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PubMed2000

Distribution and antimicrobial activity of fosfomycin in the interstitial fluid of human soft tissues.

Fosfomycin is a broad-spectrum antibiotic which is established as therapy for uncomplicated lower urinary tract infections. In addition, preliminary data indicate that fosfomycin has a potential role in the treatment of soft tissue infections. However, the use of fosfomycin has not been established for this condition, and it is unclear whether the level of fosfomycin penetration into human soft tissues is high enough to eradicate relevant pathogens. To better characterize the antibiotic potential of fosfomycin, we applied a combined in vivo pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For this purpose fosfomycin concentrations in vivo in the fluid of the interstitial space of human soft tissues were measured by microdialysis following intravenous infusion of 4 or 8 g of fosfomycin (n = 6). Subsequently, bacterial isolates with relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high degree of soft tissue penetration for fosfomycin, with ratios of the area under the concentration-time curve from 0 to 8 h for muscle (AUC(0-8(muscle)))/AUC(0-8(serum)) of 0.48+/-0.08 and 0.53+/-0.04 and ratios of AUC(0-8(adipose tissue))/AUC(0-8(serum)) of 0.74+/-0.12 and 0.71+/-0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with selected isolates of Staphylococcus aureus, Enterobacter cloacae, and Serratia marcescens for which MICs were 16 microg/ml, organisms were undetectable after a single dosing interval. Fosfomycin exhibits a strong ability to penetrate into the fluid of the interstitial space of soft tissues and reaches levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. We therefore conclude that fosfomycin might qualify as an alternative candidate for the therapy of soft tissue infections.

Adipose Tissue↗
PubMed2005

Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles.

The present study was performed to evaluate the ability of fosfomycin, a broad-spectrum antibiotic, to penetrate into abscess fluid. Twelve patients scheduled for surgical or computer tomography-guided abscess drainage received a single intravenous dose of 8 g of fosfomycin. The fosfomycin concentrations in plasma over time and in pus upon drainage were determined. A pharmacokinetic model was developed to estimate the concentration-time profile of fosfomycin in pus. Individual fosfomycin concentrations in abscess fluid at drainage varied substantially, ranging from below the limit of detection up to 168 mg/liter. The fosfomycin concentrations in pus of the study population correlated neither with plasma levels nor with the individual ratios of abscess surface area to volume. This finding was attributed to highly variable abscess permeability. The average concentration in pus was calculated to be 182 +/- 64 mg/liter at steady state, exceeding the MIC(50/90)s of several bacterial species which are commonly involved in abscess formation, such as streptococci, staphylococci, and Escherichia coli. Hereby, the exceptionally long mean half-life of fosfomycin of 32 +/- 39 h in abscess fluid may favor its antimicrobial effect because fosfomycin exerts time-dependent killing. After an initial loading dose of 10 to 12 g, fosfomycin should be administered at doses of 8 g three times per day to reach sufficient concentrations in abscess fluid and plasma. Applying this dosing regimen, fosfomycin levels in abscess fluid are expected to be effective after multiple doses in most patients.

Abscess↗
PubMed1977

Treatment of typhoid fever with fosfomycin alone and associated to chloramphenicol or ampicillin.

Treatment with fosfomycin alone and associated to subtherapeutic doses of chloramphenicol or of ampicillin, has been tried on 50 patients with typhoid fever and on four carriers of S. typhi in the Hospital del Rey. 15 patients were treated with fosfomycin alone, 22 with fosfomycin plus chloramphenicol and 13 with fosfomycin plus ampicillin. The treatment lasted 15-20 days. The results have been evaluated clinically and bacteriologically, haemo- and coprocultures being carried out. The sensitivity of the isolated germs has been studied, including MIC and the synergism in vitro between fosfomycin-chloramphenicol and fosfomycin-ampicillin. Fosfomycin, chloramphenicol and ampicillin determinations have been carried out on the blood. The cures obtained were 67, 82 and 92% respectively with fosfomycin, fosfomycin-chloramphenicol and fosfomycin-ampicillin. We believe that this antibiotic can be useful in the treatment of typhoid fever, associating it to chloramphenicol or ampicillin, due to the synergism existing between them and given the results we have obtained.

