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PubMed1991

Single-dose fosfomycin trometamol (Monuril) versus multiple-dose norfloxacin: results of a multicenter study in females with uncomplicated lower urinary tract infections.

The results of an open, randomized study comparing the efficacy and safety of Fosfomycin trometamol (Monuril), 3-gram single dose, and Norfloxacin (Noroxine 400), 400 mg twice daily for 5 days, are reported. Clinical and bacteriological assessments were performed before and 3-4 (short-term) and 25-30 days (long-term) after treatment. Only female patients with uncomplicated lower urinary tract infection were eligible for inclusion in the study: 33 cases were given Fosfomycin trometamol and 30 cases Norfloxacin. In the overall etiology, Escherichia coli (74% of the strains found), Proteus mirabilis (6%) and Klebsiella pneumoniae (6%) are highly predominant. With regard to bacteriological efficacy, the percentages of eradication in the two groups were similar: after the short-term test, 93.9% (31 of 33 patients) in the Fosfomycin trometamol group and 86.6% (26 of 30) in the Norfloxacin group, and after the long-term tests, 73.3% (22 of 30) in the Fosfomycin trometamol group and 77.89% (21 of 27) in the Norfloxacin group. There are no statistically significant differences. The duration of the reported side effects was significantly lower in the Fosfomycin trometamol group. The simplified dosage regimen (single dose) and its favorable benefit/risk ratio justifies the use of Fosfomycin trometamol as a treatment for uncomplicated urinary tract infections in female patients.

Drug Evaluation↗
PubMed2005

Synergistic effect of fosfomycin and fluoroquinolones against Pseudomonas aeruginosa growing in a biofilm.

Ulifloxacin is the active form of the prodrug prulifloxacin and shows a highly potent antipseudomonal activity. In this study, we examined the combined effect of fosfomycin and ulifloxacin against Pseudomonas aeruginosa (P. aeruginosa) growing in a biofilm using a modified Robbins device with artificial urine, and compared it to that of the combination of fosfomycin and ciprofloxacin or levofloxacin. An ATP bioluminescence assay was used to evaluate the antibacterial activity of the agents against sessile cells in a mature biofilm developed on a silicon disk. The total bioactivity of P. aeruginosa growing in a biofilm that had not been fully eradicated by fosfomycin or any of the fluoroquinolones alone at 10 times the MIC decreased after combination treatment with fosfomycin and fluoroquinolones. Morphological changes occurred in a time-dependent fashion; namely, swollen and/or rounding cells emerged within a couple of hours after combination treatment, marking the initial stage in the process leading to the destruction of the biofilms. We could not find any difference among the 3 fluoroquinolones with regard to their synergistic effects when administered with fosfomycin. The combination treatment of fosfomycin and fluoroquinolones with highly potent antipseudomonal activities was effective in eradicating sessile cells of P. aeruginosa in the biofilm and promises to be beneficial against biofilm-associated infectious diseases.

Anti-Bacterial Agents↗
PubMed1993

Introducing fosfomycin for surgical prophylaxis--emergence of resistance in aerobic faecal gram-negative bacteria of in-patients, but not among strains causing infection after elective colorectal procedures.

Fosfomycin was introduced for prophylaxis of surgical infection at 6 centres in a randomized study of elective colorectal operations (fosfomycin/metronidazole, n = 251 vs doxycycline/metronidazole, n = 237). Preoperative faecal specimens from the patients showed a relatively high prevalence rate of doxycycline-resistant bacteria (aerobic Gram-negative isolates 38%, enterococci 24%, overall 35%) with constant rates over time during the 15-month study period. The resistance rates for fosfomycin were lower (overall 12%), and remained constant for enterococci (average 10%), but increased for aerobic Gram-negative isolates from 9% during the initial part to 17% during the final part of the study (p = 0.007). Most aerobic strains in wound secretions from infected patients (20/26) could not be recovered from a preoperative faecal swab of the same patient. Isolates from infection after doxycycline prophylaxis had twice as high doxycycline resistance rates (overall 63%, 82% for Gram-negative isolates) as wound isolates from infection after fosfomycin prophylaxis (30%) and preoperative faecal flora isolates (35%, p = 0.02), indicating that bacterial resistance contributed to failure of doxycycline prophylaxis. In contrast, no increase in fosfomycin resistance rates was found among aerobic isolates from infection after fosfomycin prophylaxis (10%). This suggested that the emerging fosfomycin resistance was associated with reduced bacterial virulence and thus was of less clinical significance than doxycycline resistance.

