Each 250 strains of various bacterial species were at random selected from our clinical stock cultures, and antibacterial activity of fosfomycin (FOM) toward these bacteria was determined. High antibacterial activity of FOM was observed against Salmonella strains, and followed by those toward Proteus, Pseudomonas aeruginosa, Shigella, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. It should be noted however that FOM showed high antibacterial activity toward P. aeruginosa. The bacterial strains used were resistant to various chemotherapeutic agents including TC, CP, SM, SA, KM, GM, β-lactam antibiotics, etc., while FOM showed no cross resistance to these drugs.
Therapeutic effect of FOM was examined using ICR-JCL strain mice infected with a virulent strain (116-54) of Salmonella enteritidis. Therapeutic effect was observed in mice with 4 subcutaneous administrations of FOM on day 0, 1, 3 and 5 after infection, while single or two administrations showed no therapeutic effect. From the spleens of mice showing characteristic thyphoid symptoms during therapy, FOM-resistant strains of S. enteritidis were isolated. Demonstration frequency of FOM-resistant bacteria was 10^-6 and MIC toward all resistant bacteria was 6. 25 μg/ml, while that of original Salmonella strain was 0. 19 μg/ml. Virulence of FOM-resistant Salmonella strain against mice was 1, 000 times lower than that of original one so far as examined.

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Antibacterial activity of fosfomycin was experimentally investigated both in vitro and in vivo for the purpose of its fundamental evaluation. MIC was determined with nutrient agar (Difco) as the assay medium inoculated with one loopful of 1, 000-fold dilution of overnight nutrient broth culture (Eiken, Nissan).
Fosfomycin exhibited antibacterial activity widely to Gram-positive and Gram-negative bacteria : especially, in 19 test cultures of Salmonella, the MICs were distributed between 0. 19 and 6. 25 μg/ml, the peak being found at 1. 56, μg/ml, and in P. aeruginosa cultures, the peak of the sensitivity pattern was found at 6.25 μg/ml.
In vivo experiments, disodium fosfomycin was subcutaneously and intravenously injected into male albino mice, 5-week-old ddN strain, which were intraperioneously challenged with P. aeruginosa, E. coli, or P. mirabilis isolated from clinical samples. Its chemotherapeutic effectiveness was confirmed in all these experimental infections. The mean effective dose (ED₅₀) of fosfomycin against P. aeruginosa infections resulted lower than those of carbenicillin and sulbenicillin but higher than those of gentamicin and dideoxykanamycin B.

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Susceptibility of anaerobic bacteria isolated from clinical specimens to fosfomycin was studied by agar plate dilution technique.
B. fragilis (24 strains) were resistant to 12. 5, μg/ml or more of this drug. Though 5 strains of Fusobacterium including F. nucleatum, F. russii and F. glutinosum were sensitive to 12.5, μg/ml or less of the drug, 14 strains of F. varium were resistant to 25 μg/ml or more.
Five strains of Peptococcus were sensitive to 1.56μg/ml or less, 29 strains of Peptococcus, however, were resistant to 6.25, μg/ml or more.
In addition, influence of this drug on anaerobes in human fecal flora was studied. By 4 days of administration of 1 g per day, predominant organisms in fecal flora were changed from B. fragilis ss. distasonis to B. fragillis ss. ovatus.

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Fosfomycin, a new antibiotic, has been evaluated bacteriologically, using fosfomycin Na.
1) This antibiotic has an antibacterial spectrum against Gram-positive and Gram-negative bacteria, antibacterial activity being nearly the same between both.
2) The strains isolated clinically presented mostly the sensitivity distribution similar to standard strain.
3) Various factors such as medium pH, addition of human serum, protein and inoculum size, affected the antibacterial activity of fosfomycin.
4) The type of antibacterial action was bacteriostatic at the concentration of 1/4 MIC, while bactericidal at the higher concentrations. Bacteria grew after 24 hours, and the MIC values rose in these grown bacteria.
5) No synergistic action was observed between fosfomycin and other antibiotics in E. coli.
6) As for the treatment effect for experimental infections of mice, it was almost the same as cephaloridine in the infections due to penicillin resistant Staphylococcus or E. coli, while it was inferior to cephaloridine in the infections due to Pneumococcus.

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The pharmacological actions of fosfomycin (FOM) were investigated. The actions and minimal effective doses (MED) of FOM were summarized as follows : inhibition on the excised heart of the toad (10^-3g/m1), inhibition on the excised heart of the guinea pig (10^-3g/ml), bradycardia on ECG of the rabbit (20 mg/kg), stimulation on the excised intestine of the rabbit (10^-4g/ml), dilation on the excised ear vessel of the rabbit (10^-4g/ml), inhibition on the excised tracheal muscle of the guinea pig (2×10^-3g/ml), inhibition on the excised non-pregnant uterus of the rat (10^-3g/ml), no effect on the excised intestine of the guinea pig (10^-3g/ml) and pregnant uterus of the rat (2×10^-3 g/ml), on the permeability of abdominal skin vessel of the rabbit (1, 000μg), and on blood pressure and respiration of the rabbit (80mg/kg).
These MED were much larger than minimum inhibitory concentrations and maximum blood levels in clinical uses. Therefore, it is concluded that FOM is one of the antibiotics which have less pharmacological actions.

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Fosfomycin-sensitivities of 101 strains of clinically isolated bacteria were examined by agar-dilution method, using Difco Nutrient Agar. Minimal inhibitory concentrations of the drug were mainly distributed from 3.12μg/ml to 12.5μg/ml. Of 101 strains, 12 strains were resistant to more than 100 μg/ml of the drug. Klebsiella was low sensitive and the peak of MIC for these bacteria was 12.5μg/ml.

