fosfomycin and Kidney-Diseases

Although a worldwide increasing incidence of bacterial infections with panresistant pathogens may need innovative antiinfective agents, no breakthrough developments can be expected in the near future. As a consequence, well-tried antibiotics like aztreonam, fosfomycin and colistin, are experiencing a clinical revival, particularly if they are used in an improved manner. Even penicillin G with its narrow spectrum of antimicrobial activity remains an important considerable agent of first choice in special indications compared to broad spectrum antiinfectives.

Topics: Anti-Bacterial Agents; Aztreonam; Bacterial Infections; Colistin; Fosfomycin; Humans; Kidney Diseases; Penicillin G

Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Bacteremia; Bacteria; Biofilms; Fosfomycin; Humans; Kidney; Kidney Diseases; Lymphocytes; Lysosomes; Molecular Mimicry; Neutrophils; Pseudomonas Infections

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.

Topics: Acetylglucosaminidase; Animals; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fosfomycin; Gentamicins; Histocytochemistry; Kidney; Kidney Diseases; Male; Rats; Rats, Wistar; Teicoplanin; Vancomycin

This study investigates the effect of fosfomycin on the tumoricidal efficacy of cisplatinum.. Prospective study utilizing the FaDu squamous cell carcinoma cell line and a nude mouse tumor xenograft model.. Tumor cell growth was assessed in vitro in the presence of cisplatinum and/or fosfomycin utilizing the MTT assay. An optimal cisplatinum dose and dosing schedule was established in a nude mouse tumor xenograft model of squamous cell carcinoma. Using this model, fosfomycin was tested at three dosages and tumor growth monitored over 4 weeks.. Mice treated with cisplatinum and fosfomycin had smaller tumors than those treated with cisplatinum alone (P<.01).. This study is the first demonstration that fosfomycin does not inhibit the tumoricidal efficacy of cisplatinum in vivo. This suggests that fosfomycin may be useful in preventing cisplatinum-induced ototoxicity and nephrotoxicity in humans without altering the tumor response rate.

Topics: Animals; Anti-Bacterial Agents; Carcinoma, Squamous Cell; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Fosfomycin; Hearing Loss, Sensorineural; Kidney Diseases; Mice; Mice, Inbred BALB C; Mice, Nude; Prospective Studies; Tumor Cells, Cultured

Predictive factors for the development of hemolytic uremic syndrome (HUS) were evaluated in 88 inpatients who suffered from enterohemorrhagic E. coli infections in the outbreak in Sakai, 1996. All in- and outpatients received oral or intravenous fosfomycin within acute phase of hemorrhagic colitis, and HUS complicated 1.4% of them. Persistence of bloody stools and diarrhea were longer in HUS patients than in non-HUS patients, but persistence of abdominal pain was not different in either group. Leukocytosis with leukocyte counts over 15,000/microliters and/or elevated CRP level over 2.0 mg/dl at admission, and fever and/or vomiting in the course of hemorrhagic colitis were more frequent in HUS patients than in non-HUS patients. Early intensive treatments including gammaglobulin, urinastatin, aspirin, and dipyridamole were employed in 34 high risk patients for prevention of HUS. These patients were estimated to be at risk of developing HUS because of incomplete HUS, nephropathy, elevated LDH level, thrombocytopenia, or age younger than two years old. These treatments were clinically effective.

