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PubMed1992

The influence of anaerobiosis on the activity of fosfomycin trometamol.

MICs of fosfomycin trometamol were estimated for 40 strains of bacteria (20 gram-positive cocci, 20 gram-negative bacilli) by the agar incorporation method (Iso-Sensitest agar) in the presence of the potentiating agent, glucose-6-phosphate (25 mg/l). Titrations were carried out in duplicate under aerobic and anaerobic conditions. For 22 strains (12 gram-negative bacilli), a fourfold or greater reduction in MIC was observed in tests conducted under anaerobic conditions. The effect was particularly marked with Klebsiella spp., four of five strains of which showed a 16- to 32-fold reduction in MIC in anaerobic conditions. To investigate the reasons for the effect of anaerobiosis, selected strains were examined in an opacity monitoring device in which cultures can be grown in aerobic or anaerobic atmosphere. Surprisingly, the effect of anaerobiosis observed by continuous turbidimetric monitoring was much less than that seen in agar incorporation MIC titrations: under anaerobic conditions, there was little or no reduction in the concentration of fosfomycin trometamol required to cause a lytic effect on dense bacterial cultures, and a small, but variable effect on the emergence of resistant variants.

Anaerobiosis↗
PubMed1993

Fosfomycin trometamol in a single dose versus seven days nitrofurantoin in the treatment of acute uncomplicated urinary tract infections in women.

In general practice acute uncomplicated urinary tract infections in women are treated with different courses of antibiotics. In this study the efficacy and tolerability of a single dose of 3 g fosfomycin trometamol and the conventional treatment with nitrofurantoin 50 mg four times daily for seven days were compared. In a randomized, double-blind, double-dummy trial in 31 general practices in the Netherlands 231 patients with symptoms of acute dysuria, stranguria and/or urinary frequency received treatment. Evaluation was based on resolution of symptoms, dipslide results and side-effects at 4, 9 and 42 days after starting the treatment. The clinical cure rates and bacteriological cure rates were not significantly different between the treatment groups. Side-effects were reported at day 4 by 43% of the women receiving single-dose treatment, compared with 25% of the women in the seven-day treatment group, a significant difference. At day 9 the groups did not significantly differ in the number of patients with side-effects. Almost all side-effects were mild and gastro-intestinal complaints were reported most. Taking into account the convenience of taking a single dose we conclude that fosfomycin trometamol is a reasonable alternative to 7 days nitrofurantoin 50 mg four times a day in the treatment of women with symptoms of acute uncomplicated urinary tract infections in general practice.

Acute Disease↗
PubMed1993

Interpretive criteria and quality control parameters for determining bacterial susceptibility to fosfomycin tromethamine.

Studies with fosfomycin tromethamine disks containing 200 micrograms of fosfomycin and 50 micrograms of glucose-6-phosphate confirmed the following zone diameter criteria for the NCCLS method: < or = 12 mm for resistant (MIC > or = 256 micrograms/ml), 13-15 mm for intermediate (MIC 128 micrograms/ml) and > or = 16 mm for susceptible (MIC < or = 64 micrograms/ml). Additional studies defined acceptable MIC and zone diameter ranges for the following quality control strains: Escherichia coli ATCC 25922, MIC 0.5 to 4.0 micrograms/ml, zone diameter 23 to 29 mm; Staphylococcus aureus ATCC 25923, zone diameter 26 to 32 mm; Pseudomonas aeruginosa ATCC 27813, MIC 2.0 to 8.0 micrograms/ml; and Enterococcus faecalis, ATCC 29212, MIC 16 to 64 micrograms/ml.

Bacteria↗
PubMed1988

Isolation and study of fosfomycin-resistant mutants of group A and B streptococci.

Eighty-nine fosfomycin-resistant mutants of group A and B streptococci were isolated. The mutants differed essentially from the parent strains in cell-wall characteristics, such as morphology of cocci and chains, sensitivity to detergents and hydrophobic properties. At the same time, the recipient activity of the investigated mutants was not changed. It is supposed that resistance of mutants to fosfomycin is connected with a transport block of glycerol 3-phosphate--important lipoteichoic acid (LTA) structural component. Fosr mutants can be useful for experimental examination of Beachey's hypothesis about the importance of LTA or its complex with the M protein for adhesion.

Drug Resistance, Microbial↗
PubMed2003

Enhancement of antimicrobial effects of various antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) by combination with fosfomycin.

