This article reviews structure-activity relationships and biological properties of a new oral cephem, cefdinir (CFDN). It also describes a hypothesis concerning the absorption mechanism from the intestine.
Antibacterial activities and the oral absorption efficiencies were studied with regard to 3-vinyl cephalosporins with various 7-acyl side chains. From the study, 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl group was selected and various 3-substituents were screened. As a result, it was found that the vinyl compound, CFDN, showed excellent antibacterial activity and good oral absorption in rats.
In vitro and in vivo antibacterial activities, the affinity for PBPs and the stability to β-lactamases revealed that CFDN had well balanced antimicrobial activities against Gram-positive and Gramnegative bacteria and good biological properties.
The pharmacokinetics of CFDN in healthy volunteers showed that serum concentration and half life were good enough to make CFDN an effective therapeutic agent. The mechanism of intestinal absorption of CFDN and related oral cephems are discussed and a hypothesis for molecular recognition by the carrier protein in the intestine is proposed.

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The pharmacokinetics of 14C-cefepime dihydrochloride (C-CFPM), were studied in rats upon both single and repeated intravenous administration.
1. Blood level of radioactivity was 59.27μg eq./ml at 5 minutes after single intravenous administration at a dose of 20 mg/kg, and declined biexponentially thereafter. The values of AUC and T 1/2 were 70.1μg eq.hr/ml and 38.0 hours, respectively.
2. Blood level of radioactivity was 59.41μg eq./ml at 5 minutes after administration on the 7th day of repeated intravenous administration at a daily dose of 20 mg/kg, and declined more slowly as compared to the case of single administration. The values of AUC and T 1/2 after repeated administration were 159.7μg eq.hr/ml and 44.5 hours, respectively.
3. Urinary and fecal excretion rates after single administration were 93.3% and 3.3%, respectively.
4. Urinary and fecal excretion rates were almost constant throughout the repeated administration; 88.4-90.7% and 2.3-3.7%, respectively.
5. 14C-CFPM distributed rapidly to the whole body except to the central nervous system. Although the radioactivity was removed rapidly from tissues, high levels of radioactivity remained in the kidney and the spleen as compared to other tissues.
6. Tissue concentrations' of radioactivity at 5 minutes after the final dose of repeated administration were about the same as those after single administration but they declined more slowly than those after single administration. High levels of radioactivity were found in the kidney and the spleen as were found upon single administration. The ratios of these levels between repeated and single dosing were 4.3and2.6 for kindney and spleen, respectively.
7.Data obtained with autoradiograms of the whole body were consistent with measured tissue distribution obtained in both cases of single and repeated administration.

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The pharmacokinetics of 14C-cefepime dihydrochloride (14C-CFPM), was studied in dogs after single intravenous administration at a dose of 20 mg/kg. Protein binding was also investigated both in vitro and in vivo.
1. Blood level of radioactivity was 83.53 ug eq./ml at 5 minutes after single intravenous administration, and declined biexponentially thereafter. The values of AUC and T 1/2 were 229 μg eq.hr/ml and 90 hours, respectively.
2. Urinary and fecal excretion rates were 95.1% and 2.7%, respectively.
3. The in vitro protein binding at 1 to 100μg/ml of drug concentration was 7.9 to 12.7% in rat, 12.4 to 18.6% in human, and 12.5 to 14.5% in dog. In vivo protein binding, which increased with time after administration, was 10.8 to 92.9% in rat and 17.5 to 64.9% in dog at 5 minutes to 6 hours.