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The antimicrobial activities of fosfomycin were studied in vitro. The results obtained are summarized as follows.
1. The minimum inhibitory concentrations (MIC) of fosfomycin against stock culture strains were ranged 0.2 to 50 μg/ml.
2. The MICs of fosfomycin against Staph. aureus isolated from patients were ranged 3.12 to 25 μg/ml and the peak was at 12.5 μg/ml, and the peaks of MIC against E. coli and Ps. aeruginosa were at 50μg/ ml.
3. The antimicrobial activities were more effective at low pH value, and less effective in serum added medium.

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Fosfomycin (1-cis-1, 2-epoxypropyl phosphonic acid) is a new antibiotic active against a broad spectrum of gram-positive and gram-negative microorganisms.
Eight cases with pulmonary infectious diseases were treated with this drug. A daily dose of 2.0-3. 0g o fosfomycin capsule was given orally for 7 days.
The results obtained were excellent in 1 case, good in 3 cases, fair in 1 case and poor in 3 cases.As to the side effect with fosfomycin, no remarkable one was observed.

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Laboratory investigation on fosfomycin-a new antibiotic with simple structure-was carried out, and the following results were obtained.
1) Antibacterial activity of fosfomycin (FOM) against 10 strains of S. aureus, 10 E. coli, 9 Ps. aeruginosa and 4 Klebsiella were measured using the method recommended by the committee. Marked decrease of MIC values were found in case of E. coli and Ps. aeruginosa with the decrease of inoculum size.
2) In some investigations on antibiotic assay method of FOM, the results obtained were as follows :
i) As to the test organism, a clinical isolate of S. aureus strain was found to be inferior to Proteus sp. (MB 838) whose MIC were 1.6μg/ml respectively.
ii) As for the diluent of standard, good results were obtained from tris buffer and balanced salinesolution. Phosphate buffer was not satisfactory.
iii) It is unlikely that the assay data were influenced by the method of keeping blood samples.The rest of results is included in the proposal of the committee.
3) In investigation on absorption and excretion following oral 1.0g preprandial adminstration in 5 human subjects, peak blood level of 3.7μg/ml was found at 2 hours. Dispersed values of blood level and urinary excretion were obtained.
4) In study of intravenous administration in human subjects, the following values were worked out from the results ; serum half-life : about 2 hours, volume of distribution : 0.3L/kg, rate of removal from blood : about 40%, and renal clearance of FOM : 140-190 ml/min. These data suggest that pharmacokinetic property of FOM is similar to that of aminoglycosides.

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Basic and clinical studies were made on fosfomycin-Ca. The MIC was low especially against Proteus sp. A parallel relationship was almost observed between the blood concentration and urinary excretion of the drug. though the blood concentrations were obtained with variety of the degree in the peak-time and the concentration.
The active substance in the blood and urine was inferred to be FOM according to the spot obtained by the bioautogram. In the clinical study, although the number of cases was very small and the infections varied in severity according to patients, the result did not seem so favourable as expected.No symptoms considered to be side effects were noted.

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Fosfomycin was used orally 1. 5-3.0g daily for 6-10days in 8 patients of respiratory infectious diseases (bronchitis 3, bronchiectasis 2, pneumonia 3).
1. The clinical results were good in 5 patients, fair in 2 patients and poor in only 1 patient, and daily dose of 2.0 g or over was effective in all 7 cases.
2. Side effects were observed in 4 patients. Mild gastro-intestinal symptoms occurred in 2 patients, nausea 1, diarrhea 1, but none was severe enough to warrant discontinuation of the drug. Elevations of serum glutamic oxaloacetic transaminase (GOT) and of serum glutamic pyruvic transaminase (GPT) after therapy were observed in 2 patients.
3. Elevations of GOT and GPT were observed in 2 patients who were given 3.0g daily, and became normal 10-15days after cessation of the drug.
But abnormality was not observed in serum lactic dehydrogenase, alkaline phosphatase or serum bilirubin level.
4. These data suggest that daily dose of 2.0g is recommended considering these clinical results and elevations of GOT and GPT, and liver function test should be examined periodically during therapy.

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The results obtained from the studies on a new antibiotic, fosfomycin were as follows.
1. The MIC values of most strains of a variety of Gram-negative bacilli isolated from clinical specimens ranged from 1.6 to 50, ug/ml.
2. Organ levels following oral administration of fosfomycin to mice ranked in order of kidneys, lungs and liver.
3. Clinically two patients with acute urinary tract infection due to E. coli responded well, one with chronic urinary tract infection due to Pseudomonas aeruginosa responded poor, and in one with respiratory infection the evaluation was, indefinite.

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Fosfomycin (FOM) is a new broad spectrum antibiotic which was developed in the Research Laboratories of Merck, Sharp & Dohme (USA) and CEPA (Spain). Clinical trial and some fundamental studies on FOM were done in our hospital. The results were obtained as follows ;
1) Susceptibility of fosfomycin to gram-negative microorganisms clinically isolated was studied. MIC of FOM against E. coli was 6.25-12.5, μg/ml. Most of strains of Klebsiella were not highly susceptible to FOM. MIC of FOM against Pseudomonas aeruginosa was 1.6-12.5, μg/ml.
2) The absorption and excretion of the calcium salt of fosfomycin were studied in 3 patients. Determination of FOM concentration in serum was done in these patients who had been treated with 3, 000mg daily oral dosis (1, 000mg every 8 hours) until 8 hours before the test. The average concentrations were 6.2μg/m1 to 6.9, μg/ml at 1, 2, 4, and 6 hours after oral administration of 1, 000mg, and these results showed cumulative effects which reached a plateau. In one case, drug concentrations were 6.5, 6.5, 7.5 and 7.8, ug/ml at 1, 2, 4 and 6 hours after oral administration. These high concentrations would be owing to the administration of sodium bicarbonate with FOM.
3) Ten patients with respiratory infection or urinary-tract infection were treated orally with 3g per day. Fosfomycin was effective against half of 4 patients with respiratory infection and all of 6 patients with urinary-tract infection, including 2 chronic cases.
4) No side effects were clinically seen, and no abnormal findings were shown in laboratory test.

