Azithromycin (AZM) in 10% fine granules, a newly developed azalide antibiotic, was administered at a standard dose of 10 mg/kg once daily for 3 to 5 days (89.5% received 3 day administration) to children with infectious diseases and the efficacy and the safety of AZM were investigated. In addition AZM concentrations were determined in blood samples from 18 patients and in urine samples from 17 patients to examine of pharmacokinetic characteristics of AZM.
1. Absorption and excretion: C_max's in 16 patients who received 10 mg/kg and 2 patients who received 20 mg/kg were 0.29±0.24μg/ml and 0.75μg/ml, respectively, while T 1/2's were 42.0±11.8 hours for the former and 51.3 hours for the latter. AUC_0-∞'s were 10.72±5.00μg·hr/ml in the former and 28.83μg·hr/ml in the latter.
Urinary concentrations of AZM peaked at 48 to 72 hours after the administration of 10 mg/kg AZM in 14 patients, while it peaked at 24 to 48 hours in the patients who received 20 mg/kg. Urinary recovery rates in the first 120 hours after the start were 9.1±2.6% for 10 mg/kg and 10.8 ±3.4% for 20mg/kg.
2. Clinical efficacy: The study received 619 entries and 564 cases were evaluated for drug efficacy. The remaining were not evaluated because of dropout or exclusion. The efficacy rate, combining both “Excellent” and “Good” cases was 94.3% in 246 cases where pathogens were identified, classified as Group A. The efficacy rate was 90.7% for the remaining 321 cases, classified as Group B, where causative pathogens were unidentified. The difference between the two groups was no statistical significance. The combined efficacy rate was 92.2%. For the 116 cases where the patients had failed to respond to previous chemotherapies instituted for 3 days or longer, the efficacy rate for AZM was 94.0%.
3. Adverse reactions and abnormal laboratory tests: Incidents of diarrhea, soft stool, skin rashes, or vomiting were found in 15 patients (2.5%) of 596 cases eligible for evaluation. These reactions, however, were all transient and mild to moderate in severity in the 15 patients including 4 patients for whom the treatment was discontinued, all resolved in time. Abnormal changes in laboratory tests were found as follows: decrease in WBC in 23 patients (5.6%), increase in eosinophils in 28 (7.1%), increase in platelet count in 2 (0.5%), decrease in platelet count in 1 (0.3%), elevation of GOT in 3 (0.8%), and elevation of GPT in 6 (1.6%). The abnormalities were transient and did not require particular intervention. Moreover, none of the patients indicated clinical signs associated with the abnormal changes of laboratory tests.
4. Compliance: 614 cases of patients were counted as eligible for evaluation, excluding 14 cases claiming “unknown.” Of 600 cases, 47 (7.8%) claimed that the drug was “very easy to take, ” while 312 (52.0%) reported that the drug was “easy to take.” The cases who reported the drug to be “very easy to take” and “easy to take” combined to be 59.8%, while those who claimed “ordinary” totaled to be 217 (36.2%). In contrast, 18 (3.0%) claimed that AZM fine granules were “difficult to take” and 6 (1.0%) responded that the fine granules were “impossible to take”.
The findings presented above support the conclusion that administration of AZM at a reference dosage of 10 mg/kg, once daily, for 3 days is a useful therapeutic regimen in the treatment of ordinary pediatric infections