Administration, Oral↗
PubMed1998

Single-dose treatment of acute cystitis with fosfomycin tromethamine.

OBJECTIVE: To review the clinical pharmacology of fosfomycin tromethamine, a new antimicrobial agent for the treatment of uncomplicated lower urinary tract infections (UTIs). DATA SOURCE: Publications in English on fosfomycin, fosfomycin tromethamine, and fosfomycin trometamol (MEDLINE, 1970-1997), as well as unpublished studies submitted to the Food and Drug Administration (FDA), were reviewed. STUDY SELECTION: Comparative, randomized, controlled studies were used to analyze the efficacy and safety of fosfomycin tromethamine. DATA SYNTHESIS: Fosfomycin tromethamine is an oral antimicrobial indicated for the treatment of uncomplicated lower UTIs. This agent is active in the urine against common uropathogens that are associated with cystitis in women, including organisms resistant to other antibiotics. A single dose of fosfomycin tromethamine is well absorbed and produces therapeutic concentrations in the urine for 2-4 days. Comparative clinical trials suggest that a single dose of fosfomycin tromethamine 3.0 g is as clinically effective as 7- to 10-day treatment regimens of standard agents used to treat UTIs, such as nitrofurantoin, norfloxacin, and trimethoprim/sulfamethoxazole. Fosfomycin tromethamine is well tolerated and appears safe to use during pregnancy. CONCLUSIONS: Fosfomycin tromethamine is the only antimicrobial to be approved by the FDA for single-dose therapy in women with acute cystitis. It is as effective and safe as multidose comparators and appears safe to use during pregnancy. The acquisition cost of this new drug will need to be weighed against the improved compliance and convenience associated with its use in the treatment of uncomplicated UTIs.

Acute Disease↗
PubMed1999

Effect of early fosfomycin treatment on prevention of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection.

OBJECTIVE: To clarify the effect of early fosfomycin treatment, an antimicrobial agent in common use in Japan, on children with E. coli O157 with the aim of preventing hemolytic uremic syndrome (HUS). PATIENTS AND METHODS DESIGN: Non-randomized prospective study for development of HUS among inpatients with E. coli O157. SETTING: The hospitals where the 292 inpatients were treated. CASES: A total of 292 inpatients aged six to eleven years with E. coli O157 infection, 36 (12.3%) of whom were HUS cases. RESULTS: Most of the HUS inpatients (91.7%) developed this complication between the sixth and ninth day of illness. We therefore analyzed the effects of antimicrobial therapy, especially that of fosfomycin, on prevention of HUS within the first five days of illness, because fosfomycin was the most frequently used (88.0%). To clarify the effect of fosfomycin alone on prevention of HUS, we carried out an analysis using the data for 130 inpatients who received fosfomycin alone or did not receive any antimicrobial agents, within the first five days of illness. multivariate analysis, controlled for age, gender and presence of fever, showed that all adjusted odds ratios for the development of HUS with the use of fosfomycin within the first three days of illness were less than 1.0, with the use of fosfomycin on the second day of illness achieving statistical significance (adjusted OR, 0.09; 95% CI, 0.01-0.79). Furthermore, inpatients who took fosfomycin within the first two days of illness developed HUS significantly less often than those who did not (adjusted OR, 0.15; 95% CI, 0.03-0.78). On the other hand, fosfomycin therapy on and after the third day of illness was not associated with the prevention of HUS. CONCLUSION: The early use of fosfomycin within the first two days of illness might prevent the development of HUS.

Anti-Bacterial Agents↗
PubMed1999

Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection.

