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A procedure for protoplasts formation from Escherichia coli and Serratia marcescens by treatment with fosfomycin alone is described. This method gives high and low yields of stable protoplasts from E. coli and S. marcescens respectively. In the last case numerous spheroplasts were obtained. Electron micrographs of intact cells, protoplasts and spheroplasts are shown.
Pregnancy induces anatomical and physiological changes in the urinary tract. In this condition a bacteriuria, even asymptomatic, may lead more frequently to pyelonephritis. Asymptomatic bacteriuria in pregnant women has therefore got to be treated. According to recent studies, long course antibiotherapy did not prove to be more effective than a single-dose one in the case of non-complicated bacteriuria. Moreover, the maternal and foetal toxicity should be reduced in the latter regimen. In this paper we present the preliminary results of our study comparing a single-dose treatment by fosfomycin trometamol (3 g) and nitrofurantoin (200 mg per day during a week).
Single dose fosfomycin trometamol (3 g) was used to treat 20 hospitalised patients with UTI. Tolerance was good or excellent in 19/20 patients; a satisfactory bacteriological outcome was recorded in 11/17 of patients with sensitive organisms and a satisfactory clinical outcome was noted in 12/16 symptomatic individuals.
The influence of 5 g fosfomycin i.v. every 12 hours on the intestinal and pharyngeal flora was studied in eight healthy, male volunteers. The Escherichia coli counts were markedly reduced during application and returned to normal in all subjects within a maximum period of 12 days. The total count of Enterococci was reduced by one to two decimal potencies under medication. There was no change in the counts of Bacteroides and anaerobic lactobacteria. No selection of Clostridium difficile was observed. Throughout the study period the pharyngeal flora of all subjects was consistent, and no changes were seen. No selection of Candida spp. was observed.
The purpose of this study was to evaluate the therapeutic effect of cefotaxime (CTX) and fosfomycin (FOS), alone or in combination, in an experimental meningitis, with cerebrospinal fluid (CSF) concentrations of the two antibiotics reproducing those obtained in human CSF during bacterial meningitis. With a dose of 50 mg/kg of CTX and 100 mg/kg of FOS injected i.v. (CTX over 0.5 h and FOS over 3 h), CSF concentrations were comparable to those observed in man. In a series of five rabbits per treatment group, the bacterial population was counted before and after treatment (two doses with a six-hour interval) with CTX, FOS or CTX + FOS (CTX over 0.5 h before the end of FOS infusion). By the 12th hour of treatment, the percentage of bacteria surviving in CSF compared to the initial population was 4.35% for CTX, 0.20% for FOS and 0.19% for CTX + FOS. Thus, it seemed that CTX + FOS was not more active than FOS alone. In another series of four rabbits per group, the bactericidal effect was followed at T0, T6, T12, T24 and T48 after treatment (two doses with a six-hour with a six-hour interval). With CTX, a variable drop in bacterial count from one rabbit to the other occurred during the first 12 h, and then a bacteriostasis followed. With FOS, a quick bactericidal effect was observed during the first 12 h, becoming slower during the following 36 h (0.03% of bacteria surviving at the 48th hour). With CTX and FOS in combination, a quick bactericidal effect was achieved, remaining steady over a 48-hour period (0.001% of bacteria surviving at the 48th hour).
The in vitro activity of combinations of sparfloxacin/oxacillin, sparfloxacin/fosfomycin, and oxacillin/fosfomycin was investigated against 16 methicillin-resistant Staphylococcus aureus (MRSA) isolates and 12 methicillin-resistant Staphylococcus epidermidis (MRSE) isolates moderately resistant to sparfloxacin. Synergic interactions were observed more frequently against MRSE than against MRSA strains. The most effective combination on both species was fosfomycin plus oxacillin, synergistic against ten of 16 MRSA and eight of 12 MRSE strains.
Multiple studies were performed to define the quality control ranges for susceptibility tests of fosfomycin tromethamine. For disk diffusion tests, the limits proposed are 22 to 30 mm for Escherichia coli ATCC 25922 and 25 to 33 mm for Staphylococcus aureus ATCC 25923. Broth microdilution tests were not reproducible. For agar dilution tests, ranges proposed are 0.5 to 2.0 micrograms/ml for Escherichia coli ATCC 25922, 0.5 to 4.0 micrograms/ml for Staphylococcus aureus ATCC 29213; 2.0 to 8.0 micrograms/ml for Pseudomonas aeruginosa ATCC 27853, and 32 to 128 micrograms/ml for Enterococcus faecalis ATCC 29212.
