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PubMed1985

Inability of gentamicin and fosfomycin to eliminate intracellular Enterobacteriaceae.

The ability of gentamicin and fosfomycin to kill Salmonella typhimurium and Escherichia coli in a HeLa cell culture system was investigated. Antibiotic activity against extracellular, cell membrane-attached and intracellular bacteria were determined. Both gentamicin and fosfomycin had the same low ability to kill intracellular bacteria. The efficacy of fosfomycin against extracellular bacteria was also low, whereas gentamicin rapidly killed such bacteria. These observations show that intracellular enterobacteria are protected from the bactericidal activity of gentamicin and fosfomycin.

Anti-Bacterial Agents↗
PubMed1989

An increase in the antimicrobial activity in vitro of fosfomycin under anaerobic conditions.

Fosfomycin showed lower MIC values under anaerobic culture conditions than those under aerobic conditions for four Gram-positive and 18 Gram-negative bacterial isolates. The degree of change in MICs was dependent on the culture media and strains tested. The growth-inhibitory diameter in the paper disc assay increased in parallel with the decrease in the redox potential of the agar medium. Bacteriolytic activity was also potentiated in anaerobiosis. The increase of the bio-activity of fosfomycin in anaerobic culture was neither due to the change of medium pH nor to the change of mobility of drug in agar. However it is possible that the uptake of fosfomycin through the cell membrane increased in anaerobiosis. The anaerobic MICs of fosfomycin were better correlated than the aerobic MICs with the ED50 values in a mouse systemic infection model.

Anaerobiosis↗
PubMed1998

Escherichia coli O157 interactions with human intestinal Caco-2 cells and the influence of fosfomycin.

It is not clear how Escherichia coli O157 invades human enteric epithelium and causes the haemolytic uraemic syndrome (HUS), and nor has the most appropriate treatment of E. coli O157 infection been established. Verotoxins, leucocytes and proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-8, are considered essential for the development of HUS. We used the Caco-2 cell monolayer system, well-known as an in-vitro model of human intestinal infection, to determine how E. coli O157 interacts with intestinal epithelial cells and also studied the influence of fosfomycin on the virulence of the bacteria. Results showed that the E. coli O157 used in this study did not penetrate the Caco-2 cell monolayer system, unlike Salmonella typhimurium SL1344, and verotoxin 1 (VT 1), but not VT 2, translocated across the system. In an in-vitro conventional assay, fosfomycin increased the amount of verotoxins but it did not influence penetration of bacteria and translocation of verotoxins in the Caco-2 cell monolayer system. The production of both IL-8 (a potent neutrophil activator) and TNF-alpha in the human monocytic THP-1 cell line was reduced by fosfomycin-treated basolateral medium in this system. These results indicate that fosfomycin may be a potent drug for preventing HUS caused by E. coli O157 infection.

Anti-Bacterial Agents↗
PubMed2001

The effect of fosfomycin on neutrophil function.

Fosfomycin (cis-1,2-epoxypropyl phosphonic acid) is a cell wall synthesis-inhibiting antibiotic. We investigated the effect of fosfomycin on several indices of neutrophil function. Neutrophil phagocytosis was analysed by flow cytometry. Cytosolic calcium kinetics were assessed fluorometrically and neutrophil bactericidal ability was assessed by fluorescence microscopy. Intracellular reactive oxygen intermediate (ROI) production was analysed by flow cytometry and extracellular ROI by cytochrome c reductase assay. After fosfomycin incubation, phagocytosis was unaffected as assessed by the FACS assay. Fosfomycin incubation resulted in enhanced bactericidal ability, in increased intracellular calcium concentrations, elevated extracellular ROI production and decreased chemotaxis but it did not affect intracellular ROI production and chemokinesis.

Anti-Bacterial Agents↗
PubMed1988

Supplemental fosfomycin and/or steroids that reduce cisplatin-induced nephrotoxicity.

