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PubMed2006

Is single-dose fosfomycin trometamol a good alternative for asymptomatic bacteriuria in the second trimesterof pregnancy?

Untreated asymptomatic bacteriuria has been associated with acute pyelonephritis, which may have a role in many maternal and fetal complications. Acute pyelonephritis in pregnancy is related to anemia, septicemia, transient renal dysfunction, and pulmonary insufficiency. A randomized study was conducted to assess the clinical and microbiological efficacy of a single dose of fosfomycin trometamol for the treatment of asymptomatic bacteriuria in the second trimester of pregnancy compared with a 5-day regimen of cefuroxime axetyl. Forty-four women received fosfomycin trometamol and 40 women received cefuroxime axetyl. There were no statistically significant differences between both groups regarding the mean age and mean duration of pregnancy. Therapeutic success was achieved in 93.2% of the patients treated with fosfomycin trometamol vs 95% of those treated with cefuroxime axetyl. A single dose of fosfomycin trometamol is a safe and effective alternative in the treatment of asymptomatic urinary tract infections in the second trimester of pregnancy.

Adult↗
PubMed2005

In vitro activity of fosfomycin alone and in combination with amoxicillin, clarithromycin and metronidazole against Helicobacter pylori compared with combined clarithromycin and metronidazole.

In order to evaluate the suitability of fosfomycin in combination with other agents for the treatment of Helicobacter pylori infections, the susceptibility profiles of 65 H. pylori strains were determined against multiple antimicrobial agents and combinations thereof using the agar dilution method. For fosfomycin alone, the range of minimum inhibitory concentration (MIC) results and the MICs at which 50% and 90% of strains were inhibited were 0.5-32 microg/ml and 2 and 4 microg/ml, respectively. For the combination of fosfomycin with amoxicillin, clarithromycin or metronidazole, the means calculated for the minimum and maximum fractional inhibitory concentration index were 0.70-1.17 and 1.15-2.03, respectively, suggesting partial synergy or indifference in the majority of strains. The combination of clarithromycin and metronidazole showed synergistic activity against 14 of 28 H. pylori strains tested. The in vitro activity results suggest the combination of fosfomycin with either amoxicillin or clarithromycin may be a promising alternative for the treatment of H. pylori infection. However, the clinical efficacy of these regimens remains to be investigated.

Amoxicillin↗
PubMed2000

Medium compositions and culture conditions for the assay of fosfomycin susceptibility by Etest.

The Etest (AB Biodisk, Solna, Sweden), a susceptibility testing method, was used for fosfomycin and was evaluated by comparison with the agar dilution method for 73 clinical isolates of Escherichia coli, including two resistant strains, and an optimal Etest method for fosfomycin was determined. Media and culture conditions greatly affected the minimum inhibitory concentrations (MICs) determined by the Etest for fosfomycin, as shown for the agar dilution methods. Our results showed that the most favorable conditions for the Etest for fosfomycin were with Mueller-Hinton agar (Becton-Dickinson Japan, Tokyo, Japan) under aerobic conditions. However, the MICs for the resistant strains were much higher than those determined by agar dilution methods, using Nutrient agar (Becton-Dickinson Japan) under anaerobic conditions. The addition of glucose-6-phosphate did not significantly affect the Etest results.

Agar↗
PubMed1992

Fosfomycin enhances the expression of penicillin-binding protein 2 in methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains.

The effects of fosfomycin on penicillin-binding proteins (PBPs) were studied on the methicillin-resistant Staphylococcus aureus strain CIP (Collection de l'Institut Pasteur, Paris, France) 65-25 and on a methicillin-susceptible S. aureus strain CIP 65-6. The combinations of fosfomycin and oxacillin were synergistic, additive or antagonistic, depending on antibiotic concentrations. Fosfomycin induced modifications of the PBP profile of the two strains studied. In particular, it increased the expression of PBP2. This suggested that this protein is inducible; the only PBP not affected by fosfomycin was PBP3.

Bacterial Proteins↗
PubMed1992

In vivo activity of the combination of daptomycin and fosfomycin compared with daptomycin alone against a strain of Enterococcus faecalis with high-level gentamicin resistance in the rat endocarditis model.