The in vitro activity of fosfomycin in combination with ceftazidime, imipenem, amikacin, or ciprofloxacin was studied by an agar plate checkerboard method against 40 clinical isolates of Pseudomonas aeruginosa with various antibiotic resistance profiles. Fosfomycin/ciprofloxacin appeared to be the most effective combination (synergy 15%, addition 80%, indifference 5%), followed by fosfomycin/amikacin (synergy 7.5%, addition 52.5%, indifference 40%), fosfomycin/imipenem (addition 37%, indifference 63%), and fosfomycin/ceftazidime (addition 20%, indifference 80%). The effects of the combinations were not significantly influenced by the antibiotic susceptibility patterns of the strains.
Single-dose therapy has been documented in defined groups of adults. For children, this type of treatment requires further investigation. Children to be studied should have uncomplicated UTI and the drugs should optimally have a broad antibacterial spectrum, a low tendency to select for resistant bacteria, and pharmacokinetic properties allowing maintenance of inhibitory antibiotic levels in urine for at least two to three days. Fosfomycin trometamol, trimethoprim and co-trimoxazole are oral antibacterials that may prove effective for single-dose therapy in children, as has been suggested in some studies.
Adherence of three strains of group A streptococci and their fosfomycin-resistant mutants to HEp-2 tissue culture cells was compared with some cell-surface characteristics, i.e. ultrastructure and hydrophobicity. Among Fosr mutants, both well-adhering and weakly adhering mutants were found. Clonal analysis of the mutants proved their greater stability in the adherence. Well-adhering parent strains of streptococci and Fosr mutants exhibited surface fibrillae in contrast to weakly adhering Fosr mutants which were devoid of fibrillae or contined fibrillae of lower electron density. Decrease of adherence of Fosr mutants of two strains was accompanied by a decrease of their hydrophobicity.
Changes in serum KL-6 levels after intravenous fosfomycin (FOM) administration in idiopathic interstitial pneumonia (IIP) were studied. Seventeen patients who were diagnosed with usual interstitial pneumonia by surgical lung biopsy were selected as subjects. In these patients, FOM was administered intravenously, at a dose of 2 g twice daily, for 14 days, and serum KL-6 was determined before and after its administration. FOM administration resulted in a reduction of serum KL-6 in all 17 patients (1273 +/- 132 U/ml [mean +/- SEM] to 1023 +/- 101 U/ml; P < 0.01). FOM may reduce serum KL-6 in IIP and may be an appropriate therapeutic drug for this condition.
The effect of coadministration of fosfomycin (FOM) on nedaplatin-induced nephrotoxicity in rats was investigated for 6 days. FOM decreased nedaplatin-induced nephrotoxicity, as shown by reduced blood urea nitrogen (BUN), serum creatinine levels, and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Further, there were fewer histopathological signs of nephrotoxicity in the groups treated with the combination of nedaplatin and FOM as compared with the nedaplatin-alone group. The concentration of nedaplatin was significantly lower in the renal cortex of rats treated with the combination of nedaplatin and FOM as compared with those treated with nedaplatin alone (p < 0.05). In conclusion, the concomitant administration of FOM and nedaplatin may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of nedaplatin.
The effect of coadministration of fosfomycin (FOM) on glycopeptide antibiotic-induced nephrotoxicity for 3 days was investigated in rats. To induce nephrotoxicity in a short time, gentamicin (GM) was also coadministered. In the present study, FOM decreased glycopeptide antibiotic-induced nephrotoxicity as shown by reduced urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) as well as fewer histopathological signs of nephrotoxicity in the groups treated with the combination of glycopeptide and FOM as compared with a glycopeptide alone. In addition, the higher the dose of FOM, the more it decreased urinary NAG levels, suggesting that the role of FOM in alleviating nephrotoxicity is dose dependent. The accumulation of teicoplanin and vancomycin was significantly lower in the renal cortex of rats treated with the combination of glycopeptide antibiotics and FOM as compared with glycopeptide antibiotics alone (P < 0.05). In conclusion, the concomitant administration of FOM and glycopeptide antibiotics may help to achieve a chemotherapeutic strategy that reduces the nephrotoxic effects of glycopeptide antibiotics.