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Susceptibilities of 117 clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) to aminoglycosides and fluoroquinolones were investigated during 1987 and 1990. Gentamicin, tobramycin, sisomicin, micronomicin, and astromicin showed the bimodal antimicrobial activity pattern against MRSA, revealing cross-resistance to these antibiotics. However, amikacin, netilmicin, isepamicin and arbekacin (ABK) exhibited the monomodal antimicrobial activity pattern, suggesting the presence of less resistant strains. All 117 MRSA strains were susceptible to ABK with MICs less than 3μg/ml. MRSA also showed the bimodal antimicrobial susceptibility pattern to fluoroquinolones such as ofloxacin (OFLX), ciprofloxacin (CPFX) and tosufloxacin (TFLX). Frequencies of TFLX susceptible MRSA isolates decreased progressively from 1987 to 1989 when this drug was not even in general clinical use. The cross-resistance of MRSA between TFLX and OFLX or CPFX persisted. Cross-resistance between aminoglycosides and fluoroquinolones, however, was less frequently observed.

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As arbekacin (ABK) has a highly potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), its combined effects with fosfomycin (FOM) and clavulanic acid/ticarcillin (CVA/TIPC) against MRSA were examined. The obtained results are summarized as follows.
1. Against MRSA either combination, FOM + ABK or CVA/TIPC + ABK showed a strong antibacterial effect at the MIC or the sub MIC of ABK in the blood expected from clinical observations. The MIC of ABK by the combination use seemed to be equivalent to the MBC value.
2. Effective concentrations of antibiotics in these combinations appeared to be strongly dependent on the effective concentration of ABK and less dependent on that of FOM or CVA/TIPC. Therefore, the antibacterial activity of a combination seems to mostly depend on the antibacterial activity and the concentration of ABK.
3. As FOM and CVA/TIPC have antibacterial activities against Pseudomonas aeruginosa, combinations of ABK with these antibiotics are likely to be effective against double infection with P. aeruginosa in MRSA infected patients.

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Combined antibacterial effects of imipenem (IPM) +arbekacin (ABK) and cefminox (CMNX) +ABK against methicillin-resistant Staphylococcus aureus (MRSA) were examined and the obtained results are summarized below.
1. Either combination, IPM+ABK or CMNX+ABK, showed a strong antibacterial effect against MRSA when blood concentration of ABK were sustained at MIC as could be expected in clinical situations. While at sub MICs of ABK the antibacterial effect of these combination was slightly less than those of the previously reported combinations of ABK and other antibiotics.
2. Antibacterial effects of the combinations against MRSA were strongly dependent on the concentration of ABK and less dependent on the concentration of IPM or CMNX. As were observed in the previously tested combinations of ABK with other antibiotics, the antibacterial effect of the combination appeared to be highly dependent on the antibacterial activity and the concentration of ABK.
3. As IPM has potent antibacterial activities against Gram-negative bacteria (GNB) including Pseudomonas aeruginosa while CMNX has potent antibacterial activities against GNB except P. aeruginosa, it is likely that the combinations of IPM+ ABK or CMNX+ ABK are useful for treatment of infections with MRSA together with GNB.

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Antimicrobial activities were examined for major antibacterial agents against clinically isolated microbial strains which were isolated and identified from materials collected from inpatients with various infections in 1988, 1989 and 1990, and the following conclusions were obtained.
1. Among strains isolated each year, methicillin-resistant Staphylococcus aureus (MRSA) were found frequently.
2. CEPs-resistant Escherichia coli strains were observed among strains isolated each year.
3. Increasing tendencies in resistances of Citrobacter freundii, Enterobacter spp., Serratia marcescens to cephems and new quinolones were observed.
4. Increasing tendencies in resistances of Proteus vulgaris to ceftazidime (CAZ) and new quinolones appeared to exist.
5. Among strains isolated each year, resistances of Pseudomonas aeruginosa to CAZ and quinolones were observed in high rates, but also their resistances to imipenem appeared to increase.
6. Many of recently increasing multiple resistant bacteria seem to have different sites of drug action and / or to have non-hydrolytic modes of resistance.

