Antibacterial activity of doxycycline (DOTC, α-6-deoxyoxytetracycline) was compared with that of 3 tetracycline derivatives; chlortetracycline (CTC), oxytetracycline (OTC) and tetracycline (TC). The bacterial strains used were 27 gram-negative rod bacteria, 100 Shigella and 100 staphylococci, and were of clinical origin. Level of DOTC resistance in most of the gram-negative bacteria including Shigella strains was sim ilar to other TC derivatives. In TC resistant strains, however, DOTC was found to be slightly effective than OTC or CTC. Among the TC resistant Shigella strains, some strains showed high sensitivity to DOTC. In TC resistant staphylococci, the mean of DOTC was 8 times or more effective than 3 other TC derivatives. In TC sensitive staphylococci, DOTC and CTC were slightly effective than OTC and TC. In vitro acquisition of DOTC resistance was studied by cultivation on the plate c ontaining serial concentrations of the drug. Stepwise increase in drug-resistance took place but high degree of drug-resistance was not obtained so far as tested.

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Therapeutic effect of doxycycline (α-6-deoxyoxytetracycline, DOTC) was compared with that of tetracycline (TC) in experimental acute infection of Staphylococcus aureus in mice. The ED₅₀ of DOTC was half of that of TC in subcutaneous therapy and th e former was one sixth of the latter in oral therapy. No significant differ ence was observed between the effect of both drugs in the infection with Escherichia coli.

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A total of 394 strains of recently isolated pathogens from clinical materials, i. e. pneumococci, . hemolytic streptococci, enterococci, Staphylococcus aureus, Haemophilus, Escherichia, Pseudomonas, and several species of anaerobes, were tested for their in vitro susceptibility to doxycycline and other: 114 CHEMOTHERAPY MAR. 1969 tetracyclines by a plate dilution method. Among doxycycline, demethylchlortetracycline and tetracycline, doxycycline is most effective in vitro to gram-positive cocci, but to gram-negative bacilli demethylchlortetracycline is rather effective than doxycycline. Among three tetracyclines, tetracycline is least effective to almost all sepcies of pathogens. ' Minimum inhibitory concentration of doxycycline for one strain of Staphylococcus aureus was effected by the size of the inoculum, but not effected by the change of medium pH between 6. 5 and 7. 7.

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As for doxycycline, a new tetracycline antibiotic, we have studied the sensitivity on 55 strains of E. coil, 16 of Klebsiella, 14 of Citrobacter, 26 of Proteus group, and 75 of Staphylococcus isolated from clinical specimens. In addition, we have compared the antibacterial effect of the drug with that of tetracycline, oxytetracycline, methacycline and demethylchlortetracycline. In these experiments, doxycycline showed a high er antibacterial effect compared to the other drugs, and this was definite in Staphylococcus.

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Inhibitory effect of six tetracyclines was studied on Mycoplasma pneumoniae MAC and six strains. from patients.
Minimum inhibitory concentration was determined with color change of CRANocK's fluid medium, supplemented with glucose and phenol red. Reading was made when the color of drug free liquid medium turned final yellow by the acid production of Mycoplasma.
The mycoplasmostatic effect was observed in the following order: doxycycline, demethylchlortetracycline, methacycline, and chlortetracycline.
The experimental meth od for the mycoplasmostatic effect and its meaning was discussed.

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The new tetracycline derivative, doxycycline, has 'the same antibacterial spectrum as tetracycline but the in vitro antibacterial activity is 2 to 4 times more potent. Especially the interesting thing about the results of the sensitivity studies on approximately 100 clinical isolates of staphylococci is that approximately 60% of the strains showed high resistance to tetracycline with MIC of 100 mcg/ml and approximately 20% of those showed a somewhat sensitive tendency to doxycycline with MIC of 25-50 mcg/ml, and this tendency of sensitivity increase became marked by decreasing the inoculum size. The remaining 80% of the strains showed complete cross resistance, the MIC against doxycycline being also 100 mcg/ml.
On the other hand, doxycycline showed 2 to 4 times more activity against tetracycline sensitive, strains.
The same tendency for the change in sensitivity due to the addition of serum protein was seen as with 'tetracycline. Doxycycline was somewhat more stable in regard to the influence by the change of pH. In experimental infections in the mouse, therapeutic results with doxycycline in hemolytic streptococcal infections were superior to tetracycline but the results in E. coli infections were the same as tetracycline. There would be a need to conduct further studies on additional staphylococcal strains.

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1) The newly isolated 55 strains including 32 gram (+) cocci and 23 gram (--) rods were tested for the sensitivity to TC and DOTC. From the results obtained concerning MIC value, DOTC, showed more active than TC especially in the former group including Staphylococcus aureus strains.
2) The TC and DOTC serum levels after each single oral administration of 1, 000 mg and 200 mg respectively were measured by modified standard method of Pfizer Laboratory, and also antistaphylococcal activity of these sera were analyzed by their effects on the growth curve of 209 P strain automatically recorded by biophotometer (Jouan).
From the results, it was demonstrate d by both methods that DOTC appears in serum earlier than TC, and smaller dose is sufficient enough to obtain an effective concentration there than TC.