This multicenter clinical trial compared single-dose fosfomycin tromethamine with a 7-day course of nitrofurantoin for the treatment of acute uncomplicated lower urinary tract infection (UTI) in female patients. Healthy females with symptoms of acute uncomplicated UTI were enrolled in a double-masked, randomized clinical trial. Assessable patients had >10(5) colony-forming units per milliliter of a uropathogen in a clean-voided midstream urine sample. Patients received a single 3-g dose of fosfomycin tromethamine plus 7 days of placebo capsules or a single 3-g dose of placebo plus 7 days of nitrofurantoin monohydrate/macrocrystal 100-mg capsules. Treatment efficacy was assessed by both bacteriologic and clinical response 5 to 11 days after the initial treatment dose (visit 2) and 5 to 11 days (visit 3) and 4 to 6 weeks (visit 4) after the last day of medication. Of the 749 patients initially enrolled in the study, 375 received fosfomycin and 374 received nitrofurantoin. There were no clinical differences in patient characteristics between the 2 groups at study entry. Overall, 94% of pretreatment isolates were susceptible to fosfomycin and 83% were susceptible to nitrofurantoin. Bacteriologic cure rates at the first follow-up visit (5 to 11 days after initiation of treatment) were 78% and 86% for fosfomycin and nitrofurantoin, respectively (P = 0.02). At visit 3 (1 week posttreatment), they were 87% and 81% for fosfomycin and nitrofurantoin, respectively (P = 0.17). Both treatment groups had an 80% overall clinical success rate (cure and improvement). Twenty patients (5.3%) who received fosfomycin and 21 patients (5.6%) who received nitrofurantoin reported an adverse effect related to study medication. The most common side effects related to fosfomycin treatment were diarrhea (2.4%), vaginitis (1.8%), and nausea (0.8%). Both bacteriologic and clinical cure rates observed with a single 3-g dose of fosfomycin were comparable to those achieved with a 7-day course of nitrofurantoin in female patients with acute uncomplicated UTI.

Acute Disease↗
PubMed1994

Kinetics, stoichiometry, and identification of the reactive thiolate in the inactivation of UDP-GlcNAc enolpyruvoyl transferase by the antibiotic fosfomycin.

Fosfomycin [(1R,2S)-1,2-epoxypropylphosphonic acid] has been shown to exert its antibiotic effect through the inhibition of UDP-GlcNAc enolpyruvoyl transferase [Kahan, F. M., et al. (1974) Ann. N.Y. Acad. Sci. 235, 364], the enzyme responsible for catalyzing the first committed step in bacterial cell wall biosynthesis. Time-dependent inactivation of MurZ by fosfomycin was found to be greatly accelerated by the presence of cosubstrate UDP-GlcNAc but could also be speeded appreciably by the unreactive substrate analog 3-deoxy-UDP-GlcNAc. These results argue against a reaction-based participation of the cosubstrate and suggest that UDP-GlcNAc has a role in influencing active site conformation critical to the inactivation event. A study of the influence of UDP-GlcNAc and fosfomycin on the kinetics of inactivation allowed the determination of dissociation constants for fosfomycin (KF = 8.6 microM) and UDP-GlcNAc (KS = 14 microM), in addition to a limiting inactivation rate constant (k(inact) = 7.4 min-1) at saturating UDP-GlcNAc and fosfomycin concentrations. Mass spectrometry of inactivated MurZ demonstrated an increase in molecular weight of 138, consistent with the covalent addition of a molar equivalent of fosfomycin (136 kDa). Titration of MurZ with fosfomycin revealed a stoichiometry of 1 molecule of inhibitor per active site when assessed using either enzyme activity or mass spectrometry as an index of modification. Peptide mapping of tryptic digests of fosfomycin-inactivated MurZ revealed modification of a unique 41-mer, the sequence of which revealed that Cys115 was the site of attachment of fosfomycin.

Alkyl and Aryl Transferases↗
PubMed1977

Fosfomycin in the treatment of bacterial infections: summary of clinical trials in Japan.