The protective effects of fosfomycin and steroids on the nephrotoxicity induced by cisplatin in lung cancer patients were studied by measuring N-acetyl-beta-D-glucosaminidase (NAG) activity in 24-hour urine, creatinine clearance, serum creatinine and blood urea nitrogen as factors of nephrotoxicity. In control patients treated with anticancer drugs containing cisplatin but no supplemental fosfomycin or steroids, the 24-hour urine NAG level increased two-fold (15.5 +/- 7.5, p less than 0.01) over the pretreatment level (8.0 +/- 5.2) 3 days after anticancer therapy. Supplemental fosfomycin or steroids inhibited an increase in urinary NAG level 3 days after the anticancer therapy. There were, however, no significant changes in creatinine clearance, serum creatinine and blood urea nitrogen levels before and after anticancer and/or supplemental therapies. These results suggest the possibility that supplemental treatment with fosfomycin, like that with steroids, reduces cisplatin-induced nephrotoxicity, especially proximal tubular damage.

Acetylglucosaminidase↗
PubMed1997

Effect of antimicrobial agents, especially fosfomycin, on the production and release of Vero toxin by enterohaemorrhagic Escherichia coli O157:H7.

In 1996, Japan had several large outbreaks of enterohaemorrhagic Escherichia coli (EHEC) O157:H7 infection. We surveyed physicians who examined and treated these patients, and found that most of the patients (95.9%) received antimicrobial agents as treatments, in particular, fosfomycin comprised 84.0% of the prescribed treatment. Since the administration of antimicrobial agents for EHEC infection is under discussion, we also analyzed the effects of 7 antimicrobial agents including fosfomycin on the production and release of Vero toxins (VTs) by EHEC. The addition of fosfomycin into EHEC culture in CAYE broth at 5 h after the start of incubation caused a marked increase of VT1 release and production, as revealed by an immunological toxin assay (RPLA). However, a cytotoxicity assay of Vero cells showed a small increase of biological activity in the specimens treated with fosfomycin because the Vero cell assay reflects total cytotoxicity of VT1 and VT2. These results indicate that further study is necessary before concluding whether antimicrobial agents actually worsen an EHEC infection.

Animals↗
PubMed1989

In vitro synergism between daptomycin and fosfomycin against Enterococcus faecalis isolates with high-level gentamicin resistance.

Daptomycin and fosfomycin are two agents which inhibit different steps in peptidoglycan synthesis. We studied the in vitro activities of these drugs, alone and in combination, by time-kill techniques against 21 clinical isolates of Enterococcus (Streptococcus) faecalis demonstrating high-level resistance to gentamicin. Combinations of fosfomycin and daptomycin exhibited synergistic bactericidal activity (100-fold decrease in CFU per milliliter at 24 h compared with daptomycin alone) against all strains (mean +/- standard deviation of increment in killing = 2.7 +/- 0.7 log10 CFU/ml). In a subgroup of strains against which daptomycin (5 micrograms/ml) alone was bactericidal (greater than 3 log10 killing), synergistic activity was demonstrable only when the concentration of daptomycin was lowered to 0.25 to 0.5 microgram/ml. A 50% dilution of human serum diminished the bactericidal activity of daptomycin alone at 24 h but did not affect killing observed with the daptomycin-fosfomycin combination. The inhibition of peptidoglycan synthesis by the combination was greater than the inhibition observed with either drug alone. The combination of daptomycin and fosfomycin exhibited consistent synergistic bactericidal activity against strains of E. faecalis possessing high-level resistance to gentamicin. This synergism may be the result of sequential inhibition of early steps in peptidoglycan synthesis.

Anti-Bacterial Agents↗
PubMed1990

Beta-lactam-fosfomycin antagonism involving modification of penicillin-binding protein 3 in Pseudomonas aeruginosa.

Antagonism between fosfomycin and antipseudomonal penicillins, cefotaxime, and ceftriaxone was observed in Pseudomonas aeruginosa RYC212. Fosfomycin, a non-beta-lactam antibiotic that acts on bacterial cell wall synthesis, decreased the expression of penicillin-binding protein 3 and induced beta-lactamase. The antagonistic effect was reduced in the presence of high concentrations of the beta-lactamase inhibitor tazobactam or in fosfomycin-resistant mutants. We suggest that products resulting from fosfomycin cell wall damage could interact with a system that regulates penicillin-binding protein and beta-lactamase production.

Anti-Bacterial Agents↗
PubMed1991

In vitro susceptibility testing procedures for fosfomycin tromethamine.

