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PubMed1990

Synergism between cefotaxime and fosfomycin in the therapy of methicillin and gentamicin resistant Staphylococcus aureus infection in rabbits.

An experimental model of infected subcutaneous fibrin clots in rabbits was used to study the synergism between cefotaxime and fosfomycin in infection with methicillin and gentamicin resistant Staphylococcus aureus (MGRSA), and to determine the efficacy of a simplified schedule of administration. The bactericidal activity of cefotaxime and fosfomycin against MGRSA was investigated giving the drugs in one full or two divided doses either alone or in combination. The pharmacokinetics of the drugs were correlated with the antibacterial efficacy obtained over 12 hours of treatment. The results confirmed that the combination of cefotaxime and fosfomycin is highly synergistic in experimental MGRSA infection. Higher bactericidal activity was obtained with a regimen of 6-hourly drug administration which resulted in persistent levels of both drugs in serum as well as at the site of infection.

Analysis of Variance↗
PubMed1986

Factors influencing the activity of the trometamol salt of fosfomycin.

The antibacterial activity of trometamol fosfomycin and its potentiation by glucose-6-phosphate were found to vary considerably in different culture media, although not all bacteria tested were equally affected. In general, the lowest MICs were obtained in the presence of glucose-6-phosphate in nutrient broth and Eugonbroth. The influence of inoculum size, pH and potentiation by glucose-6-phosphate were investigated by agar incorporation MIC titrations on nutrient agar. The activity of trometamol fosfomycin against many strains increased as the pH was lowered from 7.9 to 5.5. Only 9% of the strains showed an inoculum effect when tested at pH 5.5 in the presence of glucose-6-phosphate compared with 37% of the strains tested at pH 7.1 and 22% of the strains tested at pH 7.9. In the absence of glucose-6-phosphate, about 10% of the strains showed an inoculum effect at all three pH levels. The addition of glucose-6-phosphate to culture media seems reasonable for the testing of fosfomycin susceptibility.

Bacteria↗
PubMed1991

Characterization of staphylococcal plasmids hybridizing with the fosfomycin resistance gene fosB.

The distribution of the fosB gene, coding for fosfomycin resistance, in 105 fosfomycin-resistant isolates of Staphylococcus from various geographical areas, was studied by Southern blot hybridization. Nucleotide sequences related to fosB were detected in 36 strains belonging to five species. Plasmids bearing fosB were often of a size similar to that of pIP1842 (2.54 kb) in S. epidermidis, most often small (2.4 to 4.1 kb) in other species including S. aureus where a 2.7-kb plasmid was found in 16 out of the 18 strains studied. The fosB gene was geographically dispersed since it was present in six different locations in France and also in Japan. The weak hybridization observed with plasmid DNA of certain strains of S. aureus, S. epidermidis, S. haemolyticus, S. saprophyticus, and S. warneri may indicate gene heterogeneity for fosfomycin resistance in Staphylococcus spp.

Blotting, Southern↗
PubMed1994

Determination of fosfomycin in biological fluids by capillary electrophoresis.

A capillary electrophoresis method was developed for the determination of the antibiotic fosfomycin in serum, cerebrospinal fluid and aqueous humor. The technique uses indirect UV detection and the working buffer includes an organic cation to improve fosfomycin mobility. The electrophoretic time of migration is less than 7 min in both fluids. The limit of quantification is 2.5 and 1 microgram/ml in serum and aqueous fluids, respectively (signal-to-noise ratio = 3). The method was validated in serum and water over the concentration range 2.5-200 micrograms/ml. The calibration graph for serum was linear with a correlation coefficient r = 0.999. At a fosfomycin concentration of 2.5 micrograms/ml in serum, the intra- and inter-day precisions (coefficients of variation) were 5 and 5.2%, respectively. The mean recovery in serum was 94.5% (S.D. = 2.4%).

Aqueous Humor↗
PubMed1995

The comparative effects of sodium thiosulfate, diethyldithiocarbamate, fosfomycin and WR-2721 on ameliorating cisplatin-induced ototoxicity.