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Minimum inhibitory concentrations (MICs) were determined for major oral antibacterial agents for clinically isolated microbial strains from materials collected from outpatients with respiratory tract infections in 1988, 1989 and 1990, and the following conclusions were obtained.
1. Methicillin-resistant Staphylococcus aureus (MRSA) appeared to be responsible for community-acquired respiratory tract infections, but there also was a tendency showing that MRSA increased year by year.
2. A tendency was observed indicating that benzylpenicillin (PCG)-insensitive Streptococcus pneumoniae (PISP) increased year by year.
3.Beta-lactamase-producing strains of Haemophillus influenzae were observed in a certain ratio, and also those of Branhamella catarrhalis were found in high ratios.
4. A tendency of increasing resistance of Klebsiella pneumoniae to new quinolones was observed.
5. It is of a great importance to evaluate methods of selecting primary choice antibiotic agents since increasing numbers of new oral antibacterial agents are becoming rapidly available.

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To investigate antibacterial activities of sisomicin (SISO), MICs of SISO as well as other aminoglycosides (AGs) were determined against many clinical isolates which were obtained in 1991.
Results are summarized below:
1. No SISO-resistant strains were observed among isolates of Escherichia coli, Citrobacter diversus, Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter aerogenes, Proteus mirabilis and Morganella morganii.
2. In comparison with the results of our previous study against isolates obtained in 1986, the rate of methicillin-resistant Staphylococcus aureus (MRSA) was higher, and SISO-resistant strains were observed at a high rate among the MRSA. Also, SISO-resistant strains of Serratia marcescens increased. However, the rate of SISO-resistant strains of Pseudomonas aeruginosa decreased, and among Citrobacter freundii, Enterobacter cloacae and Proteus vulgaris, SISO-resistant strains did not increase over the years.
3. MICs of SISO against Providencia rettgeri and Providencia stuartii were high, suggesting that antibacterial activities of SISO was weak against genus Providencia.
4. For comparison, according to MICs of ofloxacin and imipenem, new quinolone-resistant strains were observed at a high rate among various organisms, and carbapenem-resistant strains were observed at a high rate among S. marcescens and P. aeruginosa.
5. SISO is still one of the useful AGs in the 1990's since it maintains its strong antibacterial activities against most clinical isolates obtained in recent years and its potential as a combination drug with β-lactams is being reported.

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The combination therapy of sulbactam/cefoperazone (SBT/CPZ) and piperacillin (PIPC) was evaluated in 49 patients with severe infections associated with hematological disorders.
Clinical responses in 43 evaluable patients out of the 49 patients were excellent in 12, good in 18, thus, overall efficacy rate was 69.8% (excellent plus good). Efficacy rates of this combination therapy were 60% (3/5) for sepsis, 75% (21/28) for suspected sepsis, and 50% (4/8) for pneumonia. The efficacy rate was 71.4% (10/14) in patients with neutrophil counts less than 200/μl; this combination therapy was highly effective even in the neutropenic patients.
Transient increases in hepatic function test values were observed in 2 patients, but no other side effects were observed during the combination therapy.
From these observations it appears that the combination therapy of SBT/CPZ and PIPC is a very useful empiric therapy for severe infections associated with hematological diseases.

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A randomized controlled study was conducted to compare effects of imipenem (IPM)(1.0-1.5g/day) with those of aztreonam (AZT)(4g/day) +lincomycin (LCM)(1,200-2,400mg/day) in patients with malignant tumors or hematological diseases and severe infections.A total of 95 patients entered the study between October 1989 and March 1991.Forty-seven patients were treated with IPM and the remaining 48 patients were given AZT+LCM. No statistically significant differences existed in age, sex or underlying diseases between the 2 groups.
Overall, the clinical cure rate of the IPM group was 53%;This was significantly higher than the 31% cure rate obtained in the AZT+LCM group (P<0.05).The difference was significant in patients whose granulocyte counts were less than1, 0004/1, but not in those whose granulocyte counts were1,000μEl or higher.
Side effects were observed in 5 patients given IPM and one given AZT+LCM.In conclusion, no significant differences appeared to exist regarding clinical efficacy and safety between the 2 treatment regimens.

