/nalidixic acid against Serratia marcescens. An acceleration of the fosfomycin action on the bacterial cells and the speed of bacteriolysis was observed in weakly acid medium (pH 6.0), in the presence of 10% active human serum and with increasing glucose-6-phosphate concentrations in the test medium. There is no parallel resistance between gentamicin and fosfomycin against Pseudomonas aeruginosa.

Anti-Bacterial Agents↗
PubMed1982

Structural changes induced by subinhibitory concentrations of fosfomycin on Staphylococcus aureus and Bacillus cereus.

Exposure of Staphylococcus aureus ATCC 6538 and Bacillus cereus ATCC 11778 to 1/2 MIC fosfomycin for 3 and 6 h was studied by transmission and scanning electron microscopy. After 3 h, a loss of density and irregularity of shape in the septum was noted, while after 6 h a delayed separation of newly formed cells was observed in both species. In Staphylococcus aureus this resulted in the formation of chains of intact cells and cells in lysis. In Bacillus cereus, it produced filamentous forms with multiple septa. the differences between the effects observed at 3 h and 6 h may be due to time-related variations in cell permeability to fosfomycin, or to the existence of indirect mechanisms enabling fosfomycin to interfere with the enzymatic activity regulating the normal separation of cells, or to a combination of these factors.

Anti-Bacterial Agents↗
PubMed1981

Comparison of systemic prophylaxis with metronidazole-fosfomycin and metronidazole-cephalothin in elective colorectal surgery.

A comparative randomized study was designed to evaluate the prophylactic effect of two different combinations of antimicrobials, i.e. metronidazole-fosfomycin (n = 30) and metronidazole-cephalothin (n = 28), in elective colorectal surgery. The study was strictly consecutive and the treatment groups comparable. The total rate of surgical septic complications was low (10%) in both treatment groups. No anaerobic infections could be demonstrated and the clinical course was mild in all patients developing septic complications. No other antimicrobial therapy was given. Peroperative bacteriological sampling yielded aerobes and anaerobes in 51 and 32, respectively, of 58 patients. A high percentage of the isolated aerobes and anaerobes were cephalothin-resistant, whereas most aerobes were sensitive to fosfomycin. Only aerobes were isolated from surgical septic sites. The absence of anaerobic sepsis must be ascribed to the metronidazole prophylaxis; the probable reason for the low rate of surgical aerobic septic complications is that antimicrobials, active against aerobes, were included in the prophylactic regimens. The combination, metronidazole-fosfomycin, seems adequate and safe for continued evaluation.

Anti-Bacterial Agents↗
PubMed1981

[Prerequisites for enhancement of the efficacy of fosfomycin by glucose-6-phosphate in treatment of experimentally infected animals (author's transl)].

In chemotherapy of otherwise fatally infected mice (intraperitoneally) the effective dose50 (ED50) of fosfomycin (2 single doses, subcutaneous application 1 and 6 h post infect.) was decreased significantly by supplementing the antibiotic solution with 100 mg glucose-6-phosphate (G-6-P) per kg animal and per injection if also the MIC of the infecting strain (Klebsiella oxytoca and K. aerogenes II) was lowered by addition of G-6-P (25 mg/l) to the nutrient medium (Table 1 and 2). With strains not exhibiting any influence on the MIC no such effect was observed (Table 1). From this it is concluded that the enhancement of antimicrobial activity of fosfomycin in vivo is based on the same mechanism as in vitro. This mechanism is the initiation of a second route of transportation into the bacterial cell (7), the hexose-6-phosphate transport system that apparently is inducible not only in vitro but also in vivo. Blood levels of G-6-P sufficient or above to induce this system in vitro (5 mg/l) were being held with doses of 100 mg/kg body weight in dogs during 70 to 120 min (Fig. 3) and 45 to 70 min (Fig. 4) when applied subcutaneously or intravenously respectively. These periods of contact area adequate to induce a considerable decrease of the MIC. With the strain used (K. oxytoca) the MIC of 128 mg/l was lowered by contact with G-6-P during 60 or 120 min to 16 or 8 mg/l respectively (Fig. 5). For full induction of the hexose-6-phosphate system resulting in a MIC of 2 mg/l however, 8 h were necessary. From the above findings it is concluded that clinical studies are necessary. As G-6-P is a (short-lived) physiological product of cell metabolism and nontoxic such studies are justifiable in cases where therapeutic use of fosfomycin can be regarded as an indication.

Animals↗
PubMed1980

Serum and lung tissue levels of fosfomycin in humans.

Fosfomycin levels were determined in the serum and the lung tissue removed during 26 pulmonary operations following intramuscular or intravenous administration of 2 g fosfomycin. In the serum the level was about 32 micrograms/ml 1--2 h subsequent to the administration. At the same time, the removed lung tissue showed 12--16 micrograms/g concentration in the apparently intact parts, amounting to 32--52% of the serum level, whereas in the tumorous lung tissue roughly half of this concentration was present. The fosfomycin levels found in the lung tissue are effective only against a group of bacteria causing respiratory inflammation.