The present study was designed to evaluate the efficacy of fosfomycin used in combination with drugs that were found to be less effective against methicillin-resistant Staphylococcus aureus (MRSA). Twelve different antibiotics were tested against 32 strains of MRSA isolated from the wounds of burn patients admitted to the Burn Unit at Tokyo Women's Medical University Hospital. These antibiotics - fosfomycin (FOM), flomoxef sodium (FMOX), imipenem (IPM), cefotiam (CTM), cefmetazole (CMZ), ampicillin (ABPC), sulbactam/cefoperazone (SBT/CPZ), minocycline (MINO), ofloxacin (OFLX), and panipenem (PAPM) - were used either alone or in combination. Arbekacin (ABK) and vancomycin (VCM) were used for comparing efficacy in controlling bacterial growth. While both ABK and VCM were, as expected, found to be effective in suppressing in vitro bacterial growth, all ten other agents when used alone were found to be ineffective. In contrast, these agents, when used in combination with FOM, showed remarkable efficacy against all strains of MRSA tested. Based upon the in vitro findings, it is suggested that FOM, in combination with other antimicrobial agents, such as IPM, PAPM, CMZ, and SBT/CPZ may be used instead of ABK and/or VCM to curtail the emergence of Staphylococcus aureus strains that are resistant to these latter two drugs.

Anti-Bacterial Agents↗
PubMed2002

Effectiveness of fosfomycin combined with other antimicrobial agents against multidrug-resistant Pseudomonas aeruginosa isolates using the efficacy time index assay.

We investigated the effectiveness of fosfomycin combined with other antibiotics, such as piperacillin, cefepime, ceftazidime, imipenem, meropenem, aztreonam, gentamicin, or levofloxacin, against 30 Pseudomonas aeruginosa strains, including multidrug-resistant strains, isolated from clinical specimens, using the efficacy time index (ETI) assay. The assay refers to the result of pharmacokinetics obtained from adult men volunteers, and yields an ETI to evaluate the effect of a combination of antimicrobial agents. With the ETI, based on serum concentration 3 h after the administration of two antimicrobial agents, the effectiveness of antimicrobial combinations was evaluated as follows: poor, ETI < 0.5; fair, 0.5 < or = ETI < 1; good, 1 < or = ETI < 8; and excellent, ETI > or = 8. The combination of fosfomycin and cefepime (efficacy rate [excellent plus good], 76.7%) and fosfomycin/aztreonam (efficacy rate, 76.7%) appeared to be the most effective, followed by fosfomycin/meropenem (efficacy rate, 76.6%), fosfomycin/imipenem (efficacy rate, 73.3%), fosfomycin/ceftazidime (efficacy rate, 70%), fosfomycin/gentamicin (efficacy rate, 70%), fosfomycin/piperacillin (efficacy rate, 66.7%), and fosfomycin/levofloxacin (efficacy rate, 66.7%). Fosfomycin/cefepime, fosfomycin/aztreonam, and fosfomycin/meropenem may be clinically useful in selected patients, particularly for P. aeruginosa. The ETI assay provided information on the minimum inhibitory concentration (MIC) of many pairs of combined antimicrobial agents simultaneously. The ETI assay may be a useful technique with which to investigate the effect of combinations of antimicrobial agents against P. aeruginosa, including multidrug-resistant strains.

Drug Resistance, Bacterial↗
PubMed1989

Plasmid-mediated resistance to fosfomycin in Staphylococcus epidermidis.

Staphylococcus epidermidis strain BM2641, isolated from a patient, was resistant to penicillin G, methicillin, aminoglycosides, chloramphenicol, macrolide, lincosamide and streptogramin B-type (MLS) antibiotics, and to high levels of fosmycin. Resistance to forsfomycin and/or to MLS was lost at low frequencies either spontaneously or after curing with novobiocin. The plasmid DNA from BM2641 and its cured derivatives was purified, analyzed by agarose gel electrophoresis and transferred to a nitrocellulose sheet. Comparative analysis of the resistance phenotypes with the plasmid content of the strains indicated that fosfomycin and MLS resistance were encoded by plasmids pIP1842 (2.5 kb) and pIP1843 (2.6 kb), respectively. Southern hybridization with a probe specific for gene fosA of Serratia marcescens showed that the fosfomycin resistance determinant in Staphylococcus is not homologous to that of Gram-negative bacteria.

Conjugation, Genetic↗
PubMed1990

Correlation between the effects of fosfomycin and chloramphenicol on Escherichia coli.