Colon↗
PubMed2001

Protective effects of fosfomycin on cisplatin-induced nephrotoxicity in patients with lung cancer.

SUBJECTS, MATERIAL AND METHODS: Protective effects of fosfomycin on cisplatin-induced nephrotoxicity have been previously reported, however, the proper time, duration and dosage of its administration were uncertain. Therefore, we investigated the protective effect of concurrent administration of twice-daily doses of 2 g fosfomycin for 5 days in 13 cisplatin-naïve lung cancer patients who were due to receive a single dose per cycle of 100 mg/m2 cisplatin. On each chemotherapeutic cycle, patients were randomly given cisplatin alone or cisplatin plus fosfomycin every 4 weeks for a maximum of 4 consecutive cycles. Indicators of nephrotoxicity, urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, serum creatinine (Scr) and creatinine clearance (Clcr) were determined the day before and at day 3 and day 6 after cisplatin administration. Results were compared and statistically analyzed by the non-parametric Mann-Whitney's test. We found that the NAG activities obtained on day 0, day 3 and day 6 of the fosfomycin cycles were comparable to values obtained during the control cycles (p > 0.05). Moreover, the NAG activities on day 3 of both treatment cycles were significantly elevated from baseline (p < 0.01) and had normalized on day 6. There were no significant changes in serum creatinine and creatinine clearance. CONCLUSION: High-dose cisplatin induced reversible elevation of urinary NAG and concurrent administration of low-dose fosfomycin for 5 days had no effect on the enzymuria. In the prevention of cisplatin nephrotoxicity, a further study using dose escalation (8 to 12 g/d) of fosfomycin administered 2 to 3 days prior to cisplatin are required to demonstrate its nephroprotective effects.

Acetylglucosaminidase↗
PubMed2005

In vitro activity of fosfomycin in combination with vancomycin or teicoplanin against Staphylococcus aureus isolated from device-associated infections unresponsive to glycopeptide therapy.

Fosfomycin is a molecule that inhibits the early stage of peptidoglycan synthesis and shows a broad-spectrum bactericidal activity against Gram-positive and Gram-negative bacteria. Using the Killing-curve method, we tested the in vitro bactericidal activity of fosfomycin alone or in combination with vancomycin or teicoplanin at a concentration of 8 microg/mL, that is easily achievable in serum at standard dosing regimens, against seven methicillin-resistant Staphylococcus aureus strains, isolated from patients with well documented device-associated infections unresponsive to or relapsing after glycopeptide therapy. MICs of vancomycin ranged from 1 to 4 microg/mL, MICs of teicoplanin from 2 to 8 microg/mL; MICs of fosfomycin were 8 microg/mL for two strains and >128 microg/mL for the remaining strains. The seven strains proved tolerant when tested for vancomycin and teicoplanin used alone at 2x MIC concentration. Fosfomycin was bactericidal (reduction of 2 log of the inoculum) only against the two susceptible strains. In all cases both vancomycin and teicoplanin in combination with fosfomycin developed bactericidal synergism already at a concentration of 1x MIC. If these results are confirmed by in vivo experiments, the combination of fosfomycin with glycopeptides might be useful for treating device-associated infections, and in preventing the phenomenon of increasing MICs for glycopeptides.

Anti-Bacterial Agents↗
PubMed1985

Pharmacokinetic aspects of cerebrospinal fluid penetration of fosfomycin.

