The anaerobic bacteria of the female genital tract in healthy women, both pregnant and nonpregnant, were investigated during the period from Jan. 1973 to May 1976. The study was based on findings observed in 802 women.
In the vagina, the effects of the various pH levels on the growth of anaerobes are of great importance. The percentage of successful bacterial isolation decreased as the state of vagina became clean. Fifty five of 104 (52.9%) specimens from healthy nonpregnant women with a pH range from 4.0 to 6.8 yielded anaerobes. As to the cleanliness and the isolation of anaerobes, Grade I (pH 4.0-4.6) showed 8.3%(3 of 36 cases), Grade II (pH 4.2-5.6) 64.9%(24 of 37 cases), Grade III (pH 5.6-6.8) 90.3%(28 of 38 cases).
During pregnancy, the much increased vaginal secretion is represented normally by a thick, white discharge. Its pH varied from 3.8 to 6.2 according to the increased production of lactic acid. In healthy pregnant women anaerobic bacteria were isolated from 54 of 120 cases (45.0%). As to the cleanliness and the isolation of anaerobes, Grade I (pH 3.8-4.6) showed 8.6%(3 of 35 cases), Grade II (pH 4.2-5.6) 44.2%(23 of 52 cases), Grade III (pH 5.6-6.2) 84.4%(28 of 33 cases). Thus, acidicpH played a significant role in keeping the vagina free of bacteria.
The normal Fallopian tubes were found to be completely free of bacteria in both pregnant and nonpregnant state.
Anaerobes were found rarely in the uterine cavity of the healthy nonpregnant women (7.1 %).
In pregnant and nonpregnant women, the lack of anaerobes in the normal cervical flora was in contrast to their high incidence in vagina, Anaerobes were found in cervical cultures from 20.7 per cent of nonpregnant women who had delivered previously with the contrast to 8.7 per cent of nonpregnant women who had never borne a child. During the third trimester of pregnancy in multiparas, anaerobes were isolated from 9 of 120cervical cultures (7.5%).
Comparison of the anaerobic bacteria isolated from the flora of the cervix and vagina showed that the organisms which constituted a large part of the vaginal flora were not necessarily observed in cervix.
Six samples of clear amniotic fluid obtained by abdominal amniocentesis and 18 samples obtained in the Cesarean Section without the rupture of the membrane were cultivated aerobically as well as anaerobically. No growth of organisms was observed.
On the contrary, of 19 amniotic fluid taken from patients (12 to 48 hours after the rupture of the membrane) 8 showed anaerobes (42.1%).
Without the rupture of the membrane, the anaerobic bacteria were found rarely even in the turbid amniotic fluid. In 35 cases anaerobes were isolated only in 2 (5.7%).
The anaerobic bacteria were present in large numbers in the external genitals of the healthy pregnant women. Therefore, the vaginal examinations late in pregnancy and the manipulations in labor are attended with danger to introduce bacteria into the genital tract.

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In order to examine the effectiveness and safety of S-6436 (a new long-acting preparation of cephalexin), a double blind controlled study was carried out in acute simple cystitis on S-6436 and cephalexin (CEX). S-6436 or CEX was administered at the daily dose of 1g for 4 days. The results obtained were as follows:
1. The number of cases evaluated on drug efficacy was 65 for S-6436 and 70 for CEX, and no significant difference was observed in the clinical efficacy between S-6436 500mg b.i.d. group and CEX 250mg q.i.d. group.
Excellent S-6436 52 cases: CEX 53 cases
Good S-6436 11 cases: CEX 16 cases
Poor S-6436 2 cases: CEX 1 case
2. Bacteriological efficacy of the drugs in both groups was satisfactory and no significant difference was found between two groups.
3. Recurrence after completion of the treatment was observed in 13.3% in 30 cases with S-6436 and 15.6% in 32 cases with CEX, the difference being not significant.
4. Adverse effects noted were limited to slight gastrointestinal symptoms. In only one case with CEX, the medication was discontinued due to nausea and palpitation. No significant difference was observed between two groups in the incidence of adverse effects. The ratio of the incidence of side effect was 3.6% in 84 cases with S-6436 and 2.4% in 84 cases with CEX.
These results indicated that S-6436 was equal to CEX in the effectiveness and safety in the therapy of acute simple cystitis. Accordingly it is considered that S-6436 administered twice a day is more acceptable and more convenient for patients than CEX administered four times a day.

