One hundred ninety-eight patients with severe infections associated with hematopoietic disorders were treated with imipenem/cilastatin sodium (IPM/CS), and the efficacy and safety of the drug were evaluated. The results obtained are summarized below.
1. Out of 182 patients in whom efficacies are evaluable, responses were excellent in 50 patients, good in 52, fair in 21 and poor in 59, and the efficacy rating was 56.0%.
2. The efficacy rating in 87 patients who had failed to respond to prior treatment with other antibiotics was 58.6%.
3. There were significant differences in efficacy ratings when patients were grouped according to differences the number of neutrophils after treatment, less than 100, 101,500 and over 501/mm³.
4. The eradication rate in 38 patients from whom causative organisms were isolated was 75.8%.
5. Out of 197 patients in whom the safety was evaluable, side effects were observed in 19 patients (9.6%) and abnormal laboratory test values in 15 (7.6%).

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Pharmacokinetic, bacteriological and clinical studies on imipenem/cilastatin sodium (IPM/CS) were performed in neonates. The results were as follow:
1. A total of 27 patients consisting of 17 mature and 10 immature infants were treated with IPM/CS. Each dose was 20mg/20mg/kg, and it was administered 2-3 times daily, in a 1-hour intravenous drip infusion for 3-12 days. The clinical efficacy of IPM/CS in 10 patients with bacterial infections (2 with sepsis, 3 with suspected sepsis, 2 with pneumonia, 2 with urinary tract infection and 1 with acute omphalitis) was evaluated as excellent in all patients, with an efficacy rate of 100%. All 5 causative organisms found in 5 patients (Staphylococcus aureus in 1, Staphylococcus epidermidis in 1, Escherichia coli in 2 and Flavobacterium meningosepticum in 1) were eradicated. Among 27 patients administered IPM/CS, adverse reactions were observed in 2 patients. These were rash and diarrhea. As for abnormal laboratory test values, elevations of GOT and GPT were observed.
2. MICs of IPM against 14 clinical isolates (S. epidermidis 1, S. aureus 6, Streptococcus agalactiae 4, E. coli 1, Enterobacter cloacae 1 and F. meningosepticum 1) from neonatal patients with bacterial infections were examined. IPM showed good antibacterial activity comparable to that of cefotaxime against S. agalactiae; however, the activity against methicillin-resistant S. aureus was poor.
3. Serum levels of IPM and CS were investigated in a total of 22 patients consisting of 15 mature and 7 immature infants after 20mg/20mg/kg of IPM/CS was administered. IPM and CS produced peak serum levels at the end of the drip infusion. In mature infants, peak serum levels of IPM and CS were 31.8μg/ml (17.1-59.0μg/ml) and 59.9μg/ml (35.6-99.0μg/ml), respectively. In low birth weight infants, these were 25.0μg/ml (16.8-41.8μg/ml) and 55.2μg/ml (33.8-82.4μg/ml), respectively. Half-lives of IPM and CS were 1.0-2.7 hrs. and 0.9-7.4 hrs. in mature infants, and 1.6-3.0 hrs. and 1.3-9.7 hrs. in immature infants, respectively. Generally the longer half-lives were observed in the younger neonates. Serum levels of CS remained higher and half-lives of CS were longer than those of IPM. The pharmacokinetics in neonates were different from those in adults or children.
Based on the above results and the extremely broad spectrum of antibacterial activity of IPM/CS, it is considered that IPM/CS is a promising antibiotic which is usable as a single agent for the primary treatment of severe infections in neonates. However, additional investigations in areas such as the dosage pattern for purulent meningitis and the combination ratio of IPM and CS will be required.