The fosfomycin resistance determinant of the transposon Tn2921 has been localized and cloned into the plasmid pBR322. A DNA fragment of 1 kb contains all the information required for full expression of the resistance. The level of resistance was unaffected by the plasmid copy number and by the orientation in which the fragment was cloned. Studies in minicells showed that this 1-kb fragment directed the synthesis of a single polypeptide with a molecular mass of 16 kDa.
Capillary zone electrophoresis with indirect ultraviolet detection was used for the determination of fosfomycin in serum. Running buffer consisted of a mixture of 200 mM sodium borate with 10 mM phenylphosphonic acid used as ultraviolet absorbing background electrolyte. Relationships between the pH of the buffer and the efficiency of the separation (migration times and selectivities) or the sensitivity of detection were investigated. The method was then validated over a 10-100 micrograms ml-1 concentration range to be applied to further therapeutic drug monitoring. The choice of ethylphosphonic acid as internal standard is discussed. The specificity and the linearity of the technique are demonstrated. The inter-day precision was satisfactory with a relative standard deviation of less than 2%. Accuracy was calculated with a standard error near 0.5 and 18% for 100 and 10 micrograms ml-1, respectively.
Fosfomycin tromethamine (FT) is effective in vitro in extended spectrum beta-lactamase (ESBL)-producing Escherichia coli strains. The aim of this study was to evaluate the effect of FT in the treatment of ESBL-producing E. coli-related lower urinary tract infection. All patients were aged >18; had dysuria or problems with frequency or urgency in passing urine; had >20leukocytes/mm(3) in urine sediment and an ESBL-producing E. coli urine culture (>10(5)cfu/mm(3)); no leukocytosis or fever; and were treated with FT between September 2004 and July 2006 in our outpatient clinic and hospital. ESBL detection was performed by double disk synergy tests. All patients had received FT (3gx1 every other night, three times) and had a control urine culture taken 7 to 9 days after this therapy. Clinical success was defined as resolution of symptoms on the control visit; microbiological success was defined as a sterile control urine culture. In all, 52 patients (aged 55.0+/-18.3, range 19-85; 25 males, 27 females) were included in the study. Overall clinical and microbiological success was 94.3% (49/52) and 78.5% (41/52), respectively. Although it is not a randomized controlled study, these data show that FT may be a suitable, effective and cheap alternative in the treatment of ESBL-producing E. coli-related lower urinary tract infection.
Patients with cystic fibrosis can develop multi-resistant organisms and may have poor intravenous access making antibiotic treatment difficult. This case discusses the successful use of fosfomycin via the subcutaneous route in a paediatric patient with cystic fibrosis.
We investigated the influence of fosfomycin (FOM) on the production and the mRNA expression of interleukin-8 (IL-8) by monocytes. In the incubation of whole blood stimulated by N-Formyl-Met-Leu-Phe (FMLP), FOM significantly suppressed the production and the mRNA expression of IL-8 by monocytes and its inhibitory action was concentration-dependent (FOM: 50-200 microg/ml). However, FOM did not influence the production and the mRNA expression of IL-8 in the incubation of fractionated mononuclear cell stimulated by FMLP. The supernatant of FMLP-stimulated polymorphonuclear leukocyte (PMNL) could induce the mRNA expression of IL-8 by monocyte. The supernatant of FMLP-stimulated PMNL which was pre-treated with FOM significantly (P < 0.05) inhibited the expression of IL-8 mRNA by monocyte. Moreover, FOM suppressed the production of leukotriene B4 (LTB4) from neutrophil in a concentration-dependent manner. When LTB4 was added to the fractionated mononuclear cells directory, the expression of IL-8 mRNA was enhanced (P < 0.05). The present study indicated that FOM suppress the production of LTB4 from neutrophils and suppress the expression of IL-8 mRNA by LTB4 from monocytes. It was also demonstrated that LTB4 produced by neutrophil is one of the factor which promotes the expression of IL-8 mRNA in monocytes.