Cefminox (CMNX), one of newly developed cephamycin antibiotics, was administered to 7 cases of diffuse peritonitis associated with infantile acute appendicitis to determine its concentrations in the blood, the appendiceal tissue and the purulent ascites and simultaneously to investigate its clinical efficacy.
CMNX was intravenously injected at a dose of 20 mg/kg (at a maximum amount of 1.0 g/body) before operation and intravenously by bolus injection or by drip infusion twice daily after operation for 3 to 11 days in a total dose of 2.36 to 14.06 g.
Fourteen strains of bacteria were isolated from the purulent ascites: Escherichia coli was isolated from 6 cases but superinfections in 5 cases. MICs of CMNX against these isolated organisms were at or lower than 3.13 μg/ml for 12 out of 14 strains.
CMNX penetrated into the appendiceal tissue and the purulent ascites very well. The concentrations in the pus reached higher than those in the tissue in about 1 hour after administration and were found to reach as high as 9.63 μg/ml in 5 hours after administration.
Its clinical efficacies were excellent in 4 cases, good in 2 cases and poor in 1 case.
No subjective or objective adverse reactions were observed nor any abnormalities were found in laboratory examinations.

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Antimicrobial activities of gentamicin (GM), compared with activities of other aminoglycosides (AGs) and β-lactam antibiotics, were studied against clinical isolates obtained during a period of July-December 1989.
1. GM-resistant strains were noted in 24% of Staphylococcus aureus, 12% of Enterobacter spp., 24% of Serratia marcescens, 7% of Morganella morganii and 26% of Pseudomonas aeruginosa, but no GM-resistant strains were observed among isolates of Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Proteus vulgaris.
2. A majority of GM-resistant strains of S. aureus were methicillin-resistant S. aureus (MRSA) and a large number of GM-resistant strains of Enterobacter spp. was also resistant to new quinolones. GM showed, however, strong antimicrobial activities against new quinolones-resistant strains of S. marcescens, M morganii and P. aeruginosa.
3. Among all the isolates tested of S. marcescens, 24% were GM-resistant, 72% were tobramycin (TOB)-resistant, 86% were dibekacin (DKB)-resistant and 64% were amikacin (AMK)-resistant, hence the incidence of GM-resistant strains was the lowest. This tendency was also observed with P. vulgaris. However, among P. aeruginosa, 26% were GM-resistant, 14% TOBresistant, 18% DKB-resistant and 22% AMK-resistant, thus the incidence rate for GM-resistance was somewhat higher. These results suggest that different AGs-modification enzymes were produced by various clinical isolates under the present condition.
4. Comparing the ratio of GM-resistant strains in the present study with those in 1980 and 1983, the ratio increased among S. aureus, while decreases were observed among Enterobacter spp., S. marcescens, P. vulgaris and P. aeruginosa, indicating that a unilateral tendency of increases in GM-resistant strains did not exisist among clinical isolates over the years.

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Imipenem (IPM) and β-lactams have been reported to possess a synergistic relationship in their activities against methicillin (DMPPC)-resistant strains of Staphylococcus aureus (MRSA).
The purpose of this study was to determine activities of IPM and ampicillin (ABPC) singly and in combination against MRSA.
Activities of the 2 antibiotics against 19 strains of S. aureus resistant to DMPPC were investigated by means of the checkerboard method, the disk diffusion technique and the killing-curve method.
MICs of DMPPC against these strains determined using the agar dilution method were >100 μ9/ml and MICs of IPM and ABPC ranged from 12.5 to 100 μg/ml and from 12.5 to 50 μg/ml, respectively, when used singly.
The following results were obtained with the checkerboard method: Synergistic effects and additive effects were found against 13/19 and against 6/19 strains, respectively, and no antagonistic effect was found according to the FIC (fractionary inhibitory concentration) index.
The disk diffusion technique indicated synergistic results.
Killing-curves with the following drug concentration combinations were examined in MUELLERHINTON broth against 5 fosfomycin (FOM)-resistant and 5 FOM-susceptible stains: (1) IPM 12.5 μg/ml,(2) ABPC 25 μg/ml,(3) IPM 12.5, μg/ml-FABPC 25 μg/ml,(4) IPM 6.25 μg/ml+ABPC25μg/ml,(5) IPM 6.25 μg/ml+ABPC 12.5 μg/ml,(6) IPM 6.25 μg/ml+ABPC 12.5 μg/ml+ FOM (fosfomycin) 25 μg/ml,(7) IPM 12.5 μg/ml+ ABPC 25 μg/ml+ FOM 50 μg/ml,(8) FOM 50 μgml.
The following results were obtained with the killing-curve method;
(1) Synergistic effects were found against 8/10 strains and no antagonistic effect was found with the combinations of IPM and ABPC.
(2) Synergistic effects were found against 3/5 strains and no antagonistic effect was found with the combinations of IPM, ABPC and FOM against 5 FOM-susceptible strains.Conclusions: IPM in combination with ABPC produced synergistic effects against MRSA.
This combination therapy should be evaluated in treating MRSA infections.