Fosfomycin tromethamine (previously fosfomycin trometamol) is an orally administered fosfomycin which may be used for single-dose therapy of uncomplicated urinary tract infections. Fosfomycin tromethamine, norfloxacin, and trimethoprim-sulfamethoxazole inhibited greater than 90% of 352 bacterial isolates representing 25 different species; trimethoprim and nalidixic acid had narrower spectrums of activity. Strains of Escherichia, Citrobacter, Enterobacter, and Klebsiella species were much more susceptible when glucose-6-phosphate was added to the test medium, but isolates belonging to other genera were not affected.

Bacteria↗
PubMed1995

In vitro interactions between different beta-lactam antibiotics and fosfomycin against bloodstream isolates of enterococci.

The effects of 16 different beta-lactam-fosfomycin combinations against 50 bloodstream enterococci were compared by a disk diffusion technique. Cefotaxime exhibited the best interaction. By checkerboard studies, the cefotaxime-fosfomycin combination provided a synergistic bacteriostatic effect against 45 of the 50 isolates (MIC of cefotaxime at which 90% of the isolates were inhibited, >2,048 micrograms/ml; MIC of fosfomycin at which 90% of the isolates were inhibited, 128 micrograms/ml; mean of fractional inhibitory concentration indexes, 0.195). By killing curves, cefotaxime (at 64 micrograms/ml) combined with fosfomycin (at > or = 64 micrograms/ml) was bactericidal against 6 of 10 strains tested.

Anti-Bacterial Agents↗
PubMed1995

Comparative efficacies of ciprofloxacin and pefloxacin alone or in combination with fosfomycin in experimental endocarditis induced by multidrug-susceptible and -resistant Pseudomonas aeruginosa.

The in vivo efficacy of ciprofloxacin or pefloxacin alone or in combination with fosfomycin was evaluated in experimental aortic valve endocarditis induced in 133 rabbits by a multidrug-susceptible or multidrug-resistant strain of Pseudomonas aeruginosa. Therapy was initiated early (12 h after infection), when bacterial counts in aortic valve vegetations were relatively low, or late (48 h after infection), when vegetations contained a larger inoculum. Antibodies were administered as a continuous 24-h intravenous infusion. Mean steady-state levels of ciprofloxacin (64 mg/kg), pefloxacin (64 mg/kg), and fosfomycin (300 mg/kg) in serum were 2.5, 4.2, and 63.9 mg/liter, respectively. For the multidrug-susceptible strain, all regimens except pefloxacin alone significantly reduced the number of CFU per gram of vegetation versus controls, whether treatment was performed early or late. For the multidrug-resistant strain, none of the regimens showed differences from untreated controls, except ciprofloxacin-fosfomycin, which significantly reduced bacterial counts in vegetations compared with controls when therapy was begun early (4.1 +/- 1.1 log10 CFU/g of vegetation; P < 0.001 versus the control). These data suggest that combination of fosfomycin with ciprofloxacin or pefloxacin is more effective than ciprofloxacin or pefloxacin alone for the therapy of severe infections caused by multidrug-susceptible P. aeruginosa.

Animals↗
PubMed1995

Combination effect of fosfomycin and ofloxacin against Pseudomonas aeruginosa growing in a biofilm.

We examined the combined effect of fosfomycin and ofloxacin against Pseudomonas aeruginosa in biofilms by using an in vitro experimental system with a modified Robbins device. Sessile cells in a mature or immature biofilm, developed on a silicon disk, were used, and an ATP bioluminescence assay was employed to assess antibacterial effects. A synergistic effect of fosfomycin and ofloxacin was clearly detected when concentrations at which each drug independently produced no detectable decrease in the bioactivity of sessile cells were used. Exposure of the cells in a mature biofilm to fosfomycin at concentrations of one-eighth of the MIC to 10 times the MIC (6.25 to 500 micrograms/ml) and ofloxacin at three or 10 times the MIC (18.75 or 62.5 micrograms/ml) resulted in reduction of the bioactivity to 1.5 to 4.5% after 72 h. Young sessile cells in an immature biofilm were more susceptible to this combination therapy. With a combination of fosfomycin at three times the MIC and ofloxacin at three times the MIC, complete eradication was confirmed by both ATP assay and scanning electron microscopy.

Adenosine Triphosphate↗
PubMed1998

Fosfomycin reduces CD15s-related antigen expression of Streptococcus pyogenes.