It was speculated that the increase of the UDP-GlcNAc pool observed with chloramphenicol can modulate the residual PEP:UDP-GlcNAc-enolpyruvate activity of fosfomycin-treated cells. This provided an explanation on how chloramphenicol can insure the formation of enough UDP-MurNAc-pentapeptide to sustain peptidoglycan synthesis at a rate that will antagonize fosfomycin-induced lysis.

Bacteriolysis↗
PubMed2006

[Uncomplicated urinary tract infections, what about fosfomycin and nitrofurantoin in 2006?].

Since 2000 to 2005 we assessed the prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated urinary tract infections (UTI). A total of 19 618 bacteria were studied, fosfomycin, fluoroquinolones, nitrofurantoin were in vitro the most potent drugs with more than 80% of susceptibility. If we compare year 2000 to 2005 we observed a significant decrease of susceptibility for fluoroquinolones. For the same point of comparison, fosfomycin and nitrofurantoin showed a favourable evolution. Rationale and prudent use of antibiotics must now moved us to prescribe parsimoniously fluoroquinolones especially for some indications such as uncomplicated UTI though there are some others "old antibiotics" with a role may be underestimated for this specific indication.

Anti-Bacterial Agents↗
PubMedDate not supplied

[Comparison of fosfomycin-penicillin M and penicillin M-gentamycin. Apropos of 35 severe infections caused by methicillin-sensitive Staphylococcus aureus].

Two combined antibiotic treatments were compared in 35 cases of methicillin-sensitive Staph. aureus infection. Eighteen patients (including 17 with septicaemia) received penicillin M (methicillin or oxacillin) and gentamicin daily for a mean period of 11 days. Clinical and bacteriological cure was obtained in 14 cases; 2 of these 14 patients developed superinfection with gentamicin-resistant enterobacteria, 1 relapsed and 2 had renal impairment. Seventeen patients (including 15 with septicaemia) were given fosfomycin and penicillin M for a mean period of 17 days. Clinical and bacteriological cure was obtained in 16 patients; the patient with clinical and bacteriological failure died. There was no superinfection or relapse; 3 patients had hypokalaemia and 1 had renal damage caused by methicillin. The clinical and bacteriological results, therefore, were in favour of the fosfomycin-methicillin combination, but the only statistically significant difference between the two groups concerned the complications.

Adolescent↗
PubMed1990

Nucleotide sequence of the fosB gene conferring fosfomycin resistance in Staphylococcus epidermidis.

We have determined the nucleotide sequence of gene fosB of plasmid pIP1842, which confers resistant to fosfomycin in Staphylococcus epidermidis BM2641. The resistance gene was identified as a coding sequence of 417 bases pairs corresponding to a protein with a calculated Mw of 16,345 daltons. This value is in good agreement with that of 15,000, estimated by SDS-polyacrylamide gel electrophoresis of a bacterial cell-free coupled transcription-translation system. The fosB gene product exhibits 48% sequence homology with the fosfomycin resistance protein FOSA of Enterobacteriaceae. The substitutions are scattered throughout indicating that the two corresponding genes have diverged from a common ancestor. Downstream from fosB is located an open reading frame that was partially sequenced. The deduced amino-acid sequence was 50% homologous to REP alpha 1, a protein involved in the replication of the Enterococcus faecalis plasmid pAM alpha 1.

Amino Acid Sequence↗
PubMed2004

Phosphonoformate: a minimal transition state analogue inhibitor of the fosfomycin resistance protein, FosA.

Fosfomycin [(1R,2S)-epoxypropylphosphonic acid] is a simple phosphonate found to have antibacterial activity against both Gram-positive and Gram-negative microorganisms. Early resistance to the clinical use of the antibiotic was linked to a plasmid-encoded resistance protein, FosA, that catalyzes the addition of glutathione to the oxirane ring, rendering the antibiotic inactive. Subsequent studies led to the discovery of a genomically encoded homologue in the pathogen Pseudomonas aeruginosa. The proteins are Mn(II)-dependent enzymes where the metal is proposed to act as a Lewis acid stabilizing the negative charge that develops on the oxirane oxygen in the transition state. Several simple phosphonates, including the antiviral compound phosphonoformate (K(i) = 0.4 +/- 0.1 microM, K(d) approximately 0.2 microM), are shown to be inhibitors of FosA. The crystal structure of FosA from P. aeruginosa with phosphonoformate bound in the active site has been determined at 0.95 A resolution and reveals that the inhibitor forms a five-coordinate complex with the Mn(II) center with a geometry similar to that proposed for the transition state of the reaction. Binding studies show that phosphonoformate has a near-diffusion-controlled on rate (k(on) approximately 10(7)-10(8) M(-1) s(-1)) and an off rate (k(off) = 5 s(-1)) that is slower than that for fosfomycin (k(off) = 30 s(-1)). Taken together, these data suggest that the FosA-catalyzed reaction has a very early transition state and phosphonoformate acts as a minimal transition state analogue inhibitor.