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A new derivative of tetracycline, doxycycline was studied bacteriologically and clinically, and the results may be summarized as follows:
1) In a study by the agar dilution method on a total of 109 strains of 19 bacterial species, staphylococci, pneumococci, β-hemolytic streptococci and Corynebacterium diphtheriae were found to be very sensitive to the agent with the MICs of 1. 56 mcg/ml or less. And Escherichia, Klebsiella, Salmonella and Shigella were fairly sensitive with the MICs of 6. 25 mcg/ml or less. While Pseudomonas, 140 CHEMOTHERAPY MAR. 1969 tetracycline-resistant staphylococci and α-hemolytic streptococci were slightly resistant to the agent showing their MICs ranging from 6. 25 to 50 mcg/ml.
2) In order to apply the single-disc method to the sensitivity test in clinical laboratory, graphic analysis of the dose-responce data concerning the interrelationship between MIC values and diameters of inhibition zones were conducted on each of i) conventional (over-night: about 16 hours) assay, ii) delayed (about 24 hours) assay for slowly growing bacteria, iii) 4-hours rapid assay with heavy inocula and iv) 6-hours rapid assay with heavy inocula.
3) By the thin-layer cylinder-plate technique using B. subtilis PCI 219 as a test organism, the concentration of the agent was assayable to the lower limit of 0. 03 mcg/ml. Following a single oral administration of 100 mg doxycycline, seru m peak levels were obtained at 4 hour, with a persistence of serum levels at least 0. 5 mcg/ml over ensuing 24 hours. After the oral administration, effective levels were found to be obtained in sputum and in urine.
4) Treatment with doxycycline was effective in a case of acute cystitis.
5) Side effects on the digestive tract such as epigastric distress or nausea were observed in 2 cases. There was no apparent evidence of hepatic, renal or hematopoietic functional-impairment in a case treated in a dose of 300 mg for 10 days.

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Pharmacological actions of doxycycline were investigated. The movement of the excised heart of toad and rabbit were inhibited (5 x 10^-5 g/ml). Bradycardia took place at the dose of 1 mg/kg. The movement of the excised intestine of rabbit and the tonus of- the excised intestine of guinea pig were stimulated (10^-7 or 5 x 10^-7 g/ml) and inhibited (10^-4g/m1). The excised rabbit ear vessels were constricted (10^-5 g/ml) and the permeability of cutaneous vessels were stimulated (100 mcg). Temporary fall in blood pressure (5 mg/kg) and acceleration of respiration (5 mg/kg) were observed in the urethane anesthetized rabbit. Clonic convulsion was observed in the rabbit (injected in cisterna magna). Doxycycline, therefore, has not remarkable pharmacological actions at therapeutic doses.
Doxycycline has less pharmacological actions than tetracycline and some tetracyclines.

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1) In the susceptibility test of 60 strains of Staphylococcus aureus isolated from patients using plate dilution method, 24 strains were inhibited by 1. 6 mcg/ml of doxycycline and 57 strains by 50 mcg/ml. Doxycycline was found to be more active for the strains resistant to tetracycline and demethylchlortetracycline. These tetracyclines were found to have cross-resistance with each other.
2) In absorption and excretion study in human subjects, following 200 mg oral administration a sustained blood level and low urinary output (15 % of dose in 24 hours) were observed. Cup plate method produced lower values than those with vertical method in the determination of blood concentration.
3) Urinary and biliary excretion and distribution study following 5 mg/kg intravasal dose in dogs were carried out. Biliary excretion was much less than urinary excretion. Values calculated from the study are as follows: half-life 7. 0 hours, renal and biliary clearance 1. 1 and 0. 01 ml/min/kg, volume of distribution 2. 0 L/kg, and rates of removal from kidney and bile 3 96 and 0. 04 % respectively. The data seems to indicate a slower removal a ndjor inactivation of doxycycline in b ody tissue.
4) In protein binding study with bovine serum, the binding rate of doxycycline, tetrac ycline and demethylchlortetracyclinew ere found to be 40-31 %, 30-25 % and 38-35 % respectively.
5) The study on the chelating action of tetracyclinesw ith Ca++, M g++, F e++, Fe+++ and Al+++ ons were carried out. The activity of doxycycline seems to be less influenced by these metals than other tetracyclines.
6) In clinical observation of 31 cases with respiratory and other infections, treatment with doxycycline (initial 200 mg, successive 100 mg daily dose in most of patients) showed excellent or good results for 23 cases, fair for 5, and poor for 3. The side-effects of 2 cases with nausea and 2 cases with anorexia were observed.

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1. Determination of MIC of DOTC, TC and other antibiotics against 26 strains of Staphylococcus aureus isolated from sputa during the period from February to April 1968 has revealed that the values for DOTC were 1/2 to 1/4 of those for TC, and also the MIC of DOTC was lower than 25 mcg/ml with all strains examined.
2. The determination of tissue concentration of DOTC has revealed that the highest peak concentration was observed first in kidney followed by liver, lung and blood in this order. Higher level of the antibiotic is maintained for long period especially in the lung.
3. In our chemotherapeutic experiment with mice infected with pathogenic Staphylococcus (Small strain), definitely better results were obtained in DOTC treated animals than in TC treated ones.
4. Treatments with DOTC were effective in 15 patients, mostly with chronic infection o f air way, as far as the pathogen was sensitive to the antibiotic. It is remarkable that the administration of 100 mg of the antibiotic given on alternate days, differently from the usual administration schedule, to patients with chronic respiratory infections was proved to be quite effective.

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On doxycycline, fundamental experiment and clinical application were performed.
1. The minimal inhibitory concentrations of doxycycline against Stap hylococcus aureus and some strains of gram negative bacilli were one half to one quarter of tetracycline.
2. The mice, inoculated with R. orientalis intraperitoneally, w ere treated with oral administration of doxycycline and demethylchlortetracycline. Survival 'days of the mice treated with doxycycline were longer than those with demethylchlortetracycline.
3. The blood peak le vels and half life times of doxycycline at oral dose of 200 mg were little influenced by renal impairment.
4. Fifteen cases of various infections including 1 case of tsutsugamushi disease, 6 cases of pneumonia were treated with oral administration of doxycycline. This drug was effective in 12 cases and partially effective in 3 cases. No side effect excluding gastric irritation was found.