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Pharmacokinetic, bacteriological and clinical studies on imipenem/cilastatin sodium (IPM/CS)were performed in neonates. The results obtained are summarized as follows.
1. Plasma levels and urinary excretion of IPM and CS sodium were determined in 7 neonates with ages between 7 and 26 days (gestation periods were 37 to 41 weeks and birth weights were 2,410 to 3,890g) upon 1 hour drip intravenous infusion of IPM/CS at 10mg/10mg/kg, or 20mg/20mg/kg.
Mean plasma concentrations of IPM reached their peaks at the end of infusion with levels of 12.7±3.0μg/ml for the group given 10mg/10mg/kg, and 19.1±4.1μg/ml for 20mg/20mg/kg. The concentration of IPM in plasma showed a dose-response to the 10mg/10mg/kg and 20mg/20mg/kg dosages. Concentrations decreased with half-lives of 1.87±0.71 hours and 1.97±0.21hours for the low and the high dosages, and plasma levels at 8 hours after administration were0.3±0.1μg/ml and 0.8±0.3μg/ml, respectively. Mean urinary recovery rates in 8 hours afteradministration were 37.6±11.8% and 26.8±17.2% for the low and the high dosages. While, mean plasma concentrations and mean urinary recovery rates of CS were higher than those of IPM, mean plasma half-lives of CS were similar to IPM.
2. IPM/CS was administered to 11 neonatal patients (with ages between 1 and 26 days)of various bacterial infections, and clinical effectiveness, bacteriological efficacy and adverse reactions were evaluated. Clinical efficacies in cases including 7 with acute pneumonia and 1 each with suspected septicemia, intrauterine infection, acute urinary tract infection and periproctal abscess were judged excellent in 10 and good in 1 case, and the efficacy rate was 100%. Causative organisms isolated from these patients included 3 strains of Escherichia coli and 1 strain each of Streptococcus pyogenes, Streptococcus agalactiae Enterococcus faecalis and Haemophilus influenzae. All the organisms were eradicated by IPM/CS, thus the bacteriological eradication rate was 100%.
No adverse reactions were observed, but decreased platelet in 1 patient and increased GOT in 2 patients were found as abnormal laboratory test values. These changes, however were transient, and returned to normal after discontinuation of IPM/CS.
It was concluded that the clinical results of IPM/CS are indicative of excellent efficacy, safety and usefulness of the drug in the treatment of infections in neonates.

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Pharmacokinetic and clinical studies on imipenem/cilastatin sodium (IPM/CS), a β-lactam antibiotic of the carbapenem class and its renal dehydropeptidase-I inhibitor in a 1:1 ratio, were performed in neonates, premature infants and an infant.
IPM/CS was administered intravenously to 4 neonates and 5 premature infants at a dose level of 10mg/kg. Plasma levels and urinary excretion of IPM and CS were determined in 2 neonates and 2 premature infants after 30-minute infusion, and in 2 neonates and 3 premature infants after 1-hour infusion.
Plasma and cerebrospinal fluid (CSF) concentrations of IPM and CS were determined in 2 cases with purulent meningitis with ages of 2 and 26 days and 1 with purulent meningitis/bacteremia with an age of 4 days. The drug was administered to a total of 31 patients with ages between 0 and 30 days, consisting of neonates, premature infants and an infant (24 suffering with various bacterial infections, 5 treated for prophylaxis of infections and 2 treated for aseptic meningitis diagnosed at the completion of therapy) by intravenous drip infusion in a mean daily dose level of 50.1 mg/kg in 2 to 4 divided doses for 9 days on the average.
Clinical efficacy, prophylactic effectiveness and bacteriological response of IPM/CS were evaluated in 29 cases. Adverse effects and abnormal laboratory test results were examined in 31 cases including 2 drop-out cases. The results obtained are summarized as follows.
1. Plasma concentrations of IPM and CS after 30-minute infusion of the drug reached their peaks at the end of administration, and obtained values were 22.4 to 29.0μg/ml for IPM and 26.3 to 34.6μg/ml for CS, thus peak plasma levels of CS were a little higher than IPM. Plasma half-lives of IPM were 1.05 to 2.43 hours, and those of CS were 1.24 to 4.76 hours, and the half-life of CS tended to be longer than that of IPM.
Drug concentrations in plasma after 1-hour infusion of IPM/CS reached their peaks at the end of administration and the levels of CS (25.7 to 32.0μg/ml) were a little higher than those of IPM (20.8 to 23.9μg/ml). Plasma half-lives of IPM were 1.40 to 1.63 hours, whereas those of CS were 1.51 to 2.90 hours. The half-life of CS tended to be longer than IPM.
2. Urinary concentrations of IPM by 30-minute infusion of IPM/CS reached their peaks in the collecting period between 0 and 2 hours in 1 of 4 cases and between 2 and 4 hours in the remaining 3 cases with levels ranging from 183.0 to 993.7μg/ml. Peak concentrations of CS in urine were achieved in the collecting period between of 0 and 2 hours in 1 case, between 2 and 4 hours in 2 cases and between 4 and 6 hours in 1 case with levels ranging from 281.6 to 1,865.9μg/ml. Urinary recovery rates of IPM were 30.8 to 52.2% and those of CS were 63.2 to 99.4% in 8 hours after administration. The urinary recovery rates of CS were higher than those of IPM.
Urinary concentrations of IPM by 1-hour infusion of the drug reached their peaks in the collecting period between 2 and 4 hours in 4 of 5 cases and between 4 and 6 hours in the other case with levels ranging from 260.4 to 618.6μg/ml. Peak concentrations of CS in urine were achieved in the collecting period between 2 and 4 hours in 3 of 5 cases and between 4 and 6 hours in the remaining 2 cases with levels ranging from 302.8 to 553.1μg/ml. No clear differences were observed between the concentrations of IPM and CS. Urinary recovery rates of IPM were 45.7 to 71.6% and those of CS were 61.6 to 66.3% in 8 hours after administration, and the recovery rates of CS tended to be higher than those of IPM.
3. The drug concentration in CSF which was obtained at 10 minutes after completion of a 45-minute infusion of 19.4 mg/kg in a case of purulent meningitis on the 13th day of illness was 0.8μg/ml for IPM. The concentration of CS was below the detection limit. IPM concentration in CSF to that in plasma was 2.3%.