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Clinical and laboratory study on fosfomycin (FOM) had been conducted, and the results obtained are described below.
1) FOM had a broad spectrum covering gram-positive and gram-negative bacteria except for Klebsiella. The antibacterial activity against gram-positive bacteria was a little weaker than that of cephalosporin, synthetic penicillin, and kanamycin, but against gram-negative bacteria, tended to be stronger except for Klebsiella. Particularly, the antibacterial activity against Pseudomonas was definitely stronger than that of cephalosporin, synthetic penicillins and kanamycin, however, clinical effect of FOM against Pseudomonas infection could not be evaluated since we have not encountered such an infection.
2) FOM has been administered to 43 cases with various infections, good results being obtained in 16 (64. 0%) out of 25 cases with respiratory infections and 10 (66. 7%) out of 15 with urinary tract infections.
3) Of 43 cases treated with FOM, 7 (20. 6%) had side effects, 6 out of them had mild gastrointestinal disturbances which did not require withdrawal of the drug. One complained of a systemic fever feeling. Allergic manifestation such as eruption or shock was not observed.
4) Although the laboratory tests after administration of FOM revealed no abnormalities in blood picture and renal disturbance, in 2 of 20 cases, an elevation of SGOT and SGPT value was seen. One was attributed to chronic hepatitis, while the other seemed to be ascribed to FOM.
Clinical and laboratory data suggest that FOM should be especially useful in the treatment of infections due to gram-negative bacteria.

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Fosfomycin, a new antibiotic, was reported to be quite characteristic in the basic points of its action mechanism and resistance acquisition. The present authors have compared the antibacterial activity of fosfomycin with that of other available antibiotics, and examined the clinical effectof the drug as well.
As for the antibacterial activity of fosfomycin, MIC was judged for 24 hours at pH 6. 8. The result revealed that MIC of the drug is weaker than that of DKB and GM, while similar to that of KM.
As to the clinical effect of fosfomycin, the antibiotic was administered clinically in 14 cases of respiratory infections and 1 case of urinary tract infection, totalling 15 cases, without including there a so-called severe infection. As a result, effectiveness was obtained in 10 cases out of 14 cases (71. 4 %) of respiratory infection, while remarkable effect was observed in 1 case of urinary tract infection.
No noteworthy side effect was noticed with fosfomycin.

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Studies were made on fosfomycin (Phosphonomycin, FOM), a new broad spectrum antibiotic isolated from cultures of several Streptomyces strains. The results obtained were as follows :
1) Comparative studies on the in vitro susceptibility of bacteria on the media with different compositions : Nutrient agar, heart infusion agar and MULLER-HINTON agar, each with or without addition of glucose-6-phosphate and/or calf serum, were used. Generally speaking Staphylococcus strains were more susceptible than E. coli or Proteus, while Klebsiella showed high resistance to the drug. Among the media, nutrient agar was the one in which bacteria showed highest susceptibility. Contrarily to our expectations, addition of G 6 P or calf serum to the media failed to improve the susceptibility of bacteria. Influence of constituents of media seemed to be different according to the species of bacteria.
2) Blood levels and urinary excretion rate of fosfomycin in humans (assayed by cup method) : Two volunteers received oral administration of FOM-Ca 1, 000mg. The peak of the blood level wa obtained 2 hours (dosed in fasting) or 3 hours (dosed 1 hour after meal) after the administration, reaching up to 2 μg/ml in both cases. The urinary excretion rate in 10 hours was 16. 1 or 19. 1% each.
3) Clinical trials : Ten adult patients with respiratory (tonsillitis 3, pharyngitis 1, bronchitis 2 and bronchopneumonia 1) or urinary tract (pyelonephritis 2) infections, or with phlegmon (1) wer treated with oral administration of FOM-Ca (1. 53. 0 g daily, 444 days) which seemed to be effective in 7 cases. Itch ing or eruption occurred in 2 cases, but otherwise no marked side effects were encountered.

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In vitro antibacterial activity test of fosfomycin revealed that its antibacterial activity was not so strong against Staphylococcus aureus and various gram-negative bacilli. The serum concentration of fosfomycin Ca salt after oral administration was not so high. Fosfomycin Ca salt was given to a total of 4 cases (one case with furuncle and 3 with respiratory infections), each two cases of moderate and slight symptomatic effects being obtained. No side effects were noted. Clinical appraisal of fosfomycin will be studied after the result of intravenous administration of the Na salt is obtained.

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In this report, clinical studies were performed with oral fosfomycin in 6 cases of respiratory infections. The results were as follows ;
1) Excellent effect was noted in 1 case, good in 4 cases and poor in 1case.
2) The drug might be especially useful for bacterial pneumonia.
3) In 2 of 6 cases slight anorexia and abdominal inflation were observed as side-effects. However, any of all cases was not discontinued the medication during the follow-up, because these disappeared completely by combinning with a digestive.
4) After the medication the results of laboratory studies including urinalysis, hematological examina tion, liver and renal function tests were either within normal limits or negative.

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The results of clinical trials with new antimicrobial agent fosfomycin for 8 patients with pulmonary infectious diseases were reported. Excellent effects were obtained in 4 cases including bacterial pneumonia, lung abscess, bronchiectasis and acute bronchitis. In other 4 cases, beneficial effects such as fall of fever, decrease of productive cough or improvement of lung rales were noted. Three cases with excellent clinical effects were administered 3 g oral dose of fosfomycin daily for more than 2 weeks and all of these patients showed mild or moderate elevation of S-GOT and S-GPT. Although this side effect was transient and there was no other sign of serious liver damage, it is advisable not to use this drug for the patients with liver disorders.