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On a new tetracycline derivative, doxycycline (abbreviated as DOTC) several investigations were performed and the following results were obtained.
1. A majority of Staphylococcus aureus showed the M. I. C. values of 0. 1 mcg/ml or more against DOTC. Those showing M. I. C. values of more than 100 mcg/ml to TC also showed M. I. C. of 0. 8 to 25 m c g/ml against DOTC. Vari6us gram negative bacilli had almost equal M. 1. C. values against TC and D O TC.
2. DOTC had strong adsorption to red blood corpuscle.
3. The serum protein binding rate using cellop hane bag dialysis was calculated to be 50 to 61%.
4. The inactivation of DOTC by Ca and Mg ion was markedly less than that of other tetra cyclines.
5. After oral administration of DOTC to rabbits in dose of 10 mg/kg the serum concentrati on varied very much in each individual, being detectable till 8 hours and the peak level was 0. 5 mcg/ml at one h o u r on the average.
6. Urinary excretion showed also great variations, and there was no definite tendency. The peak values of tissue level ranked in the order as kidney, liver, lung and spleen, each exceeding serum, level.
7. The same kind of experiments using rats and mice showed similar pattern of DOTC distribution.
8. The values of various organ level following oral administration of TC in dose of 50 mg/kg to mice were comparable to that of DOTC 10 mg/kg.
9. On clinical applications, serum level taken a t the fixed time on successive days was maintained fairly high and urinary excretion in the urine collected each 24 hours was high as well. Fecal concentra t i o n ranged from 20 to 200 mcg/g.

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The results obtained are as follows:
1. Sensitivity
The sensitivity of coagulase-positive Staphylococcus which was highly resistant to methacycline and tetracycline was excellent.
There was no s ignificant difference of sensitivity of Escherichia coli for doxycycline, methacycline and tetracycline.
2. Blood level
With oral administration of doxycycline in a dose of 200 mg the blood concentration reached to the maximum level of 1. 13 mcg/ml after 6 hours in normal subjects. Blood level was 0. 33 mcg/ml after 24 hours. Half-life was 134 hours. In chronic renal failure higher blood concentration was maintained for long time. Continuous administration was thought to be dangerous in such case.
3. Tissue concentration With intrave nous administration of drug in a dose of 30 mg/kg to mouse the tissue concentration was found to be high in liver and kidney. In comparison with oxytetracycline the time for maximum concentration and disappearance was longer.
4. Distribution of doxycycline in mouse
The distribution of doxycycline was observed by the method of fluorescence. Specific fluorescence was found on renal tubular epithelia, hepatic cell and glandular epithelia of stomach. Chelate phenomenon with calcium was observed. The possibility of deposition of drug was discussed.
5. Clinical data
Nineteen case s were effective among 25 cases. Minimal gastro-intestinal disturbance was observed in 7 cases.

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The sensitivities of 50 strains of Staph. aureus to doxycycline, 14 strains of Strept. hemolyticus and 10 strains of Strept. viridans were, measured by the plate dilution method. The MIC to these gram positive cocci was superior than that of TC.
The sensitivities to gram negative bacilli was almost equal to that of TC.
Blood levels and urinary recoveries following an oral administration of 200 mg of DOTC were measured by diffusion method. The maximum blood levels were obtained at three hours after oral administration and the average blood level was 2. 7 mcg/ml. Effective blood levels were retained for 24 hours.
The urinary recoveries were average 24. 7 mg (12. 4 %) in 48 hours.
The binding rate to serum protein measured by ultracentrifuge method was more than 90 %.
Clinical effect: 12 patients of respiratory infections, 2 patients of pyelonephritis and 1 patient of cholecystitis were treated by DOTC and 8 out of 15 patients were improved by the treatment.

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Laboratory and clinical studies on doxycycline gave the following results:
1) Hemolytic streptococcus and Staphylococcus aureus were 2∼4 times m ore sensitive to DOTC than to TC as determined by their M. I. C. E. coli and Klebsiella also showed a similar tendency against these antibiotics though less marked than the gram (+) cocci.
2) The peak of blood level of the drug in pateints wa s attained 3 to 6 hours after the oral administration. The maximun value was about 1 to 2 mcg/ml for 100 mg dose, 1. 5 to 2. 5 mcg for 200 mg. The high blood level was long lasting and the concentration was 0. 5 to 0. 7 mcg/ml in the former and 0. 5 to 1. 5 mcg/ml in the latter at 12 hours after the administration.
3) The antibiotic gave a fairly good effect against a variety of infections in the clinic of internal medicine. About one fourth of cases complained of gastric disturbances after oral application.

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Doxycycline (DOTC), a new derivative of tetracycline (TC), was tested against 50 strains of Staphylococcus aureus (coagulase positive) and was found to be more effective than TC.
Nineteen strains of TC resistant organisms (MIC ≥100 mcg/ml) were suppressed by less than 12. 5-. ' 25 mcg/m1 of DOTC. Five strains were inhibited between 0. 4 and 0. 8 mcg/ml.
DOTC also exhibited greater in vitro activity than TC against 50 strains of E. coli isolated from the patients.
DO TC produced and sustained higher serum levels after oral administration of 100 mg than TC. This appeared adequate for treatment of most infections due to susceptible microorganisms.
DOTC was administered 100-200 mg daily for 6-20 days orally to 11 pat ients.
Six patients responded clinically and / or bacteriologically to treatment: the diagnosis were 7 cases of respiratory infection including acute pneumonia, chronic bronchitis and infectious asthma, 2 cases of acute cholecystitis and 2 cases of pyelonephritis in acute and chronic phase.
Response of 2 cases were unsatisfactory.
DOTC was well tolerated. No side effect was seen.
It was concluded that DOTC has the advantag e as improved TC of once-daily administration, which is therapeutically effective.

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Doxycycline was administered to 23 patients with serious infectious diseases.
Results were as follows:
1) Twenty-three- patients were bronchopneumonia, chronic bronchitis, follicular tonsillitis, biliary infection, pyelonephritis, cystitis and bacillary dysentery.
2) Doxycycline was given 200mg initially th en 100mg daily per os.
3) Efficacy of doxycycline was good in 18, fair in 2, not effective in 1 and undetermined in 1.
4) M. I. C. of doxycycline to 15 strains of E. coli was determined resulting in superior bacterio cidal action of doxycycline to presently available other TC. It was not effective to pyocyaneus which was same as other TC.
M. I. C. to 5 strains of coagulase-positive staphylococcus was superior to other presently available TC.
5) No serious untoward effects were noted such as elevation of GOT, GPT, NPN and BUN.