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Susceptibilities of various clinical isolates to ofloxacin (OFLX) and other antibacterial drugs were examined at 128 hospital laboratories in 36 prefectures throughout Japan between April, 1986 and March, 1987. The results were totalized with an emphasis mainly on OFLX and were compared with data obtained in the previous year. In this study, identification and susceptibility tests of the isolates were carried out at each hospital laboratory and the tests were performed according to the 1-dilution or 3-dilution disc method in which susceptibilities are classified into 4 grades: +++, ++, +, and-.
Similarly to the study performed in the previous year, species showing susceptibilities to OFLX included Staphylococcus aureus (4,205 strains), Staphylococcus epidermidis (2,009 strains), Entercoccus faecalis (1,697 strains), Streptococcus pneumoniae (702 strains), Escherichia coli (4,097 strains), Klebsiella pneumoniae (1,375 strains), Enterobacter cloacae (762 strains), Enterobacter aerogenes (296 strains), Citrobacter freundii (406 strains), Proteus mirabilis (613 strains), Morganella morganii (320 strains), Serratia marcescens (869 strains), Haemophilus influenzae (1,282 strains), Pseudomonas aeruginosa (4,206 strains), Acinetobacter calcoaceticus (351 strains), Acinetobacter sp.(415 strains), and Campylobacter jejuni (151 strains). Neisseria gonorrhoeae (26 strains) were exceptional due to their smaller number this time than that of the previous year and only the susceptibility to OFLX was investigated with this species. As results, OFLX showed strong antibacterial activities (similar to the previous year) against S. aureus, S. epidermidis, N. gonorrhoeae, E. coli, K. pneumoniae, E. cloacae, E. aerogenes, C. freundii, P. mirabilis, M. morganii, H. influenzae, A. calcoaceticus, Acinetobacter sp., and C. jejuni. However, when these susceptibilities shown in the present study were compared to those obtained in the previous year, many species showed decreases in the occurrence of +++ or increases in-, though they were rathersmall changes.
The following species were not totalized in the previous year due to their low numbers but were summarized in combination with those examined in this study: Streptococcus pyogenes (944 strains), Streptococcus agalactiae (815 strains), Enterococcus faecium (146 strains), Branhamella catarrhalis (135 strains), Citrobacter diversus (128 strains), Klebsiella oxytoca (873 strains), Proteus vulgaris (438 strains), Serratia liquefaciens (266 strains), Pseudomonas cepacia (433 strains), Pseudomonas putida (154 strains), Xanthomonas maltophilia (272 strains), Vibrio parahaemolyticus (120 strains), Bacteroides fragilis (98 strains), and Bacteroides sp.(279 strains). As results, OFLX showed strong antibacterial activities against B. catarrhalis, K. oxytoca, P. vulgaris, C. diversus, S. liquefaciens, and V. parahaemolyticus.
Susceptibilities of the main species to OFLX were compared with the proportion (in %) of+++ as the index for different sampled materials such as sputum, urine, pus and otorrhea to understand susceptibility changes occured for different species from the previous year to this year. It was recognized that many species showed decreases in the proportion of +++.
Consequently, the results show that bacteria resistant to OFLX have appeared following its widespread use and they tended to increase in number.