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Azithromycin (AZM) in 100 mg capsules, a newly developed azalide antibiotic, was administered at a standard dose of 10 mg/kg once daily for 3 to 5 days (89.9% received 3 day administration) to children with infectious diseases and the efficacy and the safety of AZM were investigated. In addition, AZM concentrations were determined in blood samples from 9 patients and in urine samples from 12 patients to examine pharmacokinetic characteristics of AZM.
1. Absorption and excretion: C. was 0.45±0.28μg/ml, T 1/2 was 52.7±20.2 hours, and AUC0-∞ was 12.09±4.93μghr/ml in the 9 patients each of whom received 8.5 to 14.3 mg/kg AZM. Urinary concentrations of AZM peaked at 48 to 72 hours after the administration of 8.5 to 14.7 mg/kg AZM in 12 patients and the average urinary recovery rate in 120 hours was 7.3±2.8%.
2. Clinical efficacy: The study received 139 entries and 119 cases were evaluated for drug efficacy. The remaining were not evaluated because of dropout or exclusion. The efficacy rate, combining both “Excellent” and “Good” cases, was 100% for 40 cases in which pathogens were identified, classified as Group A. The efficacy rate was 97.5% for the remaining 79 cases, classified as Group B, where causative pathogens were unidentified. The difference between the two groups was no statistical significance. The combined efficacy rate was 98.3%. For the 31 cases where the patients had failed to respond to the previous chemotherapies instituted for 3 days or longer, the efficacy rate for AZM was 93.5%.
3. Adverse reactions and abnormal laboratory tests: 8 incidents of diarrhea, skin rashes, urticaria, or vomiting were found in 7 patients (5.4%) of 130 cases eligible for evaluation. These reactions, however, were all transient and mild to moderate in severity in the 7 patients including 2 patients for whom the treatment was discontinued, all resolved in time. Abnormal changes in laboratory tests were found as follows: decrease in WBC in 10 patients (9.3%), an increase in eosinophils in 12 (11.4%), an increase in platelet count in 1 (1.0%), an elevation of GOT in 3 (3.1%), an elevation of GPT in 6 (6.2%), and an elevation of LDH in 1 (1.1%). The abnormalities were transient and did not require particular intervention. Moreover, none of the patients indicated clinical signs associated with the abnormal changes of laboratory tests.
4. Compliance: In the 134 eligible cases of patients, 9 (6.7%) claimed that the drug was “very easy to take, ” while 75 (56.0%) reported that the drug was “easy to take.” The cases who reported the drug “very easy to take” and “easy to take” combined to be 62.7%, while those who claimed “ordinary” totaled to be 43 (32.1%). In contrast, 6 (4.5%) claimed that AZM capsules were “difficult to take” and one (0.7%) responded that the capsules were “impossible to take”.
The findings presented above support the conclusion that administration of AZM at a reference dosage of 10 mg/kg, once daily, for 3 days is a useful therapeutic regimen in the treatment of ordinary pediatric infections.

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To objectively assess azithromycin (AZM) for its clinical efficacy, safety and usefulness in the treatment of acute odontogenic infections (periodontitis, pericoronitis and osteitis of the jaw), a double-blind, randomized, multi-center trial was conducted in which tosufloxacin tosilate (TFLX) was used as the control drug. AZM was administered to 90 patients at a once-daily 500 mg dose for 3 days, while TFLX was given to 90 patients at a 150 mg t.i.d. dose for 7 days.
1. The clinical efficacy rates calculated according to evaluation at an endpoint set on the 3rd day of treatment by a committee of experts were 85.9% (73/85) in the AZM group and 78.9% (71/90) in the TFLX group. No statistically significant difference between the treatment groups was detected, and clinical equivalence was verified (p=0.002).
2. The clinical efficacy rates according to evaluations made by investigators at the end-of-tail point was 87.1% (74/85) in the AZM group and 73.3% (66/90) in the TFLX group. The efficacy rate in the AZM group was higher than that in the TFLX group, and the difference was statistically significant (p = 0.006).
3. The bacteriological elimination rate in the AZM group was 97.5% (39/40) and that in the TFLX group was 85.7% (30/35), but the difference was deemed statistically not significant.
4. Adverse reactions were observed in 11 of 88 cases (12.5%) in the AZM group and 5 of 90 cases (5.6%) in the TFLX group. Six of 85 cases (7.1%) in the AZM group and 5 of 85 cases (5.9%) in the TFLX group showed laboratory abnormalities. However, neither adverse reactions nor laboratory abnormalities showed any differences in statistical significance between the treatment groups.
5. The safety rates, expressed as percentages of cases with no adverse events and no laboratory abnormalities, was 84.1% (74/88) in the AZM group and 90.0% (81/90) in the TFLX group. The difference between the two groups was found to be statistically insignificant. 6. The usefulness rates, the ratio of cases rated as either “Very useful” or “Useful”, was 83.9% (73/87) in the AZM group, and it was statistically higher (p=0.025) than 72.2% (65/90) obtained for TFLX group.
Judging from the above results, it has been concluded that AZM is as useful as TFLX in the treatment of acute dental infections.

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New macrolide antibiotic, azithromycin (AZM), was administered to six healthy male volunteers and its effects on their intestinal microflora were investigated. Each volunteer was given 500 mg of AZM orally, once a day for 3 consecutive days. Stool samples were obtained from them prior to the medication and 1, 7, 14 and 28 days after the third day of the medication. A slight decrease in the total aerobic bacterial count was observed. Also, several species of anaerobic bacteria showed slight decreases through the 14th day post medication. Individual varian ces were observed, however. A marked decrease in the number of Bifidobacterium was found for each of the volunteers. Clostridium difficile was detected from one of the volunteers on the 28th day post medication without diarrhea related symptoms.

