Fosfomycin [(-)-(1 R, 2 S)(1, 2-epoxypropyl) phosphonate] is an antimicrobial agent, which exhibits a unique mechanism of action and has been used worldwide for many years. The paper that first described the discovery of this antibiotic appeared in 1969. In Japan, its development for clinical use was started in the early 1970's, and its approval was obtained in 1980; since then fosfomycin has been used to treat many patients. Various clinical and basic reports on fosfomycin have recently appeared. One reason for this interest could be the recent approval of a new salt of fosfomycin (fosfomycin tromethamine) for clinical use in Europe and the United States of America. Moreover, at present, new data about bacterial cell wall peptidoglycan, whose synthesis is inhibited by fosfomycin have rapidly accumulated. This article is a review of recent advances in research on the mechanism of action of fosfomycin, its antimicrobial characteristics, and resistance to this antibiotic. Moreover, an outline of fosfomycin tromethamine is presented.

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Fosfomycin (L-cis-1, 2-epoxypropyl phosphonic acid, MW 138), a small molecule, is a broad-spectrum bactericidal antibiotic, which is structurally unrelated to all other classes of antimicrobial agents. In 1980 fosfomycin was introduced to clinics in Japan. Since then it has been used in the treatment of various infections, and its usefulness and low toxicity have been confirmed. During the past 18 years, therapeutic efficacy and response to fosfomycin in the treatment of various diseases other than infections have been described. These diseases include stomatitis, asthma, atopic dermatitis and pancreatitis. Fosfomycin has a protective effect against nephrotoxicity induced by other agents such as aminoglycosides and cisplatin.However, these newly found pharmacological activities of fosfomycin can not be explained by only the antibacterial mechanism itself. Recent advances in in vitro and in vivo research on fosfomycin have demonstrated that fosfomycin affects the host immunological response. Fosfomycin has direct immunomodulatory activities on host immune cells such as lymphocytes, monocytes, macrophages, neutrophils, basophils and eosinophils. So far the major immunological effect of fosfomycin seems to be anti inflammatory. Based on these observations, fosfomycin was administered to patients with HTLV-Iassociated myelopathy, pulmonary disease and other diseases, and improvement in these patients was observed. However, the mechanism of the nonantibacterial action of fosfomycin requires further elucidation. Further detailed studies are required to clarify the mechanisms of the new pharmacological activities and to determine appropriate applications of the antibiotic to diseases other than infections. The major emphasis of this review has been to present newly discovered pharmacological activities of fosfomycin, and to discuss the known and possible therapeutic uses of the antibiotic in a clinical setting.

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Metallo-β-lactamase is a carbapenemase identified first in a Pseudomonas aeruginosa plasmid which has a broad substrate specificity, including allβ-lactams except monobactams. Anticipating dissemination of the gene bla_IMP among other clinical strains of gram-negative bacteria, especially Enterobacteriaceae, we attempted to detect the gene using a polymerase chain reaction (PCR) technique and then measuredβ-lactamase activity. The number of bla_IMP positive strains per imipenem (IPM)-resistant strain tested was as follows: Enterobacter cloacae: 6/56, Escherichia coli: 1/8, Citrobacter freundi: 1/17, Morganella morganii: 1/5, and Serratia marcescens: 4/10. The highest frequency of bla_IMP detected was found in S. marcescens. Transmissible plasmids bearing bla_IMP were identified in four of the six E. cloacae strains.