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During the period from November1988to May1989, causative bacteria in a total of172 clinical mastitis cases observed in 66 farms in5districts with6areas in Japan were examined and frequencies of their occurrences were determined.
Susceptibilities (in MICs) of the isolates to 6β-lactam antibacterial agents were also determined.
As a result, coagulase-negative staphylococci (CNS) was identified in94out of172cases (54.7%) and were the most prevalent.Corynebacterium spp., Gram-negative bacteria and Staphylococcus aureus were found in52 (30.2%), 49 (28.5%) and43 (25.0%) cases, respectively.Four species of Streptococcus family (S.agalactiae, S.dysgalactiae, S.uberis and S.bovis) were identified in a total of58cases (33.7%).
Susceptibility testing of CNS to cefoperazone (CPZ), cefazolin (CEZ), benzylpenicillin (PCG), ampicillin (ABPC), methicillin (DMPPC) and cloxacillin (MCIPC) showed that all MIC₈₀'s (inhibiting bacterial growth of80%of all isolates) were within a range from0.10to3.13μg/ml and that there was no marked difference in antibacterial effects among the antibiotics used.The highest antibacterial effect on S.aureus was exhibited by MCIPC, which inhibited the growth of all isolates at0.39μg/ml.The MICs of DMPPC against all isolates of S.aureus were3.13μg/ml or less and no methicillin-resistant S.aureus (MRSA) was detected.
There was no difference in antibacterial activities against Streptococccus family between penicillin antibiotics (DMPPC, MCIPC, ABPC and PCG) and cephem antibiotics (CPZ and CEZ), both of which showed excellent antibacterial activities.
Cephem antibiotics exhibited higher activities against Gram-negaive bacteria than penicillin antibiotics.Especially CPZ, the third generation cephem, showed excellent antibacterial activity against Escherichia coli, Klebsiella spp., Enterobacter spp., as well as against other Enterobacteriaceae.

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We studied effectiveness and safety of combination therapy of aztreonam (AZT)(2-6 g/day) and clindamycin (CLDM)(1,200-2,400 mg/day) on severe infections in neutropenic patients with hematological diseases. We administered AZT and CLDM to 250 consecutive patients and analyzed the results of a total of 212 cases for evaluation except 38 cases of exclusions and dropouts.Hematological malignancies constituted the dominating underlying diseases which represented 90.6% of all underlying diseases.
The overall clinical efficacy of the combination therapy with AZT and CLDM was 65.6% and the following results were obtained for different categories: sepsis, 64.7%; suspected sepsis, 66.4%; and pneumonia 54.5%. Even severe patients with less than 100/μ1 of neutrophil counts showed good responses with an efficacy rate at 57.4%. Side effects were observed in only 7 cases (2.8%).
We concluded that the combination therapy with AZT and CLDM would be useful as empiric therapy against various infections in febrile neutropenic patients with hematological diseases.

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We investigated susceptibilities of clinical bacterial isolates to imipenem (IPM) and other antimicrobial agents at 459 hospital laboratories throughout Japan from September to December of 1988. In this study, identification and susceptibility testing were performed at each hospital laboratory and the tests were carried out according to the 1- dilution or 3-dilution disc technique in which susceptibilities are classified into 4 grades: +++, ++, + and-.
IPM had significantly high activity againstStreptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter cloacae, Salmonella spp., Citrobacter freundii, Proteus mirabilis, Providencia rettgeri, Acinetobacter calcoaceticus, Moraxella catarrhalis, Alcaligenes spp., Peptococcus spp./Peptostreptococcus spp., Bacteroides fragilis and Bacteroides spp. and should slightlylower activities on coagulase-negative staphylococci (CNS), Enterococcus faecalis, Haemophilus influenzae, Saluda marcescens, Proteus vulgaris, Providencia stuartii and Pseudomonas aeruginosa than on the above mentioned bacteria.
In a comparative study on activities of IPM against bacteria from different clinical sources, no remarkable differences were found due to different sources among S. pneumoniae, E. faecalis, H.influenzae, E. coli, K. pneumoniae, E. cloacae, C. freundii, P. mirabilis or A. calcoaceticus, whereas slight differences were found among Staphylococcus aureus, CNS, S. marcescens and P. aeruginosa.

