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PubMed1983

[Treatment of ventriculitis caused by Staphylococcus epidermidis on equipment with the combination of fosfomycin and an aminoglycoside. Course of ventricular levels of fosfomycin].

Five patients (4 adults and 1 child) with cerebrospinal fluid shunt infections caused by Staphylococcus epidermidis were successfully treated by fosfomycin combined with an aminoglycoside. Fosfomycin was given intravenously over 4 hours 3 times a day. The antibiotic dose was 12 g/day for adults and 200 mg/kg/day for the child. In 3 patients with an external CSF drainage system, serum and ventricular fluid samples were obtained before and after one infusion during 10 days. The serum concentrations varied greatly (48,12 +/- 31,47 and 115,07 +/- 46,5 micrograms/ml. However the drug levels in ventricular fluid were constant and similar for the 3 patients (24,48 +/- 10,28 à 27,87 +/- 8,58 micrograms/ml), well above the MICS (1 and 2 micrograms/ml).

Adolescent↗
PubMed1992

[Experimental study on intramaxillary injection of fosfomycin. Effects of fosfomycin on experimental acute sinusitis in rabbits].

We studied effects of intramaxillary injection of fosfomycin (FOM) on experimental sinusitis in rabbits. The experimental sinusitis was induced by intramaxillary injection of Staphylococcus aureus to rabbits for 3 successive days. 1. 0.5, 1, 3 or 5% FOM with saline as a control was instilled into the maxillary sinus and the maxillary sinus mucosa were examined macroscopically and light and electron microscopically. 3% and 5% FOM suppressed the damage of mucosa macroscopically and scanning electron microscopically. 2. After administration of 3% FOM and saline twice a week, the maxillary sinus mucosa was examined macroscopically and light and electron microscopically. The maxillary sinus injected with 3% FOM showed almost normal mucosa after 2 weeks while that injected with saline showed severe mucosal damage. S. aureus were decreased by 3% FOM injection and not found in the maxillary sinus in a week. The results indicate that intramaxillary injection of FOM is very effective in the treatment of sinusitis.

Acute Disease↗
PubMed1990

[Antibacterial activities and electron microscopic studies of imipenem in combination with fosfomycin against methicillin and fosfomycin resistant strains of Staphylococcus aureus].

UNLABELLED: Imipenem (IPM) and fosfomycin (FOM) have been reported to possess a synergistic relationship in their activities against both methicillin (DMPPC)-susceptible and -resistant strains of Staphylococcus aureus. However it was not concluded whether these antibacterial activities were bacteriostatic or bactericidal. The purpose of this report is to elucidate this point clearly. Activities of the 2 antibiotics against 15 strains S. aureus resistant to both DMPPC and FOM were investigated by means of the killing-curve method and electron microscopic studies. MICs of DMPPC and FOM against these strains determined using the agar dilution method were greater than or equal to 50 micrograms/ml and MICs of IPM by the broth dilution method ranged from 12.5 to 50 micrograms/ml. The killing-curves with the following drug concentration combinations were examined in Mueller-Hinton broth: 1. FOM 25 micrograms/ml, 2. FOM 25 micrograms/ml + IMP 1/2 MIC, 3. IPM 1MIC, 4. FOM 25 micrograms/ml + IPM 1 MIC and 5. FOM 25 micrograms/ml + IPM 2MIC. Morphological changes produced in 1 strain by 2 of the combinations, 2. FOM 25 micrograms/ml + IPM 1/2 MIC and 4. FOM 25 micrograms/ml + IPM 1MIC, were observed using scanning and transmission electron microscopy. The following results were obtained; (1) The synergistic effects were found in 6/15 strains (40%) and no antagonistic effect was found. (2) Electron microscopic observation showed that IPM in combination with FOM caused lysis of the cells. CONCLUSIONS: IPM in combination with FOM produced bactericidal and bacteriolytic effects on DMPPC-resistant S. aureus (MRSA). This combination therapy should be evaluated for FOM resistant MRSA infections.

Bacteriolysis↗
PubMed1984

[Can fosfomycin reduce the nephrotoxicity of aminoglycosides?].