Topics: Abdominal Pain; Adolescent; Age Factors; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Child; Diarrhea; Dipyridamole; Escherichia coli Infections; Female; Fever; Fosfomycin; gamma-Globulins; Glycoproteins; Hemolytic-Uremic Syndrome; Humans; Kidney Diseases; Leukocyte Count; Liver Diseases; Male; Melena; Platelet Aggregation Inhibitors; Risk Factors; Sex Factors; Time Factors

The protective effects of elastase (Ela) and fosfomycin against renal toxicity of cis-diamminedichloroplatinum (II) (CDDP) were evaluated in an experimental study using rats. When Ela was used concomitantly with CDDP, the elevation of urinary N-acetyl-beta-D-glucosaminidase levels in the early phase and the sharp fall in these levels in the latter phase were prevented. It was also found that the blood urea nitrogen levels and serum creatinine levels were significantly lowered. Histologically, atrophic and necrotic changes in the tubular epithelium were prevented. The total serum platinum levels showed no change with the addition of Ela; however, the platinum levels in the renal tissues were significantly reduced. These results suggested that Ela is effective against platinum deposits in the renal tissues, particularly in the tubular epithelium, thus protecting the kidneys. On the other hand, fosfomycin demonstrated no such positive results suggestive of a protective effect on the renal function parameters or during histological observation.

Topics: Acetylglucosaminidase; Animals; Blood Urea Nitrogen; Body Weight; Cisplatin; Creatinine; Female; Fosfomycin; Kidney Diseases; Pancreatic Elastase; Rats; Rats, Inbred F344

Topics: Aged; Cisplatin; Fosfomycin; Humans; Kidney Diseases; Kidney Tubules; Lung Neoplasms; Male; Middle Aged

The protective effect of piperacillin against the nephrotoxicity of cisplatin was compared with that of fosfomycin in Fischer 344 rats. Blood urea nitrogen, serum creatinine, and morphological changes were evaluated as the renal toxicological parameters. Rats receiving 2 mg of cisplatin per kg of body weight for 5 days showed significant (P less than 0.01 by multiple-comparison test) elevation of blood urea nitrogen and serum creatinine concentrations compared with rats receiving saline alone and also exhibited development of cell lesions in the pars recta of the tubules in the outer stripe of the outer medulla. However, piperacillin (250 and 1,000 mg/kg) significantly (P less than 0.01 by multiple-comparison test) reduced these toxicological parameters in comparison with results for cisplatin alone. The protective effect of piperacillin was superior to that of fosfomycin, although platinum levels in the kidney were higher with the combination of cisplatin and piperacillin than with cisplatin plus fosfomycin. Although the nephrotoxicity of cisplatin was also reduced when cisplatin was administered concomitantly with sodium chloride in mole-equivalents to 250 and 1,000 mg of piperacillin per kg, its protective effect was less than that of the corresponding piperacillin dose. These results suggest that piperacillin may have a role as a protective agent against the nephrotoxicity of cisplatin.

Topics: Animals; Blood Urea Nitrogen; Cisplatin; Fosfomycin; Kidney; Kidney Diseases; Leukemia L1210; Male; Piperacillin; Platinum; Rats; Rats, Inbred F344

From 1985 to 1986, cisplatin (CDDP) therapy was performed 61 times in 24 patients with urological cancer. Thirty nine courses used fosfomycin (FOM) 4 g/day from the day before CDDP administration to the last dose of CDDP, and we statistically evaluated the prophylactic effect of FOM on CDDP nephrotoxicity using urinary NAG and FENa as parameters (t-test). In the 1-day CDDP group (CDDP 60-70 mg/m2 x 1 day) with FOM a peak NAG was seen on the 1st day but no significant NAG change, FENa has a peak on the 1st day, no significant increase between the previous and the 1st day, but a significant decrease was seen between the 3rd and the 5th day (p less than 0.05). In the 5-day CDDP group (CDDP 20 mg/m2 x 5 day) NAG reached a peak level on the 5th day with FOM, showed significant increase (p less than 0.05; between the previous and the 5th day) and decrease (p less than 0.01; between the 6th and the 14th), compared to those without FOM. FENa change tended to be similar, showing a significant increase, (p less than 0.05; between the 2nd and 4th) and decrease (p less than 0.05; between the 4th and 7th) with FOM but no significant change without FOM. NAG changes with FOM were classified by pre-CDDP dose creatinine clearance (Ccr, ml/min) into 3 groups (under 50, 50-100, over 100). In the 1-day CDDP group with any Ccr no significant NAG change obtained, but, in the 5-day CDDP group with 50-100 Ccr seen a NAG peak on the 6th day, significant increase (p less than 0.05; between the previous and the 6th) and decrease (p less than 0.05; between 6th and 12th). With over 100 Ccr NAG has 4th day peak, significant increase (p less than 0.05; between the previous and the 4th), and decrease (p less than 0.05; between 4th and 8th). A prophylactic effect of FOM on CDDP nephrotoxicity was found in the 5-day CDDP group not in the 1-day CDDP group, using urinary NAG and FENa. PVB and single CDDP regimen (5 day CDDP group) with FOM can be performed safely, if the pre-CDDP dose Ccr is over 50.