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Eighteen immuno-compromised children (malignancies, hematological diseases, collagen diseases) with neutropenia and infections were treated with imipenem/cilastatin sodium (IPM/CS), and the efficacy and the safety of the drug were evaluated.
1. Responses to IPM/CS were excellent in 13 patients, good in 1, and fair in 4. None of the patients displayed a poor response to the treatment, thus the efficacy rate was 77.8%.
2. Of 5 patients with sepsis, 4 had excellent or good responses. IPM/CS was effective against sepsis caused by Enterococcus faecalis and Pseudomonas aeruginosa.
3. In patients with severe neutropenia (WBC< 100/mm3), the efficacy rate was 70%.
4. As for side effects, elevations of GOT and GPT were observed in 1 patient with liver cirrhosis.
These results indicate that IPM/CS is safe and effective in immuno-compromised children with neutropenia and infections.

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The efficacy and safety of early therapy with imipenem/cilastatin sodium (IPM/CS) were studied in patients who had chorioamnionitis with preterm PROM or threatened abortion and premature delivery. The following results were obtained.
1. The clinical efficacy of IPM/CS administered by intravenous drip infusion at daily dosages of 1 to 2 g as concurrent treatment with antiuteronics (ritodrine hydrochloride or terbutaline sulfate) was studied in patients with threatened abortion and premature delivery in the 11 th to 34th week of pregnancy (n=9), or premature PROM in the 23rd to 36th week (n=9).
2. Response to IPM/CS were good in all of the patients with threatened abortion and premature delivery. Latent periods were prolonged for more than 7 days in 44.4% (4/9) of the patientns with preterm PROM.
3. Changes in elastase appeared to be significant as those in CRP for inflammatory markers.
4. These findings combined with our previous results indicate that treatment of preterm PROM before the 32nd of pregnancy prolongs the latent period.

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The efficacy and safety of imipenem/cilastatin sodium (IPM/CS) were studied in patients with obstetric and gynecologic infections and in those given the drug as prophylaxis against postoperative infections.The following results were obtained:
1.Efficacy rates were 96.0% (48/50) in patients with obstetric and gynecologic infections and 100% (28/28) in those with urinary tract or other infections.The overall efficacy rate was 97.4% (76/78).Bacteriologically, 30 organisms were isolated from 28 patients.The eradication rate was 95.2% (20/21) and the efficacy rate was 96.4% (27/28).
2.Changes in blood elastase before and after treatment were compared with those in CRP, WBC, and ESR in the patients with obstetric and gynecologic infections.The changes in elastase were similar to those in CRP.
3.The efficacy rate was 98.0% (48/49) in the patients given prophylaxis against postoperative obstetric and gynecologic infections.
4.An adverse reaction was observed in only one patient (diarrhea), and abnormal laboratory findings were noted in 2 patients (elevation of GOT and GPT).
These results indicate that IPM/CS is very useful for the treatment of obstetric and gynecologic infections.

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Serum concentrations of cefminox (CMNX) and piperacillin (PIPC) and their transfer into pulmonary tissue during surgery were serially studied following 1-hour intravenous instillation of 1 g of CMNX or PIPC immediately before thoracotomy, and the following results were obtained.
Maximum serum concentrations of CMNX and PIPC were observed 1 hour after the commencement of administration, and their levels gradually decreased thereafter.The mean peak level of CMNX was 72.21, ug/ml, and T 1/2 was 1.62 hours.The mean peak level of PIPC was 43.26, ug/ml, and T 1/2 was 1.54 hours.
In the pulmonary tissue, mean concentrations of CMNX in the normal pulmonary (alveolar) tissue were 28.80, 26.50 and 17.80μg/g at 2.5, 3 and 4 hours, respectively, after the commencement of administration, and the corresponding levels for bronchiolar tissue were 19.6, 18.40 and 20.53, ug/g, respectively.The mean concentrations of PIPC in the normal pulmonary (alveolar) tissue were 18.97, 7.34 and 5.0 gg/g at 2, 3 and 4 hours, respectively, after the commencement of administration, and the corresponding levels for bronchiolar tissue were 7.2, 9.20 and less than 0.2, μg/g, respectively.PIPC also showed favorable transfer into the hilar lymph node tissue and obstructive pneumonitic lesions.
The transfer of both drugs into pulmonary tissue suggests that both drugs are useful for the treatment of respiratory infectious diseases and the prevention of postoperative infections.

