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PubMed2003

[Fosfomycin].

Fosfomycin is an natural antibiotic with an epoxide structure and low molecular weight which acts in the first stage of peptidoglycan synthesis of the bacterial wall. It has a rapid bactericide effect, and a wide spectrum, including methicillin-resistant Staphylococcus aureus and intermediate glycopeptide-susceptible or -resistant enterococci. Over the years it has maintained its activity and has shown stable rates of resistance. It has synergistic action, which is additive or indifferent with glycopeptides, linezolid, quinupristin-dalfopristin, betalactams, aminoglycosides, ansamycines, nitroimidazoles and quinolones, without antagonism. It can be administered orally or parenterally in a wide range of doses, it does not bind to plasma proteins, and has a good distribution volume, reaching high concentrations in the interstitial fluid and tissues. It is eliminated in the kidneys in its active form without metabolites and is dialyzable. It has been used in a number of indications, including urinary, respiratory, intraabdominal, obstetric-gynecologic, central nervous system and osteoarticular infections, with satisfactory overall results in 80% of cases and minimal side effects. It does not cause important changes in the normal human flora. As additional effects it has the capacity to favor phagocytosis, act as an immunomodulator and protect human cells from cisplatin, cyclosporin, aminoglycoside, vancomycin, amphotericin B and polymixin toxicity. Oral fosfomycin is currently clearly indicated in urinary infections and gastroenteritis, and parenteral fosfomycin in high doses and in combination with other drugs in severe inhospital infections caused by problematic pathogens, including multiresistant staphylococci and enterococci, and in immunodepressed patients treated with nephrotoxic drugs.

Anti-Bacterial Agents↗
PubMed2006

In vitro activity of linezolid in combination with doxycycline, fosfomycin, levofloxacin, rifampicin and vancomycin against methicillin-susceptible Staphylococcus aureus.

The objective of this paper was to investigate the in vitro effects of linezolid combined with five antistaphylococcal antibiotics--doxycycline, fosfomycin, levofloxacin, rifampicin and vancomycin--upon methicillin-susceptible Staphylococcus aureus (MSSA). Five MSSA isolates from clinical specimens of human infections--hf008, hf095, hf295, hf602 and hf946--were used in this study. The checkerboard method was used to assess synergism between linezolid and the five antibiotics, and time-kill curves were carried out with the most active combinations. Indifference was the most common result achieved by the checkerboard method when linezolid was combined with rifampicin, vancomycin or doxycycline. The combination with levofloxacin yielded antagonism for two of the five isolates. However, four isolates showed synergy for the combination of linezolid plus fosfomycin with a fractional inhibitory concentration index (FICI) > or = 0.5. Neither linezolid nor fosfomycin alone inhibited growth at 1/4x minimum inhibitory concentration (MIC); but the combination of both drugs at 1/4 the respective MIC showed a synergistic bacteriostatic effect, a 2-3 log(10) decrease with respect to the most active antibiotic alone. In summary, the combination of subinhibitory.

Acetamides↗
PubMed1991

[Therapeutic efficacy of fosfomycin and cisplatin alone or in combination on human urogenital cancer by subrenal capsule assay].

Experimental therapies of human urogenital cancer with fosfomycin and cisplatin were performed by subrenal capsule assay. The subrenal capsule assay was applied for 10 cell lines, consisted of 4 renal cell carcinomas, 2 renal pelvic carcinomas, 2 carcinomas of the urinary bladder, one prostatic carcinoma, and one testicular tumor. The efficacy of each drug was evaluated by measuring the tumor growth, and compared the mean tumor volume of treated with that of untreated groups. The growth inhibition rate in fosfomycin group was 60% and in cisplatin group was 80%, whereas that of the combination therapy of both fosfomycin and cisplatin was 50%. This indicates that the combination therapy reduced the antitumor effect. Further, the histological findings also showed a similar pattern in both kidney and tumor tissues between the treated and untreated groups.

Animals↗
PubMed1990

[Clinical evaluation of fosfomycin].

A total of 15 patients with a variety of infectious disease were treated with fosfomycin in Chang Gung Memorial Hospital, Kaoshiung. The drug was administered by iv drip infusion in doses of 204g per day for 5-28 days. The clinical response was satisfactory in 6 (100%) of 6 patients with urinary tract infection, 8 (80%) of 10 with septicemia and 1 with pneumonia. Overall, fosfomycin was effective in 13 (86%) of all patients treated. Except for 1 isolate of the pathogen, B. fragilis, and another 1 isolate of oxacillin-resistant Staphylococcus aureus, all the other 16 pathogens isolated, including Escherichia coli, Aeromonas, Klebsiella. Staphylococcus aureus, Acinetobacter, and Pseudomonas aeruginosa were successfully eradicated. Only 1 case developed skin rash. So fosfomycin is a useful agent and gram (-) organisms including oxacillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

Adult↗
PubMed1990

[Perioperative preventive antibiotic treatment with fosfomycin in heart surgery: serum kinetics in extracorporeal circulation and determination of concentration in heart valve tissue].