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Clinical effect of long-acting preparation of Cephalexin (S-6436) was investigated in comparison with Cephalexin at the identical dosage of 1, 000mg/day under the double blind test on adult patients with acute tonsillitis or acute otitis media.
The administration frequency was planned as twice a day in S-6436 and 4 times a day in Cephalexin with aid of placebo, and the following results were obtained.
1. In the treatment of 65 patients with acute tonsillitis, clinical improvement was observed in 87.5% on S-6436 group and 88.5% on Cephalexin group.
Statistical analysis revealed no significant difference between these two groups.
2. In acute otitis media, statistical analysis was impossible for lack of sufficient cases, but no difference in effectiveness was seen between two groups.
3. As the side effect, vomitting was observed in one case treated with cephalexin, but there was no adverse reaction in S-6436 group.
4. From the above results, it is concluded that S-6436 to be taken twice a day is equivalent to Cephalexin in effectiveness for acute tonsillitis and acute otitis media.

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S-6436 which is a new long-acting Cefalexin preparation, has been investigated to give the following results. Pharmacokinetics of the drug were examined in 6 healthy male volunteers following 500mg single oral administration after meal. Mean peak blood level of 2.77μg/ml was obtained 6 hours after dosing. Mean 63.3% of the administered dose was excreted in the urine over 10 hours collection period.
On the clinical evaluation of the drug, 35 cases of infectious diseases, including 17 of respiratory infections, 17 of urinary tract infections and one of biliary infection, were treated with 500mg b.i.d. orally for 2 to 14 days. Two patients were cured with excellent clinical effects, 27 were good, 3 were fair and 3 were failure. As to the side effects of the drug, nausea, anorexia and diarrhea were noticed in two patients during the treatment.

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S-6436 is a new long-acting preparation of Cephalexin. This report describes the clinical trial with this drug.
S-6436 was administered at the dose 500mg b.i.d. after meal. Clinical results of S-6436 in 18 cases of respiratory tract infections were excellent in 2 cases, good in 11 cases, slightly good in 3 cases and failure in 2 cases. In 7 cases in urinary tract infections, clinical results obtained were excellent in 1 case, good in 5 cases and slightly good in 1 case. Transient and slight increase of S-GOT and S-GPT was noted in 1 case, and S-GPT in 1 case.
It is considered that S-6436 and Cephalexin are equal in points of effectiveness and safety in the treatment of mild or moderately severe infections. Therefore, S-6436 of 500mg b.i.d. after meal may be more advantageous for the patients than Cephalexin 250mg q.i.d.

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Nine cases, including three of respiratory tract infections and six of urinary tract infections, were treated with S-6436 orally.
All cases were administrated S-6436 500mg b.i.d. for five to fifteen days.
Four of nine cases showed excellent results, three, good, one, slightly good and one, poor.
S-6436 yielded excellent or good effect to acute infections.
Vomitting, nausea and diarrhea were not observed.
Laboratory findings of hematological examination and blood chemistry obtained before and after the medication were in the normal range.

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1) S-6436 was administered to 26 cases with urinary tract infections (Acute cystitis, 23 cases; Chronic cystitis, 1 case; Simple urethritis, 1 case; Acute epididymitis, 1 case). The patients were treated with 0.5g of S-6436 b.i.d. for 3 to 12 days.
2) The clinical results were excellent in 19 cases, good in 6 cases and poor in 1 case, the effective rate being 96%. In the 23 cases with acute cystitis, the effective rate was 100%.
3) Skin eruption on the face was observed in 1 case. No side effects were observed in any other cases.