Fosfomycin is an active antibiotic on Gram positive and Gram negative bacteria with a low toxicity in animals. To treat severe infections, it is recommended to associate fosfomycin with gentamicin. Wistar rats were given one of the following regimens for eight days : 100, 500 or 1 000 mg/kg fosfomycin, 50 mg/kg gentamicin or dibekacin, association of 100, 500, or 1 000 mg/kg fosfomycin and 50 mg/kg gentamicin or dibekacin. Control rats were given a saline solution. No renal histological alterations were identified with fosfomycin 100 mg/kg. Tubular dilatation and brush border rarefaction were observed with fosfomycin 500 and 1 000 mg/kg. These abnormalities did not seem related to fosfomycin itself but rather to the sodium load induced by fosfomycin treatment. A decrease in alanine aminopeptidase activity was noted for all doses of fosfomycin. Renal concentrations of gentamicin and dibekacin were not decreased by concomitant administration of fosfomycin. Fosfomycin, 100 mg/kg, did not change the nephrotoxic potential of gentamicin or dibekacin. Fosfomycin, 500 mg/kg, protected the kidney from the action of gentamicin or dibekacin. This effect seemed to be more pronounced for dibekacin than for gentamicin. Fosfomycin, 1 000 mg/kg, did not induce a more protective effect against the nephrotoxicity of these two aminoglycosides. Thus, we observed that fosfomycin combined with gentamicin or dibekacin reduced the degree of proximal tubular cell alterations, induced less modifications in alanine aminopeptidase, less lysosomal alterations, and a minor modification in sphingomyelinase activity.

Aminoglycosides↗
PubMed2006

Evaluation of fosfomycin alone and in combination with ceftriaxone or vancomycin in an experimental model of meningitis caused by two strains of cephalosporin-resistant Streptococcus pneumoniae.

OBJECTIVES: To study the in vitro and in vivo efficacy of fosfomycin, alone and in combination with ceftriaxone or vancomycin, against two strains of Streptococcus pneumoniae: HUB 2349 (fosfomycin and ceftriaxone, MICs 16 and 2 mg/L) and ATCC 51916 (MICs 4 and 32 mg/L). METHODS: Pharmacokinetics/pharmacodynamics data were collected from the study of eight infected animals after a single intravenous dose of 300 mg/kg of fosfomycin. Time-kill curves were plotted using CSF antibiotic concentrations achievable clinically. In the rabbit model, we studied the efficacy and effects on inflammation of treatment with fosfomycin 1200 mg/kg/day, ceftriaxone 100 mg/kg/day and vancomycin 30 mg/kg/day, over 26 h. RESULTS: Fosfomycin peak level in serum was 324.48 +/- 102.1 mg/L at 0.5 h; CSF penetration was 49.2%. Time-kill curves showed that fosfomycin was bactericidal against the ATCC 51916 strain and that the addition of fosfomycin to ceftriaxone or vancomycin was synergic against the HUB 2349 strain. Resistance to fosfomycin was detected both when fosfomycin was studied alone and in combination. In the rabbit model, fosfomycin showed bactericidal activity only against the ATCC 51916 strain. Combinations of fosfomycin with ceftriaxone or vancomycin were bactericidal against both strains; they improved efficacy and decreased CSF inflammatory parameters over monotherapies, without showing statistical differences in comparison with the combination of ceftriaxone and vancomycin. CONCLUSIONS: Fosfomycin in combination with ceftriaxone or vancomycin appeared to be effective for the treatment of experimental cephalosporin-resistant pneumococcal meningitis. These combinations are possible alternatives in cases of allergy or intolerance to first-line drugs or in rare meningitis caused by highly cephalosporin-resistant pneumococci.

Animals↗
PubMed1996

In vivo activity and pharmacodynamics of amoxicillin in combination with fosfomycin in fibrin clots infected with highly penicillin-resistant Streptococcus pneumoniae.