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1. The minimal inhibitory concentration of doxycycline (DOTC) was measured by plate dilution method on bacilli and cocci isolated from tracheal sputa, bile juice, blood and other clinical substances, in comparison with tetracycline (TC), demethylchlortetracycline (DMC-TC) and methacycline (MC). On aerobic-cocci and anaerobes, minimal inhibitory concentration of DO TC was lower than that of TC, but was about the same as that of DMC-TC.
2. On anerobic bacilli, there was no differences in M. I. C. among the four drugs.
3. Some strains of E. coli and gram-negative bacilli showed cross-resistance b etween DOTC and other tetracycline drugs.
4. In clinical applications of DOTC, 8 out of 14 cases obtained effective results.
5. As the side effects, nausea was observed in only one case, and no other significant one was observed.

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The following results were obtained in studies on DOTC:
1) The antibacterial activity of DOTC is 2∼32 tim es stronger than that of TC against staphylococci, while the antibiotic has almost equal activity against gram (-) rods.
2) A single oral administration of 200 mg of DOTC produced a blood level of about 2 mcg/ml 4 hours later, and the blood concentration at 24 hours is still at the level of 0. 46 mcg/ml, suggesting its long acting property. Two hundreds mg of first dose followed by subsequent 100 mg doses given every 24 hours produced no accumulation, about 25 % being excreted into urine within 24 hours after single administration.

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1) In in vitro studies, DOTC was more effective than TC against staphylococci and E. coll.
2) By oral administration of DOTC to rats, tissue concentrations were five times or more higher than that of TC.
3) By intravenous administration of DOTC to rabbits, bile concentrations were higher than serum concentrations.
4) Serum concentrations of DOTC in man by oral administration of a single dose of 200 mg, showed as follows; maximum concentration was 1. 4 mcg/m1 after 2 hours. Serum concentration after 25 hours was 0. 5 mcg/ml and after 49 hours was 0. 3 mcg/ml. Urinary recovery rate after 24 hours was 31 %, and after 48 hours was
59 %Absorption rate of DOTC was not impaired by the ingestion of food.
5) We used DOTC for two cases, atypical pneumonia and cystitis, and good results were obtained.

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The clinical therapeutic effect of doxycycline on respiratory, urinary and other infections was studied by us. The result was summarized as follows.
1. Doxycycline was administered ora lly just after the breakfast in the single daily dosis of 100 mg to the 19 patients of respiratory infection, 9 patients of urinary infection and 2 patients with purulent skin lesion.
By doxycycline treatment good clinical result was gained in the subjective and objective symptoms and clinical examination.
2. Except one case complained of nausea, any side effect was found neither in the clinical symptoms nor in the clinical examination.
3. From above d escribed results we considered doxycycline as an effective new antibiotic with small dosis and without remarkable side effect.

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The results of studies on doxycycline (DOTC) are summarized as follows:
1. The sensitivity of 48 strains of Staphylococcus aureus, isolated from patients, to DOTC was measured by the plate dilution method. Thirty five of these strains were inhibited by less than 0. 8 mcg/ml in MIC. Thirteen strains were resistant to DOTC.
2. Blood levels of DOTC in patients reached maximum at 6 hours after oral administration of each 200 mg of the drug, ranging from 0. 78 to 1. 3 mcg/m1 and remained even as much as 0. 46 mcg / ml 24 hours later.
3. Therapeutic studies of DOTC in infected mice with Staphylococcus aureus showed more effective, compared with tetracycline.
4. Eight of 10 patients treated with DOTC obtained effective results.
No significant side effects were observed in all cases.

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Fundamental and clinical studies on doxycycline (DOTC) in the field of pediatrics were performed and results were summarized as follows:
1) The MICs of DOTC against coagu lase-positive staphylococci isolated from acute respiratory tract infections, were lower than those of other tetracyclines (TC). But it was assumed that the highly resistant strains to other TC had also cross-resistance to DOTC, and the highly resistant strains were observed very frequently.
2) Single o ral dose of 5 and 2 mg/kg produced a maximum level of 8. 5 and 2. 3 mcg/ml on the average 2 hours later, respectively. The blood level after 24 hours was still maintained at the level of 0. 34 and 0. 2 mcg/ml, respectively. By the single oral administration of 2 mg/kg on the first day, followed by 1 mg/kg/day for three successive days, the accumulation of the drug was not observed on and after the next administration. The urinary recovery rate reached to about 30% within 24 hours.
3) The efficacy of DOTC for acute respiratory tract infections in the field of pediatrics, espe cially to mycoplasma infections has well been demonstrated. Its effect was as good as other TC and it was deemed that DOTC was not effective to the infections of highly resistant strains to other TC.
4) The administration of 5-10 mg/kg b. i. d. to children will easily cause the side effe ct as diarrhoea, and the dose should be decreased lower than this dose. Optimal dose was assumed to be between 1 and 2 mg/kg/day, while the study would be pursued furthermore. Disturbance of liver function by the administration of 5-10 mg/kg/day of DOTC has not been observed.

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Clinical investigation on doxycycline, a new long acting TC derivative, has brought forth the following results:
1. Recent clinical isolates of coagulase-positive staphylococci and pathogenic coli-form bacilli showed higher sensitivity to this new derivative than to the known antibiotics of TC series.
2. Blood concentration in children given 4. 0 mg/kg reached its maximum at 6 hours after the administration and remained at a measurable level as long as 20 hours.
3. Chemotherapy of 61 children with various infections except infantile diarrhoea with this antibiotic alone produced significant effect in 90% of the treated patients, especially in acute respiratory infection. The effect on 22 patients of infantile diarrhoea was somewhat less pronounced than on other infections, the effective rate being 68%.
4. The administration schedule in the present study consisted of a single first dose of 4∼7 mg/kg on the first day and subsequent daily dose, given once a day, of about one-half of the first dos.
5. Vomiting in only one case was seen in the treatment of 61 patients except infantile diarrhoea, while adverse effects of vomiting and nausea were seen in the treatment of 22 cases of infantile diarrhoea.