Bacterial Proteins↗
PubMed1997

Fosfomycin resistance protein (FosA) is a manganese metalloglutathione transferase related to glyoxalase I and the extradiol dioxygenases.

The enzyme conferring resistance to the antibiotic fosfomycin [(1R,2S)-1,2-epoxypropylphosphonic acid] originally reported by Suarez and co-workers [Area, P., Hardisson, C., & Suarez, J. E. (1990) Antimicrob. Agents Chemother. 34, 844-848] is demonstrated in this study to be a metalloglutathione transferase. The apoenzyme is a dimer of 16 kDa subunits. Electron paramagnetic resonance spectroscopy and water proton nuclear magnetic resonance longitudinal relaxation rates suggest that each subunit contains a mononuclear Mn2+ center that interacts strongly with the substrate fosfomycin (Kd = 17 microM) more weakly with the product (Kd = 1.1 mM) and very weakly or not at all with GSH. Inhomogeneous broadening of the EPR signals of enzyme-bound Mn2+ in the presence of H2(17)O indicates that three of the coordination sites on the metal are occupied by water. Sequence alignments, three-dimensional structures, and mechanistic considerations suggest that FosA is related to at least two other metalloenzymes, glyoxalase I and the Mn2+- or Fe2+-containing extradiol dioxygenases. The mechanistic imperative driving the evolution of this previously unidentified superfamily of metalloenzymes is proposed to be bidentate coordination of a substrate or intermediate to the metal center in the enzyme-catalyzed reactions.

Amino Acid Sequence↗
PubMed1999

Elucidation of a monovalent cation dependence and characterization of the divalent cation binding site of the fosfomycin resistance protein (FosA).

The fosfomycin resistance protein FosA is a member of a distinct superfamily of metalloenzymes containing glyoxalase I, extradiol dioxygenases, and methylmalonyl-CoA epimerase. The dimeric enzyme, with the aid of a single mononuclear Mn2+ site in each subunit, catalyzes the addition of glutathione (GSH) to the oxirane ring of the antibiotic, rendering it inactive. Sequence alignments suggest that the metal binding site of FosA is composed of three residues: H7, H67, and E113. The single mutants H7A, H67A, and E113A as well as the more conservative mutants H7Q, H67Q, and E113Q exhibit marked decreases in the ability to bind Mn2+ and, in most instances, decreases in catalytic efficiency and the ability to confer resistance to the antibiotic. The enzyme also requires the monovalent cation K+ for optimal activity. The K+ ion activates the enzyme 100-fold with an activation constant of 6 mM, well below the physiologic concentration of K+ in E. coli. K+ can be replaced by other monovalent cations of similar ionic radii. Several lines of evidence suggest that the K+ ion interacts directly with the active site. Interaction of the enzyme with K+ is found to be dependent on the presence of the substrate fosfomycin. Moreover, the E113Q mutant exhibits a kcat which is 40% that of wild-type in the absence of K+. This mutant is not activated by monovalent cations. The behavior of the E113Q mutant is consistent with the proposition that the K+ ion helps balance the charge at the metal center, further lowering the activation barrier for addition of the anionic nucleophile. The fully activated, native enzyme provides a rate acceleration of >10(15) with respect to the spontaneous addition of GSH to the oxirane.

Bacterial Proteins↗
PubMed2003

Mechanistic diversity of fosfomycin resistance in pathogenic microorganisms.

Microbial resistance to the antibiotic fosfomycin [(1R,2S)-epoxypropylphosphonic acid, 1] is known to be mediated by thiol transferase enzymes FosA and FosB, which catalyze the addition of glutathione and l-cysteine to C1 of the oxirane, respectively. A probe of the microbial genome database reveals a related group of enzymes (FosX). The genes mlr3345 from Mesorhizobium loti and lmo1702 from Listeria monocytogenes were cloned and the proteins expressed. This heretofore unrecognized group of enzymes is shown to catalyze the Mn(II)-dependent addition of water to C1 of the oxirane. The ability of each enzyme to confer resistance in Escherichia coli is correlated with their catalytic efficiency, such that the M. loti protein confers low resistance while the Listeria enzyme confers very robust resistance. The crystal structure of the FosX from M. loti was solved at a resolution of 1.83 A. The structure reveals an active-site carboxylate (E44) located about 5 A from the expected position of the substrate that appears to be poised to participate in catalysis. Single turnover experiments in H218O and kinetic analysis of the E44G mutant of the FosX enzymes indicate that the carboxylate of E44 acts as a general base in the direct addition of water to 1. The FosX from M. loti also catalyzes the addition of glutathione to the antibiotic. The catalytic promiscuity and low efficiency of the M. loti protein suggest that it may be an intermediate in the evolution of clinically relevant fosfomycin resistance proteins such as the FosX from Listeria monocytogenese.