Topics: Acetylglucosaminidase; Adolescent; Adult; Aged; Aged, 80 and over; Cisplatin; Creatinine; Female; Fosfomycin; Humans; Kidney Diseases; Kidney Tubules; Male; Middle Aged; Sodium; Urologic Neoplasms

Creatinine clearance and beta-D-acetyl-glucosaminidase (NAG) were useful markers for the evaluation of the renal function of 57 cases of head and neck cancer treated with 60 mg/m2 cis-platinum (CDDP). There was a significant correlation between creatinine clearance and NAG values for (r = -0.4820, p less than 0.01). The nadir of creatinine clearance and NAG values were observed between 2 and 3 weeks after administration of CDDP. After 2 courses of chemotherapy with CDDP, more nephrotoxicity was observed in the cases received prior CDDP therapy, than cases without chemotherapy statistically. Combined chemotherapy with CDDP and 5-FU (CF therapy) caused more renal damage, comparing with other combined chemotherapy such as COP therapy (CDDP, vincristine and peplomycin), and CAP therapy (CDDP, aclacinomycin and cyclophosphamide). Early recovery from the renal damage following CDDP therapy was detected in the cases given Fosfomycin (FOM). This results suggest that FOM would be effective for decreasing the nephrotoxicity by CDDP.

Topics: Acetylglucosaminidase; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Creatinine; Drug Evaluation; Female; Fosfomycin; Head and Neck Neoplasms; Hexosaminidases; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Predictive Value of Tests

The protective effect of fosfomycin (FOM) against the cis-diamminedichloroplatinum (CDDP)-induced nephrotoxicity was evaluated clinically. Thirty-six cases suffering from urogenital cancers were subjected to CDDP therapy in which 50 mg of CDDP was administered on Day 0, with one week regarded as one course of treatment. The daily excretions of urinary N-acetyl-beta-D-glucosaminidase (NAG) and beta 2 microglobulin (beta 2 MG) levels were measured on Day 1, 3 and 5. Creatinine clearance (Ccr) was also determined on Day 1. CDDP was administered once a week for 6 weeks. Group A consisted of 18 patients who were treated with CDDP alone every alternate odd week. In the other even weeks, they received both FOM 4.0 g and CDDP on Day 0 and FOM 4.0 g on Day 1 and 2. The maximum values together with the total amounts of urinary NAG and urinary beta 2 MG were measured. Group B, also consisting of 18 cases, was divided into two sub-groups, one which was always administered with CDDP alone and another which received both FOM and CDDP. The maximum values of each course in urinary NAG and beta 2 MG were measured and Ccr level was also obtained. The changing pattern in the maximum values of two parameters and Ccr level between two subgroups was compared. Group A: The maximum values of urinary NAG excretions obtained in 4th week, using the combined therapy of CDDP and FOM was significantly lower than that obtained in the 3rd week.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylglucosaminidase; Acute Disease; beta 2-Microglobulin; Cisplatin; Creatinine; Fosfomycin; Humans; Kidney; Kidney Diseases; Urogenital Neoplasms

To elucidate the influence of fosfomycin (FOM) on the anti-cancer effect of cisplatin (CDDP), experimental chemotherapy of CDDP with or without FOM was performed. A human lung cancer cell line, HLC-1 serially transplanted into nude mice was treated with CDDP 10 mg/kg (i.p.). Tumor doubling time in CDDP group and CDDP + FOM group are 26.78 +/- 6.3 days and 33.90 +/- 11.82 days respectively, and they are significantly elongated compared to control group. Serum NAG level in CDDP + FOM group was significantly lowered. Therefore, we concluded that anti-tumor effect of CDDP was not diminished by FOM combination.