Even today antibiotic therapy of postoperative or posttraumatic meningitis remains a problem. In patients in a neurosurgical intensive care unit, nosocomial microorganisms with high resistance are mainly found. There are no antibiotics available which have simultaneously a good efficacy on the higher resistant nosocomial microorganisms and a good penetration through the blood-brain or blood-cerebrospinal fluid barrier. We analysed the cerebrospinal fluid (CSF) penetration of fosfomycin carrying out the investigations in patients in whom a CSF drainage was required for a neurosurgical indication. The blood-brain barrier was considered to be largely intact (total CSF protein and cell counts with in the normal range). Five or 10 g fosfomycin were administered to adults in 30 min infusions. After administration of 5 g, the CSF concentration formed a plateau between 8.6 and 9.9 micrograms/ml 3 to 6 h after the infusion. Increasing the dose infused (10 g) markedly shortened the latency period between reaching a sufficient concentration of fosfomycin in the CSF. With repeated doses of fosfomycin (3 X 5 g/day) the concentration in the CSF did not fall below the therapeutic level. Even in the presence of an intact blood-brain barrier, fosfomycin in our investigation showed a satisfactory penetration into the CSF. This is attributable to the favourable physicochemical state of fosfomycin (relative molecular mass 182).

Adolescent↗
PubMed1980

[Fosfomycin, a new antibiotic: in vitro activity compared with mezlocillin, cefuroxime and gentamicin].

In vitro investigations with fosfomycin, mezlocillin, cefuroxime, and gentamicin against staphylococci, enterobacteriaceae an pseudomonadaceae were carried out by Agar Dilution method on Mueller-Hinton agar. The fosfomycin breakpoint for the low dosage of 2-3 times 3 g per infusion daily was defined with 16 micro g/ml and for the high dosage of 2-3 times 5 g fosfomycin per infusion with 64 micro g/ml. At a concentration of 16 micro g/l fosfomycin more than 90% of the cultures of staph. aureus (penicillin-resistant), e. coli, proteus mirabilis an proteus vulgaris examined were inhibited. At a concentration of less than 64 micro g/ml fosfomycin 80 toi 100% of the cultures of serratia marcescens, klebsiella pneumoniae, enterobacter cloacae, proteus morgani et rettgeri and pseudomonas aeruginosa (gentamicin sensitive and resistant) were inhibited. Fosfomycin showed an absolute stability against many Beta-Lactamases of different bacterial species.

Animals↗
PubMed1980

Ultrastructure and viability of K. pneumoniae treated with fosfomycin.

The effect of Fosfomycin on K. pneumoniae ATCC 10031 was studied. The morphology on the electron microscopical level and the viability were markedly altered after application of 6 micrograms/ml and 60 micrograms/ml of Fosfomycin, respectively. These were chosen because they can be attained in man by oral or parenteral administration. Until 30 min after the administration of 6 micrograms/ml, and 10 min after administration of 60 micrograms/ml the turbidity increased in the same range as in the control. Thereafter the turbidity decreased but did not fall below its minimal values; after application of 6 micrograms/ml of Fosfomycin the OD remained at higher levels than after applying 60 micrograms/ml of Fosfomycin, at all corresponding times. The number of viable cells, after application of 6 micrograms/ml of Fosfomycin, was maximally reduced for 70% of the value at the time of administration. 60 micrograms/ml quickly impaired the ability of reproduction. Consequently, the CFU were reduced continuously, e.g. by 80% after 30 min and by more than 99% after 180 min. The finestructural alterations were characterized by loss of contrast and regular shape. The occurrence of protruded protoplasts and defects in the cell wall indicate the action of Fosfomycin on the bacterial envelope, preferably on the peptidoglycan layer.

Anti-Bacterial Agents↗
PubMed1997

[Severe methicillin-resistant Staphylococcus aureus infections. Emergence of resistance to fusidic acid or fosfomycin during treatment with continuous infusion of vancomycin].