Using a clinical pneumococcal strain for which MICs were 4, 2, and 32 mg/liter for penicillin, amoxicillin, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and their combinations in the treatment of prolonged (48-h) experimental fibrin clot infection in rabbits. Treatments were as follows: amoxicillin IV at 20 mg/kg of body weight in one dose (Amo20), 50 mg/kg in one dose (Amo50), or two doses 6 h apart (Amo20 x 2 and Amo50 x 2); fosfomycin IV at a fixed dose of 50 mg/kg in one dose (Fos50) or two divided doses 6 h apart (Fos50 x 2); or the combinations of amoxicillin and fosfomycin with the same schedules. Maximum concentrations in clots were 2.03 +/- 1.02 and 2.13 +/- 0.33 mg/liter for Amo20 regimens, 3.7 +/- 1.9 and 4 +/- 1.3 mg/liter for Amo50 regimens, and 24 +/- 7 and 40 +/- 8 mg/liter for fosfomycin regimens, respectively. The mean half-lives of elimination from clots were between 2 and 3 h for amoxicillin regimens and between 5 and 7 h for fosfomycin. We observed the highest bacterial reductions (log10 CFU/gram) for Amo50 in two divided doses with or without fosfomycin. A significantly higher bacterial reduction than that with each monotherapy was observed when Amo20 was combined with fosfomycin in either one dose or two doses 6 h apart (0.16 +/- 0.8 and 1.64 +/- 1.6 log10 CFU/g for Amo20 in one and two doses, respectively, and 0.93 +/- 0.81 and 0.61 +/- 0.56 log10 CFU/g for fosfomycin in one and two doses, respectively, versus 3.46 +/- 1.26 and 3.16 +/- 1.31 log10 CFU/g for Amo20 plus fosfomycin in one and two doses, respectively [P < 0.001]). A time-dependent effect was observed with amoxicillin regimens. The time of regrowth was significantly delayed when amoxicillin was combined with fosfomycin. By using a multivariate analysis, we demonstrated that the most important parameter correlated to efficacy of the combination amoxicillin-fosfomycin was the length of the period during which the concentration of amoxicillin remained above the MIC. We demonstrated that the in vivo efficacy of the combination of amoxicillin and fosfomycin gave higher antibacterial effect than each monotherapy.

Amoxicillin↗
PubMed2000

Characterization of the fomA and fomB gene products from Streptomyces wedmorensis, which confer fosfomycin resistance on Escherichia coli.

Together, the fomA and fomB genes in the fosfomycin biosynthetic gene cluster of Streptomyces wedmorensis confer high-level fosfomycin resistance on Escherichia coli. To elucidate their functions, the fomA and fomB genes were overexpressed in E. coli and the gene products were characterized. The recombinant FomA protein converted fosfomycin to fosfomycin monophosphate, which was inactive on E. coli, in the presence of a magnesium ion and ATP. On the other hand, the recombinant FomB protein did not inactivate fosfomycin. However, a reaction mixture containing FomA and FomB proteins converted fosfomycin to fosfomycin monophosphate and fosfomycin diphosphate in the presence of ATP and a magnesium ion, indicating that FomA and FomB catalyzed phosphorylations of fosfomycin and fosfomycin monophosphate, respectively. These results suggest that the self-resistance mechanism of the fosfomycin-producing organism S. wedmorensis is mono- and diphosphorylation of the phosphonate function of fosfomycin catalyzed by FomA and FomB.

Anti-Bacterial Agents↗
PubMed1995

Activity of fosfomycin in a rabbit model of experimental pneumococcal meningitis.