The in vivo activity of the combination of daptomycin and fosfomycin against a beta-lactamase-producing, highly gentamicin-resistant strain of Enterococcus faecalis in a relapse model of rat endocarditis was studied. Minimum inhibitory concentrations (MICs) (micrograms per milliliter) for these agents against this strain were 4 (daptomycin) and 16 (fosfomycin). Time-kill studies demonstrated synergistic bactericidal activity when daptomycin (0.5 micrograms/ml) and fosfomycin (32 micrograms/ml) were combined. There was no significant difference between the number of valves sterilized by daptomycin alone [six (35%) of 17 valves sterilized] and daptomycin+fosfomycin [ten (59%) of 17 valves sterilized] p = 0.3. These results suggest that the in vitro bactericidal synergism demonstrable between these two agents against strains of enterococci will not necessarily translate into greater therapeutic efficacy in clinical infections.

Animals↗
PubMed2001

Control of Salmonella enteritidis phage type 4 experimental infection by fosfomycin in newly hatched chicks.

One hundred and twenty 1-day-old broiler chickens were divided into four groups: group I unmedicated and orally challenged with 1.5 x 10(8) cfu of Salmonella enteritidis phage type 4; group F infected and treated with 300 ppm of fosfomycin in their drinking water; group CF uninfected and treated, and group C maintained as a control group. Their performance, clinical signs, S. enteritidis PT4 reisolation and biochemistry variables were compared. Group F showed fewer symptoms and gross lesions than those from group 1. Fosfomycin treatment at 300 ppm improved body weight at 7 days of age by 42.3%. S. enteritidis PT4 reisolation in group I was higher than in the treated group, but total decontamination of challenged birds was not achieved. There was an increase in the levels of total protein and globulins in group I but not in the treated group. Fosfomycin caused no adverse effects on chickens from group CF, assessed by performance and biochemical variables. The results indicate that fosfomycin could be used in the treatment of S. enteritidis PT4 experimental infection.

Animals↗
PubMed2001

[Fosfomycin: an underrated antibiotic for urinary tract infections due to Escherichia coli].

OBJECTIVES: To evaluate the sensitivity patterns of Escherichia coli isolates obtained from urine specimens from patients with community-acquired urinary tract infections, with a special emphasis on fosfomycin trometamol for the treatment of UTI. METHODS: Retrospective analysis of the sensitivity pattern of 16,227 E. coli isolates recovered from urine cultures performed at the Microbiology Laboratory of Madrid Area 11 from 1997 to 2000. The antimicrobial agents tested included ampicillin, amoxycillin-clavulanate, cephalotin, cefuroxime, trimethoprim-sulphamethoxazol, fosfomycin trometamol, nitrofurantoin, and ciprofloxacin. Antibiotic sensitivity testing was performed with the Vitek automatic microdilution system (bioMèrieux, France). RESULTS: E. coli represented 80.1% of all uropathogens recovered. The percentages of sensitive strains to ampicillin, amoxycillin-clavulanate, cephalotin, cefuroxime, trimethoprim-sulphamethoxazol, nitrofurantoin, and ciprofloxacin were 42.25%, 81.5%, 58.75%, 87.5%, 70%, 94.75%, and 84.75%, respectively. Fosfomycin trometamol was the antibiotic with the highest activity against E. coli, with 95.5% of sensitive isolates. CONCLUSIONS: Fosfomycin trometamol (single dose) is a good alternative that should be considered for the treatment of non-complicated lower urinary tract infections.

Anti-Bacterial Agents↗
PubMed2003

Target site bacterial killing of cefpirome and fosfomycin in critically ill patients.