The Japan Research Committee of Fosfomycin was organized in the fall of 1972 to promote the basic and clinical studies on fosfomycin. First of all, a subcommittee of fosfomycin consisting of a limited number of members was organized to establish the methods of determination on its antibacterial activity and its concentration in the biological fluid, and the most applicable methods were devised. The clinical trials on its oral form in a small scale were commenced from spring in 1973, and then gradually expanded to almost all of Japan. The clinical trials on its parenteral intravenous form were also undertaken from the latter half of 1973. The basic and clinical results obtained from hospitals and institutes almost all over Japan, to which members of the above Committee belong, were presented by speakers under a hot discussion in two symposia which were held by the Japan Society of Chemotherapy; one on its oral form in June 1974, and another on its parenteral form in December 1974. I served as chairman in both of the symposia. The clinical results of fosfomycin in Japan which were mainly collected in both symposia are described below. Its antibacterial activity, and absorption and exretion will be presented elsewhere in this volume. Clinical results of its oral form: Dosage forms of fosfomycin-Ca salt, capsule and granules, were prepared for its clinical trials. It resulted effective in about 76% of 1,200 patients with infection due to gram-positive or gram-negative (Pseudomonas, Salmonella, Escherichia coli, etc.) bacteria in several fields. As far as rates of efficacy were concerned, it was more effective in surgical, urological, ophthalmic and some other fields than in internal and pediatric ones. Fosfomycin was given in a dose of 2-3 g/day for adults or 100-130 mg/kg for infants and children in most cases. Furthermore, it can be favorably mentioned that fosfomycin was proved to be effective in salmonellosis and resistant shigellosis by a certain research group specialized in the therapy of infectious enteritis. Clinical results of its parenteral form: Sterlized bulk material of fosfomycin-Na salt was prepared in a vial for clinical use. Similarly as in the case of oral form, it was applied to about 500 patients with several infections. It resulted effective in about 68% of them. This percentage was not as high because of the higher frequency of application to severe patients or patients with underlying disease. Fosfomycin was intravenously administered by one shot or drip infusion in a dose of 2-4 g/day for adults, or 100-250 mg/kg for infants and children in most cases. Adverse reactions: In oral form, the incidence of adverse reactions was about 10% but most of them were slight gastrointestinal disorders. In an extremely small number of patients a rise of SGOT and/or SGPT was observed. In parenteral form, the incidence of adverse reactions was a little higher, being about 17% including a rise of SGOT and/or SGPT, vascular pain, nausea, and vomiting, etc...

Administration, Oral↗
PubMed1974

Biosynthesis of fosfomycin by Streptomyces fradiae.

The antibiotic fosfomycin was produced as a secondary metabolite in a glucose-asparagine medium containing citrate, l-methionine, and l-glutamate. The citrate requirement for antibiotic synthesis was related to its requirement for growth. In contrast, l-methionine and l-glutamate caused a marked stimulation of fosfomycin production and had no effect on growth. l-Methionine had to be added early to effect maximal antibiotic synthesis later in the fermentation. The l-glutamate requirement was not specific, since several tricarboxylic acid cycle intermediates could replace this amino acid. l-Asparagine was the most effective nitrogen source for growth and production of fosfomycin. Glycine, an alternate nitrogen source, supported fosfomycin synthesis only when added in excess of that needed for growth. Cobalt and inorganic phosphate were required also for antibiotic production at concentrations exceeding those supporting maximal growth. Radioactive incorporation studies showed that the methyl carbon of methionine was the precursor of the methyl of fosfomycin. Carbon 1 of fosfomycin was derived from glucose carbons 1 and 6, whereas glucose-2-(14)C labeled fosfomycin carbon 2. Radioactivity from acetate-2-(14)C was distributed equally between fosfomycin carbons 1 and 2. No incorporation of acetate-1-(14)C, asparagine-U-(14)C, citrate-1,5-(14)C, or glutamate-U-(14)C occurred. The labeling pattern of fosfomycin carbons 1 and 2 was similar to that found in 2-aminoethylphosphonate from Tetrahymena.

Acetates↗
PubMed1994

In vitro interaction of cisplatin and fosfomycin on squamous cell carcinoma cultures.