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In vitro activities of ofloxacin (OFLX), a new quinolone derivative, against 29 strains of Mycoplasma gallisepticum was compared with those of 4 commonly used antimicrobial agents, doxycycline (DOXY), tylosin (TS), spectinomycin (SPCM) and thiamphenicol (TP).
Antimycoplasmal activities of the drugs were evaluated on the MIC (final MIC) and MPC (minimum mycoplasmacidal concentration) values which were determined by a broth dilution procedure.
The following results were obtained.
1: The MIC₉₀s of OFLX and DOXY were both 0.20μg/ml. The MICs of TS were distributed through a wide range (≤0.006-0.78μg/ml), and its MIC₉₀ was 0.78μg/ml. Of 29 M. gallisepticum strains, 27.6% were recognized as TS-resistant. The MIC₉₀ values of SPCM and TP were 1.56μg/mi and 3.13μg/ml, respectively. The MIC₉₀ of OFLX was equal to that of DOXY and 4-to 16-fold smaller than the values of the other 3 antibiotics.2. The MPC of OFLX was the lowest among the antibiotics tested, its MPC₉₀ value was 0.39μg/ml and was followed by DOXY (1.56μg/ml). The MPCs of TS were distributed in a wide range (0.012-3.13μg/ml), and its MPC₉₀ was 3.13μg/ml. The MPC₉₀ values of SPCM and TP were both 6.25μg/ml. Therefore, the mycoplasmacidal activity of OFLX evaluated with MPC₉₀ values was 4-to 16-fold greater than those of the other 4 antibiotics.