The efficacies of four agents in ameliorating cisplatin-induced ototoxicity were investigated. Hamsters were given a series of 5 cisplatin injections (3 mg/kg/injection once every other day, i.p.) either alone or in combination with 1600 mg/kg/injection sodium thiosulfate (STS), 300 mg/kg/injection diethyldithiocarbamate (DDTC), 18 mg/kg/injection WR-2721, or 300 mg/kg/injection fosfomycin (n = 10/group). Ototoxicity was assessed electrophysiologically by auditory brainstem responses (ABRs) and anatomically by cochlear histology. The greatest auditory protection was given by STS, followed by DDTC. WR-2721 and fosfomycin did not provide any protection. All of the animals in the STS and DDTC groups survived, while some fatalities occurred in the fosfomycin, WR-2721, and cisplatin-only groups. Thus, the agents that were protective against ototoxicity were also protective against mortality. The ABRs also provided evidence of cisplatin-induced neuropathy. In summary, STS and DDTC hold promise for ameliorating the ototoxic effects of cisplatin chemotherapy and the hamster proved to be an excellent model of cisplatin ototoxicity.

Amifostine↗
PubMed2005

Synergistic effect of fosfomycin and arbekacin on a methicillin-resistant Staphylococcus aureus-induced biofilm in a rat model.

Biofilms are a major concern for clinicians in the treatment of infectious disease because of the resistance to a wide range of antibiotics. Using a rat air pouch model, methicillin-resistant Staphylococcus aureus (MRSA) growing as a biofilm was treated with a combination of fosfomycin (FOM) and arbekacin (ABK) or by the agents alone. This model has the advantage of permitting frequent sampling of exudates for bacterial counts and anti-bacterial activity, and morphological examination of the biofilm structure and inflammatory process in the pouch tissues. A clear synergistic effect was observed in the rats treated with a combination of fosfomycin and arbekacin. Morphological studies using scanning electron microscopy and histological staining showed dramatic changes of the biofilm structure as well as the inflammatory response in the rats. These results suggested an enhancement of bactericidal activity of arbekacin penetrating through the biofilm layer by virtue of fosfomycin. A possible mechanism of the synergistic effect is discussed.

Aminoglycosides↗
PubMed2005

Fosfomycin resistance proteins: a nexus of glutathione transferases and epoxide hydrolases in a metalloenzyme superfamily.

Three similar but mechanistically distinct fosfomycin resistance proteins that catalyze the opening of the oxirane ring of the antibiotic are known. FosA is a Mn(II) and K(+)-dependent glutathione transferase. FosB is a Mg(2+)-dependent L-cysteine thiol transferase. FosX is a Mn(II)-dependent fosfomycin-specific epoxide hydrolase. The expression, purification, kinetic, and physical characteristics of six fosfomycin resistance proteins including the FosA proteins from transposon TN2921 and Pseudomonas aeruginosa, the FosB proteins from Bacillus subtilis and Staphylococcus aureus, and the FosX proteins from Mesorhizobium loti and Listeria monocytogenes are reported.

Bacteria↗
PubMed1985

Investigations on the bactericidal activity of fosfomycin using the membrane filter-agar dilution method and the time-kill technique.

Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) for a 99% and a 99.9% kill can be reproducibly determined for fosfomycin by the agar dilution procedure when placing the inoculum on top of membrane filters. In 88.7% (85%) of 80 bacterial strains (Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus aureus) examined we found a 99% (99.9%) kill at concentrations higher than the respective MIC by up to one dilution step. For 5% (10%), the bactericidal concentrations were more than two steps higher. Both the MIC and the MBC were influenced by the culture medium. The influence of the medium on fosfomycin activity was also shown by the time-kill curves. In nutrient broth, Mueller-Hinton broth, Iso-Sensitest broth and human plasma water (with and without glucose-6-phosphate) we found different killing rates, different killing maxima and different times of regrowth of the cultures. The bactericidal activity of fosfomycin against Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, and Pseudomonas aeruginosa ATCC 27853 was more pronounced in plasma water, nutrient broth, and Mueller-Hinton broth than in Iso-Sensitest broth.

Agar↗
PubMed2002

In vitro susceptibility of vancomycin-resistant enterococci (VRE) to fosfomycin.

We evaluated the in vitro activity of fosfomycin against 75 clinical isolates of vancomycin-resistant enterococci (VRE). Using the NCCLS breakpoint for susceptibility of urinary tract isolates to fosfomycin (MIC > or = 256), 51 out of 52 Enterococcus faecium and all Enterococcus faecalis isolates tested were susceptible or intermediate to fosfomycin.

Anti-Bacterial Agents↗
PubMed1989

Synergism between ciprofloxacin and fosfomycin against gram-negative bacteria in vitro.

A combination of ciprofloxacin and fosfomycin was evaluated for synergism employing time-kill experiments. A total of 59 clinical isolates of gram-negative bacteria was examined. All organisms were moderately sensitive or resistant to ciprofloxacin; 72.9% also showed moderate sensitivity or resistance to fosfomycin. After 24 h, synergism was seen in 22% of the strains, i.e. less than reported by other authors. There was no correlation between synergistic action and sensitivity to ciprofloxacin and fosfomycin, respectively.