We employed an in-vivo pharmacokinetic/in-vitro pharmacodynamic method to simulate bacterial killing in plasma and the interstitium of skeletal muscle tissue after intravenous administration of 2 g of cefpirome and 8 g of fosfomycin alone and in combination to patients with sepsis. Interstitial antimicrobial concentrations were determined by use of in-vivo microdialysis. CFU/ml of Staphylococcus aureus (ATCC 29213) and Pseudomonas aeruginosa (clinical isolate) decreased by approximately 2log(10) for plasma and muscle tissue 6 h after cefpirome and fosfomycin administration compared with the baseline, respectively. The simulation of plasma and tissue pharmacokinetics for the combined administration of these antibiotics resulted in complete eradication of S. aureus within 5 h after drug exposure. No bacterial re-growth occurred in any of the simulations within 6 h. The in-vitro simulation of in-vivo plasma and tissue pharmacokinetics of cefpirome and fosfomycin has shown that both antimicrobial agents kill S. aureus and P. aeruginosa strains effectively after single dose administration. This effect was most pronounced by the combined use of these antimicrobial agents. Therefore, this data corroborates antimicrobial strategies of simultaneous administration of cefpirome and fosfomycin in patients with severe soft tissue infection.

Anti-Bacterial Agents↗
PubMed2003

Why fosfomycin trometamol as first line therapy for uncomplicated UTI?

Uncomplicated urinary tract infection (UTI) is one of the most common conditions requiring diagnostic and therapeutic intervention. The aetiology and the treatment of these infectious diseases have changed little during last years of the 'antibiotic era'. Escherichia coli is the most prevalent uropathogen (85->90%) and treatment is aimed at eradicating the infection using shorter regimes that typically may employ a 3-day course with once-a-day dosing of a selected drug or a single dose of a particular efficacious antibiotic. Antibiotic resistance to commonly used agents, such as trimethoprim and ampicillin, often now exceeds 30-50%, while fosfomycin trometamol, despite many years of usage, continues to be characterized by an extremely low incidence of E. coli resistant strains (about 1%) worldwide. Many factors may have contributed to preserve fosfomycin trometamol antibacterial activity including single dose usage limited to urinary infections, very high and sustained urinary concentrations that rapidly kill bacteria reducing the opportunity for mutant selection. In addition there is no animal feed that contains the drug, resistance is most commonly acquired by chromosomal mutations that do not spread easily and the biological cost of these genetic modifications is high. To these parameters fosfomycin trometamol adds excellent tolerability and safety. Although nowadays, microbial resistance limits available resources and some drugs can no longer be recommended as reliable agents, fosfomycin trometamol, because of its properties, remains a drug of choice for the eradication of uncomplicated UTI.

Animals↗
PubMed1998

A comparison between single-dose fosfomycin trometamol (Monuril) and a 5-day course of trimethoprim in the treatment of uncomplicated lower urinary tract infection in women.

This study is a comparison of the microbiological and clinical efficacy of single-dose fosfomycin trometamol therapy and a 5 day course of trimethoprim in the treatment of uncomplicated urinary tract infection in female patients. Urine dip-slide samples were obtained from 547 female patients aged 18-65 by 22 General Practitioners (GPs) participating in the study from 21 centres in the UK. All patients were diagnosed as having a urinary tract infection by their GP on the basis of history and clinical examination. Patients were randomised to receive either single dose fosfomycin trometamol or a 5 day course of trimethoprim in a 2:1 ratio. Patients who had significant bacteriuria (> or = 10(5) c.f.u/ml) at the first visit (300) were included in the microbiological analysis. The two commonest urinary pathogens isolated were Escherichia coli and Staphylococcus saprophyticus. Trimethoprim resistance was more frequent amongst E. coli isolates whereas fosfomycin trometamol resistance was more common amongst S. saprophyticus isolates. Microbiological cure was demonstrated in 83.3% of the trimethoprim treated group and 83% of the fosfomycin trometamol treated group. Persistence of the infecting bacteria was seen in 17% of each treatment arm.

Adult↗
PubMed1996

Structure of UDP-N-acetylglucosamine enolpyruvyl transferase, an enzyme essential for the synthesis of bacterial peptidoglycan, complexed with substrate UDP-N-acetylglucosamine and the drug fosfomycin.