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Fosfomycin was given to 8 cases with respiratory infections, cholecystitis, and cystitis at the dose of 2-3g/day by oral route. In respiratory tract infections, excellent, good and fair effects were obtained in each one case. In one case with cystitis, excellent was obtained.
Liver function test conducted on 2 out of the above 8 cases 12 to 18 days after administration of fosfomycin revealed that GOT, GPT, LDH were increased. All of which, however, returned to normal values after discontinuance of the drug. Diarrhea was observed in 2 cases 1-2 days after administration, but it improved in the course of therapy without any special treatment, though the drug was continued.

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Fosfomycin is a new antibiotic active against a broad spectrum of gram-positive and gram-nagative microorganisms.
Twelve patients with respiratory infections were treated orally with fosfomycin at a dosage of 3. 0g per day for 5 to 25 days. Six patients had acute bronchopneumonia, four patients had bronchiectasis, one patient had chronic bronchitis, and one patient had abscess of the lung.
Eight cases of these 12 respiratory infectious disease were effected in the treatment of fosfomycin, while the others not effected, although bacteriological study in the sputum was failed except only in 1 case. Most of effected cases improved in symptoms within first 7 days. Side effects, such as anorexia, and gastrointestinal discomfort were observed in 2 cases.
These data suggest that fosfomycin is indicated in the therapy of respiratory infections

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Basic and clinical studies on fosfomycin newly developed have been conducted, and results obtained are summarized below.
1) Remarkable difference occurred between the antibacterial activity measured by the Standard Method of the Japan Society of Chemotherapy and that by the Method of MIC Measurement Commission, the MIC obtained by the former being higher. Fosfomycin showed strong antibacterial activities especially against Salmonella, Rettgerella and Pseudomonas aeruginosa. Salmonella, Rettgerella and Pseudomonas aeruginosa tested were distributed mostly (100%, 100%, and 91% respectively) below 12.5, μg/ml of fosfomycin.
2) The concentration of fosfomycin in the internal organs of rats was highest in the kidney being followed by the serum, lung, and liver in order.
3) The drug concentration in blood was determined after oral administration at the dose of 1, 000 mg one time after meal in 4 healthy adults. The average maximum level was 4.4, μg/ml, being attained 4 hours after administration. The recovery rate was 9.1%.
4) Clinical evaluation of fosfomycin has been made on 4 cases of respiratory infections. Among them, a fair effect was obtained in one, a poor effect in 2, and an unknown in one. As to the side effect, 2 of 4 cases showed the increase of serum transaminase, one of which was accompanied with eosinophilia. These symptoms disappeared after discontinuance of the drug.

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Fosfomycin is a new antibiotic active against a broad spectrum of gram-positive and gram-negative microorganisms.
Twelve patients with some infections in pediatrics field were treated orally with fosfomycin at a dosage of 20 to 100mg per kg per day for 4 to 7 days. The rate of effectiveness amounted to 75. 0% in total cases treated. No clinical side effects nor recognizable change in laboratory findings were observed to be suspected due to medication.

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Fourteen cases of bacterial infection in children were treated with fosfomycin.
The subjects consisted of pyelonephritis (5 cases), bronchopneumonia (3), pyothorax (2), follicular tonsillitis (2), peritonitis (1) and pyoderma (1).
On the basis of clinical and laboratory findings, 12 patients were remarkably improved, whereas 2 patients were slightly improved after administration of fosfomycin.
From 9 of them, etiological agents were recovered : 5strains of E. coli, 2 of Staphylococcus aureus, 2 of Streptococcus hemolyticus, 1 each of Pseudomonas aeruginosa, Klebsiella and Enterococcus.
In vitro sensitivity tests revealed that all of the isolates except one strain of Klebsiella were sensi-tive to fosfomycin with MIC ranging from 0.8 to 25.0μg/ml.
During the administration of fosfomycin, slight diarrhea was observed in 5 cases.

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The clinical experiments have been carried out with fosfomycin, a new antibiotic, and the result were obtained as follows.
1) Fosfomycin was administered orally to 39 cases of the infantile infections at the dose of 100mg/ kg/day for 3 to 60 days. The results obtained were remarkably effective in 2 cases, effective in 18 cases, fairly effective in 7 cases, effective ratio being 79. 4%.
It is considered that the increase of the dosage and the parenteral use of the drug seem to be necessary in the treatment of serious cases. Further study for this point will be necessary.
2) As to the side effects of fosfomycin, out of 34 cases in which the clinical observation was made, 7 cases had diarrhea, 1 soft stool, and 1 black hairy tongue. No particular abnormal finding was noticed in blood, liver and kidney function test.

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As the result of the MIC test employing Salmonella, it has been revealed that all organisms recently isolated were susceptible to fosfomycin. Salmonella infections were treated with fosfomycin and results obtained are summarized below.
1) MIC for Salmonella recently isolated was 1. 56, ug/m1 in most cases.
2) The blood concentration of the drug reached a peak 2 hours after oral administration, the hig level being maintained in 6 hours after adminitration.
3) Active urinary excretion rate of fosfomycin within 24 hours after oral administration was 8.8 to 16.9%.
4) Fosfomycin after oral administration at a dose of 100 mg/kg/day for 3 days was detected in thefeces with the concentrations of 197 to 397 μg/g. These concentrations were more than 100 times the MIC for Salmonella, and enough to inhibit the activity of Salmonella.
5) Infantile and child S'almonellosis with acute diarrhea was well treated with a dose of 100 mg kg/day of fosfomycin, its acute symptoms disappearing 5-8days after treatment, and at the same time, no discharge of the organism was noted.
6) Fifteen patients with long period bacterial discharge in total consisting of infant, child, and adult received more than 100mg/kg/day of fosfomycin for 15days at the longest, and complete eradication of the bacteria being obtained in 14 patients.
7) Eight adult Salmonella carriers received 4-6g/day of fosfomycin for 15consecutive days and no abnormalities were observed in the tests concerning S-GOT, S-GPT, BUN which were conducted before and after treatment.
8) Fosfomycin was also effective for infantile and child acute enteritis and colitis in all cases.
9) From the above results, fosfomycin can be said to be clinically as well as bacteriologically effective for salmonellosis, for which it seems that the continuous administration of more than 100mg/kg/day is necessary to obtain a satisfactory result.