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S-6436 is a new long-acting preparation of Cephalexin, expected to provide antimicrobial concentration in the urine for a longer period in order to enhance clinical effect.
S-6436 of 1, 000mg/day (×2) was administrated to 20 cases with urinary tract infections for 1.5 to 7 days, and therapeutic efficacies were evaluated in 16 cases (8 acute cases and 8 of 12 chronic cases). As for the side effects, subjective symptom was observed in only one case, but no abnormal cases on laboratory investigations.
Antimicrobial concentrations of 8 hours-urine following 500mg administration of S-6436 and Cephalexin after meal were measured by cross over method. Peak urinary level of S-6436 was 1, 250μg/mlin 6 hours, and of Cephalexin 1, 800μg/ml in 2 hours. S-6436 and Cephalexin in 61.5% and 72.4% were recovered from the urine within 8 hours, respectively. Administration of S-6436 of 500mg provides urinary antimicrobial concentration in excess of 400μg/ml for at least 7 hours.
In all of the 4 clinically ineffective cases, MICs of Cephaiexin against causative organisms were≥ 400μg/ml, but in all cases in which the causative organisms were eliminated, MICs to the causatives were ≤200μg/ml.
In clinically failured cases, the bacteria did not disappear despite of 6-hours persistence of urinary drug concentration in excess of 400μg/ml. Therapeutic efficacy should be discussed not only from the viewpoint of urinary drug antimicrobial concentration and MIC to the bacteria, but also from the view point of the biological reaction of the host.
At any rate, S-6436 can be rated as an excellent and convenient drug for clinical use with minimum side effects. The most impressive is its long acting ability and persistence of high urinary concentration.

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S-6436, a new long-acting preparation of cephalexin (CEX), was studied both basically and clinically in the urological field and the results obtained were as follows:
1. In vitro antibacterial activity
MICs of CEX against clinically isolated 73 strains of E. coli were distriblited among ≤0.2≥100μg/ml with inoculum size of 10⁸ cells/ml but the majority of MICs was ≥100μg/ml. On the other hand, with inoculum size of 10⁶ cells/ml a peak of MIC distribution was 3.12μg/ml.
MICs of CEX against clinically isolated 15 strains of Klebsiella pneumoniae were distributed among 50-≥100μg/ml mostly ≥100μg/ml, with inoculum size of 10⁸ cells/ml but with 10⁶ cells/ml a peak was 3.12μg/ml.
MICs of CEX against clinically isolated 95 strains of Serratia marcescens and 18 strains of Pseudomonasaeruginosa were mostly ≥100μg/ml with both inoculum sizes of 108 and 106 cells/ml.
2. Serum level
Three healthy adult volunteers were orally administered S-6436 at a single dose of 500mg after usual meal. Mean peak serum concentration of S-6436 was appeared at five hours with 6.8μg/ml and effective serum levels continued for approximately five hours. Accordingly it is considered that therapeutic efficacy of S-6436 can be expected at a dose of 500mg b.i.d.
3. Urinary recovery
The urinary recovery of S-6436 for twelve hours was 83.1% on an average following an administration of a single dose of 500mg.
4. Clinical result
S-6436 was administered to the majority of 20 cases with urinary tract infections at a dose of 500mg b.i.d., and the clinical effects obtained were excellent in 15 cases, good in 3 cases and poor in 2 cases, effective ratio being 90%. In 13 cases with simple urinary tract infections, the effective ratio was 92% and in 7 cases with complicated urinary tract infections, the effective ratio was 86%.
5. Adverse reaction
In S-6436 administered 20 cases, no adverse reactions were complained. These results indicated that S-6436 was equal to CEX in the effectiveness and safety in the therapy of urinary tract infection. Accordingly it is considered that S-6436 500mg b.i.d. is more acceptable and more convenient for patients than CEX 250mg q.i.d.

