Cefodizime (CDZM) possesses a broad antimicrobial spectrum and a relatively long half life in the blood. In addition, it shows excellent therapeutic efficacies in the treatment of infections in leucopenic animal models, hence it is expected that CDZM may have good efficacies against various infections in immunocompromised hosts. In the meantime, sisomicin (SISO) not only has strong antibacterial activities against Gram-negative rods (GNR), but has relatively low nephrotoxicity and ototoxicity. Thus, we examined antibacterial effectiveness of the combination of CDZM and SISO against clinical isolates in vitro.
1. Antibacterial effects of CDZM+SISO combination were examined using SISO susceptible strains of Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus vulgaris, Morganella morganii and Pseudomonas aeruginosa. Observations that the combinatin of the 2 drugs showed FIC indices between < 0.5-< 1.0 against most of these strains at SISO concentrations of 1 MIC or sub MIC levels strongly suggested the presence of a synergistic action between the 2 drugs against SISO susceptible strains of GNR.
2. Of the strains tested, 10% of C. freundii, 6.7% of E. cloacae, 63.3% of S. marcescens, 23.3% of P. vulgaris and 18.0% of P. aeruginosa were found to be resistant to SISO, and little synergistic effect of the 2 drugs was observed against these strains.
3. As the synergistic effect of the 2 drugs against GNR was observed against SISO susceptible strains including those which were resistant to CDZM, but not against those strains which were resistant to SISO, it seems reasonable to conclude that the appearance of the synergistic effect between the 2 drugs depends on the activity of SISO.

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A pharmacokinetic study was performed on cefdinir (CFDN, FK482) 5% fine granules for pediatric use, and pharmacokinetic parameters were calculated.
1. Twenty school children were administered orally a dose level of 3mg/kg of CFDN fine granules either at 30 minutes before meal (14 children) or 30 minutes after meal (6 children). Plasma concentrations and urinary recovery rates of CFDN were measured. T_max, C_max,T 1/2 andurinary recovery rate (0-8 hours) following the administration before meal were 2.00±0.00 hours, 1.14±0.11μg/ml, 1.63±0.14 hours and 23.68±2.92%, respectively, T_max, C_max, T 1/2 and urinary recovery rate following the administration after meal were 3.67±0.33 hours, 0.71±0.06μg/ml, 2.18±0.16 hours and 21.76±2.36%, respectively. Earlier T_max and higher C_max were observed when the drug was administered before meal than when administered after meal. There was no statistically significant difference between the 2 groups in urinary recovery rates. However, statistically significant difference was found between the 2 groups when the cross-over technique was used in 6 school children.
Nineteen younger children (before meal) and 6 younger children (after meal) were administered with the drug in the same way, and several parameters were measured. T_max, C_max, T 1/2 and urinary recovery rate following the administration before meal were 2.11±0.11 hours, 0.98±0.14μg/ml, 1.71±0.23 hours and 23.60±1.72%, respectively, T_max, C_max, T 1/2 and urinary recovery rate following the administration after meal were 3.33±0.42 hours, 0.47±0.14 aug/ml, 2.35±0.27 hours and 12.24±2.02%, respectively. Earlier T_max higher C_max and higher urinary recovery rate were observed when the drug was administered before meal than when administered after meal.
Seven infants (before meal) and 8 infants (after meal) were administered with the drug in the same way, and several parameters were measured. T_max, C_max, and T 1/2 following the administration before meal were 4.00±0.62 hours, 0.61±0.13μg/ml and 3.14±0.62 hours, respectively, T_max, C_max and T 1/2 following the administration after meal were 3.75±0.25 hours, 0.79±0.13mg/ml and 2.44±0.42 hours, respectively. These was no statistically significant difference between the 2 groups.
2. Twenty one school children were administered orally with CFDN fine granules at 30 minutes before meal at a dose level of either 3mg/kg (14 children) or 6mg/kg (7 children). Plasma concentrations and urinary recovery rate of CFDN were measured. C_max and AUC were 1.14±0.11μg/ml and 4.44±0.41μg hr/ml, respectively, at a dose level of 3mg/kg. Cmx and AUC were 1.37±0.23μg/ml and 6.14±0.88μg hr/ml, respectively, at a dose level of 6mg/kg. Doseresponse was observed only in AUC. However, using a cross-over technique in 6 school childern, dose-responses were observed in AUC and C_max.
3. Fourteen school children, 19 younger children and 7 infants were administered orally with CFDN fine granules at 30 minutes before meal at a dose level of 3mg/kg. Plasma concentrations and urinary recovery rate of CFDN were measured. T_max in school children, younger children and infants were 2.00±0.00, 2.11±0.11 and 4.00±0.62 hours, respectively. Delayed T_max were observed in infants compared to the other children. C_max in school children, younger children and infants were 1.14±0.11, 0.98±0.14 and 0.61±0.13μg/ml, respectively. Lower C_max were observed in infants.