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(1) Fosfomycin was administered orally at a daily dose of 100 mg/kg to 32 cases of children in total consisting of 15 cases of mainly acute pharyngitis, 15 cases of mainly acute dyspepsia and 2 cases of others, and 70% of them resulted in efficaciousness.
(2) Following bacteriological examinations, fosfomycin seems to be sensitive to β-Streptococcus, Pneumococcus, α-Streptococcus, while slightly sensitive to Staphylococcus aureus, Escherichia coli, Enterobacter A and Proteus mirabilis.
(3) No special relation was observed between the results of (2) and the judgments of clinical effect.
(4) No side effect was noticed clinically with the drug through the administration of 2-7 days. Hepatic functions were examined mainly on GOT and GPT before and after the administration, and no special abnormality was observed.
(5) MIC of the drug was measured on the strains isolated through these experiments, and a difference of concentrations of bacterial liquids was investigated, as well as some bacteriological suggestions were offered on the use of blood medium.

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Fosfomycin was administered to 11cases of respiratory infections in children and 5 cases of urinary tract infections in children. Of 11 cases of respiratory infections, remarkable effect was obtained in 2 cases, ineffective in 7 cases and undecided in 2 cases. Seven cases in which the results were ineffective were all with scarlet fever. Of 5 cases of urinary tract infections, remarkably effective was obtained in 3 cases, ineffective in 1 case and undecided in 1 case. As side effect, a transient diarrhea was seen in 1 case, though no others were noticed.

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Fosfomycin is a new antibiotic with bactericidal effect, active against a broad spectrum of Grampositive and Gram-negative microorganisms. Staphylococcus aureus, Escherichia coli, Pneumococcus and some Proteus, Pseudomonas, Salmonella appear to be susceptible to this antibiotic.
In this study, four patients with urinary-tract infection (E. coli 2, Staphylococcus 1, Gram-positive bacillus 1), three with enterocolitis (Salmonella C1 group 2, Klebsiella 1), four with Pseudomonas infection in the course of other infectious diseases, three with bronchitis (Hemophilus influenzae 2, Pneumococcus 1) and five prematures with various infections, were treated orally with fosfomycin dry syrup. All of urinary tract infections and enterocolitis, fosfomycin appeared to be effective dramatically.
Pneumococcal bronchitis and two of premature were improved. There were patients, one of them with diarrhea (No.4) and another (No.15) with exanthema, but both of them need no specific therapy nor cessation of fosfomycin administration. No other toxicity occurred in this study.

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1) Clinical studies of fosfomycin dry syrup were carried out on 18 patients with various pediatric infections, consisting of 5 tonsillitis, 2 bronchitis, 3 pneumonia, 3 pyothorax and each one of rhinitis, bacterial cystitis, urethritis, otitis media and purulent meningitis. The drug was administered orally at the daily doses of 65-200mg per kg for 3-32 days. In 2 cases of them, pyothorax and purulent meningitis, fosfomycin for injection was given intravenously or intrapleurally at the same time of or after oral administration of dry syrup. The sufficient effect of the drug was revealed clinically in 83. 3% and bacteriologically in 77.7% of the patients. Each one patient of pyothorax and purulent meningitis were found to be effective for the first time after starting intrapleural or intravenous administration. Regarding to the kind of bacteria isolated Staph. aureus was most responsive, while Strept. hemolyticus and Klebsiella pneumoniae were poorly. As for the side effect there found diarrhea in 2 cases and slight increasing of S-GOT level in 1 case.
2) The antimicrobial activities (MIC) were measured on 90 strains of 7 different bacteria isolated from patients with various pediatric infections. The main distributions of MIC were as follows;1.56-6.25μgml in 14 of 21 strains of Staph. aureus, 6.25-100μg/ml in 37 of 38 strains of Strept. hemolyticus, 50-100, ug/ml in all of 5 strains of Klebsiella pneumoniae, 6.25-25μg/ml in 7 of 10 strains of E. coli.
3) CSF concentration of f osf omycin after oral and intravenous administration of each single dose of 0.3 g of the drug were measured on a 5-month-old male infant weighing 6.5 kg who had a continuous ventricular drain for hydrocephalus and purulent meningitis. The measurement was performed at theintervals of 2 hours by the techinique of cup method using Proteus sp. (MB 838), and following results were obtained. After oral adminstration the concentration became measurable-0.88μg/ml-at 4 hours after the dose and gradually increased to the level of 1.44μg/m1 at 8 hours, whereas it reached more rapidly after intravenous injection to the high level of 10.1-11. 8μg/ml at 2-4 hours and maintained still the relative high level of 4.8μg/ml at 10 hours later. From these results, f osf omycin may be used intravenously for the treatment of purulent meningitis.

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Fosfomycin dry syrup, a new antibacterial agent, was used for the treatment of urinary tract infection, infantile diarrhea and respiratory tract infection at dose of 100 mg/kg/day.
The results obtained were as follows.
1) The rate of effectiveness was 78. 7% in 33 cases consiting of 10 urinary tract infection, 10 cases of acute enteritis and 13 cases of respiratory tract infection.
2) Diarrhea was observed in 2 of 33 cases, but no other side effects were observed.