BACKGROUND: UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), catalyses the first committed step of bacterial cell wall biosynthesis and is a target for the antibiotic fosfomycin. The only other known enolpyruvyl transferase is 5-enolpyruvylshikimate-3-phosphate (EPSP) synthase, an enzyme involved in the shikimic acid pathway and the target for the herbicide glyphosate. Inhibitors of enolpyruvyl transferases are of biotechnological interest as MurA and EPSP synthase are found exclusively in plants and microbes. RESULTS: The crystal structure of Escherichia coli MurA complexed with UDP-N-acetylglucosamine (UDP-GlcNAc) and fosfomycin has been determined at 1.8 A resolution. The structure consists of two domains with the active site located between them. The domains have a very similar secondary structure, and the overall protein architecture is similar to that of EPSP synthase. The fosfomycin molecule is covalently bound to the cysteine residue Cys115, whereas UDP-GlcNAc makes several hydrogen-bonding interactions with residues from both domains. CONCLUSIONS: The present structure reveals the mode of binding of the natural substrate UDP-GlcNAc and of the drug fosfomycin, and provides information on the residues involved in catalysis. These results should aid the design of inhibitors which would interfere with enzyme-catalyzed reactions in the early stage of the bacterial cell wall biosynthesis. Furthermore, the crystal structure of MurA provides a model for predicting active-site residues in EPSP synthase that may be involved in catalysis and substrate binding.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed2003

Fosfomycin therapy for multiresistant Pseudomonas aeruginosa in cystic fibrosis.

BACKGROUND: Increasing resistance to standard antibiotics has been demonstrated in CF patients colonised by Pseudomonas aeruginosa. The antibiotic Fosfomycin has a unique mode of action against this organism, and may protect against aminoglycoside mediated renal and ototoxic effects. However, there is little published experience of this drug in IV form, and it is not licensed for use in the UK. METHODS: In combination with other antibiotics, we used Fosfomycin to treat 30 pulmonary exacerbations in 15 adult CF patients colonised by P. aeruginosa, mainly multiresistant strains. All patients gave informed consent. We cultured sputum prior to treatment and measured spirometry, renal function, and symptoms before and after treatment, and recorded any side effects. RESULTS: One patient developed nausea and Fosfomycin treatment was withdrawn. The remaining patients showed clinical resolution of their chest exacerbations (mean FEV1% predicted: pre 41.1 vs. post 49.4, P<0.001). Although there was a statistical increase in plasma urea (pre 3.9 mmol/l vs. post 4.3, P<0.03), this was still within the normal range. Plasma creatinine was unchanged. CONCLUSIONS: This study shows that IV Fosfomycin is well tolerated by adult patients with CF and can be useful in the treatment of those colonised with multiresistant P. aeruginosa.

Adolescent↗
PubMed1986

In vitro and in vivo study of fosfomycin in methicillin-resistant Staphylococcus aureus septicaemia.

Five hundred strains of methicillin-resistant Staphylococcus aureus were tested against various anti-staphylococcal agents. Vancomycin, fusidic acid and fosfomycin were found to be the most effective. Only 1 strain out of 500 was resistant to fosfomycin. Three patients with methicillin-resistant Staphylococcus aureus septicaemia were successfully treated by fosfomycin. We conclude that fosfomycin could be the drug of choice for methicillin-resistant Staphylococcus aureus infection.

Adult↗
PubMed1997

The stimulating effect of fosfomycin, an antibiotic in common use in Japan, on the production/release of verotoxin-1 from enterohaemorrhagic Escherichia coli O157:H7 in vitro.

In 1996 Japan had a big outbreak of enterohaemorrhagic Escherichia coli (EHEC) O157:H7, especially in Osaka prefecture where about 6000 patients (mainly schoolchildren) suffered from diarrhoea, haemorrhagic colitis and haemolytic uraemic syndrome (HUS) due to EHEC infection via school lunch. Our survey of doctors who took care of those patients showed that most patients had received antibiotics, especially fosfomycin which comprised 84% of the prescribed treatment. Since the administration of antibiotics for EHEC infection is under discussion, we analysed the effect of fosfomycin on production/release of verotoxins (VTs). Addition of fosfomycin into EHEC culture in CAYE broth at 2 and 5 h after start of incubation caused marked increase of VT1 release. This observation warns of the possibility of fosfomycin treatment making the disease worse.