A prospective clinical study was carried out to assess the adequacy of perioperative antibiotic prophylaxis using fosfomycin in patients undergoing open-heart surgery for valve diseases for the prevention of early postoperative endocarditis, as well as for serious mediastinal infections that are caused mostly by multiresistant staphylococci and Gram-negative bacteria. Perioperative pharmacokinetics and tissue penetration were determined within the harvested heart valves and subcutaneous tissue. Reliable bactericidal serum levels were established at the first measurement 10 min after the end of intravenous infusion (203.7 +/- 44.7 micrograms/ml) and were maintained during surgery for at least 120 min (124.6 +/- 58.4 micrograms/ml), even in cases of prolonged extracorporeal circulation. Cardiopulmonary bypass did not alter the serum elimination of fosfomycin in comparison with patients not undergoing extracorporeal circulation. Peak tissue concentrations were achieved in both aortic and mitral valves after 30 min, ranging between 27.1 and 76.9 micrograms/g for aortic valves and 39.6-69.4 micrograms/g for mitral valves, depending on the degree of valvular degeneration. MIC values of 16 micrograms/g were maintained in both valves for at least up to 60 min. There was no evidence of renal impairment, adverse reactions or infections during the postoperative course or thereafter for a period of 3 months. It is concluded that perioperative intravenous antibiotic prophylaxis using fosfomycin (5 g t.i.d. in adults), beginning with induction of anesthesia and continued for 48 h postoperatively, provides rapid, reliable bactericidal serum levels and valvular tissue concentrations that will inhibit most Gram-positive and Gram-negative organisms that cause bacterial endocarditis and other serious infections following cardiac surgery.

Aged↗
PubMed1989

Pharmacokinetics of fosfomycin in normal and burn patients. Effect of probenecid.

The pharmacokinetics of fosfomycin are modified in burn patients, suggesting a net tubular secretion in such patients. In an attempt to verify this hypothesis, five healthy normal volunteers were studied The pharmacokinetics of fosfomycin were studied with and without probenecid. In the absence of probenecid, the renal clearance of the drug was equal to that of creatinine. With probenecid, the renal clearance of fosfomycin decreased, whereas creatinine clearance did not. This result suggests the existence of a tubular secretion, which might be enhanced in burn patients.

Adult↗
PubMed1987

[Experimental studies of the nephroprotective effect of fosfomycin].

We studied in an experimental rat model, if fosfomycin reduces the tubulotoxicity induced by tobramycin, teicoplanin, cisplatin or ciclosporine A and is thus a nephroprotective agent. 10 female wistar rats per dose and compound were used, measures of tubulotoxicity were urinary excretion rates of tubular cells and malate dehydrogenase on 5 successive days. Fosfomycin proved to be a potent nephroprotector against all 4 nephrotoxins. Its activity was not based on pharmacokinetic interactions but on a pharmacodynamic effect. Presumably, fosfomycin stabilises the membranes of lysosomes in tubular cells.

Acute Kidney Injury↗
PubMed1988

Antibacterial activity in human urine of fosfomycin trometamol in an in vitro model of the urinary bladder.

The urinary concentrations of fosfomycin trometamol, norfloxacin, pipemidic acid and cotrimoxazole were studied at various times after oral administration of drugs in healthy volunteers. Using the same urine, the bactericidal activity of four antimicrobial agents against Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae in an in vitro model simulating the treatment of bacterial cystitis was also evaluated. The results obtained show that very high concentrations of the drugs were achieved in urine particularly after the oral administration of the fosfomycin trometamol. In the bladder model bactericidal activity of fosfomycin trometamol, norfloxacin and pipemidic acid were higher than that of cotrimoxazole; no resistant mutants to drugs were selected over a period of 24 h.

Administration, Oral↗
PubMed1986

Influence of pH, inoculum and media on the in vitro bactericidal activity of fosfomycin trometamol, norfloxacin and cotrimoxazole.