Adult↗
PubMed1978

[Investigations on the antibacterial activity of fosfomycin on DST-agar (author's transl)].

Since in some European countries the activity of antimicrobial substances are assessed on Disc-Sensitivity-Test (DST)-agar, routinely, it has been investigated whether and under which conditions Fosfomycin might be tested on DST-agar with the agar-dilution and -diffusion technique. A total of 320 strains representing 7 species were used as teststrains, and Mueller-Hinton (MH)-agar was employed as reference medium. On DST-agar the MIC-values were increased for some genera like Klebsiella by a factor of 128, a fact that was explained by the sixfold concentration of antagonistically acting Phosphate in DST-agar. Addition of glucose-6-phosphate (G-6-P) enhanced the sensitivity towards Fosfomycin only with some species. As the endpoint of growth is difficult to determine on DST-agar its use for agar-dilution tests with Fosfomycin can not be recommended. For agar-diffusion tests, however, this medium may be used provided that a thin film of growth or single colonies within the inhibition zones are being disregarded and that the disc content is increased from 50 microgram as being usual at present to 100 or 200 microgram. Diameters of inhibition zones that were obtained with such discs on DST-agar correlated very well (r = --0,89 und --0,93, respectively) with MIC-values derived from agar-dilution tests on MH-agar (+ G-6-P). With discs containing only 50 microgram no inhibition zones are formed by strains that should still be classified as "sensitive" (MIC: 8--32 microgram/ml).

Agar↗
PubMed2002

Crystal structure of a genomically encoded fosfomycin resistance protein (FosA) at 1.19 A resolution by MAD phasing off the L-III edge of Tl(+).

The fosfomycin resistance protein (FosA) catalyzes the Mn(II)- and K+-dependent addition of glutathione to the oxirane of the antibiotic fosfomycin. The crystal structure of FosA from Pseudomonas aeruginosa was solved at a resolution of 1.19 A by multiwavelength anomalous diffraction at the L-III edge of a Tl+ derivative. The structure solution took advantage of the ability of Tl+ to substitute for K+. The existence of multiple Tl sites in the asymmetric unit suggests that this may be a generally useful technique for phasing protein crystal structures. A 1.35 A resolution structure with phosphate bound in the active site shows that the Mn(II) center has a rare four-coordinate geometry. The structure of the fosfomycin complex at 1.19 A resolution indicates that the Mn(II) center is close to five-coordinate with trigonal bipyramidal geometry and a ligand set consisting of two histidines (H7 and H64) and one phosphonate oxygen occupying the equatorial sites and the carboxylate of E110 at one of the apical sites. The oxirane oxygen of the substrate is located at the other apical site but is 0.2 A beyond the average Mn-O distance for five-coordinate Mn(II). The Mn(II) center is proposed to stabilize the alkoxide in the transition state, while the nearby hydroxyl group of T9 acts as a proton donor in the reaction. The K+ ion located 6.5 A from the Mn(II) appears to help orient the substrate for nucleophilic attack.

Bacterial Proteins↗
PubMed1971

Influence of culture media on the antistaphylococcal activity of fosfomycin.

Antagonism or double zones of inhibition (or both) resulted when Staphylococcus aureus was exposed to fosfomycin in Brain Heart Infusion, tryptic/papaic digest of casein/soybean, and Mueller Hinton culture media; neither occurred with a totally defined, completely synthetic medium. The extent of antagonism was quantitated by determination of the absolute minimal inhibitory concentration of fosfomycin in each medium. By using the synthetic medium and inducers, the hexose-phosphate transport system appeared to be more important than the alpha-glycerophosphate transport system in providing ingress of fosfomycin into staphylococci.

Amino Acids↗
PubMed2002

On the transformation of (S)-2-hydroxypropylphosphonic acid into fosfomycin in Streptomyces fradiae--a unique method of epoxide ring formation.

(1S,2S)- and (1R,2S)-2-hydroxy-[1-D(1)]propylphosphonic acid were synthesised from (1S,2S)-2-benzyloxy-[1-D(1)]propanol, which was obtained by horse liver alcohol dehydrogenase catalysed reduction of the corresponding aldehyde. When (1S,2S)-2-hydroxy-[1-D(1)]propylphosphonic acid was fed to Streptomyces fradiae, the deuterium was retained to the same extent in fosfomycin (cis-epoxide) and its co-metabolite trans-epoxide. Removal of the hydrogen (deuterium) atom from the C-1 atom of deuterated 2-hydroxypropylphosphonic acids is a stereospecific process (the hydrogen atom of (S)-2-hydroxypropylphosphonic acid is pro-R). The formation of the O--C-1 bond of fosfomycin occurs with net inversion of configuration, the formation of the O--C-1 bond of the trans-epoxide with net retention.

Anti-Bacterial Agents↗
PubMed2004

Capillary electrophoresis analysis of fosfomycin in biological fluids for clinical pharmacokinetic studies.