Anti-Bacterial Agents↗
PubMed2003

Antimicrobial susceptibility of vancomycin-resistant Enterococcus faecium: potential utility of fosfomycin.

The increasing prevalence of vancomycin-resistant enterococcal (VRE) infections has necessitated a search for drugs that are effective in treating these infections, and a need to determine whether currently available antimicrobials are effective. 75 consecutive clinical isolates of vancomycin-resistant Enterococcus faecium (VRE faecium) (40 blood and 35 urine isolates) isolated over 1 y at the Cleveland Clinic Foundation were tested for susceptibility to linezolid, quinupristin-dalfopristin, fosfomycin and nitrofurantoin using the Etest. The minimum inhibitory concentrations were read independently by 3 observers and compared, and a final reading was obtained by predetermined criteria. The proportion of isolates susceptible to linezolid, quinupristin-dalfopristin, fosfomycin and nitrofurantoin was 100%, 98.7%, 98.7% and 78.7%, respectively. No single isolate was resistant to more than 1 of the 4 drugs tested. Etest presented significant unexpected difficulties in testing for VRE faecium susceptibility to nitrofurantoin. Fosfomycin may be a useful alternative to linezolid and quinupristin-dalfopristin in the treatment of VRE infections in certain clinical situations, e.g. uncomplicated urinary tract infections. In addition, the use of fosfomycin could limit the use of newer agents, thus reducing the chance of development of further resistance in the enterococci.

Anti-Bacterial Agents↗
PubMed1995

Effects of combination of benzylpenicillin and fosfomycin on penicillin-resistant Streptococcus pneumoniae.

The in vitro activity of benzylpenicillin in combination with fosfomycin against 51 clinical isolates of penicillin-resistant Streptococcus pneumoniae [minimal inhibitory concentrations (MICs) of benzylpenicillin > or = 0.5 mg/liter] was investigated. The fractional inhibitory concentration (FIC) index using the checkerboard method ranged from 0.38 to 0.75 (mean: 0.63). A synergy was also demonstrated in the killing curve on S. pneumoniae TW-1303 (MIC of benzylpenicillin, 2 mg/liter; MIC of fosfomycin, 32 mg/liter: FIC index, 0.38). Fosfomycin inhibited the production of all penicillin-binding proteins (PBP) except PBP 2B of S. pneumoniae TW-1303 and it decreased that of PBP 2B when it was combined with benzylpenicillin. These results suggest that the combination of benzylpenicillin and fosfomycin could be considered as the alternative treatment of penicillin-resistant pneumococcal infections.

Bacterial Proteins↗
PubMed1983

Comparative study of fosfomycin activity in Mueller-Hinton media and in tissues.

Fosfomycin utilizes two uptake systems as ways of entry into microorganisms: the L-a-glycerophosphate and the hexose phosphate transport system. The latter is inducible by glucose-6-phosphate. The relationship between glucose-6-phosphate (concentration range 0-100 mg/l) and the susceptibility of Staphylococcus aureus was studied in Mueller-Hinton broth. An almost maximal enhancement of fosfomycin activity was found at 25 mg/l glucose-6-phosphate. Fosfomycin activity against Staph. aureus, Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Klebsiella spp., Serratia spp., and Pseudomonas aeruginosa was studied by use of the broth and the agar dilution method, in the presence and absence of glucose-6-phosphate (25 mg/l). The minimum inhibitory concentrations (MICs) of fosfomycin against Staph. aureus Streptococcus faecalis, E. coli, Ent. cloacae, Pr. mirabilis, and Ps. aeruginosa were estimated in particle free supernatants of 25% tissue homogenates (liver, kidney, lung, heart) and in parallel in Mueller-Hinton broth. With few exceptions the MICs in Mueller-Hinton broth (with glucose-6-phosphate) were similar to those found in tissues (no glucose-6-phosphate added).

Animals↗
PubMed1983

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.

Anti-Bacterial Agents↗