An in vitro study was made of the bactericidal activity against Escherichia coli of fosfomycin trometamol, a new fosfomycin salt characterized by high bioavailability in relation to the pH, inoculum and culture medium, the latter being nutrient broth or human urine. Cotrimoxazole and norfloxacin were used for comparison. The results obtained show that both in nutrient broth and human urine, fosfomycin trometamol had higher bactericidal action than that of the other two antimicrobial agents.

Culture Media↗
PubMed1986

[In vitro study of the effects of an imipenem-fosfomycin combination against clinical strains of Staphylococcus].

In vitro antibacterial activity of imipenem-fosfomycin (IMP-FOS) combinations were studied against 31 clinical isolates of Staphylococcus strains: methicillin susceptible S. aureus (MSSA, 11 strains), methicillin resistant S. aureus (MRSA, 11 strains), methicillin resistant S. epidermidis (MRSE, 9 strains). The study was carried out by means of a microtiter checkerboard method (FICs and FBCs index) and killing-curves (3 strains). Imipenem antibacterial activity was good against MSSA (mean MICs of 0.12 micrograms/ml) but reduced against MRSA (16 micrograms/ml). Fosfomycin was regularly effective (CMI less than or equal to 64 micrograms/ml) against most strains. IMP-FOS combination was strongly synergistic (FIC less than 0.125) against MSSA and still synergistic with achievable therapeutic concentrations against heterogeneous MRSA and MRSE strains (mean FIC of 0.125, MIC in the combination of 1 microgram/ml). The bactericidal activity (FBCs and killing-curves) was limited against homogeneous MRSA and MRSE needing higher concentrations (8 micrograms/ml in the combination). In the 3 cases fosfomycin concentrations in combination remained low (1 to 2 micrograms/ml).

Drug Combinations↗
PubMed1987

Treatment of lower urinary tract infections in children: single dose fosfomycin trometamol versus pipemidic acid.

Fifty-one children suffering from symptomatic and asymptomatic recurrent urinary tract infections were treated at random in a comparative study. A single dose of 2 g fosfomycin trometamol was administered to 24 children (2 males and 22 females, mean age 6.7 +/- 3.3 yr) and two 200 mg doses of pipemidic acid (400 mg in children weighing more than 25 kg) were administered daily to 27 children (3 males and 24 females, mean age 6.6 +/- 3 yr) for 7 days. Bacteriological results showed that at the end of followup (1 month) urine was sterile in 17 out of 24 children treated with fosfomycin trometamol (70.8%) and in 19 out of the 27 children treated with pipemidic acid (70.3%). One persistant infection and six reinfections were observed in the follow-up period in the fosfomycin group and 8 reinfections in the pipemidic acid group, usually in patients with urinary complications. No side effects were reported. The microbiological study of feces showed that neither of the drugs caused the emergence of resistant bacteria.

Adolescent↗
PubMed1986

[Determination of urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion as a parameter of nephrotoxicity due to cis-platin and the effect of fosfomycin (FOM) on its nephrotoxicity].

CDDP is often dose-limited owing to its nephrotoxicity. Urinary NAG was measured to evaluate the nephrotoxicity of CDDP in 18 patients (DIV: 12 patients, Intra-Peritoneal: 6 patients) with or without Fosfomycin. The gradual increase in urinary NAG activity was noted on repeating the therapy. 24 hour NAG excretion was correlated with that of urinary beta 2-microglobulin. However, urinary NAG was not correlated with Ccr 24 or BUN. Though Ccr 24 and BUN were normal, urinary NAG and beta 2-microglobulin markedly increased during CDDP therapy. Fosfomycin administration significantly decreased urinary NAG, which was increased by CDDP. These results indicate that: The measurement of urinary NAG and beta 2-microglobulin are most useful in estimating the nephrotoxicity of CDDP. Fosfomycin decreases the nephrotoxicity of CDDP.

Acetylglucosaminidase↗
PubMed1986

[Intraocular penetration of fosfomycin in man and rabbits].

The intraocular distribution of fosfomycin was studied in 32 patients undergoing cataract surgery and or vitrectomy and in 8 rabbits after experimental infection of one eye by Staphylococcus aureus. In subjects perfused with 4 g of fosfomycin, concentrations ranged from 14 to 18.8 mg/l in aqueous humour (AH) and from 8 to 12.5 mg/l in vitreous fluid (VF) between 1 and 6 hours after the end of the perfusion; these levels were higher than MICs for 80-90 per cent of bacteria found in endophthalmitis. In rabbits the concentration in infected eyes with respect to healthy eyes was found to be from 2.5 to 5 times in AH and from 4.9 to 19.2 times higher in VF. Therefore fosfomycin in association with third generation cephalosporins (ceftriaxone) or with new quinolones can be recommended in the prevention and early treatment of endophthalmitis.