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The present authors have carried out the clinical laboratory examination and investigated the clinical effects in pediatric infections. The sensitivity wa s measured by the plate dilution method with 45 strains of Staph. aureus and 16. strains of E. coli isolated from patients. Doxycycline sensitivity of 37. 9 % of staphylococci was ranged in 0. 39, ∼0. 78 mcg/m1 and of 30. 0% of E. coli in 0. 78∼3. 13 mcg/ml. The activity of doxycycline against staphylococci was rather active than. DMCT and TC, but the activity against E. coli was similar to that of DMCT and TC. Doxycycline was given to 4 children, with a single oral dose of 4 mg per kg of b ody weight. The maximum blood levels were reached at 4∼6 hours respectively after administration. At 24 hours after administration, the blood level was 0. 20∼0. 93 mcg/ml. Doxycycline was effective in 13 of 21 cases of pediatric infections. Two patients were occurred the side effects of nausea an d abdominal pain.

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Doxycycline was effective in 25 cases out of 29 acute infections in pediatric patients and without effect in 4, the effective ratio being 86%. A transient diarrhoea was observed in only 1 case a nd any serious side effect was not noted. Children were willingly to take the syrup preparation of the antibiotic. It was an additional advantage that a small volume of the drug was sufficient.

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Twenty patients and 42 carriers of the bacillary dysentery were treated with doxycycline (DOTC). Daily dose of 100-200 mg in adult was administrated once a day for 5 days. Dosage was double on the first day of administration.
1) Clinical eff ects: Average days after the administration were as follows;
in adult in infant
Remission of fever 1. 2 days 0. 9 days
Normalization of the defecations frequency 2. 9days 3. 1 days
Recovery of stool findings 3. 1days 3. 5days
2) Effects against bacilli discharge: Average days until the bacilli disappeared and % of disappearance of the bacilli are as follows;
Patients adult 2. 7 days 88. 9% (8/9)
infant 2. 6days 61. 5% (8 /13)
Carriers adult 3. 1days84. 4 days (27/32)
infant 3. 3days 61. 5% ( 8/13)
Cases with resistant strains 3. 4 days 66. 7% (32/48)
Cases with sensitive strains 2. 0days 100. 0% (19/19)
Reappearance and continuous discharge of the bacilli were seen in 45. 8% in the cases with resistant strains and 0% in the cases with sensitive strains.
3) Side effects: Nausea and vomiting we re complained in 3. 2%, abdominal distress were 4. 896, but these complaints were slight.
In 5 cases, authors d etected BSP, alkaliphosphatase, cholesterol, globuline reaction and transaminase.. All cases showed no changes. In addition, clinical effects of DOTC against the cases with TC-sensitive strains are better than those of TC before reported. Simple adminitration, once a day, is convenient to use.
4) Laboratory observation; The sensitivity test of Shigella to DOTC and another usually used antibiotics (CP, TC, SM) was carried out in 100 newly isolated strains. The minimal inhibitory concentration (MIC) is as follows;
Cross-resistance between DOTC and TC is as Figure 1.

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The sensitivity of hemolytic streptococci to doxycycline (DOTC) was tested with a result as shown in Table 1, indicating that they were not so sensitive to the antibiotic. Unexpectedly, however, when the antibiotic was administered orally to patients carrying hemolytic streptococci in their pharynges, the positive culture turned into negative as early as 6 to 10 hours after the administration, provided that the cocci were sensitive to tetracycline (TC).
Then, oral application of DOTC was attempted in a daily single dose of 100 m g for 5 days to patients (children) with scarlet fever at acute phase. It was found that the therapeutic effect of DOTC upon scarlet fever depended upon whether the cocci carried by the patient were sensitive or resistant to TC. Although DOTC should not be administered without selection to all patients with scarlet fever in view of the fact that the TC resistant hemolytic streptococci constitute more than 30% of recent isolates from patients in Japan, it should be noted that the antibiotic exerts marked effects on patients infected with sensitive cocci and that the return of positive culture and febrile recurrence were rarely encountered. In addition, oral daily administration of DOTC only in a small single dose provides much convenience for its use.

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Doxycycline, a-6-deoxy-5-oxytetracycline, is prepared by hydrogenation of methacycline. Our clinical and laboratory study on the drug was summarized as follows. Minimal inhibitory concentrations of doxycycline against Staphylococcus aureus 209 P, SmrrH, NEWMAN, TERAJIMA, were all the same and they were 0. 4 mcg/ml, while those of HCI-TC were 0. 4 mcg/ml, 0. 8 mcg/ml, 0. 8 mcg/ml and 1. 5 mcg/ml, respectively. The sensitivity distribution of coagulase-positive Staphylococcus cultured from surgical infections against doxycycline was different from that against HC1-TC, especially those of resistant strains. There were sensitive strains to doxycycline, among the resistant to Hel-TC.
Average serum concentration of doxycycline, when it was given orally in 200 mg as single dose, was 0. 27 mcg/ml after 30 minutes, 1. 50 mcg/ml after 1 hour, 2. 20 mcg/m1 after 2 hours, and we could as say 0. 8 mcg/ml even after 24 hours.
Its maximum serum conc entration was obtained on the end of 2nd hour and was 2. 20 mcg/ml. The urinary concentrations given orally in 200 mg of doxycycline were 2. 5∼7. 0 mcgiml in the first 30 minutes, 13. 0∼19. 0 mcg/m1 30∼60 minutes, 58. 0∼60. 0 mcgiml 1-2 hours, 89. 0∼95. 0 mcg/rnl 2∼4 hou rs, 18. 5∼26. 0 mcginal 6-24 hours. And 24 hours' urinary recovery was 14. 2 %.
Fifty cases of trial surgical infections were treated on trial with oral administration.
The recommended dose was 200 mg or 400 mg on the first day of trea tment and 100 mg or 200 mg daily on the following days.
The results were succe ssful in 66. 0 % of patients and failed in remaining 34. 0 %. Seven patients (14. 0%) complained of nausea, vomiting and abdominal pain after taking the drug.