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To clarify the pathogenicity of (1-3)-β-D-glucan (β-glucan), the immunomodulatory activity of three types of particulate (water-insoluble) β-glucan and three water-soluble β-glucans, were compared in respect to the production of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMN) in vitro. The production of ROS was measured by a chemiluminescence (CL) assay in which luminol was added to the samples and the PMN were subsequently stimulated with a particulate β-glucan (curdlan, zymosan or zymocel) and a water-soluble β-glucan (CM-curdlan, laminarin or sonifilan). This assay was also used to test the ability of each of the three water-soluble β-glucans and lipopolysacchalide (LPS) to augment the priming effects on the production of ROS from PMN. Each particulate β-glucan induced the apparent CL of PMN in a dose-dependent manner, while water-soluble β-glucans and LPS could not at any concentrations tested. PMN were incubated for 60 min at 37t with LPS and three types of water-soluble β-glucan, and the integrated CL response induced by phorbol myristate acetate (PMA) was measured for 20 min, which permitted comparisons of the priming effects of LPS in combination with each water-soluble β-glucans. Preincubation with LPS resulted in an increase in the CL response of PMN at concentrations of more than 100 ng/ml. Similar results were obtained in the PMN sample, which included a small amount of serum after only 10 min incubation with LPS. However, no significant priming effect was observed when PMN were incubated for 10 and 60 min with various concentrations (1 ng-10 μg/ml) of CM-curdlan, laminarin or sonifilan. PMN-CL induced by particulate β-glucans such as curdlan or zymocel and Candida albicans was significantly prevented when PMN was preincubated with more than 10μg/ml of the water-soluble β-glucans for 60 min at 37C° and then exposed to particulate β-glucan and C. albicans. These inhibitory effects were dose-dependent. Also, the effect of three antifungal agents, amphotericin-B (AMPH-B), fluconazole (FLCZ) and miconazole (MCZ) on the CL response of PMN were studied in vitro. After 60 min incubation with more than 1μg/ml of AMPH-B, CL values of PMN during phagocytosis of curdlan were significantly enhanced, whereas these values were suppressed with FLCZ at the concentration of more than 1μg/ml. There was no significant effect on the CL response of PMN in treatment with MCZ. These findings indicate that these β-glucans and antifungal agents modulate the oxygen metabolism of human PMN, however, further studies are required to elucidate the mechanisms responsible for this immunomodulatory effect and to establish its clinical relevance.

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Between November 1995 and March 1997, we compared the clinical efficacy and cost-effectiveness of imipenem/cilastatin (IPM/CS) with those of β-lactam antibiotics other than carbapenems, as the first-line treatment for infections in patients with hematological disorders. Sixty-six patients were included in the IPM/CS group and 63 patients in the β-lactam group. Sepsis and infections suggestive of sepsis were involved in 49 cases in the IPM/CS group and 50 in the β-lactam group, and represented about 80% of the infections. We calculated the direct costs (pharmaceutical and screening costs) up to the day of healing in cases that were cured or over a 4-week period in cases that required a change to other drugs when the first-line drugs failed. The efficacy rates were 71.2%(47/66) in the IPM/CS group and 50.8%(32/63) in the β-lactam group. The IPM/CS group showed a significantly higher efficacy rate than the β-lactam group (p<0.05). The efficacy rates among patients not receiving granulocyte colony-stimulating factor were 73.7%(28/38) for IPM/CS and 48.5%(16/33) for β-lactams, and this difference was significant (p<0.05). In patients with neutrophil counts under 100/μl at the start of treatment, the efficacy rates were 78.8%(26/33) and 56.7%(17/30) with the two groups, respectively. The median medical cost (direct cost) per a person with an effective outcome was 148, 254 yen in the IPM/CS group, and 207, 790 yen in the β-lactam group. These results suggest that IPM/CS is a clinically cost-effective antibiotic for the first-line treatment of infections in patients with hematological disorders.

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We studied the efficacy of daily oral administration of etoposide in 14 patients with non-Hodgkin lymphoma who had visited our hospital from July 1992 to September 1997. Twelve patients had received previous chemotherapy and were considered to be incurable. The other two patients were too old to be treated with intensive chemotherapy. Etoposide was administered at 25 or 50 mg per body per day for 2-5 weeks. The total response rate was 57.1%(8/14), including 1 CR. When diffuse large cell lymphoma (DLCL) was excluded, the response rate was 88.8%(8/9). In DLCL cases, neither complete nor partial responses were obtained. Interestingly, two patients with T cell lymphoma responded to the therapy and the skin lesions disappeared. The median response duration was 39.2 weeks. Adverse effects were observed in 4 patients-mild diarrhea in 3 and stomatitis in 1. Bone marrow toxicity was tolerable, and no blood transfusion was required. Taking into consideration the complications and the quality of life of the patients, we believe daily administration of oral etoposide is a safe and useful therapy for elderly or relapsed patients with non-Hodgkin lymphoma, although it is not useful for DLCL.

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