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A multi-center open study was conducted to investigate cefodizime (CDZM), a newly developed cephem antibiotic, from pharmacokinetic, bacteriological and clinical aspects, in the pediatric field with the participation of 17 institutions and their related facilities. The results are summarized as follows:
1. Serum concentrations and urinary excretion:
The pharmacokinetics in pediatric patients was investigated with a dose of 20mg/kg, via a bolus intravenous injection or intravenous drip infusion over 30 or 60 minutes. The results were nearly the same as those in adult patients.
Mean serum concentrations 5 minutes after a bolus intravenous injections were: 105.5, 264.0 and 461.7μg/ml with 10, 20 and 40mg/kg, respectively, and T1/2 (β)'s for the 3 dosages were 1.75, 1.92 and 1.88 hours, respectively.
With 30-minute intravenous drip infusion, mean serum concentrations at the end of infusion were: 90.5μg/ml with a dose level of 10mg/kg, 178.3μg/ml with 20mg/kg, and 322.8μg/ml with 40mg/kg, and T 1/2 (β)'s for these dosages were 1.90, 2.15 and 1.93 hours, respectively.
With 60-minute intravenous drip infusion, mean serum concentrations at the end of infusion were: 66.3μg/ml with a dose level of 10mg/kg, 136.0μg/ml with 20mg/kg and 259.2μg/ml with 40mg/kg, and T 1/2 (β)'s for these dosages were 1.43, 2.05 and 1.46 hours, respectively.
In 8 hours after administration of CDZM, urinary excretion rates were 82.1, 77.7 and 76.5% for bolus intravenous injections of 10mg/kg, 20mg/kg and 40mg/kg, respectively, and 83.3, 71.3and 68.1% for 30-minute intravenous drip infusions of 10mg/kg, 20mg/kg and 40mg/kg, and 84.4 and 84.3% for 60-minute intravenous drip infusions of 20mg/kg and 40mg/kg, respectively.
2. Concentrations in cerebrospinal fluid:
Penetrations into cerebrospinal fluid in patients with purulent meningitis reached levels of 1.96-9.48μg/ml with administration of CDZM at 50mg/kg in acute cases within 6 days after onset. The penetration rates of CDZM were about a median range among injectable β-lactamagents.
3. Clinical results:
Of 457 cases treated with CDZM, 53 cases were excluded from the clinical evaluation.
Clinical efficacies were evaluated as “excellent” in 126 and “good” in 78 out of 221 cases from which causative agents were isolated, with an efficacy rate of 92.3%. Efficacies were “excellent” in 97 and “good” in 69 out of 183 cases from which pathogens were not isolated, giving an efficacy rate of 90.7%.
With regard to microbiological effect on pathogens, 213 out of a total of 230 strains isolated as pathogens were eliminated with a high eradication rate of 92.6%.
Among Gram-positive bacteria, 31 out of 32 strains of Streptococcus pneumoniae were successfully eliminated with a high eradication rate of 96.9%. An excellent elimination activity of CDZM was also noted against Streptococcus pyogenes, with all 6 strains of this species were eliminated. On the whole, 64 out of 76 strains of Gram-positive bacteria were eliminated, giving an eradication rate of 84.2%.
For Gram-negative bacteria, the following causative microbes were eliminated including all the strains of Branhamella catarrhalis (15), Escherichia coli (21), Klebsiella pneumoniae (4), Haemophilus influenzae (82) and Proteus mirabilis (4). In total, 149 out of 154 strains of Gram-negative bacteria were eradicated with a very high eradication rate of 96.8%.
The clinical effects of the drug by causative agents were evaluated as “good” or “excellent” in 204 out of 221 cases with an efficacy rate of 92.3%. Noteworthy was the effectiveness of CDZM against mixed infections of 2 or 3 species; the drug was effective in 30 out of 33 cases, the rate being as high as 90.9%.

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Microbiological and pharmacokinetic studies were carried out on flomoxef (FMOX, 6315-S), a new oxacephem parenteral antibiotic, in the ophthalmologic field. The results obtained are summarized as follows.
FMOX has a broad antimicrobial activity spectrum against Gram-positive and Gram-negative bacteria. The MIC distribution against Staphylococcus aureus isolated from clinical cases was≤0.20-≥100μg/ml with the peak value of 0.39μg/ml.
Concentrations of FMOX in aqueous humor and ocular tissues were determined after intravenous injection of 50mg/kg to rabbits.
FMOX showed a peak level of 2.2μg/ml in the aqueous humor at 1/2 hour after administration with the ratio to serum level of 3.4%.
Levels of FMOX in external and internal ocular tissues were 12.7-76.5μg/g, <0.8-34.4μg/g(ml)at 1/2 hour after administmation, respectively.
From these results, we concluded that FMOX may be expected to be a useful and valuable agent against infections in the ophthalmologic field.

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Clinical effectiveness of cefoperazone (CPZ) was studied for 46 elderly patients with respiratory infections.
1. Clinical efficacy rate of CPZ was 80.6% (29/36).
2. Adverse reactions occurred in 2 patients as systemic rush and fever. Laboratoryabnormalities were observed in 5 patients. These included elevation of transaminase value.
3. The serum concentration of CPZ at 12 hours after administration of 2 g CPZ was not reflected in creatinine clearance and total bilirubin, and those 2 values appearedto have little effects on CPZ excretion.
4. The administration of CPZ at 4g/day for less than 3 weeks had no effects on therenal function.
As a result of this study, CPZ was found to have little undesirable effect on renal functions and to be a useful drug for the treatment of respiratory infections in elderly patients.