OBJECTIVES: To evaluate the development of resistance to fosfomycin or fucidic acid in severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and to assess the relationship with serum levels of vancomycin METHODS: A retrospective study was performed in patients hospitalized in our intensive care unit during a 3-year period (1993-1995) who were treated for severe MRSA infection with continuous infusion vacomycin and fosfomycin or fucidic acid. We analyzed the development of resistance and serum levels of vancomycin. RESULTS: During this period, only 20 patients received continuous infusion vancomycin plus fucidic acid or fosfomycin. MSRA resistant to fucidic or fosfomycin developed in 9. Vancomycin serum levels were significantly lower in patients who developed resistance to focidic acid or fosfomycin, both during the first 5 days of treatment (16.68 +/- 1.07 micrograms/ml vs. 22.64 +/- 1.05 mg/ml, p < 0.01) and throughout treatment duration (17.29 +/- 1.07 micrograms/ml vs. 21.85 +/- 0.78 microgram/ml, p < 0.01). CONCLUSIONS: Our findings confirm that in spite of continuous vancomycin infusion at an initial rate of 2 g/24 h, Staphylococcus aureus resistance to fosfomycin or fucidic acid an develop during ongoing treatment. Vancomycin levels of at least 20 micrograms/ml should be obtained as rapidly as possible.

Anti-Bacterial Agents↗
PubMed1990

Effect of topical fosfomycin on polymyxin B ototoxicity.

Fosfomycin is an antibiotic that has been found to reduce the ototoxicity of aminoglycoside antibiotics and cisplatin when systemically coadministered. Polymyxin B, an antibiotic frequently used in ototopical preparations, has been shown to be ototoxic in experimental studies. To investigate the effect of fosfomycin on polymyxin B ototoxicity, topical administration of the two agents into the middle ear cavity was performed. Two groups of chinchillas were used. One group received applications of polymyxin B alone, and the second group received polymyxin B combined with fosfomycin. It was found that application of polymyxin B produces severe damage to the cochlea. However, when polymyxin B was given in combination with fosfomycin, cochlear damage was dramatically reduced. It is likely that in clinical use, a combination of polymyxin B and fosfomycin would demonstrate reduced risk of ototoxicity.

Administration, Topical↗
PubMed1990

Single dose fosfomycin trometamol versus multiple dose norfloxacin over three days for uncomplicated UTI in general practice.

The aim of this study was to carry out a small-scale bacteriological comparison between a standard therapy with norfloxacin 400 mg twice daily, and fosfomycin trometamol (3 g) in single dose in uncomplicated urinary tract infections (UTI) in women. Only patients with UTI with cultures showing a bacterial count of 10(5) or more bacteria/ml were included in the study (n = 32; ages 16-75 years). After one week sterile cultures were obtained in 14 of 16 cases in the fosfomycin trometamol group, and in 14 of 16 cases in the norfloxacin group. After one month eradication was confirmed in 13 of 16 patients in the fosfomycin trometamol group, and in nine of 16 patients in the norfloxacin group. Recurrence was seen in one case in the fosfomycin trometamol group, and in five cases in the norfloxacin group. The reinfection and persistence rates were identical (1/16) in both groups. The main clinical symptoms disappeared very rapidly after initiating treatment, and the correlation with the bacteriological data after one week was excellent. Both drugs were well tolerated and the compliance for fosfomycin trometamol was 100%.

Adolescent↗
PubMedDate not supplied

Adjuvant fosfomycin medication in chronic osteomyelitis.

The therapeutic effectiveness of adjuvant therapy with fosfomycin was studied in a prospective clinical trial of 60 patients suffering from chronic post-traumatic osteomyelitis. The patients were aged between 17 and 78 years (mean 37.4 years). The chronic osteomyelitis was predominantly located in the tibia (43 patients) and in the femur (13 patients). Most of the pathogens isolated were Staphylococcus aureus (42%), coagulase-negative staphylococci (19%), Pseudomonas aeruginosa (12%), streptococci (7%) and enterococci (5%). The pathogens isolated from the osteomyelitic foci were sensitive to fosfomycin. Fosfomycin concentrations in bone samples were determined in 19 patients. In the group of patients receiving initially 5 g fosfomycin, bone concentrations ranged between 119.4 and 451.2 mg/l of interstitial fluid. In the group of patients receiving initially 10 g fosfomycin, bone concentrations ranged between 117.1 and 3684.2 mg/l of interstitial fluid. The mean MIC90 values of the isolated pathogens ranged between 2 and 64 mg/l (S. aureus and Escherichia coli 2 mg/l, Proteus vulgaris 8 mg/l, streptococci groups A and B 32 mg/l and coagulase-negative staphylococci, enterococci and P. aeruginosa 64 mg/l). The outcome of treatment was assessed after a minimum of seven and a maximum of 53 months (mean 37 months). The results were: very good 54.7%, good 3.8%, satisfactory 15.1% and unsatisfactory 26.4%.