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The influence of cefdinir (CFDN), a new oral cephalosporin, on the intestinal bacterial flora was studied in tetra-contaminated mice and in pediatric patients.
CFDN in fine granules was administered at a dose of 10mg/kg once a day for 5 consecutive days to mice contaminated with 4 different species of organism: Escherichia coli, Enterococcus faecalis, Bacteroides fragilis and Bifidobacterium breve. No remarkable changes were observed in the fecal viable cell counts except that decreases in E. coli counts were observed on the day 3 to 5 after starting administration.
The subjects in pediatric study were 7 children with infections, 3 boys and 4 girls, with their ages from 6 months to 12 years 7 months. Their body weights ranged from 5.5 to 29.2kg. CFDN fine granules was administered at each dose of 3.0mg/kg to 3.7mg/kg, 3 times a day for 4 to 14 days. During the administration of CFDN, some variations were observed in the pattern of changes in the fecal bacterial flora between subjects. Although Enterobacteriaceae and total counts of anaerobes were markedly decreased in 2 cases, total counts of aerobes were unchanged in the 2 cases, whereas main aerobes and anaerobes except enterococci hardly varied in the other cases. There was no case in which glucose non-fermenting Gram-negative rods and fungi became predominant species sustainingly. Although Clostridium difficile and C. difficile D-1 antigens were detected in 1 and 4 cases, respectively, no relationship was found between the number of C. difficile and the characteristics of the feces.
With regard to the drug sensitivities of bacteria isolated from feces before and after administration of CFDN, higher levels of resistance were found in some bacteria such as Enterococcus and Bacteroides during or after administration than before administration.
CFDN was detected in fecal samples from 2 cases during administration with concentrations ranging between 0.99-254μg/g. High value of CFDN was found in a case with low β-lactamase activity in feces, in which marked decrease of Enterobacteriaceae and total counts of anaerobes was observed.
The above results suggest that CFDN is considered to be a drug with relatively small influence on the intestinal bacterial flora. But as high concentrations of drugs were detected in feces under some circumstances, our attention will be required. Particular care is also required for the occurrence of diarrhea and microbial replacement during continuous, long-term administration of the drug.

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Bacteriological, pharmacokinetic and clinical studies on cefdinir (CFDN, FK482), a new oral cephalosporin, 5% and 10% granules, were performed in the field of pediatrics. The results are summerized below.
1. Antibacterial activities
Antibacterial activities of CFDN against Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, Escherichia coli and Klebsiella pneumoniae were studied in comparison with those of cefaclor (CCL), cefixime (CFIX) and amoxicillin (AMPC). MIC₈₀'s of CFDN against S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, B. catarrhalis, K. pneumoniae and E. coli were 0.78, 0.20≤0.025, 0.39, 0.10, 0.20 and 0.10 μg/ml, respectively. These results show that CFDN has high antibacterial activities against these organisms. MIC₈₀'s of CFDN against Gram-positive bacteria were similar to those of AMPC, and was lower than those of CCL and CFIX. As for antibacterial activities against Gram-negative bacteria (GNB), the MICgo of CFIX against H. influenzae was 0.05, μg/ml, which was slightly lower than tht of CFDN. The MIC₈₀'s of CFDN against other GNB were similar to those of CFIX.
2. Absorption and excretion
Blood concentrations and urinary excretion rates of CFDN 5% and 10% granules and 100 mg capsule were determined. The data on CFDN 10% granules Were similar to those on CFDN 5% granules. At a dose of 3mg/kg, peak blood concentrations (C_max's) of CFDN ranged from 0.20 to 2.12, μg/ml with 5% granules and from 0.50 to 1.15 μg/ml with 10% granules at 2 to 3 hours after dosing. At a dose of 6mg/kg, peak concentrations were 0.66-2.06 μg/ml and 0.70-1.52 μg/ml with 5% granules and with 10% granules, respectively. At 8 hours after dosing, blood concentrations were 0.04-0.54 μg/ ml at 3mg/kg and 0.06-0.27 μg/ml at 6mg/kg. Blood half-lives were 1.33-4.36 hours at 3 mg/ kg and 1.14-3.27 hours at 6mg/kg. AUC's were 1.7-11.0μg·hr/ml with 3mg/kg and 2.4-8.7 μg·hr/ml with 6mg/kg. With administration of single 100 mg capsule, C_max's, blood concentrations after 8 hours, T 1/2's and AUC's were 0.79-1.88μg/ml, 0.20μg/ml, 1.54-2.72 hours, and 5.2 μg·hr/ml, respectively. Urinary recovery rates in the first 8 hours ranged from 6.85 to 39.2% with 3mg/kg and 6.08-25.5% with 6mg/kg.
3. Clinical study
Clinical efficacies were examined in a total of 76 cases consisting of 9 cases of acute pneumoniae, 11 of bronchitis, 23 of purlent tonsillitis, 15 of scarlet fever, 8 of acute lymphadenitis, 2 of phlegmon, one of subcutaneous abscess, one of impetigo and 6 of UTI. Clinical efficacy rate was 98.7% (74/75), and bacteriological eradication rate was 98.6% (69/70). As for side effects, watery stools and an elevation of GPT were noted.