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1. Serum and urinary levels of S-6436 500mg P.O. were determined in two volunteers with normal renal function. In one case, S-6436 was orally administrated at 30 minutes after light meal and in another case, at 60 minutes after usual meal. The peak serum level of Cephalexin (CEX) was 6.4μg/ml at 4 hours in the former and 7μ/ml at 6 hours in the latter after oral administration. The time length, in which more than 3μg/ml serum level was kept, was 6 hours in the former and 4 hours in the latter. The peak urinary levels were 1, 350 in the former and 2, 100μg/ml in the latter in 4-6 hours after administration. The recovery rates from urine for 12 hours after the administration were 93.8% and 93.3%, respectively.
2. 72 adult U.T.I. patients were treated with daily dosage of 250mg or 500mg b.i.d. of S-6436 for 7 days. The criteria recommended by U.T.I. Drug Evaluation Committee in Japan were applied for clinical evaluation of S-6436. Eight patients were eliminated from the subject for efficacy evaluation, by the reason that their pathogen could not found before the treatment, and remaining 64 patients were evaluated for the drug efficacy. Dosage regimens administrated and the respective numbers of patients were as follows: S-6436 500mg b.i.d. after meals, 36; and S-6436 250mg b.i.d. after meals, 28.
Clinical responses of 36 patients with S-6436 500mg b.i.d. after meals for 7 days were as follows:
a) Of 18 with acute simple cystitis, 15 were rated excellent and 3, good.
b) Of 9 with chronic complicated cystitis, 3 were rated excellent, 1, good and 5, poor.
c) Of 7 with chronic complicated pyelonephritis, 1 was rated excellent, 3, good and 3, poor.
d) Other 2 cases were rated excellent.
Clinical responses of 28 patients with S-6436 250mg b.i. d. after meals for 7 days were as follows:
a) Of 26 with acute simple cystitis, 24 were rated excellent and 2, good.
b) One chronic complicated cystitis was rated good.
c) One acute simple pyelonephritis was rated excellent In acute cystitis, conclusively, S-6436 250mg b.i.d. was equal to 500mg b.i.d. in the effectiveness.
3. S-6436 was well tolerated in oral administration. Three cases of adverse reactions, mild nausea, epigastric discomfort and glossitis, respectively, were obserbed in 500mg b.i.d. group. The treatment was discontinued in only one patients of glossitis. A transient and slight rise in S-GOT, S-GPT value was observed in two patients treated with 500mg b.i.d.
4. The results suggest that S-6436 and CEX are equally effective and safe in the treatment of urinary tract infections. It is considered that S-6436 500mg b.i.d. after meals is mare acceptable and more convenient for the patients than CEX, 250mg q.i.d.

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1. Eighteen patients with infectious diseases in the obsteric and gynecological field were orally given S-6436 of 500mg to 1, 000mg b.i.d. for 5 to 7 days. The results obtained were marked effective in 2 patients, effective in 14 and ineffective in 2.2. No side effect was observed.
3. Twice daily dosage schedule of S-6436 was expected to be more acceptable and more convenient for the patients than four times of usual Cephalexin preparation.

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Clinical effect of a new long-acting preparation of Cephalexin (S-6436 and S-6437) was investigated on patients with infectious diseases in the otolaryngological fields.
S-6436 was administered at the dosis of 500mg b. i.d. and S-6437 at about 25mg/kg b. i.d., and the following results were obtained.
1) Twenty three cases were rated excellent, 9, good, 4, slightly good and 3, poor, the effective rate being 82.1%.
2) As the side effect, rash was observed in one case out of the 40 cases.
3) From above results, it is concluded that S-6436 b. i.d. is eqivalent to Cephalexin q. i.d. in effectiveness and safety for the infectious diseases in the otolaringolgical field.

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