Fosfomycin is an antibacterial substance of low molecular weight and negligible binding to plasma proteins exhibiting in-vitro activity against most pathogens involved in bacterial meningitis including pneumococci. Due to these properties the drug has been recommended for therapy of central nervous system (CNS) infections. For this reason, fosfomycin at doses of 10, 40, 80 and 160 mg/kg/h iv, was investigated in the rabbit model of pneumococcal meningitis. Bacterial counts in cerebrospinal fluid (CSF) before, and 2, 5 and 8 h after initiation of therapy were quantitated by plating on blood agar. Fosfomycin concentrations in serum and CSF were determined by the agar well diffusion method. The MIC and MBC of fosfomycin for the Streptococcus pneumoniae type 3 strain used was 4 and 32 mg/L, respectively. The MIC of ceftriaxone was 0.016 mg/L. In vitro, both drugs showed an additive effect (fractional inhibitory concentration index = 0.75). In vivo at each dose tested, fosfomycin was less active than ceftriaxone (means +/- S.D.): delta log cfu/mL/h at 10 mg/kg/h + 0.130 +/- 0.062 (n = 2), at 40 mg/kg/h -0.217 +/- 0.185 (n = 3), at 80 mg/kg/h -0.270 +/- 0.121 (n = 3), at 160 mg/kg/h -0.331 +/- 0.118 (n = 3) vs -0.647 +/- 0.193 at 10 mg/kg/h ceftriaxone (n = 3). CSF penetration of fosfomycin as estimated by the CSF-to-serum concentration ratio at 8 h was 0.55 +/- 0.22 (n = 11). For bactericidal activity CSF concentrations of at least ten times the MIC were necessary. Coadministration of both drugs (1 mg/kg/h ceftriaxone + 40 mg/kg/h fosfomycin) tended to be more active than either drug alone (in-vivo drug interaction = 1.3). In conclusion, fosfomycin at very high doses reduced bacterial counts in CSF. However, fosfomycin CSF concentrations usually observed in patients with meningitis receiving fosfomycin were not bactericidal in this model. At all doses tested the bactericidal rate was lower than that of ceftriaxone. Fosfomycin is therefore unsuitable as a single agent, but may be used as a reserve antibiotic in combination with a newer cephalosporin for pneumococcal meningitis unresponsive to conventional therapy.

Animals↗
PubMed1990

Pharmacokinetic comparison between fosfomycin and other phosphonic acid derivatives.

The pharmacokinetic comparison of phosphonic acid derivatives is based upon a survey of available literature on the whole group of compounds and on our own studies on fosfomycin. All three clinically used compounds, fosfomycin, fosmidomycin, and alafosfalin, are available for both oral and parenteral administration. The highest bioavailability is observed for the trometamol derivative of fosfomycin (37-44%); the calcium salt of fosfomycin is 2-2.5 times less absorbed and fosmidomycin has a bioavailability of 20-30%. The peak serum concentration of fosfomycin when given as the trometamol salt is about 2 times higher than the one reached with fosfomycin calcium or fosmidomycin. Urine recovery of unchanged drug is comparable after intravenous doses of fosfomycin and fosmidomycin, 80-95%, whereas the figure is only 10-20% for alafosfalin because it is extensively metabolized. After oral administration, urine recovery is highest for fosfomycin trometamol, 35-60%, compared to approximately 25% (range 18-29%) for fosfomycin calcium, 26% for fosmidomycin, and 6-17% for alafosfalin. The serum half-life of fosfomycin is 2-4 h (higher, up to 5.5 h, for some formulations of the calcium salt), 1.5-2.0 h for fosmidomycin, and about 1 h for alafosfalin. Thus, among available phosphonic acid derivatives and formulations, the trometamol derivative of fosfomycin has the most favourable characteristics. This applies to both bioavailability and urinary recovery, while at the same time the medium long half-life renders moderate fluctuation of concentrations whereby longer dosage intervals are possible.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1986

[The transport mechanism of antibiotics using microvillous membrane vesicles (placental transport of fosfomycin)].

Using the rapid filtration technique, the uptake of fosfomycin into microvillous membrane vesicles isolated from human term placental trophoblast was investigated. The microvillous membrane vesicles exhibited the uptake of fosfomycin into an osmotically reactive intravesicular space and it was indicated that the uptake of fosfomycin by microvillous membrane vesicles represented transport into membrane vesicles. The uptake of fosfomycin by microvillous membrane vesicles was not dependent on the Na+ electrochemical gradient or membrane potential. The initial uptake of fosfomycin by microvillous membrane vesicles did not exhibit saturation kinetics with respect to fosfomycin concentration, and increased linearly as the fosfomycin concentration increased. These results indicated that fosfomycin was transported across the microvillous membrane by simple diffusion. L-alanine, L-valine, L-lysine, inorganic phosphate or D-glucose did not inhibit the uptake of fosfomycin into microvillous membrane vesicles. On the other hand, fosfomycin did not inhibit the uptake of L-alanine, L-valine, L-lysine inorganic phosphate or D-glucose into microvillous membrane vesicles. These results revealed that fosfomycin did not affect the placental transport activity of other nutrients.