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Cefdinir (CFDN), a newly developed oral cephalosporin in a 10% fine granular form, was administered to 8 children and concentrations of the drug in plasma and urine and urinary recovery rates of the drug were determined. The subjects were divided into 2 groups of 4 children each; one group received 3mg/kg of CFDN at 1 hour before meal (in the fasting state), and the other, at 30 minutes after meal.
To study clinical and bacteriological effects of this drug, a mean dose of 4.8mg/kg t.i.d. was administered for 8 days on the average to 9 children with various infections; tonsillitis (3 cases), acute bronchitis (1), pneumonia (1), acute purulent otitis media (1), urinary tract infection (2), and impetigo (1). MICs were determined for 6 drugs including CFDN, cefaclor, cefixime (CFIX), methicillin, cloxacillin, amoxicillin (AMPC) against 4 strains 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 children.
The results obtained are summerized as follows.
1. Mean plasma peak levels of CFDN were observed at 2 hours after administration in the before-meal group and 4 or 5 hours after administration in the after-meal group mean peak values of 0.88 and 0.50μg/ml, respectively. Mean half-lives were 1.61 hours in the before-meal group and 2.54 hours in the after-meal group, and mean AUCs were 4.24 in the former and 3.59μg·hr/ml in the latter.
2. Mean urinary peak concentrations of CFDN were observed during 2-4 hours after dosing in the before-meal group and during 6-8 hours in the after-meal group with values of 93.3 and 44.8μg/ml, respectively, in cases for which plasma concentrations of drugs were determined. Mean urinary recovery rates during the first 8 hours after administration in the before-and after-meal groups were 16.6 and 13.4%, respectively.
3. Good clinical effects were obtained with an efficacy rate of 100% in 9 patients with 6 diseases due to bacterial infections.
4. Good bacteriological effects were also obtained against 2 strains of Streptococcus pyogenes, 2 strains of Escherichia coli and 1 strain of Haemophilus influenzae with an eradication rate of 100%. In 3 cases of these and another case (normal flora), strains present before the study were replaced by other strains.
5. MICs of CFDN against 2 freshly isolated strains of S. pyogenes were similar to or higher than those of AMPC and similar to lower than those of the other 4 drugs tested. MICs of CFDN against 2 freshly isolated strains of E. coli were almost the same as those of CFIX and similar to or lower than those of the other 4 drugs.
6. No adverse reaction nor abnormal laboratory finding due to this drug was observed in 9 patients.

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A modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), KW-2228, has some excellent properties such as high specific activity in stimulating granulocyte colonyformation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support its in clinical applications.
Patients with underlying diseases such as leukemia or cancer often have recurrent infections because of reduced number and functions of neutrophils, which mediate an early stage of host defense.
We investigated the prophylactic effect of KW-2228 against an experimental systemic infection with Pseudomonas aeruginosa in tumor-bearing mice (colon 26: BALB/c) treated with cyclophosphamide. KW-2228 (0.25-2.0μg/mouse) was administered (s.c.) once a day for 4 days before the experimental bacterial infection. As a result of KW-2228 administration, the reduction in peripheral blood neutrophils usually caused by the injection with cyclophosphamide was prevented markedly. KW-2228 displayed excellent protective potency dose-dependently against the infection with P. aeruginosa in tumor-bearing mice. These data show the possibility that prophylactic therapy with KW-2228 may augment the host defense of immunocompromised patients to infections.
It present, clinical efficacy studies on KW-2228 are under way.