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Cefdinir (CFDN) was evaluated for its efficacy and safety. The following results were obtained.
1. Pharmacokinetic study: CFDN was evaluated pharmacokinetically in 4 male children aged 9 to 13. CFDN was given orally to 3 children at a dose of 3 mg/kg. Peak plasma levels of 0.71 μg/ml, 0.78 μg/ml and 0.45 μg/ml were attained in the 3 children, respectively, at 4 hours after dosing. Half-lives of CFDN in serum were 1.78 hours, 1.48 hours and 2.23 hours, respectively. The 12-hour urinary recovery rates of CFDN were 17.4%, 28.1% and 6.2%. When CFDN was given orally to the remaining child at a dose of 6 mg/kg, the peak plasma level was attained at 4 hours after dosing with a level of 1.16 /4/ml. T 1/2 was 1.78 hours. The 12-hour urinary recovery rate of CFDN was 15.0%.
2. Clinical study: CFDN 5 percent fine granules were given to 26 patients with infections; 2 with pneumonia, 4 with acute bronchitis, 1 with chronic bronchitis, 12 with pharyngitis, 4 with scarlet fever, 1 with otitis media and 2 with skin and soft tissue infections. Therapeutic responses were “excellent” in 15, “good” in 8, “fair” in 1 and “poor” in 2, with an efficacy rate of 88.5%.
3. Adverse reactions: As for adverse reactions, diarrhea was noted in 1 patient.
It was concluded that CFDN is a useful drug for the treatment of the bacterial infections in pediatrics.

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A new oral cephem, cefdinir (CFDN) was evaluated for its efficacy, safety and pharmacokineticsin 13 children. The results are summarized as follows.
Plasma concentration peaked at 3-4 hours after administration of 3 mg/kg of CFDN with C_maxranging from 0.57-0.89 μg/ml except 1 case in which the absorption of the drug was poor.Recovery rates in urine averaged at 13.4%, with a large individual variation.
Ten children with 12 bacterial infections were treated with 9 mg/kg/day of CFDN fine granule.Clinical responses were good in 10 patients and fair in 1 patient, with an efficacy rate of 90.9%. No clinical adverse reactions nor abnormal laboratory findings were encountered

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Clinical evaluations of cefdinir (CFDN, FK482) were carried out. The obtained results are summarized as follows.
1. Clinical responses to CFDN of 43 patients with pediatric infections were excellent in 23, good in 15, fair in 4 and poor in 1. The overall efficacy rate was 88%.
2. Bacteriologically, the eradication rate for 34 isolates presumed to be pathogens was evaluated and the eradication rate was 85.3%.
3. Side effects observed were diarrhea in 4 of 48 patients. The incidence was 8.3%. Abnormal laboratory findings were an elevation of GOT, an elevation of eosinophile and an increase in platelet counts.
The results suggested that CFDN might be a very useful and safe drug for the treatment of pediatric infections.

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We performed pharmacokinetic, bacteriological and clinical studies on cefdinir granules (CFDN, FK482), and obtained the results summarized below.
1. Serum levels of CFDN when granular form was given in a single dose of 6 mg/kg before meal peaked at 0.81 μg/ml 6 hours after dosing. The serum half-life of the drug was 2.45 hours.
2. CFDN was administered to 18 patients with bacterial infections which consisted mainly of respiratory tract infections in doses of 1.3-7.4 mg/kg three times daily for 3-9 days. Clinical efficacies were “excellent” in 10 patients, “good” in 7, and “poor” in one, with an overall efficacy rate of 94.4%.
3. As for bacteriological effects on 20 strains of causative organisms, all the 10 strains of Gram-positive organisms were eradicated, with an eradication rate of 100%. Meanwhile, the eradication rate on 10 strains of Gram-negative organisms was 87.5%. Overall, bacteriological effect was “eradicated” in 17 strains, “decreased” in one, and “unknown” in 2, with an eradication rate of 94.4%.
4. No side effects nor abnormal laboratory test values were noted in any of the patients.
We have concluded that cefdinir is useful in the treatment of infection in the pediatric field.