OBJECTIVE: Fosfomycin has been shown to be otoprotective and nephroprotective against cisplatin-induced toxic reactions. This study tests whether fosfomycin inhibits the anticancer effect of cisplatin. METHODS: Three squamous cell carcinoma cell lines were used to determine the effect of fosfomycin on cisplatin-induced tumoricidal activity. Cells were grown in 96 well plates with fosfomycin alone, cisplatin alone, or fosfomycin and cisplatin together. Cell survival was then measured by a colorimetric technique using 3-4,5-dimethylthiazol-2-yl 2,5 diphenyltetrazolium bromide (MTT). RESULTS: There was no decrease in the effectiveness of cisplatin in killing human squamous cell carcinoma in vitro when fosfomycin was present in concentrations of up to 400 mg/L. One cell line also showed killing at high concentrations of cisplatin, but not at low concentrations. CONCLUSIONS: Fosfomycin protects against cisplatin-induced toxic reactions and does not inhibit tumoricidal activity in vitro. In addition, one cell line showed relative resistance to cisplatin at low doses, but was effectively killed with high doses of cisplatin. This is the ideal situation for use of fosfomycin so that higher doses of cisplatin may be given with renal and otologic protection.

Carcinoma, Squamous Cell↗
PubMed1990

Fosfomycin trometamol versus ofloxacin/co-trimoxazole as single dose therapy of acute uncomplicated urinary tract infection in females: a multicentre study.

20 urologists took part in a single blind, randomized study. Female patients with acute uncomplicated UTI were recruited. The patients received either a single dose of 3 g fosfomycin trometamol versus 200 mg ofloxacin or 1.92 g co-trimoxazole. Follow-up examinations were carried out after one and four weeks. Of 562 patients 446 could be evaluated for efficacy and 496 for tolerance. Patients were analysed according to the amount of bacteriuria: "significant" (greater than or equal to 10(5)/ml), "low count" (10(2) - 10(4) ml) and "no bacteriuria" (less than or equal to 10(1)/ml), as well as according to the sensitivity of the infecting organisms: sensitive (resistant): fosfomycin trometamol less than or equal to 16 mg/l (greater than or equal to 128 mg/l), ofloxacin less than or equal to 1 mg/l (greater than or equal to 8 mg/l), co-trimoxazole less than or equal to 2/38 mg/l (greater than or equal to 16/304 mg/l). Up to one week the following results could be achieved: clinical improvement was attained in patients with "significant" bacteriuria (fosfomycin trometamol-150, ofloxacin-89, co-trimoxazole-69) in 94.7% for fosfomycin trometamol, in 95.4% for ofloxacin, and in 94% for co-trimoxazole; in patients with "low count" bacteriuria (fosfomycin trometamol-44, ofloxacin-18, co-trimoxazole-30) in 95.2% for fosfomycin trometamol, in 93.7% for ofloxacin, and in 96.4% for co-trimoxazole; and in patients with no bacteriuria (fosfomycin trometamol-11, ofloxacin-6, co-trimoxazole-4) in 81.8% for fosfomycin trometamol, in 100% for ofloxacin and in 100% for co-trimoxazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMedDate not supplied

Fosfomycin-ampicillin versus gentamicin-ampicillin in the treatment of critically ill patients with pneumonia.

Thirty-two patients with severe pneumonia (22 on assisted ventilation) were entered into a prospective randomised trial, in which fosfomycin plus ampicillin (17 patients) was compared with gentamicin plus ampicillin (15 patients). Treatment was either 4 g fosfomycin or 80 mg gentamicin every 8 h and 1 g ampicillin every 6 h. Complete or partial clinical success was attained in 94% (16/17) in the fosfomycin group and in 80% (12/15) in the gentamicin group. Bacteriological success was 87.5% with fosfomycin-ampicillin and 90% with gentamicin-ampicillin. An intermediary sensitive Klebsiella pneumoniae strain developed complete resistance in the fosfomycin group, and an in vitro sensitive Pseudomonas aeruginosa strain was resistant in vivo in the gentamicin group. Two of three patients in the fosfomycin group receiving the infusion through a peripheral vein developed thrombophlebitis. No other side-effects were observed. We conclude that fosfomycin is at least as effective as gentamicin. Since fosfomycin is widely atoxic and may be given in large doses, irrespective of kidney function, it is considered to have advantages over gentamicin in the combined therapy of pneumonia.