Bacterial Proteins↗
PubMed2004

Oxygenase activity in the self-hydroxylation of (s)-2-hydroxypropylphosphonic acid epoxidase involved in fosfomycin biosynthesis.

The last step of the biosynthesis of fosfomycin is the conversion of (S)-2-hydroxypropylphosphonic acid (HPP) to fosfomycin by HPP epoxidase (HppE), which is a mononuclear non-heme iron-dependent enzyme. The apo-HppE from Streptomyces wedmorensis is colorless, but turns green with broad absorption bands at 430 and 680 nm after reconstitution with ferrous ion under aerobic conditions. Resonance Raman studies showed that this green chromophore arises from a bidentate iron(III)-catecholate (DOPA) complex, and the most likely site of modification is at Tyr105 on the basis of site-specific mutagenesis results. It was also found that reconstitution in the presence of ascorbate leads to the formation of additional DOPA that shows (18)O-incorporation from (18)O(2). Thus, HppE can act as an oxygenase via a putative high valent iron-oxo or an iron-hydroperoxo intermediate, just like other members of the family of non-heme iron enzymes. The oxygen activation mechanism for catalytic turnover is proposed to parallel that for self-hydroxylation.

Amino Acid Sequence↗
PubMed2006

Coexpression of virulence and fosfomycin susceptibility in Listeria: molecular basis of an antimicrobial in vitro-in vivo paradox.

Discrepancies between resistance in vitro and therapeutic efficacy in vivo are generally attributed to failure of laboratory susceptibility tests to reflect an antibiotic's pharmacokinetic or pharmacodynamic properties. We show here that this phenomenon can result from differential in vitro-in vivo expression of bacterial determinants of antibiotic susceptibility. We found that an in vivo-induced virulence factor, Hpt, also mediates uptake of fosfomycin in Listeria monocytogenes. These bacteria therefore seem resistant to fosfomycin in vitro, although they are in fact susceptible to the antibiotic during infection.

Anti-Bacterial Agents↗
PubMed2005

Prevention of recurrent lower urinary tract infections by long-term administration of fosfomycin trometamol. Double blind, randomized, parallel group, placebo controlled study.

Three hundred and seventeen non pregnant females, suffering of recurrent lower urinary tract infections (UTIs; at least three episodes in the preceding 12 months) were enrolled in a double blind, randomized placebo (PL) controlled, parallel group clinical study, addressed to evaluate the efficacy and safety of fosfomycin trometamol (CAS 78964-85-9, FT, Monuril) in the prevention of infectious recurrences of lower urinary tract. One hundred and sixty six and 151 patients were allocated at random to FT or to PL treatment. The assigned treatment, i.e. one sachet containing FT equivalent to 3 g. of fosfomycin or PL, was taken by patients every 10 days during 6 months; thereafter they were followed up for another 6 consecutive months. Three hundred and two evaluable patients, completed the study as per protocol, 158 in the FT and 144 in the PL group, respectively. The analysis of the number of urinary tract infections/patient-year (primary end point) showed a result of 0.14 infections/patient-year in the FT group and of 2.97 infections/patient-year in the PL group. The difference was highly significant (p < 0.001). The time to first infection recurrence was significantly longer in the FT (38 days) than in the PL group (6 days); p < 0.01. The number of patients with at least one episode of recurrent infection and the number of episodes/patient during the treatment as well as during the follow-up period were statistically significantly lower in the FT group than in the PL group. Both treatments were well tolerated; only one adverse reaction possibly treatment related, i.e. an allergic skin reaction, was reported in both groups. Haematology and blood chemistry variables explored for safety at the end of the study did not show any significant difference between the two groups. The compliance with the treatment in the 302 evaluable patients was excellent. The results of this trial indicate that FT is higly effective in the prophylaxis of UTI recurrences; this beneficial effect is evident also in the 6 months of the follow-up.

Adolescent↗