Ciprofloxacin↗
PubMed2001

Elementary steps in the acquisition of Mn2+ by the fosfomycin resistance protein (FosA).

The fosfomycin resistance protein, FosA, catalyzes the Mn(2+)-dependent addition of glutathione to the antibiotic fosfomycin, (1R,2S)-epoxypropylphosphonic acid, rendering the antibiotic inactive. The enzyme is a homodimer of 16 kDa subunits, each of which contains a single mononuclear metal site. Stopped-flow absorbance/fluorescence spectrometry provides evidence suggesting a complex kinetic mechanism for the acquisition of Mn(2+) by apoFosA. The binding of Mn(H(2)O)(6)(2+) to apoFosA alters the UV absorption and intrinsic fluorescence characteristics of the protein sufficiently to provide sensitive spectroscopic probes of metal binding. The acquisition of metal is shown to be a multistep process involving rapid preequilibrium formation of an initial complex with release of approximately two protons (k(obsd) > or = 800 s(-1)). The initial complex either rapidly dissociates or forms an intermediate coordination complex (k > 300 s(-1)) with rapid isomerization (k > or = 20 s(-1)) to a set of tight protein-metal complexes. The observed bimolecular rate constant for formation of the intermediate coordination complex is 3 x 10(5) M(-1) s(-1). The release of Mn(2+) from the protein is slow (k approximately 10(-2) s(-1)). The kinetic results suggest a more complex chelate effect than is typically observed for metal binding to simple multidentate ligands. Although the addition of the substrate, fosfomycin, has no appreciable effect on the association kinetics of enzyme and metal, it significantly decreases the dissociation rate, suggesting that the substrate interacts directly with the metal center.

Bacterial Proteins↗
PubMed1999

Lysine 22 in UDP-N-acetylglucosamine enolpyruvyl transferase from Enterobacter cloacae is crucial for enzymatic activity and the formation of covalent adducts with the substrate phosphoenolpyruvate and the antibiotic fosfomycin.

UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) catalyzes the first committed step in the biosynthesis of the bacterial cell wall component peptidoglycan. The enzyme is the target of the antibiotic fosfomycin. A lysine residue (K22), strictly conserved in MurAs and the structurally and mechanistically related 5-enolpyruvylshikimate 3-phosphate synthases (EPSPS), is located near the active center of the enzyme. This residue is thought to be involved directly in the binding of the substrate phosphoenolpyruvate (PEP) and also to participate in the conformational change leading to the formation of the catalytically competent enzyme complex. Using site-directed mutagenesis, we have replaced this lysine with arginine (K22R), valine (K22V), and glutamate (K22E). These mutant proteins were expressed, purified, and characterized in comparison to wild-type MurA and a previously described inactive C115S mutant protein. It was found that all three K22 mutant proteins had less than 0.5% of the wild-type activity. Using isothermal titration calorimetry, it could be shown that the binding parameters for the UDP-sugar nucleotide substrate are not affected by the mutations, except for the K22E mutant protein. Similarly, binding of PEP was found to be unaffected in the K22 mutant proteins as demonstrated by tryptophan fluorescence quench titrations. On the other hand, the level of formation of a covalent adduct with either PEP or fosfomycin with the thiol group of cysteine 115 was diminished. The propensity to form an adduct with PEP decreased in the following order: wild type >> K22R > K22V > K22E. A comparable effect was found on the formation of the inhibitory covalent adduct of MurA and the antibiotic fosfomycin. These results are discussed in terms of an involvement of lysine 22 in a conformational change of MurA.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1986

[Studies of the penetrating ability of fosfomycin into the aqueous humor and vitreous body of the eye].

Fosfomycin is an antibiotic with a new simple chemical structure and a broad spectrum of antibacterial activity, especially against staphylococci. In the study reported here, the penetration of fosfomycin into the aqueous humor and vitreous body was investigated after intravenous infusion of 4 and 8 g. The highest average concentration approximately 2 hours after administration was 28.3 micrograms/ml after the 4 g dose and 52 micrograms/ml after the 8 g dose. Both the 4 g and 8 g doses thus produced aqueous humor levels exceeding the minimum inhibitory concentrations required for most gram-positive and gram-negative organisms commonly responsible for bacterial endophthalmitis, including strains of pseudomonas aeruginosa. Extremely high aqueous humor levels of fosfomycin were observed in two patients with inflamed eyes because of a change in the blood-aqueous barrier.