We have previously shown the immunological mimicry of human sialyl-Lewis(x) (CD15s) by a surface antigen of Streptococcus pyogenes. This mimicking surface antigen may act as a ligand to the selectin family and may induce antibody production against CD15s on host cells, suggesting a possible role in the pathogenesis of S. pyogenes. In this study, the effects of antibiotics on the CD15s-related antigen expression of S. pyogenes were examined at a concentration below the MIC (sub-MIC). The amounts of CD15s on the surfaces of S. pyogenes cells and on the surfaces of S. pyogenes biofilms were determined by a whole-cell enzyme-linked immunosorbent assay and by laser scanning fluorescence microscopy, respectively, by using an anti-CD15s monoclonal antibody. At the sub-MICs, fosfomycin (1R,2S-1,2-epoxypropyl phosphonic acid), its enantiomer (1S,2R-1,2-epoxypropyl phosphonic acid), and benzylpenicillin significantly inhibited the CD15s expression of all strains studied. The effects of fosfomycin and its enantiomer on biofilms were also observed by scanning electron microscopy. Incubation of S. pyogenes with the sub-MIC of fosfomycin or its enantiomer, which has no antibacterial activity, reduced the amount of CD15s on the biofilm surface and made it smooth. These results suggest that fosfomycin or its enantiomer might be useful for preventing S. pyogenes adherence to human CD15s receptors and the resulting immunological pathogenicity.

Anti-Bacterial Agents↗
PubMed2003

In vitro and in vivo functional activity of Chlamydia MurA, a UDP-N-acetylglucosamine enolpyruvyl transferase involved in peptidoglycan synthesis and fosfomycin resistance.

Organisms of Chlamydia spp. are obligate intracellular, gram-negative bacteria with a dimorphic developmental cycle that takes place entirely within a membrane-bound vacuole termed an inclusion. The chlamydial anomaly refers to the fact that cell wall-active antibiotics inhibit Chlamydia growth and peptidoglycan (PG) synthesis genes are present in the genome, yet there is no biochemical evidence for synthesis of PG. In this work, we undertook a genetics-based approach to reevaluate the chlamydial anomaly by characterizing MurA, a UDP-N-acetylglucosamine enolpyruvyl transferase that catalyzes the first committed step of PG synthesis. The murA gene from Chlamydia trachomatis serovar L2 was cloned and placed under the control of the arabinose-inducible, glucose-repressible ara promoter and transformed into Escherichia coli. After transduction of a lethal DeltamurA mutation into the strain, viability of the E. coli strain became dependent upon expression of the C. trachomatis murA. DNA sequence analysis of murA from C. trachomatis predicted a cysteine-to-aspartate change in a key residue within the active site of MurA. In E. coli, the same mutation has previously been shown to cause resistance to fosfomycin, a potent antibiotic that specifically targets MurA. In vitro activity of the chlamydial MurA was resistant to high levels of fosfomycin. Growth of C. trachomatis was also resistant to fosfomycin. Moreover, fosfomycin resistance was imparted to the E. coli strain expressing the chlamydial murA. Conversion of C. trachomatis elementary bodies to reticulate bodies and cell division are correlated with expression of murA mRNA. mRNA from murB, the second enzymatic reaction in the PG pathway, was also detected during C. trachomatis infection. Our findings, as well as work from other groups, suggest that a functional PG pathway exists in Chlamydia spp. We propose that chlamydial PG is essential for progression through the developmental cycle as well as for cell division. Elucidating the existence of PG in Chlamydia spp. is of significance for the development of novel antibiotics targeting the chlamydial cell wall.

Alkyl and Aryl Transferases↗
PubMed2006

[Activity of fosfomycin against extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae].