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Minimum inhibitory concentrations (MIC) of 52 strains of Staphylococcus aureus from surgical infections for DOTC were distributed from 50 to 0. 09 mcg/ml. Forty-four strains (90. 4 %) were inhibited to grow at 0. 39, 0. 19 and 0. 09 mcg/ml. The maximal blood levels of DOTC of 100 and 200 mg orally administered in adult were 1. 4 and 2. 6 mcg/ml respectively at 6th hour, showing the longer-acting tendency than the other tetracyclines.
There were no effects of DOTC on e xperimental staphylococcal subcutaneous infections which were performed by inoculation of 10⁷ and 10⁸ order Staphylococcus aureus on rabbit ears. All the strains isolated from abscesses on 7th day had the same MIC (0. 09 mcg/ml) as those on the inoculation.
Response to DOTC therapy for the patients with surgical infections was considered excellent in 15 cases out of 17, by 200 mg/day on the first day and 100 mg/day on the latter days.
Five cases showed alimentary tract disorders as a side effect of oral DOTC administration The symptoms were abdominal pain, nausea, vomiting, loose bowel and diarrhea, and none of these appeared after taking a cup of water with DOTC capsules.

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1) The maximum blood concentration was 3. 47 mcg/ml in average of 3 cases at 3 hours after single oral administration of 200 mg of DOTC. The blood concentration was still 1. 38 mcg/m1 even at 24 hours after the administration of the antibiotic. Subsequent daily dosage of 100 mg gave the value of 2. 98 and 2. 20 mcg/m1 at 12 hours after the first and second administration, respectively. In average of 3 cases, 16. 5% of orally administered 200 mg of the drug was excreted in urine within 24 hours.
2) The concentration of the drug excreted into pus following oral administration of 200 mg of the drug reached the maximum value somewhat dalayed that of blood level, followed by a parallel reduction with the latter.
3) While Streptococcus isolated from lesions showed 2 to 4 times higher drug sensitivity to DOTC than to TC, no such difference was found with E. coli.
4) DOTC was given to 32 cases of surgical infec tions and effective in 71%. As the main side effect, gastric disturbances such as nausea, vomiting, or abdominal pain were noted in 6 cases.

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From the clinical studies on doxycycline, the following results were obtained.
Among 55 cases of surgical purulent infection treated with doxycycline orally, the clinically effective results were obtained in 81. 8%, no disturbances of haematopoietic, renal and hepatic functions were caused, and the isolated gram-positive cocci were known to be highly sensitive to doxycycline in 100% by the disc sensitivity test, while it was revealed by the disc test that gram-positive cocci, especially Staphylococcus. aureus, isolated in our hospital during a period from May to October 1968, were highly sensitive to doxycycline in 93∼100%.

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1) Two-hundreds mg of DOTC was given orally to 14 healthy persons. The peak of blood concentration, 2. 97 mcg/ml (cup method) or 3. 25 mcg/ml (agar diffusion method), was observed at 3-4 hours after administration followed by gradual decrease. The concentration of 0. 07 mcg/ml (diffusion_ method) still remained even 72 hours after administration.
2) The total amount of DOTC excreted in urine within 24 hours after a single oral administration of 200 mg was 43. 8 mg (cup method) or 47. 5 mg (diffusion method) in average, corresponding to 21. 9iand 23. 8%, respectively.
3) The a ntibacterial activity of DOTC was tested against 38 strains of Staph. aureus, 37 of E. coli, 55 of Ps. aeruginosa, 27 of Pr. vulgaris and 27 of Klebsiella. The result showed that the staphylococci were more sensitive to DOTC than to TC while others showed roughly equal sensitivity to both antibiotics.
4) Clinical studies of DOTC with 33 cases of surgical infections treated in our clinic during the period from Nov. 1967 to April 1968 revealed that it was effective in 27 cases (81. 8 %) and without effect in 6. The effect of DOTC on staphylococcal infection was most pronounced. It was effective in 15 out of 16 cases and without effect in only 1.
5) When DOTC was given before meal, 6 pat ients out of 11 complained of gastric disturbances, such as nausea, vomiting, and gastric pain. When taken after meal, however, vomiting was seen in only 2 out of 57 pati ents and milk regurgitation in 1. None of 18 patients given DOTC showed any abnormality in tests for renal and hepatic functions and on examination of blood smear.

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Doxycycline chemically known as a-6-deoxyoxytetracycline was administrated orally, to 26 patients with a surgical infection in our surgical clinic and the observation on clinical effects as well as basic experiments were performed.
We obtained the following results.
This drug was proved to be most effective in 5 out of 26 cases and moderately effective in 19 cases, and not effective in 2 cases. Only the minimal side effects in the alimentary tract were noted and no disturbances of the hepatic or renal functions were found.
This drug showed higher levels in blood and billiary excretion and kept an effective serum concentration for longer period by the oral administration in comparison with other analogous drugs.

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On a new antibiotic, doxycycline, we performed laboratory and clinical studies in the orthopedic infectious diseases. With 123 strains of Staph. aureus isolated from the patients of osteomyelitis, the sensitivities to DOTC and TC were measured by the plate dilution method. The former, the peaks of MIC being 0. 39 and 25 mcg/ml, was better in 2∼4 geometric titers than the latter.
Blood and pus levels following an oral administration of 100 mg kept in effe ctive levels for so many long time over 24 hours.
DOTC administere d to 14 cases in our clinic, at the first day in a dose of 200 mg, from the next 100 mg daily for 3 to 14 weeks was found to be more effective. Effective in 11 cases, fair in 1 and ineffective in 2 were observed.
As for the side effec t of DOTC, slight gastroenteric disturbance was observed in only one case and no other complications were found in all cases.