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Fosfomycin was given to 27 cases of acute bacterial infections in the field of pediatrics at a dose of about 200 mg/kg/day divided into 3 or 4 doses in dry syrup, and the results are summarized below.
1) Among 27 cases, excellent result was obtained in 13 cases, good in 11 cases, and failure in 3, the efficacy rate being 88.9%.
2) In intestinal tract infections, the drug rapidly eradicated causative bacteria, the symptoms disappearing rapidly as well, while on urinary tract infections, an efficacy rate of 84.6% was obtained, but rather longer days on average were required until the major symptoms disappeared. In this respect, there seems to be a limitation in the effectiveness of the drug in the treatment of urinary tract infections by oral administration.
3) No serious untoward effects were observed.
4) Despite large oral doses, the course of administration was well, the drug appearing to have a good tolerance for infants and children.
5) From the above, the drug is considered to be a useful therapeutic agent in the treatment of acute bacterial infections, especially the acute intestinal tract infections in the pediatric field. The proper dosage seems to be 200 mg/kg/day divided into 3 or 4 doses.

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Fosfomycin was given to 6 hospitalized children with complicated infectious diseases in the department of pediatrics.
The daily dosage was 100 to 150 mg/kg in three divided doses after meals.
The results were as follows :
(1) The clinical effect was good in 3, poor in 3 with the total efficacy of 50%.
(2) The causative organisms became negative in 2 out of 3 cases, in which the causative organisms, E. coli was identified.
(3) The adverse reactions such as gastrointestinal disturbances, impairment of liver functions, and rash of urticaria type were not observed in all cases.

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Fosfomycin is a new broad spectrum antibiotic which is produced by several strains of Streptomyces and has several unique characteristics.
Ten of 12 patients with respiratory infection were considered to have had a successful outcome, and 2 to have failed. In each of 6 patients with skin and soft-tissue infection was obtained a satisfactory result. Two of 6 patients with urinary-tract infection had a success, and 3 failed, the remaining patients was difficult to evaluate because of her urinary-tract anomaly. Three patients with enteritis responded satisfactorily in each instance. After fosfomycin administration, 4 of 5 premature wit Pseudomonas infection were observed to have no isolates of Pseudomonas from their throats and faeces, and in one Pseudomonas was positive.
As the therapeutic result of 33 patients, “excellent” results were obtained in 14 of the patients, “good” in 12 patients, failures in 6 and one was indeterminable. Accordingly, the clinical effective rate was 81.2%.
One patient experienced transient loose stools, and another complained of transient discomfort. In 2 prematures, serum transaminase (GOT) activity was transiently elevated. No abnormalities were noted in hematological, biochemical and renal function tests performed before and after treatment.
Thus, in this study, oral fosfomycin appears to be effective in the treatment of infectious iseases of children caused by gram-positive and gram-negative microorganisms.

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In 12 cases of children, including 2 cases of low birth weight infant, fosfomycin was given orally, and the efficacy was examined clinically. The dosage was 100mg/kg/day to 200mg/kg/day, divided 3 times daily respectively.
Excellent effects were obtained in a case of staphylococcal osteomyelitis, which had been delayed to heal over during 60 days since onset in spite of injections with sensitive MCI-PC for 6 weeks, a case of staphylococcal scald skin syndrome, a case of biliary tract infection, which findings showed the complete obstructive jaundice, a case of diarrhea with E. coli and 2 cases of urinary tract infection, one of which was due to E. coli and the other with sensitive Pseudomonas bacilli. Urinary findings of the last case were relapsed with an alternated of resistant Klebsiella. Furunculosis with Staphylococcus aureus resistant to many antibiotics responded well to fosfomycin. Although the cocci on skin were eradicated, they were isolated from nostrils after 17 days administration of the drug. Generally the clinical response seems to be consistent with the sensitivity of pathogenic bacteria to fosfomycin. In this trials, Klebsiella infections were the most inadequate objects to give the new antibiotic.
No serious side effect was recognized. Any unfavourable sign was not found in 2 low birth weight neonates, .though no desirable effect expected was gotten. As a minor one mild diarrhea was accompanied in an infant. The remarkable elevation of serum transaminase was occurred in a case of osteomyelitis, without any other abnormal findings in liver function test. The mechanism has been obscure, whether it was happened due to the damage of liver with the drug, or due to other cause. That is a problem to be clarified.

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Basic and clinical studies on fosfomycin have been performed, and the results obtained are summarized below.
1) Antibacterial spectrum of fosfomycin : The antibacterial activity against Gram-positive and Gram-negative bacteria could not be found to be remarkably good.
2) Effect of inoculm size on the antibacterial activity : The effect of inoculum size on MIC of fosfomycin was studied. As a result, it was revealed that the MIC of fosfomycin was mostly over 100μg/ml in the original bacterial solution, while it was low in the 1, 000 times diluted solution. This phenomenon was remarkable in Staph. aureus and Pseudomonas.
3) Stability : The stability of fosfomycin was studied using human serum, urine, rat serum and extracted solution of the kidney. No potency was influenced within 24 hours either at room temperature or in the ice box, but a slight drop of potency was noted after 1 week in the ice box.
4) Concentration in the blood and urine : Cup method study employing Moni-trol serum as standard revealed that administration of 500 mg orally at fasting produced a peak level at 2 hours with average of 2.9μg/ml. In the group given after meal, a peak level of 2.4μg/ml was attained at 4 hours after administration. The peak concentration of 261 μg/ml in the urine obtained at 1 hour after administration in the group given at the fasting state, while in the group after meal, a peak concentration of 287 μg/ml obtained at 4 hours. The urinary recovery rate within 6 hours after administration was 13.3% in the group given at fasting and 17.4% in the group after meal.
5) Concentration in internal organs : Fosfomycin was administered orally at a dose of 20 mg/kg in a group consisting of 3 SD strain rats, and the level was the highest in the kidney followed by serum, lungs, heart, and spleen in order. In the group given at fasting, higher concentrations were obtained than that in the group given after meal. The concentration in the urine of rats was 1, 537 μg/ml at the highest, while the concentration in the bile was slightly below.
6) In vivo metabolism : Metabolism of fosfomycin was studied employing human urine. Bioautogram was prepared by thin layer chromatography using two solvent systems. As a result, fosfomycin was found not to be metabolized in vivo.
7) Clinical results : Fosfomycin was used in the treatment of 23 cases of surgical infections, a good result being obtained in 16 of 20 cases except for 3 cases with unknown result, and a poor in 4 cases. As to side effects, among 23 cases diarrhea was observed in one case and severe rash in another case, leading to discontinuance of the drug. No other particular noteworthy effects were encountered.