Biological Transport↗
PubMed2001

In vitro activity of fosfomycin in combination with various antistaphylococcal substances.

Using the chequerboard technique we studied the in vitro activity of the broad spectrum antibiotic fosfomycin in combination with vancomycin, rifampicin, linezolid, quinupristin/ dalfopristin, cefazolin, meropenem and moxifloxacin against two Staphylococcus epidermidis strains (ATCC 12228, DSM 3269) and five Staphylococcus aureus isolates (ATCC 29213, DSM 683, DSM 46320, GISA 323/93, MRSA 3558/00). The phenomena of 'trailing' and 'skipped wells' did not present a problem. Synergy was the most common effect of all drugs tested in combination with fosfomycin; only combination with vancomycin showed antagonism for two of seven isolates. Using a killing-curve technique fosfomycin showed cidal activity, where increasing the drug concentration above the MIC did not enhance killing velocity. Inhibitory concentrations of vancomycin plus fosfomycin against DSM 46320 caused effects identical to those observed with vancomycin alone. The combination of fosfomycin plus linezolid exerted the bacteriostatic effect found with linezolid alone. Fosfomycin plus quinupristin/dalfopristin exhibited the bactericidal effect found with fosfomycin alone (in contrast to the rapidly bactericidal effect of quinupristin/dalfopristin). Electron microscopy showed that fosfomycin given in combination with linezolid, quinupristin/dalfopristin or moxifloxacin (substances that do not cause morphological alterations when given alone) resulted in 'cauliflower-shaped' distortion as caused by fosfomycin alone. Our in vitro data indicate considerable potential for fosfomycin used in combination with other antistaphylococcal antimicrobials, especially linezolid or quinupristin/dalfopristin.

Anti-Bacterial Agents↗
PubMed2006

Mutators among CTX-M beta-lactamase-producing Escherichia coli and risk for the emergence of fosfomycin resistance.

OBJECTIVES: Fosfomycin is a possible oral treatment for lower urinary tract infections caused by Escherichia coli with CTX-M extended-spectrum beta-lactamases but is vulnerable to mutational resistance. Hypermutability among natural E. coli populations might facilitate the emergence of resistance to fosfomycin. We therefore examined the prevalence of mutators amongst urinary isolates of E. coli producing CTX-M beta-lactamases. METHODS: Urinary E. coli isolates with CTX-M beta-lactamases (n = 220) were screened for resistance to both rifampicin and fosfomycin, as well as a mutator phenotype, by rifampicin and fosfomycin disc assays. Mutation frequencies for 10 isolates, identified as mutators by the initial disc screen, were determined in triplicate on agar with rifampicin or fosfomycin at 4x MIC and with fosfomycin or nitrofurantoin at 256 mg/L. RESULTS: The disc screen identified 10 likely mutators and quantitative tests indicated that 9 of these had mutation frequencies of 8.0 x 10(-6)-1.5 x 10(-4) for fosfomycin and 0.1-2.3 x 10(-6) for rifampicin. These mutators were diverse in terms of PFGE type and 4 of the 10 were confirmed as strong mutators with rifampicin and fosfomycin. Only the strongest mutator isolate and hypermutable MutS(-) control strain consistently gave single-step mutants resistant to 256 mg/L fosfomycin. No nitrofurantoin-resistant mutants were selected from any isolate, although they could be selected from the hypermutable MutS(-) control strain. CONCLUSIONS: Mutator phenotypes were found among E. coli expressing CTX-M beta-lactamases and were independent of strain type. These had an increased propensity to fosfomycin resistance.

Anti-Bacterial Agents↗