Topics: Adenocarcinoma; Animals; Cisplatin; Drug Therapy, Combination; Female; Fosfomycin; Kidney Diseases; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Transplantation

The protective effect of piperacillin against the nephrotoxicity of cephaloridine and gentamicin was examined in experimental animals. In rabbits, piperacillin was infused at a dose of 1 mg/kg (body weight) per min over 225 min and cephaloridine (300 mg/kg) was intravenously administered as a bolus 45 min after the start of a drip infusion. Blood urea nitrogen, serum creatinine, and N-acetyl-beta-D-glucosaminidase (NAG) in urine were measured as the renal toxicological parameters before and 24 h after cephaloridine dosing. Although the single administration of cephaloridine significantly elevated these parameters, the elevation was prevented by the concomitant administration of piperacillin. The protective effect of piperacillin was superior to those of cephalothin and fosfomycin. In rats, piperacillin (1,000 mg/kg) was intravenously administered and immediately followed by the intramuscular administration of gentamicin (100 mg/kg) every 24 h for 5 days. When piperacillin was concomitantly administered with gentamicin, the elevations of blood urea nitrogen, serum creatinine, and urinary NAG were significantly lower than when gentamicin was given alone. The concomitant administration of piperacillin resulted in a significant protective effect against the nephrotoxicity of cephaloridine in rabbits and of gentamicin in rats. Histopathological observation also supported the protective effect of piperacillin. The protective mechanism of piperacillin might be the inhibition of transport from the peritubular side to tubular cells for cephaloridine and from both the peritubular and luminal sides for gentamicin.

Topics: Animals; Cephaloridine; Cephalothin; Fosfomycin; Gentamicins; Kidney Cortex; Kidney Diseases; Kidney Medulla; Male; Piperacillin; Rabbits; Rats; Rats, Inbred Strains

The protective effect of fosfomycin against aminoglycoside (dibekacin)-induced ototoxicity was studied in rats. Rats were injected with 100 or 50 mg/kg of dibekacin with or without 500 mg/kg of fosfomycin for 60 or 120 consecutive days. Inner ear damage appeared to be more reduced histopathologically in animals given both dibekacin and fosfomycin than in animals given dibekacin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of dibekacin and fosfomycin. The mechanism of reduced ototoxicity may be as follows: fosfomycin inhibits the accumulation of dibekacin in the kidney, and reduces its concentration in the kidney and serum. Consequently, the amounts of dibekacin reaching the inner ear are decreased, and ototoxicity is reduced.

Topics: Acetylglucosaminidase; Aminoglycosides; Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Cochlea; Dibekacin; Fosfomycin; Hair Cells, Auditory; Kidney; Kidney Diseases; Labyrinth Diseases; Perilymph; Proteinuria; Rats

The protective effect of fosfomycin against cisplatin-induced ototoxicity was studied in rats. Sixty-four Fischer rats were injected intravenously with daily doses of 1, 2, 5, and 10 mg/kg of cisplatin with or without 300 mg/kg of fosfomycin for a varying period from 1 to 10 days. The total dose of 10 mg/kg of cisplatin was given equally in all animals. Inner ear damage appeared to be more reduced histopathologically in animals given both cisplatin and fosfomycin than in animals given cisplatin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of cisplatin and fosfomycin.