INTRODUCTION: Infection due to extended-spectrum beta-lactamase (ESBL)-producing microorganisms is an emerging problem in the community; a high proportion of these microorganisms have been isolated from urine samples of women with uncomplicated urinary tract infections (UTI). The options for oral treatment of uncomplicated UTI are limited because of the multiple drug resistance typical of ESBL-producing strains. METHODS: The in vitro activity of fosfomycin (FOS) was determined against 428 ESBL-producing strains, including 290 (68%) E. coli and 138 (32%) K. pneumoniae. Activity of fosfomycin was compared with that of amoxicillin-clavulanate (AMC), ciprofloxacin (CIP) and cotrimoxazole (SxT). MICs of AMC, CIP, and SxT, and detection of ESBL production were tested by the broth microdilution method, whereas FOS MICs were determined by the agar dilution method. ESBLs were characterized by isoelectric focusing, polymerase chain reaction (PCR) and direct sequencing of encoding genes. The genetic relationship among the isolates was determined by REP-PCR. RESULTS: Among the 428 ESBL-producing isolates studied, 417 (97.4%) were susceptible to FOS (MIC < or = 64 microg/mL). The resistance rate of E. coli to FOS was 0.3%, and was lower than resistance to AMC (11.7%), whereas the resistance rate of K. pneumoniae was 7.2% and was equal to resistance to AMC. SxT and CIP were the least active antibiotic agents against ESBL-producing isolates (sensitivity < 50%). There were no differences in fosfomycin activity against strains expressing different types of ESBLs. CONCLUSION: Fosfomycin showed maintained activity against ESBL-producing strains and did not present co-resistance with other antimicrobial groups.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1977

The action of fosfomycin on the growth of Pseudomonas aeruginosa.

A study was made of the effect of the inoculum size and the culture conditions on the MIC of a strain of Pseudomonas aeruginosa that was sensitive to fosfomycin. The increase of the inoculum and the conditions which favour the cellular multiplication considerably increase the MIC. Phosphates inhibit the action of the antibiotic. Fosfomycin produces a logarithmic decrease in the number surviving 1 h after being added; the bacterial lysis measured by the decrease in the OD depends on the medium and is hardly noticeable in ordinary broth. In a minimum medium the antibiotic does not affect the growth. The determination of the variation in the consumption of oxygen is a rapid and accurate method of evaluating the effect of fosfomycin. A spontaneous mutant glpT was isolated which was more than 128 times more resistant than the isogenic parental strain. The growth curves of this mutant, the sensitive parental strain and a naturally resistant strain that was isolated in a patient were similar to each other in complex media. In synthetic media the naturally resistant strain shows shorter phases of latency, but the generation times are analogous. This would seem to indicate that the resistance to fosfomycin in P. aeruginosa has no influence on the speed of growth.

Anti-Bacterial Agents↗
PubMed1977

Sensitivity of Bacteroidaceae to fosfomycin.

The sensitivity of 116 strains of Bacteroides fragilis and 60 strains of Sphaerophorus to fosfomycin was studied. Of the 178 strains that were tested, 156 were isolated from pathological products in our department and the remainder came from the following collections: NCTC, ATCC and the Institut fur Mikrobiologie of the University of Bonn. Identification was made morphologically and biochemically in accordance with the scheme which we usually employ and which has previously been published. The sensitivities were determined by the progressive dilution method in a solid medium with a surface inoculation of the strain. The results obtained show that no matter what kind of B. fragilis was tested, none of them were sensitive to concentrations of 200 mug/ml fosfomycin. On the other hand, all strains of Sphaerophorus were sensitive to lesser concentrations than the aforementioned. The majority of these concentrations subsequently lie within therapeutic margins. The conclusion drawn from our results is that the sensitivity to fosfomycin constitutes a test for differentiating Bacteroides from Sphaerophorus and that fosfomycin is ineffective in injections caused by Bacteroides, although it is an active antibiotic against infections caused by Sphaerophorus.

Anti-Bacterial Agents↗
PubMed1977

Interactions of fosfomycin with other antibiotics.

We selected 100 strains of organisms that were isolated in our hospital, which came from pathological products and which had an MIC of fosfomycin of 256 mug/ml or more and belonged to the genera Klebsiella, Pseudomonas, Escherichia coli, Serratia, Enterobacter, Proteus, Acinetobacter, Levinea and Staphylococcus. We have studied the effect of the association of fosfomycin with 15 antibiotics (beta-lactamins, cephalosporins, aminoglycosides, etc.) and 5 chemotherapeutics. The 11 selected strains were studied by the 'chess board' technique in agar. A study was also carried out on the action of fosfomycin on E. coli K12 E711 in the phase of logarithmic growth. The 11 selected strains were studied by the 'chess board' technique in agar. Synergic effect with fosfomycin associated to other antimicrobials was found in 9 strains.

Anti-Bacterial Agents↗