Acute Disease↗
PubMed2002

Role of fosfomycin in a synergistic combination with ofloxacin against Pseudomonas aeruginosa growing in a biofilm.

We examined the combined effect of fosfomycin and ofloxacin against Pseudomonas aeruginosa biofilms of four clinical isolates with different susceptibilities to ofloxacin. A clear synergistic effect was detected in all four strains in accordance with their susceptibilities to ofloxacin. To clarify the mechanism of this synergistic action, changes in cellular accumulation of ofloxacin into fosfomycin-pretreated cells and morphological changes in cells treated with fosfomycin, ofloxacin, or fosfomycin plus ofloxacin were investigated. Pretreatment with fosfomycin significantly enhanced cellular uptake of labeled or unlabeled ofloxacin in biofilm cells as well as in floating cells. The accumulation of ofloxacin into fosfomycin-pretreated biofilm cells was further enhanced by treating cells simultaneously with ofloxacin and fosfomycin. Morphological studies using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and confocal laser scanning microscopy (CLSM) demonstrated that fosfomycin induced dramatic changes in cell shape and the outer membrane structure responsible for the altered membrane permeability of both surface and embedded biofilm cells. The resulting increased accumulation of ofloxacin in multilayers of biofilm cells was correlated with the kinetics of biofilm cell eradication, and this synergistic killing effect was confirmed by a combined study using SEM, TEM, and CLSM.

Anti-Bacterial Agents↗
PubMed2004

Protective effect of fosfomycin on gentamicin-induced lipid peroxidation of rat renal tissue.

Fosfomycin is clinically recognized to reduce the aminoglycoside antibiotics-induced nephrotoxicity. However, little has been clarified why fosfomycin protects the kidney from the aminoglycosides-induced nephrotoxicity. Gentamicin, a typical aminoglycoside, is reported to cause lipid peroxidation. We focused on lipid peroxidation induced by gentamicin as a mechanism for the aminoglycosides-induced nephrotoxicity. The aim of this study is to investigate the effect of fosfomycin on the gentamicin-induced lipid peroxidation. In rat renal cortex mitochondria, fosfomycin was shown to depress the gentamicin-induced lipid peroxidation, which was evaluated by formation of thiobarbituric acid reactive substances (TBARS). Interestingly, this effect was observed in rat renal cortex mitochondria, but not in rat liver microsomes. However, fosfomycin did not affect lipid peroxidation of arachidonic acid caused by gentamicin with iron. Fosfomycin inhibited the gentamicin-induced iron release from rat renal cortex mitochondria. These results indicated that fosfomycin inhibited the gentamicin-induced lipid peroxidation by depressing the iron release from mitochondria. This may possibly be one mechanism for the protection of fosfomycin against the gentamicin-induced nephrotoxicity.

Animals↗
PubMed1996

Characterization of a Cys115 to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers resistance to inactivation by the antibiotic fosfomycin.