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Cefdinir (CFDN), a newly developed oral cephalosporin in 5% fine granular form, was administered to 10 boys at 1 hour before meal (in the fasting state) and concentrations of the drug in plasma and urine and its urinary recovery rates were determined. The subjects were divided into 2 groups of 5 boys each; one group received 3 mg/kg of CFDN, and the other, 6 mg/kg. To 6 of the 10 children the drug was administered in the two different dose levels using the cross-over method.
To study clinical and bacteriological effects of this drug, a mean dose of 4.6 mg/kg t. i. d. was administered for 8 days on the average to 40 children with various infections; pharyngitis (4 cases), tonsillitis (2), acute bronchitis (2), pneumonia (8), scarlet fever (6), acute purulent otitis media (1), urinary tract infection (12), impetigo (2), phlegmon (1), lymphadenitis (1) and subcutaneous abscess (1). MICs were determined for 6 drugs including CFDN, cefaclor, cefixime (CFIX), methicillin, cloxacillin (MCIPC), amoxicillin (AMPC) against 13 strains of 6 species freshly isolated from children receiving CFDN. An inoculum size of 10⁶ cfu/ml was used in the MIC-determinations.
Adverse reactions and abnormal laboratory findings attributable to this drug were also examined in these patients.
The results obtained are summarized as follows.
1. Mean plasma peak levels of CFDN were observed at 3 hours after administration in both the 3 mg/kg and 6 mg/kg groups with mean peak values of 0.68 and 1.35 μg/ml, respectively. Mean half-lives were 2.06 hours in the 3 mg/kg group and 1.61 hours in the 6 mg/kg group, and mean AUCs were 3.5 in the former and 6.5 μg·hr/ml in the latter. Thus, dose-response between the 2 doses was observed in plasma levels and AUCs.
2. To 3 patients, CFDN was given in the two different doses using the cross-over method. Mean plasma peak levels of CFDN were 0.71 and 1.31 μg/ml in the doses of 3 mg/kg and 6 mg/ kg, respectively. Half-lives were 1.39-2.90 hours in the 3 mg/kg group and 1.21-1.48 hours in the 6 mg/kg group, with AUCs of 3.4-3.7 and 4.1-7.5, μg · hr/ml, respectively. Dose response between the 2 doses was observed in plasma levels in the 3 patients. Dose response in AUC was observed in only one case, however. AUCs in the other two cases were influenced by the difference in half-life values, and no dose response was observed.
3. Mean urinary peak concentrations of CFDN were observed during 4-6 hours after dosing in the 3 mg/kg group and during 2-4 hours in the 6 mg/kg group with values of 67.2 and 149.0 gg/ml, respectively, in cases for which plasma concentrations of the drugs were determined. Dose response between the two doses was observed in urinary concentrations. Mean urinary recovery rates during the first 8 hours after administration in the 3 mg/kg and 6 mg/kg group were 18.4 and 19.3%, respectively.
4. In the 3 patients given the drug using the above-mentioned cross-over method, urinary peak concentrations of CFDN were observed with values of 41.7-67.8, ag/ml in the 3 mg/kg group and 81.5-256 gg/ml in the 6 mg/kg group. Dose-response between the two doses was observed. Mean urinary recovery rates during the first 8 hours after administration in the 3 mg/kg and the 6 mg/kg groups were 17.8 and 19.3%, respectively.
5. Good clinical effects were obtained with an efficacy rate of 90% in 40 patients with 11 diseases due to bacterial infections. Good bacteriological effects were also obtained against 21 strains with an eradication rate of 85.7% (in 1 case, a strain was replaced by other strains).
6. With regard to Gram-positive cocci, MICs of CFDN against 4 freshly isolated strains ofStaphylococcus aureus were lower than those of other drugs tested except MCIPC. MICs of CFDN against 3 freshly isolated strains ofStreptococcus pyogenes were similar to those of AMPC and lower than those of other 4 drugs.

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