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It is well known that the tetracycline (TC) and TC-derivatives accumulate in the mineralizing bone tissue. This effect has been utilized as TC labelling of the osseous tissue. However, this may cause the disagreeable yellow pigmentation of the bone and teeth after administrating clinically the antibiotics. Doxycycline offered from Pfizer Taito Co., is a new tetracycline derivative. In the present study, we examined experimentally the binding of doxycycline to bone, and studied clinically the effect of the drug in the infectious diseases of bone and joint. Less staining ability was confirmed in young rats administered intra peritoneally doxycycline than those receiving an equivalent dosage of oxytetracycline and demethylchlortetracycline. To check if there might be the difference also in vitro, af ter shaking each TC with tribasic calcium phosphate and the human cortical bone powder, the residual supernatant TC and the adsorbed TC in precipitate were measured by ultraviolet resorption at 380-370 mg and fluorometry at 510 mp. The percentage of TC fixed to calcium phosphate and the powdered bone were lower in doxycycline than others. Clinical use: Our cases administered doxycycline were 17; subacute or chronic pyogenic osteomyelitis 5, secondary osteomyelitis after open fracture 4, purulent arthritis 2, and the infection of the soft tissue 6. All p atients were administered orally 200 mg of the drug on the first day, followed by 100 mg daily, and some were given the combined surgical treatment. It is concluded from our results that doxycy cline is a satisfactory effective antibiotic to the infectious bone and joint diseases, moreover that it may be safe TC-derivative in a viewpoint of less staining of bone and teeth.

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1. Absorption and excretion of doxycycline
The blood concentration was de termined with 3 healthy adults orally given 200 mg of the antibiotic. Blood samples were drawn 1, 2, 4, 6, 8 and 12 hours after the administration and their drug concentrations were measured by diffusion tests in tubes. The average values of 3 individuals were 0. 85, 1. 28, 1. 19, 0. 99, 0. 85, and 0. 70 mcg/m1 at 1, 2, 4, 6, 8, and 12 hours, respectively. Eight andhalf per cent (mean value) of the amount administered was excreted in the urine. Moreover, detectable amounts of the antibiotic were also found in umbilical cord sera, genital excretion, and milk.
2. Antibacterial activity
MICs against 25 clinical isolates of coagulase (±) Staphylococcus aureus, 12 strains of E. coil, 11 strains of Klebsiella, Proteus and other gram (-) rods were determined by 2 fold dilution tests on heart infusion agar plates. The value for staphylococci was 0. 32 mcg/ml or less and distributed over the range between 0. 39 and 25 mcg/ml. The antibiotic was also active to 10 to 13 strains that were 330 CHEMOTHERAPY MAR. 1969 highly resistant to TC (100 mcg/m1 of MOTC or DMCT).
3. Therapeutic effects
The antibiotic was given to 36 cases with various infections including intrapelvic infection, gonorrhoea, and urinary tract infection and was effective in 28 cases among them (77. 8%).

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1) In vitro MICs of doxycycline against TC-resistant staphylococci, E. coli, and Pseudomonas were fairly low as compared with TC. But, almost same value was obtained against Proteus and Alkaligenes faecalis strains.
2) The concentra t ion of the antibiotic was higher in the blood of umbilical cord than in maternal blood.
3) The amounts of the antibiotic excreted in milk and amniotic fluid were smaller than those of other antibiotics.
4) No pigmentation of foetus bone was found as far as known from the observation of 3 cases at 8∼9th week of pregnancy who had received 200 mg of DOTC daily for 3∼5 days.
5) Good results were obtained in patients with general gynecologic in f ections. Only 1 out of 4 patients with post-operative (cervical cancer) pyelonephritis showed favorable response.

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The authors report on the results of the studies conducted on doxycycline, a derivative of tetracycline.
1) Absorption and excretion The antibiotic blood level after a single dose of 200 mg of doxycycline in four patients, determined by the superimposing method, was as follows: 0. 85 mcg/ml at 1 hour, 1. 55 mcgiml at 4 hours, 0. 73 mcg/ ml at 12 hours, and 0. 24 mcg/m1 at 24 hours, the urinary recovery being 22. 7 mg or 11. 4%, in 24 hours.
2) Antibacterial activity The sensitivity of clinical isolates of staphylococci and E. coli to doxycycline and tetracycline, determined by the agar plate method, was as follows: The sensitivity of most of Staphylococcus aureu s 200 strains to tetracycline ranged from 0. 39-0. 78 mcg/ml and from 100∼> 100 mcg/ml while to doxycycline it showed two peaks of 0. 2 mcg/m1 and 12. 5 ∼>100mcg/ml. On the other hand, there was no definite difference observed between tetracycline and doxycycline in the MIC of 50 strains of E. coli
3) Clinical results Doxycycline, 200 mg the first day and 100 mg once daily thereafter, was administered for 4∼12 days to 8 cases with upper and lower urinary tract infections, 10 cases with infection of the appendages, 5 cases with infection of the skin and soft tissue and 8 cases with upper respiratory infection, a total of 31 cases. The results were marked in 1, good in 10, fair in 6, no effect in 10 and unknown in 4.
There was some gastrointestinal disturbance during the antibiotic administration.

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Doxycycline(Vibramycin), synthesized from methacycline in Pfizer Laboratory, has good antibacterial effect and resorption.
This drug was used in the obstetrical and gynecological fields. It is the antibiotic agent in tetracycline series, not only effective for gram positive but also for gram negative bacilli. The range of minimum inhibitory concentration, was from 0. 19-6. 25 mcg/ml to Staphylococcus aureus, isolated from infected foci. Doxycycline is more effective than tetracycline.
Maximum blood concentration reached the peak at 2-4 hours after 100 mg oral administration and by 200 mg also the peak showed 2 hours after. The total urinary excretion in 24 hours was 25. 2 mg and this corresponded to 12. 6% of administered drug.
The level of milk concentration was 60-70% of blood but from 3 rd day, it was over the blood concentration. And concentration in umbilical blood and amnion water were moderately high.
Daily dose was 200 mg in 1st day, and then 100 mg daily. It was effective in 5 out o f 6 cases in. cystitis, 1 out of 3 in urinary infection, and 3 out of 4 in adnexitis.
Clinically, the total effectiveness was about 70%. Side e ffects were the gastrointestinal disorders, for examples, nausea, vomiting, gastralgia, etc. Liver function was not disturbed.