Adolescent↗
PubMedDate not supplied

Activity of the trometamol salt of fosfomycin in an in vitro model of the treatment of bacterial cystitis.

The response to trometamol fosfomycin of four strains of Escherichia coli was studied in an in vitro model in which the hydrokinetic aspects of the treatment of bacterial cystitis can be stimulated. Two strains of E. coli that were fully susceptible to fosfomycin, and a strain of intermediate susceptibility responded well to relatively low concentrations of the trometamol salt: doses achieving peak concentrations of 50 or 250 mg/l suppressed bacterial growth for at least 18 h; however, the emergence of resistance was completely suppressed only when a peak concentration of 2500 mg/l was achieved in the bladder model. A strain of E. coli that was fully resistant to fosfomycin in conventional minimum inhibitory concentration titrations responded to the highest dosage used, but this did not prevent further resistance from emerging. These results were obtained in the absence of the potentiating agent, glucose-6-phosphate, which is commonly used in susceptibility tests of fosfomycin. The implications of the results for fosfomycin dosage in bacterial cystitis and for the interpretation of susceptibility tests is discussed.

Administration, Oral↗
PubMed2004

Differential effects of fosfomycin and corticosteroid on the molar ratio of interleukin-1 receptor antagonist/interleukin-1beta in the culture supernatants of mononuclear phagocytes from patients with sarcoidosis.

We compared the effects of fosfomycin, an antibiotic reported to possess immunomodulatory activities, and prednisolone on the production of interleukin-1 receptor antagonist (IL-1ra) and IL-1beta by bronchoalveolar lavage fluid (BALF) macrophages obtained from sarcoidosis patients. The molar IL-1ra/IL-1beta ratio in the culture supernatants of BALF macrophages obtained from sarcoidosis patients, which was lower in sarcoidosis patients than in healthy nonsmokers, was significantly increased in the presence of fosfomycin, but decreased by prednisolone. Further, the molar IL-1ra/IL-1beta ratios in the culture supernatants of peripheral blood mononuclear cells isolated from four of five patients after fosfomycin administration for 14 days were higher than the ratios measured before fosfomycin administration. Fosfomycin showed an anti-inflammatory effect in a different way, when compared with that of prednisolone.

Adult↗
PubMed1997

Alteration of cytokine levels by fosfomycin and prednisolone in spontaneous proliferation of cultured lymphocytes from patients with HTLV-I-associated myelopathy (HAM/TSP).

Fosfomycin has recently been reported as an antibiotic with immunomodulatory activities. To evaluate the possibility of clinical administration of fosfomycin in patients with human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), the effects of this agent on the HTLV-I-induced in vitro phenomenon were studied. The influence of fosfomycin on in vitro spontaneous proliferation (SP) of peripheral blood mononuclear cells (PBMCs) from four patients with HAM/TSP was measured by thymidine incorporation into the cells, and the concentration of several cytokines in the culture supernatants was examined in three HAM/TSP patients. Enzyme-linked immunosorbent assays (ELISAs) were employed to detect the concentrations of interleukin-4 (IL-4), IL-6, IL-10, interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF-beta1), and macrophage inflammatory protein-1alpha (MIP-1alpha). The data were compared to the changes by prednisolone which is known to regulate the HTLV-I-associated in vitro phenomenon and to have a therapeutic benefit in patients with HAM/TSP. Production of IL-6, IFN-gamma and MIP-1alpha from the spontaneously proliferating cells were demonstrated. Fosfomycin could not suppress the HTLV-I-associated SP, but had the properties to decrease the levels of TGF-beta1 and MIP-1alpha. It was also demonstrated that the concentrations of IFN-gamma and MIP-1alpha in the cultures in the presence of prednisolone were apparently decreased, suggesting a possible involvement of these cytokines in the pathogenesis of HAM/TSP. These findings support the hypothesis that fosfomycin may have immunomodulatory potentials in HTLV-I-related cellular interactions in a different manner from ordinary immunomodulatory agents.