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Fosfomycin-calcium (FOM-Ca) is a new broad spectrum antibiotic providing many unique and novel characteristics, bactericidal action by virtue of interferrence With bacterial cell wall synthesis. Our attention was focussed on the reports, concerned with its antimicrobial activities in vitro with various drug resistant microorganisms. This study was designed for the reason to evaluate the efficacy of FOM-Ca in vitro, and to get further informations on the clinical utilization in surgery.
Brief summaries will be given as follows.
1. Average levels of FOM-Ca in plasma in 4 healthy volunteers after oral administration of a single dose of 500 mg of FOM-Ca, are shown in Fig. 1. Peak drug concentration of 6.0 μg/ml was achieved in 1 case, in other 3 cases 2. 9-3.2 μg/ml were observed.
2. The in vitro activity of FOM-Ca against 168 strains isolated from clinical materials were studied to make comparison with CER, CEX, ABPC and KM. Results were shown in Tables 1, 2 and 3.
1) For 32 strains of Staph. aureus, MICs ranged ≤0. 19-12. 5μg/ml of FOM-Ca. It seems to be respective result, that 24 out of 32 (75%) strains were inhibited the growth by lower concentration than 6.25 μEg/ml, but the effectiveness of FOM-Ca disclosed somewhat inferior to other drugs.
2) For E. coli it is to be highly effective. Forty out of 47 (85%) were inhibited with MICs of less than 6.25, μg/ml.
3) For Pseudomonas : 13 out of 19 (68. 2) were inhibited with MICs less than 6. 25 μg/ml.
3. Thirty-five patients were treated with FOM-Ca. A summary is shown in Table 5. Twelve were subcutaneous infections, 4 acute mastitis, 8 acute lymphadenitis, 4 periproctal abscess, 3 infected atheroma, and the rests were a case of thrombophlebitis, a bite wound, a burn wound with more than 30% of body surface, and a panempyema of left pleural cavity. In this series, 23 patients were underwent minor surgical treatment.
Conclusion : Although there are many difficulties to give a distinct or decisive evaluation on therapeutic of antibiotics in a variety of disease, we classified the clinical responses into excellent, good, poor, effect nil, and unknown. Twenty-seven of 35 patients responded “good” to FOM-Ca therapy.

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Fosfomycin capsule was administered at a daily dose of 2g (except 150mg in a case of infant) for 2 to 17 days (5 days on an average) in 30 outpatients consisting of 28 cases of infections of soft tissues and 2 cases of suppurative lymphadenitis, and the clinical results were obtained as follows.
1) Among 30 cases treated by fosfomycin, the results obtained were effective in 15 cases, slightly effective in 14 cases, and unknown in 1 cases, effective ratio being 100%.
2) No side effect was observed throughout 30 cases treated with fosfomycin.

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Oral FOM-Ca was given for acute infections of the soft tissues, and effective responses were observed on 27 of all 28 patients. In addition the serum level and urinary excretion were investigated using a bioassay procedure.
FOM-Ca was identified as a new antibiotic highly effective for acute infections of the soft tissues in the field of surgery.

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Fosfomycin was administered to 16 cases of the infections in surgical field, especially, superficial infections at the dose of 2 g (except 1 case received 3 g/day) a day in capsules.
Except 1 case discontinued the drug, excellent or good effect was obtained in 66. 7%. No cases with poor effect or exacerbation were observed.
In 9 cases (82%) out of 11 cases due to Staphylococcus aureus, excellent or good result was obtained. The effect against Staphylococcus epidermidis was somewhat inferior.
Diarrhea was observed in 3 out of 16 cases, and no other untoward effects were noted.

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A new antibiotic fosfomycin was administered clinically in capsule for 45 cases consisting mostly of superficial suppurative infections. The dosage was 1 capsule (500mg) or 2 capsules (1, 000mg) 3 or 4 times daily for 3 to 19days. The patients treated include 26males and 19females, age being between 8years to 86years. The clinical effects were judged from redness, swelling, pain, tenderness, local heat and pus discharge, referring to pyrexia and blood sedimentation rate in some cases. The results were divided into five; good, fair, unchanged, worse and interrupted. The drug effectiveness was obtained in 32cases out of 45cases, effective ratio being 84.4%. Bacterial culture of pus was performed11 times in 9 cases, and bacteria was detected 8 times ; Gram-negative bacillus 4 times, Gram-positive Streptococcus 1 time, Staphylococcus 2 times and Gram-positive diplococcus 1 time. As for the relation between detected bacteria and clinical effect, the drug seems to be effective against Gram-negative bacillus, Streptococcus and Staphylococcus. As a side effect with the drug, the administration was interrupted only in 2 cases, though 4 cases complained of diarrhea, epigastric malaise and anorexia. From the above results, fosfomycin capsule may be expected to be effective for the treatment of superficial suppurative infections and the prophylaxis of infections after minor operation.