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The frequencies of isolation and susceptibilities to antimicrobial agents were investigated on 1,032 bacterial strains isolated from patients with urinary tract infections in 10 hospitals during the period of June 1989 to May 1990. Of the above total bacterial isolates, Gram-positive bacteria accounted for 30.8% and a majority of them were Enterococcus faecalis. Gram-negative bacteria accounted for 69.2% and most of them were Escherichia coli.
1.Enterococcus faecalis
Imipenem (IPM) sho wed the highest activity against E. faecalis isolated from patients with urinary tract infections. The followings, ampicillin (ABPC) and vancomycin (VCM) showed potent activities, with the MIC₉₀s of 2μg/ml. Piperacillin (PIPC), minocycline (MINO) and chloramphenicol (CP) were also active with the MIC₉₀s of 8 μg/ml. The others were not so active with the MIC₉₀s of 32 μg/ml or above.
2.Staphylococcus aureus
VCM showed the high est activity against S. aureus with the MIC₉₀ of 1μg/ml. Dicloxacillin (MDIPC) and arbekacin (ABK) were active with the MIC₉₀s of 2μg/ml. MINO showed the MIC₉₀ of 4μg/ml. All other agents except ciprofloxacin (CPFX) showed lower activity.
3.Staphylococcus epidermidis
MINO showed the highest activity against S. epidermidis. Its MIC₉₀ was 0.25μg/ml. The followings, ABK and VCM were also active with the MIC₉₀s of 0.5μg/ml, 2μg/ml, respectively. The others except CPFX were not so active.
4. Coagulase-negative staphylococci (CNS)
Most of the agents were active against CNS. IPM, ABK and MINO showed the highest activities with the MIC₉₀s of 0.125μg/ml or below. MDIPC, cefazolin (CEZ), cefotiam (CTM) and VCM were also active with the MIC₉₀s of 1μg/ml. Clindamycin (CLDM) showed lower activity, with the MIC₉₀ of 128μg/ml.
5.Streptococcus agalactiae
CEZ, cefuzonam (CZO N), IPM and CLDM showed the potent activity, all strains were inhibited at the MIC of 0.125μg/ml or below. The followings, cefmenoxime (CMX) and erythromycin (EM) were active with the MIC90s of 0.125μg/ml or below. PIPC and VCM were also active with the MIC₉₀s 0.25μg/ml and 0.5μg/ml, respectively. Amikacin (AMK) showed lower activity.
6.Escherichia coli
IPM, CTM, fl omoxef (FMOX), CMX, carumonam (CRMN), norfloxacin (NFLX), ofloxacin (OFLX) and CPFX showed the highest activities against E. coli. The MIC₉₀s of them were 0.125μg/ml or below. Ceftazidime (CAZ) and CZON were also active with the MIC₉₀s of 0.25μg/mi. Penicillins except mecillinam (MPC) were not so active showing the MIC₉₀s of 32μg/ml or above.
7.Klebsiella pneumoniae
FMOX, CMX, cefixime (CFIX), IPM, CRMN and NFLX showed the highest activities against K. pneumoniae. The MIC90s of them were 0.125μg/ml or below. CZON and OFLX were also active with the MIC₉₀s of 0.25μg/ml. Penicillins except MPC showed lower activities. All other agents were active with the MIC₉₀s of 4μg/ml or below.
8.Enterobacter cloacae
IPM and OFLX showed the highest activities against E. cloacae. The MIC₉₀s of them were 0.25μg/ml. The followings, gentamicin (GM) and NFLX were active with the MIC₉₀s of 0.5μg/ml. Penicillins and cephems generally showed lower activities.
9.Proteus mirabilis
Most of the agents were active against P.mirabilis. Cephems were generally active with the MIC₉₀s in a range of ≤0.125μg/ml-4μg/ml. CRMN, NFLX and CPFX were active with the MIC₉₀s of 0.125μg/ml or below. However MPC and MINO were not so active with the MIC90s of 32 fig/mi.

