1. Thirty-two strains of Staphylococcus aureus isolated from the lesions of pyoderma were studied as to the resistance to TC, DMCT, methacycline and doxycycline. The percentages of resistant strains were 562 % in the first, 53. 1% in the second and the third, and 43. 7% in the fourth.
2. Serum levels after the oral administration of 200 mg to 3 healthy f asting volunteers were studied. Peak concentrations were obtained at the 1 to 2 hours. At 24 hours, 0. 2, 0. 21, 0. 26 mcgiml were detected in each subject.
3. Of the 17 cases of pyoderma given after a meal either a single or double oral daily doses of 100 m g of doxycycline, 5 showed excellent result, 4 good result, 6 fair result and 2 poor result. Nausea and vomiting was seen in 2 cases. However, very high incidence of such side effects were seen when the drug was given to the hungry subjects.

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Following results were obtained by our fundamental and clinical studies of doxycycline (DOTC).
1) The in vitro antibacterial activity of DOTC against 73 strains of staphylococci isolated from pycoderma and other skin diseases were examined with plate dilution method. Fifty strains (68. 5%) of all were inhibited by 0. 195 mcg/m1 or less of DOTC. Comparing with tetracycline (TC), DOTC was more active than TC against both sensitive and resistant strains.
2) Inactivative action of DOTC against α-hemolysin was estimated. Comparing with TC and chloramphenicol, DOTC was more active than others. It was considered that DOTC was useful in the treatment of the early infectious lesions with both antibacterial and this action, because α-hemolysin would be associated with the development of early stage of pyoderma.
3) DOTC was clinically applied to 20 cases of pyoder ma. Effective therapeutic results were obtained in 18 cases. No noticeable side effects were observed except nausea in 3 patients.

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We have recently obtained the result described below through the clinical and experimental studies on doxycycline.
1) The minimal inhibitory concentration in doxycycline was measured by plate agar dilution method. Doxycycline inhibited by <0.19-0.39 mcg/ml against coagulase-positive Staphylococcus aur e us 40 strains. Doxycycline showed higher sensitivity than other antibiotics.
2) The level of blood concentration in doxycycline was determined by the average of 3 cases for adult. The maximal level reached 3. 2 mcg/ml in 4 hours after per os, as the result measured by single oral administration of 200 mg. And blood level still maintained 0. 82 mcg/ml in 24 hours after per o s.
3) The urinary excretion was determined by the average of 3 cases for adult. The urinary total excretion showed 17. 9 mg within 12 hours after oral administration of 200 mg. Urinary recovery showe d a low level such as 4. 2∼11. 9 per cent of the total dosage.
4) The pus concentration could not be measured at 6 hours after oral administration of 200mg in the operation of maxillary sinusitis.
5) Rat tissue concentration showed that kidney indicated the highest activity of doxycycline and other tissues were in the following order; liver, spleen, lung and heart.
6) By oral administration (100200 mg) or local application (5 ragiml solution) on 34 cases of infections in otorhinolaryngologic field, doxycycline produced a good result of 73. 5% (25 cases).
7) Side effects: Oral administration of doxycycline occurred the side effects to 3 cases; nausea and vomiting, for which its administration was terminated. Yet on the local administration no such s i de effects were observed. The comparative examinations of liver, kidney and electrolyte, audiogra m before and after administration showed no significant disturbances.

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The present authors have carried out the clinical application of doxycycline hydrochloride chiefly to the infections in the field of otorhinolaryngology.
1. From the results of sensi tivity test of Staphylococcus aureus against TC and DOTC, DOTC showed more remarkable activity than TC. When 100 mg of doxycycline hydrochloride were administrated to the adults, the peak of blood concentration was found after 4 hours, and the blood concentration after 19 hours was as high as the blood concentration after 8 hours.
2. Thirty-three cases of the infections were treated with doxycycline h ydrochloride, and the results were obtained as follows: remarkably effective for 20 cases (60. 6%), improved for 6 cases (18. 2%), ineffective for 6 cases (18. 2%), and effective ratio (78. 8%) (refer to Table).
3. As for the side effect of doxycycline hydrochloride, no damage o f hearing and equilibrium was observed in all cases so far as the above doses concerned, hypersensitivity and eruption were not encountered, but only one case of stomachache was found 3 days after administration of doxycycline.