The antibiotic fosfomycin inhibits bacterial cell wall biosynthesis by inactivation of UDP-GlcNAc enolpyruvyl tranferase (MurA). Prior work has established that Cys115 of Escherichia coli and Enterobacter cloacae MurA is the active site nucleophile alkylated by fosfomycin and implicated this residue in the formation of a covalent phospholactyl-enzyme adduct derived from substrate, phosphoenolpyruvate (PEP). On the basis of sequencing information from putative MurA homolog from Mycobacterium tuberculosis, we generated a C115D mutant of E. coli MurA that was highly active but fully resistant to time-dependent inhibition by fosfomycin. Fosfomycin still bound to the active site of C115D MurA, as established by the observed reversible competitive inhibition by fosfomycin. Fosfomycin still bound to the active site of C115D MurA, as established by the observed reversible competitive inhibition vs PEP. In contrast to the broad pH-independent behavior of wild-type (WT) MurA, C115D mutant activity titrated across the pH range examined (pH 5.5-9) with an apparent pKa approximately 6, with kcatC115D ranging from approximately 10kcatWT at pH 5.5 to <0.1kcatWT at pH9.0. Km(PEP)115D was relatively constant in the pH range examined and increased approximately 100-fold relative to Km(PEP)WT. A fosfomycin-resistant C115E mutant with -1% activity of the C115D mutant was found to follow a pH dependence similar to that observed for C115D MurA. The contrasting pH dependences of WT and C115D MurA was also observed in the reaction with the pseudosubstrate, (Z)-3-fluorophosphoenolpyruvate, strongly suggesting a role for Cys/Asp115 as the general acid in the protonation of C-3 of PEP during MurA-catalyzed enol ether transfer. The difference in nucleophilicity between the carboxylate side chains of Asp115 and Glu115 and the thiolate group of Cys115 suggests that covalent enzyme adduct formation is not required for catalytic turnover and, furthermore, provides a chemical rationale for the resistance of the C115D and C115E mutants to fosfomycin inactivation.

Alkyl and Aryl Transferases↗
PubMed2003

Target site penetration of fosfomycin in critically ill patients.

OBJECTIVE: The present study was undertaken to investigate the target site penetration properties of fosfomycin, an antibiotic particularly suitable for treatment of soft tissue infections (STIs) in critically ill patients. METHODS AND RESULTS: The study population included nine patients with sepsis. Penetration of fosfomycin into the interstitial space fluid of skeletal muscle was measured using the microdialysis technique, following a single intravenous administration of 8.0 g of fosfomycin to patients. The median (range) fosfomycin area under the concentration versus time profile for plasma and skeletal muscle were 673 (459-1108) and 477 (226-860) mg x h/L (P < 0.011), respectively. Interstitial maximum concentrations were lower than plasma values (P < 0.029). Median fosfomycin concentrations in the interstitium and plasma exceeded 70 mg/L throughout the observation period of 4 h and covered MICs for Streptococcus pyogenes, Staphylococcus aureus and Pseudomonas aeruginosa. Simulation of bacterial growth inhibition of S. pyogenes, based on tissue concentration data, confirmed the bactericidal properties of fosfomycin described in previous studies. CONCLUSION: Fosfomycin concentrations in muscle interstitium and plasma exceeded the MICs for a range of clinically relevant pathogens in critically ill patients. Thus, fosfomycin exhibits a tissue pharmacokinetic profile, which appears to offer an alternative to other broad-spectrum antibiotics in intensive care patients suffering from STI.

Aged↗
PubMed1997

Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections.

Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3 g oral dose, peak urinary concentrations occur within 4 hours and remain high (> 128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. beta-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication.

Acute Disease↗
PubMed1986

Microbiological basis for the use of fosfomycin trometamol as single-dose therapy for simple cystitis.

Fosfomycin trometamol (FOT), a new soluble salt of fosfomycin, was developed especially for single-dose treatment in uncomplicated urinary tract infections. In this study, the minimum inhibitory concentrations (MICs) of FOT were measured both in nutrient broth and human urine and compared with calcium fosfomycin, pipemidic acid and cotrimoxazole. A total of 300 bacterial strains of different species from recent urinary infections were studied. Staphylococcus aureus showed the lowest MIC (0.38 micrograms/ml) and Pseudomonas spp. the highest (50 micrograms/ml) with fosfomycin salts in nutrient broth. The MIC of fosfomycin resulted in being higher than those for pipemidic acid and cotrimoxazole against Escherichia coli and Proteus rettgeri and lower for all the other species considered. The MIC values increased about ten times when urine was used as medium. No differences were observed between the two fosfomycin salts. The fosfomycin concentrations of 137-1500 micrograms/ml, easily obtained in urine of healthy adult subjects after a single dose of FOT (3g of fosfomycin), were able to kill all the strains, with the exception of Streptococcus faecalis. The bacterial adhesion of a resistant microorganism (P. aeruginosa) to the cells of the urinary tract, showed a 50% reduction after FOT treatment.

Bacteria↗