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Fosfomycin has a very simple structure quitely different from other antibiotics already known. And this is known to show a broad antibacterial activity against Grampositive bacteria and Gramnegative bacteria (except Klebsiella) which appear very often in clinical surgery. These were proved by the results of other researchers and accorded to our results on the MIC distribution of this substance to various clinical isolates.
By oral administration of 500 mg in 3 cases, the maximum blood concentrations reached to 2. 8 μg/ml only on average. However, the clinical results were very excellent, and therefore the fact reveals the unparallel tendency in the relation between the clinical effects and the distribution of MIC. In 12 cases of surgical infections, the clinically therapeutic results were as follows ;
excellent… 3 cases good… 8 cases fair… 1 case failure… none
As to the side-effects, none of all cases showed abnormal results in the clinical laboratory tests and their clinical symptoms. There are few at present of orally effective antibiotics for surgical infections induced by Gramnegative bacillus. And therefore fosfomycin may be expected an important role in clinical surgery in the participation.

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Eighteen patients with inflammatory biliary disease were treated orally with fosfomycin at dosag ranging from 2. 0 to 3.0g per day for periods ranging from 4 to 28 days.
Four patients had cholecystolithiasis, three cholecystocholedocholithiasis, two choledocholithiasis, four hepatolithiasis, one cholangitis after choledochojejunostomy, two carcinoma of papilla duodeni, and two carcinoma of extrahepatic bile duct.
Results were evaluated clinically as excellent in three cases, good in eight, fair in four, poor in two and unknown in one, and so an over-all efficacy was 61. 1%. No adverse side effects were found in either clinical signs or laboratory data, except a mild diarrhea occurring in a single patient.
Fosfomycin susceptibility to 41 strains isolated from infected bile of patients with biliary diseases was measured by agar dilution technique. It was found that about 90% of isolates including Staphylococcus aureus, Staphylococcus epidermidis, E. coli, Enterobacter, Klebsiella, Pseudomonas aeruginosa, Citrobacter, Serratia and Bacterium anitratum was susceptible to the drug. The lowest MIC was found to be 0. 39, ug/m1 for a strain of Enterobacter and the highest >100 pg/ml for two strains of En-terobacter and a strain of Bacterium anitratum.
The biliary excretion after single oral administration of 1 g of the drug was determined in two patients with common bile duct drainage. Biliary level of the drug in a patient was 1. 5, 1. 6 and 1. 6gglml at 6, 7 and 8 hours respectively. Recovery rates in urine for 8 hours in these two patients were 11. 2% and 6. 2% respectively.

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Fosfomycin was administered to 9 cases of chronic osteomyelitis, suppurative arthritis, suppurative ilio-psioitis and bedsore caused by spinal paralysis. A daily dosage of 2 g was orally administered continuously for 10 to 60 days. A local administration of the drug was combindely performed in 4 cases of obsolete wound caused by Pseudomonas employing the preparation of the drug for intravenous use. The results obtained were remarkably effective in 1 case, effective in 6 cases, ineffective in 2 cases. Especially it was noticeable that it was effective in chronic osteomyelitis and bedsore infected by Pseudomonas. As side effect, transient eruption was seen in 1 case and stomachache in 1 case.

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Fosfomycin was orally given to a total of 5 cases consisting of 4 cases of suppurative osteomyelitis and one of suppurative arthritis at the dose of 3, 000 mg a day, a good result being obtained in 2 cases, and unknown in one. The causative organisms of the cases with a good result were Staphylococci and α-Streptococci, those of the unchanged cases were Staphylococci and Pseudomonas, and the unknown case was complicated with Staphylococci and Streptococci. The treatment lasted for a long period over 21 to 32 days, but no particular gastrointestinal, renal, and hepatic disturbances were observed except for one with slight elevations of GOT, GPT, and alkaline phosphatase.

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Fosfomycin calcium salt possessing a unique chemical structure was administered to 20 cases suffering from orthopedic infections, excellent results in 2 cases, good in 5, fair in 10, and poor in 2 being obtained respectively.
The changes of the isolated organisms and clinical course were discussed. The information on the sodium salt of the drug will be described in the second report.

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Fosfomycin was given to 4 cases of purulent infections recently encountered (3 cases of osteomyelitis and one of myositis). Out of them 3 cases showed satisfactory results (2 cases of excellent effect and one of good).
In this series, fosfomycin was orally administered at the dose of 3.0 g/day after meals to adults and 1.5g/day to children.
No side effects were noted in these 4 cases.

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Fosfomycin was administered to treat urinary tract infections, and the following results were obtained.
1) Fosfomycin was administered at a daily dose of 3g for 6-7 days in 4 cases of acute cystitis due to Escherichia coli, and the effectiveness was obtained in all the cases.
2) Fosfomycin was administered at a same daily dose for 4-14 days in 5 cases of chronic cystitis due to Escherichia coli, and the effectiveness was obtained in 3 cases of them.
No relapse was noticed through the observation of an effective case for a long period of time.

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Fosfomycin is a new antibiotic developed by American Merck in cooperation with Spanish CEPA.
MIC of fosfomycin against clinically isolated strains revealed that it was 25 μg/ml for Klebsiella, 3. 12μg/ml for Pseudomonas and 6. 25-12. 5 Pg/ml for Escherichia coli.
In simple acute infections, 94% and complicated chronic infections 20% was effective.
Side effect was seen in 3 cases out of 24 cases (12. 5%) and after oral administration, no abnormality was observed in hematological and hemochemical findings.

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Fosfomycin-calcium was given in a trial of 45 outpatients comprising 29 cases with acute cystitis, 8 cases with chronic cystitis, 6 cases with pyelonephritis and each of a case with subacute prostatitis and gonorrheal urethritis.
The overall effective rate was 88. 9%. In 11 cases side effects were observed, most of which were gastrointestinal disturbances. Two patients could not continue the treatment because of side effects.

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