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From the laboratory and clinical studies on doxycycline, a new antibiotic belonging to the series of tetracyclines, the following results were obtained.
1. Single oral doses of 200 mg of the drug produced the serum peak at 7 hours. Its avearge level was 2. 5 mcgml in 3 adults.
Serum concentration fell then gradually, but it was still 0. 9 mcg/ml at 24 hours after administration of the drug.
2. Tissue concentrations of doxycycline in tonsils were measured. An average tissue level of 0. 7 mcg/g was obtained at 4 hours after oral administration of 200 mg.
3. The sensitivity of 37 strains, isolated from the pathological materials in our clinic, to doxycycline was measured by plate dilution method. Seventy-one per cent of gram positive cocci including staphylococci, streptococci and diplococci, were inhibited to grow by the presence of 0. 78 mcg/ml or less. Gram negative bacilli were highly resistant to this antibiotic except a strain of E. coil which 420 CHEMOTHERAPY MAR. 1969 was sensitive to 3. 12 mcgirni. Doxycycline was found to have almost complete cross resistance with tetracycline in 24 strains of coagulase-positive Staphylococcus aureus, but doxycycline was more active against these strains than tetracycline.
4. Doxycycline was clini cally used to 22 cases of ear, nose and throat infections and it was effective in 77. 3% of them.
5. No side effe ct was observed in all cases.

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1) Doxycycline (Vibramycin) administered to 37 cases of chronic sinusitis in doses of 100 mg daily for 4 weeks was effective in 8 (21. 6%), fairly effective in 15 (40. 5%), and ineffective in 14 (37. 8%).
The side effects of doxycycline were gastralgia in 2 cases (5. 0%) and glossitis in one (2. 5%). No serious side effect developed.
Peripheral hemato l ogic examinations, urinalysis, and liver functional tests performed before and after administration of doxycycline in 17 cases found nothing abnormal.
2) No particular relationship was present between the bacteria detected from the middle nasal meatus and the effectiveness of doxycycline. This antibiotic was found effective for a broad spectru m of bacterial infections.
3) The minimal inhibitory concentration of doxycycline against 16 strains of coagulase-positive. staphylococci isolated from clinical otorhinolaryngological cases was a little lower than the minimal inhibitory concentration of tetracycline.

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In our clinic, doxycycline was orally administered to the patients with various extraocular and corneal infections. Observation on clinical effect as well as basic experiment was made.
1) MIC of Staph. aureus of 28 out of 42 strains distributed from 0. 19 m cg/ml to 1. 56 mcg/ml.
2) With 100 mg/kg oral administration, the blood concentration in the rabbit reached to t he maximum level in 2 hours and aqueous humor concentration of the rabbit reached to the maximum level in 3 hours.
3) Twenty-six patients with corneal infiltrate and extraocular infection were treated with 50 mg doxycycline p. o., b. i. d. or 100 rag p. o., q. i. d. Seventy-seven per cent of these cases improved by the treatment. Thirty-three per cent of these cases suffered from side effects, i. e. poor appetite, nausea and vomiting.
4) Doxyc ycline promises to be a useful antibiotic agent in ophthalmological clinic.

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The results of laboratory and clinical experiments for ophthalmic use of doxycycline (Vibramycin) were summarized as follows.
1) The minimum growth inhibitory concentration of doxycycline was somewhat superior to tetracycline: 0. 1 mcg/ml for KOCH-WEEKS bacillus, 0. 39 mcg/ml for MORAX-AXENFELDdi plobacillus, 0. 04∼0. 78 mcg/ml for Pneumococcus, 0. 04∼0. 19 mcg/ml for Corynebact. diphtheriae, 0. 04 mcg/ml for Gonococcus, . 0. 19∼0. 39 m cg/m1 for Streptococcus, 0. 19∼0. 78 mcg/ml for Staphylococcus and 12. 5∼25 m cg/ml for Ps. aeruginosa.
2) The distribution of the sensitivity for 100 strains of Staph. aureus was in the range of ≤0. 1∼ 25 mcg/ml and majority of them (95%) were in ≤2. 5 mcg/ml.
3) Single oral dose of 200 mg doxycycline produc ed peak levels after 2 hours, and measurable. amounts were present in serum after 24 hours.
4) In rabbits, aqueous level by the ora l administration of 40 mg/kg doxycycline attained to the peak after 2 hours and maintained still after 24 hours. By the instillation or the subconjunctival injection? more favourable aqueous levels were obtained than the oral administration.
5) The tissue concentration by the instillation was higher than the oral administration except the retina and choroid. The highest tissue concentration was obtained by the subconjunctival injection, especially in the outer segment of the eye.
6) The oral application of doxycyclin e revealed excellent effects on 12 cases of hordeolum, 2 cases of lid abscess, 3 cases of acute conjunctivitis, each one case of acute dacryocystitis and orbital cellul itis, 3 cases of corneal infiltrate, 9 cases of corneal ulcer, 5 cases of preventive application against postremoval of foreign body on the cornea and one case of purulent iridocyclitis. Postoperative infection ?was prevented in all of the 23 cases.
7) The side, effects were noted in 6 of all 60 cases: 3 cases were anorexia, 2 cases were nausea and tone case was vomiting, but any other severe side effects, such as allergic reaction, were not noticed.