Topics: Animals; Body Weight; Cisplatin; Cochlea; Fosfomycin; Hair Cells, Auditory; Kidney Diseases; Labyrinth Diseases; Male; Rats

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.

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Creatinine; Drug Therapy, Combination; Female; Fosfomycin; Kidney Diseases; Rats; Rats, Inbred Strains

Topics: Animals; Anti-Bacterial Agents; Dibekacin; Fosfomycin; Hair Cells, Auditory; Kanamycin; Kidney; Kidney Diseases; Labyrinth Diseases; Rats

Male Wistar rats received 20 mg/kg/day of amikacin (AMK) with or without 200 mg/kg/day of fosfomycin (FOM) for 5 days. Accumulation of AMK in renal lysosome-containing fraction was inhibited by FOM. FOM was reported to interfere with the nephrotoxic properties of aminoglycosides. Our observation supports the finding.

Topics: Amikacin; Aminoglycosides; Animals; Anti-Bacterial Agents; Fosfomycin; Kidney; Kidney Diseases; Male; Rats; Rats, Inbred Strains

Protection by fosfomycin of the nephrotoxicity of dibekacin was studied using Fischer 344 rats and urinary parameters such as volume, osmolality, protein, N-acetyl-beta-D-glucosaminidase, leucine aminopeptidase, lactate dehydrogenase and nucleated cells were determined as markers of nephrotoxicity. The duration of treatment was 11 d. Fosfomycin reduced polyuria, proteinuria, enzymuria and cyturia induced by dibekacin best by the concomitant administration, followed by pre-treatment, but not by post-treatment. Protection was effective in the dose ratio of dibekacin: fosfomycin = 1:2 - 1:32, regardless of administration routes. As judged from urinalysis, protection by fosfomycin (320 mg/kg) was almost complete for the experimental nephrotoxicity induced by 10 mg/kg of dibekacin, and still significant for that by 40 mg/kg. This was supported by the histo-pathological and ultrastructural improvement of proximal tubules and by suppressed blood urea nitrogen and creatinine values. Protective activity of fosfomycin was more potent than that of cephalothin, when compared on the weight basis.

Topics: Animals; Anti-Bacterial Agents; Cephalothin; Chemical Phenomena; Chemistry; Dibekacin; Dose-Response Relationship, Drug; Fosfomycin; Kanamycin; Kidney Diseases; Male; Rats; Rats, Inbred F344; Time Factors

The nephrotoxicity, pharmacokinetic and therapeutic activity of fosfomycin were investigated in female wistar-rats. Measures of nephrotoxicity were urinary excretion of tubular cells and of the enzymes MDH, LDH, and GOT. Histological investigations and estimation of serum urea concentration and proteinuria were also evaluated. The doses of 500, 1000, 2000, 3000, and 5000 mg/kg/d were administered in 9 single doses with 12 hours interval. The lowest dose which induced a significantly increased tubular cell excretion was 1000 mg/kg/d and therefore in the same range as the tubulotoxic threshold doses of cephalosporins. Chemotherapy of the chronic estrogen induced pyelonephritis revealed equally favourable results for fosfomycin and cefuroxim at dosages of 2 X 150 mg/kg/d. The pharmacokinetics of fosfomycin at a single dose of 150 mg/kg/d were equivalent to those of cefuroxim. These animal experiments showed fosfomycin to be of value as a therapeutic alternative to cephalosporin antibiotics.

Topics: Animals; Anti-Bacterial Agents; Female; Fosfomycin; Kidney Diseases; Kinetics; Pyelonephritis; Rats

Topics: Anti-Bacterial Agents; Bacterial Infections; Fosfomycin; Humans; Kidney Diseases; Polycystic Kidney Diseases; Pyelitis; Pyelonephritis

Topics: Aminoglycosides; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cephalosporins; Chloramphenicol; Erythromycin; Fosfomycin; Humans; Kidney Diseases; Penicillins; Peptides; Rifampin; Tetracyclines