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Clinical background was investigated on 1, 197 bacterial strains isolated from patients with urinary tract infections (UTIs) in 10 hospitals during the period from June, 1989 to May, 1990.
1. Distribution of sex and age
A majority of female patients with UTIs accounted for a twenties and thirties. The proportion of male patients with UTI has increased with age, accounting for majority in patients 70 years or older.
2. Distribution of infection types and age
Most cases among twenties or thirties w ere uncomplicated UTIs. Fifties and older cases were most frequent in complicated UTIs.
3. Distribution of isolated bacteria and age
Escherichia coli was most frequent on the whole, followed by Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus spp. and Klebsiellaspp. E. coli had declined with age, and on the other hand, E. faecalis and P. aeruginosa had increased with age.
4. Administration of antibiotics and pathogens isol ated from UTIs
In uncomplicated UTIs, pathogens, after administration of an tibiotics, isolated from patients have obviously decreased from 439 to 4. Before an administration of antibiotics, E. coli was mainly detected, but after an administration of antibiotics, E. coli has decreased into two strains. After administration of antibiotics, pathogens of complicated UTIs, without indwelling catheter, have decreased from 324 to 19: E. coli has decleased from 86 to 2, but E. faecalis, Staphylococcus spp., Enterobacter spp. and P. aeruginosa have increased. Pathogens of complicated UTIs with indwelling catheter, have decreased from 156 to 14 after administration of antibiotics, and mainly isolated pathogens were E. faecalis and P.aeruginosa.

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Susceptibilities of Citrobacter spp., Enterobacter spp.,Escherichia coli, Klebsiella spp., Proteus mirabilis, Pseudomonas aeruginosa, Serratia spp. isolated from patients with urinary tract infections (UTIs) in 10 hospitals during June 1989 to May 1990 to various antimicrobial agents were compared with those in the same period of previous years according to a classification, uncomplicated UTIs, complicated UTIs without indwelling catheter, and complicated UTIs with indwelling catheter.
As for Citrobacter spp.,P. mirabilis and Serratia spp., which were detected very few in 1989, their susceptibilities were not observed an obvious change. As for Enterobacter spp., the susceptible strains to flomoxef, cefixime, cefuzonam and ceftazidime increased in complicated UTIs with indwelling catheter. The susceptibilities of E. coli to penicillins increased slightly in complicated UTIs with indwelling catheter. Against Klebsiella spp., a good activity of minocycline or cephems was found. The susceptibilities of P. aeruginosa to ciprofloxacin and new quinolones increased in uncomplicated UTIs.
These data should be considered in clinical treatment of various urinary tract infections.

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A comparison was made for frequencies of isolati on of glucose non-fermentative Gram-negative rods ((G) NF-GNR) from clinical specimens during a period from July, 1986 to June, 1987 (the first period) and that from January, 1994 to December, 1994 (the second period). Also, minimum inhibitory concentrations of principal drugs were determined against these isolates. The obtained results are summarized as follows:
1. Thirty four (34) sp ecies of (G) NF-GNR were found from 35,200 clinical specimens in the two periods. Numbers of strains of (G) NF-GNR obtained were 4,575 during the first period and 4,704 during the second period, thus no significant difference existed in numbers of strains isolated in the two periods.
2. Am ong the 34 species to which the 4,704 strains were classified into, Pseudomonas aeruginosa comprised 68.4%, Stenotrophomonas maltophilia 6.9%, Acinetobacter baumannii 5.6%, Burkholderia cepacia 3.1%,Acinetobacter lwoffii 2.6%, Alcaligenes xylosoxidans subsp. xylosoxidans 2.4%, Flavobacterium indologenes 1.7%, Pseudomonas putida1.1%,Acinetobacter junii 1.1% and Moraxella subgenus Moraxella lacunata 0.9%. When these frequencies of isolation were compared with those in the first period, it was found that B. cepacia decreased significantly (P< 0.01) and that S. maltophilia increased significantly (P< 0.001).
3. MIC determinations revealed multiple drug resistance strains in many different species of bacteria. Minocycline, however, were active against many such strains, and ofloxacin was found to have strong antibacterial activity against some strains.

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We performed the pharmacokinetics of balofloxacin in plasma and intraocular tissues in pigmented rabbits upon its oral administration. The penetrations of balofloxacin into plasma and aqueous humor of the anterior chamber reached their peaks of 6.46μg/ml and 0.70μg/ml, respec tively, and the ratio of drug concentration in aqueous humor to that of plasma was 0.12 at 1 hour after an oral administration of 20 mg/kg. Concentrations in plasma and aqueous humor of the anterior chamber reached 0.27μg/ml and 0.18μg/ml, respectively, at 24 hours after administration.
The T 1/2 (α) and T 1/2 (β) of the drug in aqueous humor were longer than th ose in plasma at a dose of 20 mg/kg.
The concentratio ns in iris and ciliary body were much higher than in any other intraocular tissue in 24 hours after single administration of 20 mg/kg, and those concentrations remained at high levels for a long time.

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