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Doxycycline, a new antibiotic derived from tetracycline, was administrated orally to 74 patients suffered from diseases of the oral regions. The dose schedule was 200 mg for the initial day, followed by a single 100 mg dose on subsequent days. Seventy-four cases were divided into 2 groups, the one consisted of 50 cases treated for infections of the oral regions, for instance, osteomyelitis, LuDwIo's angina, lymphadenitis and others, and the other one consisted of 24 cases intended to prevent infections after the operation or the traumatic injuries of the oral regions, for instance, excision of tumors, ostectomy, jaw fractures and others. Among the 50 cases of the first group, 9 cases (18%) showed superior result, 27 cases (54%) good result, 9 cases (18%) fairly good result, and 5 cases (10%) proved no effectiveness of doxycycline. The side effects were seen in 9 cases (12. 2%). They were stomach disorder, stomachache, nausea and stomach discomforts.

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The tetracyclines are said to combine with the bivalent metal ions and deposit on the growing hard. tissues such as the bone and tooth. The authors observed the influence of the antibiotic a, 6-deoxyoxytetracycline, newly developed by Pfizer, on the hard tissue histologically by fluorescence microscope and also conducted absorption tests using synthetic hydroxyapatite, obtaining the following results:
1) When 20 mg/kg of a tetracycline antibiotic were injected into the Wister strain rat intraperit oneally once a day for 60 days, fluorescence was observed in the tooth and bone in the doxycycline group of animals as in the tetracycline group. A stripe pattern in the dentine showing the interval between administrations was observed, but in the doxycycline group the width of the fluorescence seemed to be somewhat wider.
2) Also in the group of pregnant rats and mother rats in the lactation period administered with doxycycline, fluorescence was observed in the tooth and bone of the embryo and the infant. Thus, it seems that doxycycline seems to have an influence on the hard tissue of the embryo and infant.
3) The result of measuring the absorption rate in vitro of synthetic hydroxyapatite and tetracycline antibiotic using Hitachi's ultraviolet ray absorption apparatus showed 55 % for tetracycline, 58 for oxytetracycline, 62 96 for methacycline and 37 % for doxycycline, doxycycline showing the lowest rate. Although the in vitro results can not be always applied in vivo, it may be said, that the deposition of doxycycline on the tooth and bone would be small compared to the other tetracyclines.

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Studies on a new tetracycline derivative, doxycycline, were conducted in regard to the distribution of the antibiotic into the human saliva, sensitivity to the antibiotic of the strains isolated from the suppurative foci of the jaw and the strains of Actinomyces isolated from actinomycosis and clinical effect.
1) To 5 normal subjects a single dose of 200 mg of doxycycline was administered and the antibiotic levels of the blood and especially of the parotid saliva were determined at various intervals. In both the peak level was observed at 6 hours after administration and the antibiotic was still present even after 24 hours. There was a tendency for the saliva level of doxycycline to parallel generally the blood level and the antibiotic was present in the blood and saliva for a long period.
2) The MICs of doxycycline, tetracycline and penicillin-G for 29 strains isola ted from the suppurative foci were determined.
3) Doxy cycline was administered to 42 cases with suppurative lesions of the jaw and 25. postoperative cases for prophylaxis of infection, and in 57 cases (85. 1%) the effect was markedly effective or fair. Side effects were observed in 10 cases, among which the administration was discontinued in 2 because of vomiting. The other side effects were mild gastric symtoms, and the administration of the antibiotic was continued.

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