Aqueous Humor↗
PubMed1980

[Comparison of activity of fosfomycin, oxacillin and penicillin G against staphylococci and micrococci (author's transl)].

The in vitro sensitivity against fosfomycin, oxacillin and penicillin G was tested in 65 Staphylococcus aureus strains, 71 coagulase negative staphylococci and 46 micrococci. Fosfomycin was very effective against staphylococci. Cross resistance with simultaneously tested penicillins could not be demonstrated. Fosfomycin was only partially effective against micrococci for which penicillin G was most effective.

Anti-Bacterial Agents↗
PubMed1999

Alteration of a single amino acid residue reverses fosfomycin resistance of recombinant MurA from Mycobacterium tuberculosis.

Mycobacterium tuberculosis has innate resistance to a range of broad-spectrum antimicrobial agents. This may in part reflect the relative impermeability of the mycobacterial cell wall, but additional specific mechanisms may also be important. In the case of fosfomycin, it has been suggested that a key difference in the active site of the M. tuberculosis MurA enzyme might confer resistance. In Escherichia coli, fosfomycin covalently binds to a cysteine normally involved in the enzymic activity, while protein alignments predict an aspartate at this position in the M. tuberculosis MurA. In the present study, it is demonstrated that the wild-type M. tuberculosis MurA is indeed resistant to fosfomycin, and that it becomes sensitive following replacement of the aspartate residue in position 117 by a cysteine. In addition, the study illustrates the use of an inducible expression system in mycobacteria to allow functional characterization of an M. tuberculosis enzyme that is unstable during constitutive expression.

Alkyl and Aryl Transferases↗
PubMed1980

Plasmid-determined resistance to fosfomycin in Serratia marcescens.

Multiple-antibiotic-resistant strains of Serratia marcescens isolated from hospitalized patients were examined for their ability to transfer antibiotic resistance to Escherichia coli by conjugation. Two different patterns of linked transferable resistance were found among the transconjugants. The first comprised resistance to carbenicillin, streptomycin, and fosfomycin; the second, and more common, pattern included resistance to carbenicillin, streptomycin, kanamycin, gentamicin, tetracycline, chloramphenicol, sulfonamide, and fosfomycin. The two types of transconjugant strains carried a single plasmid of either 57 or 97 megadaltons in size. Both of these plasmids are present in parental S. marcescens strains resistant to fosfomycin. The 57-megadalton plasmid was transformed into E. coli.

Anti-Bacterial Agents↗
PubMed1990

Purification of a glutathione S-transferase that mediates fosfomycin resistance in bacteria.

The enzyme that modifies fosfomycin by formation of an adduct with glutathione was purified 12-fold with a 56% activity yield by passage through DEAE Sephacel and high-performance liquid chromatography molecular exclusion columns. Its functional form was a homodimer of two 16,000-dalton polypeptides, which possibly showed an antiparallel alpha tertiary structure and which lacked marked hydrophobic regions. Visualization of the reaction was achieved by precolumn derivatization of glutathione and the adduct, separation by high-performance liquid chromatography, and fluorescence detection of both compounds. Temperature and pH optima were 20 to 30 degrees C and 8.25, respectively; Mn2+, Fe2+, and Co2+ enhanced the rate of modification; and Km values were 9.4 and 11 mM for fosfomycin and glutathione, respectively. Phosphoenolpyruvate did not interfere with fosfomycin modification. The enzyme was stable at 4 degrees C for at least 6 months but progressively lost its activity upon being heated for 60 min at temperatures over 30 degrees C.

Amino Acids↗
PubMed1995

Product of fosC, a gene from Pseudomonas syringae, mediates fosfomycin resistance by using ATP as cosubstrate.

Pseudomonas syringe PB-5123, a producer of fosfomycin, is resistant to high concentrations of the antibiotic. Two possible mechanisms of resistance have been detected: (i) impermeability to exogenous fosfomycin, even in the presence of sugar phosphate uptake inducers, and (ii) antibiotic phosphorylation. The gene responsible for this last activity, fosC, encodes a ca. 19,000-Da protein and is immediately followed by a second open reading frame, which shows sequence similarities to glutathione S-transferases. FosC uses ATP as a cosubstrate in an inactivation reaction that can be reversed with alkaline phosphatase. Other nucleotide triphosphates cannot be substituted for ATP in this reaction. No relationship between fosC and the previously described genes of fosfomycin resistance was found.

Adenosine Triphosphate↗