Adult↗
PubMed2003

Fosfomycin inhibits NF-kappaB activation in U-937 and Jurkat cells.

Fosfomycin exerts anti-inflammatory effects through inhibiting the production of proinflammatory cytokines. Transcription of the genes for these proinflammatory cytokines is regulated by NF-kappaB. We tested the hypothesis that fosfomycin inhibits the activation of NF-kappaB induced by tumor necrosis factor-alpha (TNF-alpha) in human monocytic U-937 cells, and a T cell line (Jurkat). Western blot analysis demonstrated that fosfomycin inhibits NF-kappaB activation in both cells. Flow cytometry revealed that fosfomycin suppresses NF-kappaB activation in both cells in a dose-related manner. These findings are consistent with the idea that fosfomycin suppresses the production of proinflammatory cytokines via inhibition of NF-kappaB activation.

Anti-Bacterial Agents↗
PubMed2002

Efficacy of calcium fosfomycin for the treatment of experimental infections of broiler chickens with Escherichia coli O78:K80.

Two trials were made to assess the efficacy of including calcium fosfomycin in the drinking water or in the feed for four days to control the adverse effects of experimentally induced colibacillosis in broiler chickens. Trial 1 had five groups of 15 chicks each: one group of negative controls; an untreated infected control group and three groups treated with 50, 100 or 200 ppm of calcium fosfomycin in drinking water. Trial 2 had the same groups but the antibiotic was incorporated into the feed. The chickens were infected via their air sacs with 1.7 x 10(8) - 3.6 x 10(8) CFU/chick of Escherichia coli O78:K80. The morbidity and mortality, a score for the gross lesions, the relative weight of the liver and spleen, performance and re-isolation of the challenge bacteria were recorded. Calcium fosfomycin in the drinking water controlled the colibacillosis, particularly in the group treated with 200 ppm. However, no effect of the antibiotic was seen when calcium fosfomycin was incorporated into the feed, the mortality, score of lesions and re-isolation of E. coli from the organs in the three treated groups being similar to those for the infected unmedicated group. The amount of antibiotic ingested in trial I was three times more than in trial 2. These results suggest that calcium fosfomycin is best used in the drinking water for the treatment of colibacillosis.

Administration, Oral↗
PubMed1987

Bactericidal effect of ofloxacin alone and combined with fosfomycin or vancomycin against Staphylococcus aureus in vitro and in sera from volunteers.

The bactericidal activity of ofloxacin alone and in combination was evaluated against strains of Staphylococcus aureus by measuring MBCs, FBC indexes and by the killing curve technique. Bactericidal titres were determined in sera from volunteers given ofloxacin alone or in combination with fosfomycin or vancomycin. FBC indices less than 0.75 were observed with fosfomycin, showing moderate synergy. FBC indices of 1 were seen with vancomycin. Killing kinetic experiments indicated that ofloxacin (1 and 4 mg/l) exerted a rapid bactericidal effect (99.9% killing in 4 h); the combination of ofloxacin and fosfomycin was synergistic for one of three strains, while killing kinetics of ofloxacin were unaltered by fosfomycin for two of three strains or by vancomycin for the three strains. Sera collected two hours after ofloxacin or fosfomycin had been administered had bactericidal titres less than 1/2. Bactericidal titres were significantly greater in sera from volunteers given the combination of these two drugs. Similar bactericidal titres were obtained in sera after the administration of vancomycin alone or in combination with ofloxacin. A loading dose of 400 mg ofloxacin with subsequent doses of 200 mg had no significantly prolonged effect on bactericidal titres.

Adult↗