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[in Japanese]

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Antibacterial activity of doxycycline against 170 gram-negative urinary tract pathogens was tested by the plate dilution method and compared to that of tetracycline and oxytetracycline.
Serum level and urinary excretion after a single oral dose of 200 m g were measured, and the urinary excretion decreased in a case with impaired renal function.
And the ratio of the renal tissue level to serum level decreased according to degrees of impaired renal function.
Clinical responses of doxycycline on 13 females with acute cystitis were reported, resulting that excellent response was seen in 8 cases, good in 4 cases and non effective in 1 case.

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Minimal inhibitory concentration of doxycycline was determined by the plate dilution method for Enterobacteriaceae isolated from urinary tract, compared with that of tetracycline. This drug suppressed the growth of the isolates in same or lower concentration as tetracycline in vitro in exception of some strains of Rettgerella.
Almost all or ganisms subjected to be examined here were resistant strains, and the difference of its MIC from tetracycline was so little that it appeared insignificant to compare the both drugs in clinical effectiveness.
It is convenient that the renal clearance is low and rather high serum level is maintained, but it will be less indicable to urinary tract infection because urinary concentration of the drug may not be overlooked in this infection.

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1) The peaks of serum level of doxycycline hydrochloride in normal subjects after oral administration of 200 mg were between 4. 5 and 6. 0 mcg/ml, and those of tetracycline in normal subjects after oral administration of 1, 000 mg were between 1. 7 and 4. 5 mcg/ml.
2) The urinary concentrations of doxycycline hydroc hloride in normal subjects after administration of 200 mg were between 1. 25 and 1. 5 mcg/ml, and those of tetracycline in normal subjects after administration of 1, 000 mg were between 3. 1 and 5. 0 mcg/ml.
3) Effective results were obtained in 76. 5 % of simp le urinary infections.
4) No significant side effect was observed, but nausea, vomiting and loss of appetite were observed in 3 out of 20 cases.

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Basic and clinical studies with DOTC gave the following results:
1) Against staphylococci isolated from urinary tract infection, th ere were 2 peaks in their sensitivity distribution curve to DOTC at 100 and 3. 12, -0. 78 mcg/ml, indicating about 2 ? 4 times higher sensitivity of these strains to DOTC than to TC. E. coli showed similar sensitivity to DOTC as TC..
2) Blood level and urinary excretion of DOTC: The maximum blood level after a single a dministration of 200 mg of DOTC was 1. 68 mcg/m1 at) hours after which the blood concentration decreased gradually, but still remained above the effective level even at 24 hours after its administration. The urinary excretion of DOTC was 20 to 40 96, being fairly high as compared with TC.
3) Clinical observation: DOTC was a dministered to 24 patients with urinary tract infections. It was markedly effective in 11 cases, effective in 4, and without effect in 9, the effective rate being 62. 5 96.
4) Side effects: Three cas es among 24 complained of unpleasant feeling in stomach.

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Doxycycline(Vibramycin): (each capsule contains 100 mg potency) was orally administered in order to determine its blood and urine concentrations. Then the drug was given to 34 patients with various urological infections to evaluate the clinical effectiveness.
The results are summarized as follows.
1. After oral administration of doxycycline 100 mg, the blood concentration reached to the peak (0. 83 mcg/ml) in 4 hours, and the blood concentration after 24 hours was 0. 22 mcg/ml.
2. After oral administration of doxycycline 100 mg, the urinary concentration was the highest during 6 to 8 hours.
3. In 34 patients with various urological infections who were treated with doxycycline, excellent, marked and no effects were obtained in 7, 17 and 10 cases respectively, with the effectiveness being 69. 1%. 4. The most remarkable effect was observed in acute cases, although some effects were expectable even in chronic cases.
5. The drug was most effective against Staphylococcal infections. The effectiveness against E. coil infection was recorded as 72. 4% which was also remarkable.

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DOTC was studied experimentally and clinically, and the following data were obtained.
1) The MIC value of DOTC to 41 strains of pathogenic organisms was almost the same with that of TC except to 6 strains of E. coli and to 1 strain of Pseudomonas.
2) The concentration in the blood and urinary exc retion of DOTC were studied after an oral administration of 200 mg of DOTC. The former reached to 3. 1 mcg/ml the highest after 2 hours, and decreased gradually until' 24 hours, and the latter excreted 20. 1 % of administered drug in urine within 24 hours.
3) DOTC was clinically applied to 13 cases of simple cystitis and 22 cases of complex cystitis by three methods of administrations: A is initially 200 mg and successively 100 mg, B consists of 100 mg every day and C 100 mg every 12 hours.
4) Three methods gave a remark able effect in the treatment of simple cystitis, but the ineffective cases of 59. 1 96 were experienced in complex cystitis.
5) DOTC is recommendable especially in th e treatment of E. coli, Klebsiella, and each cocci, but not in Proteus, Pseudomonas, Paracoli infections.
6) No significant side effect was obse rved.

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1) Antimicrobial activities of both Doxycycline (DOTC) and tetracycline (TC) were studied by the plate dilution method to determine the minimum inhibitory concentration (MIC) against 130 strains of Staphylococcus aureus isolated from pyoderma cases. The results are shown below. It is quite clear that DOTC has a much stronger antibiotic action than TC.
2) With regard to the relation between MIC and phage typing, of the tested 130 strains of Staphylococcus aureus, in 36. 6% of the group I cases (including strain 81 case) the MIC of DO TC was 0. 39-0. 78 mcg/ml and in 51. 2% it was 25-50 mcg/ml. In group II, in 83. 8% the MIC was 0. 3 9? 0. 78 m cg/ml and in group III the results were not clear, because of the limited number of st r a ins. The MIC against the strains which could not be classified into one group were varied.
3) Doxycycline was administered to 10 cases comprised of 6 cases of furuncle and 1 case each of furunculosis, carbuncle, folliculitis and panaritium. The doses administered were 200 mg100 mg daily for the first day and followed by 100 mg per day from the second day. The marked effect was demonstrated in 80 per cent and fair effect in 10 per cent.

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