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Combinations of cefotaxime (CTX) or other five β-lactams with rolitetracycline (RTC) were examined using the checkerboard method for their synergistic effects against 27 strains of methicillin-resistant Staphylococcus aureus (MRSA), and the combination of CTX andRTC was further evaluated for its synergistic effect in vitro and in vivo against 1 or 2 strains. Synergy occurred against 44% of the strains when RTC was combined with CTX, 22 to 30% with cefazolin, methicillin, and ceftizoxime, and 4 to 11% with latamoxef and cefmetazole. No antagonism was found with any combinations tested. Killing curve studies also showed that CTX/RTC was synergistic between 3 and 24 hours after the beginning of exposure, and the synergy was especially strong at 24 hours and potencies of combined bactericidal effect determined at 24 hours were in the following order: the 2 antibiotics given simultaneously, CTX given 2 hours before RTC, and CTX given 2 hours after RTC. In addition, the 2 drugs in combination synergistically inhibited (a) mortality in mice infected intraperitoneally with MRSA and (b) formation of subcutaneous abscess induced by MRSA in mice. The results of our study indicate that β-lactams, especially CTX, had synergistic effects in vitro when combined with RTC against MRSA and that the combination of CTX and RTC was also synergistic in vivo.

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Antimicrobacterial activities of cefteram (CFTM) against clinical isolates collected in 1988 were compared with those of new β-lactams.
1. Antibacterial activities of CFTM against Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Branhamella catarrhalis isolated from acute respiratory tract infections were 8-to 16-fold higher than those of cefaclor (CCL).
2. Activities of cefixime (CFIX) were superior to those of CFTM against B. catarrhalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, but were inferior to CFTM against S. pneumoniae, S. pyogenes, Staphylococcus saprophyticus and Staphylococcus aureus.
3. Activities of cefuroxime were superior to those of CCL against each of the 4 tested bacterial species from acute respiratory tract infection and S. aureus by 4-fold, but were inferior to CFTM and CFIX against most of Gram-negative rods.
4. Sultamicillin (SBTPC) is considered to have an activitity to inhibit β-lactamase, but its MICs did not exceed the MICs of ampicillin by itself. SBTPC showed poor antibacterial activities against methicillin-resistant S. aureus (MRSA).
Considering these observations, it is apparent that we are faced with a variety of factors in selecting antibiotics for best results.

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The clinical effectiveness and safety of roxithromycin (RU 28965, RU), a new macrolide antibiotic, were compared with those of josamycin (JM) using a double-blind method in the treatment of orofacial odontogenic infections.
The diseases covered in this study were periodontal infections, pericoronal infections and osteitis of jaws. Drugs were administered for 3 to 7 days at daily doses of 300 mg (RU) and 1,200mg (JM). A total of 270 cases was evaluated in this study.
Results obtained are summarized as follows:
1. The clinical efficacy was evaluated through the judgement of doctors in charge of 247 cases (128 in the RU group and 119 in the JM group) and by a committee on the 3rd day of treatment in 243 cases (126 in the RU group and 117 in the JM group).
Clinical efficacy rates according to the committee judgement were 78.6% for the RU group and 82.1% for the JM group. As for the evaluation through the doctors' judgement, they were 79.7% for the RU group and 73.1% for the JM group.
There was no significant difference in clinical effectiveness between 2 groups according to these 2 methods of judgement.
2. Some side effects were observed in 4 cases (2.9% out of 136) treated with RU and in 3 cases (2.4% out of 126) treated with JM. No severe symptoms were observed. Abnormal changes in laboratory test values were noted among 7.9% in the RU group and 4.0% in the JM group.
There were no significant differences in their safety between the 2 groups.
3. In terms of clinical usefulness, there were no significant differences between the 2 groups as well.
From these results, it has been concluded that RU (daily dose 300 mg) is as effective as JM (daily dose 1,200 mg) in the treatment of orofacial odontogenic infections.

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