A feasible capillary zone electrophoresis (CZE) method with indirect UV and contactless conductivity detection was developed for the determination of fosfomycin, an antibiotic, in human plasma and microdialysis samples. Samples were collected from test persons during a clinical trial. The background electrolytes used consisted of 25 mM benzoic acid and 0.5 mM hexadecyltrimethylammonium bromide, adjusted with tris(hydroxymethyl)aminomethane solution to pH 6.95 for plasma, and to pH 8.05 for microdialysis samples. CZE separations of the anionic analyte were carried out with reversed electroosmotic flow directed towards the anode. The limit of detection was between 0.6 and 2 microg/mL, depending on the matrix and the detection method. No sample preparation was needed for microdialysis samples; for plasma samples, proteins were precipitated with methanol (1+2, v+v), and the supernatant was analyzed. The yield determined with spiked samples was about 100%, the reproducibility of the entire method, expressed by the RSD% of three independent determinations of fosfomycin in triplicate after spiking Ringer's solutions and plasma samples, respectively, was better than 8%. The method is thus well-suited for clinical studies for the determination of the antibiotic in biological fluids.

Benzoic Acid↗
PubMed1995

Cloning and nucleotide sequence of fosfomycin biosynthetic genes of Streptomyces wedmorensis.

The biosynthetic pathway for production of the antibiotic fosfomycin by Streptomyces wedmorensis consists of four steps including the formation of a C-P bond and an epoxide. Fosfomycin production genes were cloned from genomic DNA using S. wedmorensis mutants blocked at different steps of the biosynthetic pathway. Four genes corresponding to each of the biosynthetic steps were found to be clustered in a DNA fragment of about 5 kb. Nucleotide sequencing of a large fragment revealed the presence of ten open reading frames, including the four biosynthetic genes and six genes with unknown functions.

Acetaldehyde↗
PubMed1990

Prophylactic chemotherapy with fosfomycin trometamol during transurethral surgery and urological manoeuvres. Results of a multicentre study.

The aim of the present open prospective study is to evaluate the efficacy and safety profile of fosfomycin trometamol in the chemoprophylaxis of urinary tract infections following transurethral diagnostic and/or therapeutic manoeuvres. 712 patients were enrolled in 72 urological surgical centres. All the enrolled patients received an initial dose of fosfomycin trometamol (Monuril sachet containing 3 g of active drug in powder) 3 h before and a second dose 24 h after the transurethral manoeuvres. Clinical and microbiological examinations were carried out before the intervention, and then on the second and seventh days after the manoeuvres. 94 patients with positive baseline tests were excluded from the microbiological follow-up for non-compliance with the main inclusion criteria. Out of 618 patients with sterile urine or with bacteriuria less than 10(5) ml on baseline screening, 20 (3.2%) developed UTI on the second day and 22 (3.6%) on the seventh day after treatment. Clinical follow-up is in agreement with these microbiological data. Overall, a total of 24 side effects were observed (3.3%), 16 of which were associated with Monuril treatment. The results of this open study agree with the preliminary observations in the controlled studies.

Female↗
PubMed1990

Prophylactic chemotherapy with fosfomycin trometamol versus placebo during transurethral prostatic resection.

A prospective randomized controlled double-blind study was performed on 61 patients undergoing transurethral resection of the prostate. The first group of 31 patients received 3 g fosfomycin trometamol p.o. each on the evening before and after the operation; the second group of 30 patients received a placebo. Urine samples were taken by catheter puncture 24 and 48 h postoperative. After removal of the catheter (day 5) the first midstream urine was collected for culture, and from that moment on all patients were treated with a nitrofurantoin derivative for two weeks. Although the same strict antiseptic measures were standard practice for both groups, the incidence of early postoperative urinary tract infections was significantly lower for the fosfomycin trometamol group (0/31 versus 6/30 in placebo recipients). None of the patients suffered from a major symptomatic or complicated infection. There were no side effects registered.

Administration, Oral↗
PubMedDate not supplied

Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges.

Serum and cerebrospinal fluid (CSF) concentrations of fosfomycin were evaluated in 45 patients. Mean serum concentration was 260.1 mg/l at 15 min postinfusion in 35 patients receiving a 5 g bolus dose, and 440 mg/l in five patients receiving a 10 g bolus dose. Mean distribution volume was 18.5 l (5 g dose), the total clearance was 118.8 ml/min, half-life was nearly 2 h, and the determined AUC were 420.95 mg/l.h (5 g dose) and 423.57 mg/l.h (10 g dose). The average peaks at 360 min in CSF reached 11.6 mg/l (5 g dose) and 17.7 mg/l (10 g dose). The CSF/serum ratio was 9.24% (5 g dose), and 13.81% (10 g dose). The CSF levels were not below 30 mg/l from the second day on in patients receiving 3 X 5 g fosfomycin per day. Meningeal inflammation increased the CSF concentrations from 30 mg/l at 6 h up to 150 mg/l at 120 h in the saturation phase, e. g., up to 300% more in comparison to non-inflamed meninges.

Adolescent↗