Adolescent↗
PubMed1985

Methicillin- and gentamicin-resistant Staphylococcus aureus: susceptibility to fosfomycin, cefamandole, N-formimidoyl-thienamycin, clindamycin, fusidic acid and vancomycin.

The in vitro activity of fosfomycin against 90 strains of methicillin- and gentamicin-resistant Staphylococcus aureus was studied in an in vitro microtitre system using Mueller-Hinton broth supplemented with glucose-6-phosphate. In parallel the antistaphylococcal activity of cefamandole, N-formimidoyl-thienamycin, clindamycin, fusidic acid and vancomycin was determined with the same organisms. The following MIC50 (MIC95) values were obtained: fosfomycin 8 (128) mg/l, cefamandole 8 (greater than 64) mg/l, clindamycin 0.25 (16) mg/l, fusidic acid less than 0.25 (less than 0.25) mg/l, vancomycin 1 (2) mg/l and N-formimidoyl-thienamycin 4 (16) mg/l. A high MIC/MBC ratio was noted for cefamandole, in contrast to fosfomycin.

Cefamandole↗
PubMed1985

Pharmacokinetics of fosfomycin in hemodialyzed patients.

The pharmacokinetics of fosfomycin, an original antimicrobial agent, were investigated in 11 voluntary hemodialyzed patients. Fosfomycin, 2 g, was administered intravenously, 15 minutes before hemodialysis began in group 1 (6 patients), and just after hemodialysis in group 2 (6 patients). Blood samples were collected during 8 hours (group 1) and during 44 hours (group 2). Antibiotic concentrations were determined microbiologically. In group 1, half-life was 4.2 +/- 0.27 hours, total clearance 65.1 +/- 7.1 ml/mn and clearance by hemodialyzer 103 +/- 10 ml/mn. In group 2 plasma levels were 60 mg/l at the 44th hour and half-life was 48.8 +/- 17.5 hours. These results suggest that fosfomycin is actively eliminated by the hemodialyzer in group 1, and largely retained between two dialysis sessions in group 2. As for therapy, intravenous administration of 2 g after dialysis and further administration after each succeeding session are proposed.

Adult↗
PubMed1985

Fosfomycin levels in human aqueous humor after intravenous administration.

Following intravenous infusion of an 8 g single dose of the antibiotic agent fosfomycin, its penetration into human primary aqueous humor was investigated. 1-2 h after the start of infusion, peak values of 35 to 60 micrograms/ml were reached. These concentrations in the aqueous humor would inhibit a high percentage of gram-positive and gram-negative strains commonly causing bacterial endophthalmitis. The infusion of an 8 g dose of fosfomycin immediately preceding intraocular surgery thus constitutes effective peri-operative prophylaxis. Moreover, as a broad-spectrum antibiotic, fosfomycin is indicated as initial therapy in intraocular bacterial infections.

Aged↗
PubMed1981

[Kidney tolerance of fosfomycin in humans with normal kidney function (author's transl)].

In a study with informed healthy volunteers Fosfomycin and their renal tolerance was under investigation. 6 volunteers received 15 g Fosfomycin on three consecutive days. The activity of the brush border enzyme alanine-aminopeptidase (AAP) in 24-hour urine has been measured. It could be demonstrated that these high dosages of Fosfomycin have been without any influence on the membrane integrity. Functional parameters as creatinine-clearance remained unchanged as well.

Adult↗
PubMed1983

[Combination between fosfomycin and oxacillin or cefotaxime against methicillin-resistant Staphylococci and Enterococci].

The resistance of Gram positive cocci to oxacillin and cephalosporins do not appear to be in relation with the synthesis of a beta-lactamase, thus fosfomycin (FOS) could enhance the action of beta-lactam antibiotics by blocking another stage of the peptidoglycan synthesis. When FOS is combined with oxacillin (OXA) or cefotaxime (CTX) against fosfomycin sensitive strains (25 S. aureus 4-16 mg/l, 20 S. epidermidis 2-32 mg/l and 20 Enterococci 16-64 mg/l) one can see a dramatic synergistic effect of these two combinations. Respectively with S. aureus, S. epidermidis and Enterococci, FIC indices are 0.17-0.39 and 0.43 for FOS-OXA and 0.29-0.47 and 0.29 for FOS-CTX. If one considers the CSF concentrations of these three antibiotics, the combination of fosfomycin with oxacillin or cefotaxime may be used in the treatment of meningitis due to methicillin resistant Staphylococci.

Anti-Bacterial Agents↗