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KW-2228, a mutationally modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), possesses some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasrna, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support such an application on human infectious deseases.
In this paper, we examined combination effects of KW-2228 with various chemotherapeutic drugs in experimental infections in mice. A combination effect of KW-2228 with ceftazidime (CAZ) was evaluated in a systemic infection with Pseudomonas aeruginosa in normal mice. Combination effects of KW-2228 with CAZ, astromicin and amphotericin B were also evaluated in experimental systemic infections caused by P. aeruginosa, Serratia marcescens and Candida albicans in immunosuppressed mice treated with cyclophosphamide. Synergistic effects were generally observed at KW-2228 doses from 1 to 5μg per mouse with all combinations.
We concluded that combination therapies of KW-2228 with various chemotherapeutic drugs in experimental infections in mice showed that it should be effective in normal and immunosuppresed host. These results of our laboratory studies suggest that KW-2228 in combination with anitibiotics would be useful in the clinical treatment of microbial infections.
Recently, clinical efficacy studies of KW-2228 have been initiated in Japan.

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A modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), KW-2228, has some excellent properties such as high specific activity in stimulating granulocyte colonyformation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support its clinical applications. Patients with underlying diseases such as leukemia and cancer often have recurrent infections because of reduced numbers or functions of neutrophils, which mediate an early stage of host defense.
In out present study, we established a new method to evaluate in vivo potency of G-CSF in colon 26 tumor-bearing mice. By using the method, we examined combination effects of KW-2228 with aminoglycoside antibiotics against a systemic infection caused by Pseudomonas aeruginosa. KW-2228 (1μg/mouse/day) was administered (s.c.) once a day for 4 days before the bacterial infection was introduced in colon 26 tumor-bearing mice receiving cyclophosphamide 3 days after the transplantation of tumor. Antibiotics were administered (s.c.) 2 hours after the introduction of the bacterial infection. ED₅₀ of gentamicin (GM) alone and that of the combination with KW-2228 were 40.7mg/kg and 3.6mg/kg, respectively. ED₅₀ of astromicin (ASTM) alone and that of the combination with KW-2228 were 386mg/kg and 17.8mg/kg, respectively. Thus the combination therapy of KW-2228 with GM or ASTM exhibited excellent protective effects in comparison to the treatment with antibiotic alone.
These results suggest that KW-2228 in combination with aminoglycoside antibiotic would be useful in the protection of immunocomplomised patients against opportunistic infections such as those by P. aeruginosa.

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A modified recombinant human granulocyte colony-stimulating factor (rhG-CSF), KW-2228, has some excellent properties such as high specific activity in stimulating granulocyte colonyformation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo. Recently, the application of G-CSF against infectious diseases has been considered, and some animal experiments have been carried out to support its clinical applications.
In this paper, we investigated protective effects of KW-2228 against systemic infections caused by Klebsiella pneumoniae in mice with leukopenia induced by the administration of cyclophosphamide. KW-2228 (1 μg/mouse) was administered (s. c.) once a day for 4 days following cyclophosphamide administration, then mice were challenged with K. pneumoniae (i. p.) 4 hours after the last administration of KW-2228. An antibiotic was administerd (s. c., p. o.) 2 hours after the bacterial challenge. Combination effects of KW-2228 with cefazoline, cefmetazole, ceftazidime or cefaclor were evaluated in the systemic infection with K. pneumoniae. Each combination therapy using KW-2228 with each of the cephems exhibited an excellent protective effect in comparison to the therapy with a cephem alone. These results show the possibility that KW-2228 could be of use in treating obstinate infections not successfully treated with an antimicrobial agent alone.

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KW-2228 is a novel derivative of a recombinant human granulocyte colony-stimulating factor (rhG-CSF) with a modification. KW-2228 has some excellent properties such as high specific activity in stimulating granulocyte colony-formation in vitro, great biological stability in plasma, good pharmacokinetic profile and high potency in granulopoiesis in normal mice in vivo.
In the present study, we investigated the effect of KW-2228 on phagocytic capacity and killing action of polymorphonuclear neutrophils (PMNs) obtained from normal rats which had been treated with KW-2228 using various microorganisms, such as Candida albicans, Escherichia coli and Pseudomonas aeruginosa. We also investigated the effect of KW-2228 on the production of superoxide anion using a luminol-chemiluminescence method. KW-2228 enhanced the phagocytosis and killing activity of PMNs of rats against C. albicans and E. coli. PMNs treated with KW-2228 showed some bactericidal activity against P. aeruginosa. These data obtained with PMNs treated with KW-2228 show a correlation between the bacterial susceptibility to phagocytosis and killing action and the lunimol-dependent chemiluminescence response. These results suggest the significance and the efficacy of KW-2228 used in an additional therapy to that of antibiotics in the treatment of infections diseases.
KW-2228 is currently in Phase III clinical trials in Japan.

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