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The efficacy and safety of a combination regimen using flomoxef (FMOX) and tobramycin (TOB) were evaluated in the treatment of infections complicated with hematlogical disorders. The primary diseases in 40 patients included acute leukemia, malignant lymphoma and others. Complicated infections included 35 cases with suspected septicemia, 4 cases with septicemia and 1 case with pleuritis. Clinical responses were excellent in 10 (25.0%), good in 14 (35.0%), fair in 2 (5.0%) and poor in 14 (35.0%). The efficacy rate was 73.1% in patients with neutrophil counts higher than 501/μl after administration, but it was 35.7% in patients with counts less than 501/μl; the difference was statistically significant. No side effects were observed in any of the 40 patients. Abnormal laboratory data in liver functions were identified in 1 patient (2.5%). Degree of this abnormality was very slight, and the continuation of treatment was not disturbed. In conclusion, this combination therapy of FMOX and TOB thus appears to be useful and safe in therapies for infections complicated with hematological disorders.

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The clinical effectiveness of flucytosine (5-FC) was evaluated in 52 patients with urinary fungal infections which were diagnosed because of the presence of both funguria (z 104 cfu/ml) and pyuria (5 WBC/hpf). The patients received oral daily doses of 5-FC ranging 20 to 150 mg/kg, with a mean treatment duration of 11 days. The 57 fungus strains isolated from urine specimens consisted of 51 Candida spp. including 28 Candida albicans, 10 Candida glabrata, 4 Candida tropicalis and 6 Trichosporon beigelii. Forty-seven (92.2%) and 4 (66.7%) of the 51 Candida spp. and 6 T. beigelii strains isolated were eradicated by the treatment, respectively, giving an overall eradication rate of 89.5%. Clinical responses in 32 patients, from whom only fungi were submitted, were excellent in 5, moderate in 22, and poor in 5, thus the overall efficacy rate was 84.4%, based on the criteria of Japanese UTI Committee. Of the 18 strains of Candida spp. tested, 5-FC showed 0.20 iug/ml or less of the minimum inhibitory concentrations (MICs) against 16 strains and higher than 100 itg/ml against the remaining 2 strains. The MICs of the 5 T. beigelii strains tested were between 3.12 and 6.25 fig/ml. As adverse reactions, only 2 patients (3.8%) experienced diarrhea but did not require treatment cessation. These results suggest that flucytosine is an effective drug for urinary fungal infections.

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In the development of infectious diseases at non-pregnancy and at pregnancy, correlations between bacterial flora in the vagina and portio vaginalis and the ascending infections of those bacteria have recently been discussed. To clarify the cause of those infectious diseases, we studied the localization of microorganisms in genital regions.
Patients undergone abdominal total hysterectomy (n=172) were employed as subjects, and microorganisms isolated from 4 genital regions were studied. In addition, the preventive effect of cefmetazole (CMZ) against postoperative infections was analyzed in 479 cases including the hysterectomy cases mentioned above.
The results obtained are summarized as follows:
1. The isolation rate of microorganisms at non-pregnancy, from subjects of 30 to 69 years old, was 65.6% (82/125) in the vagina and portio vaginalis, 52.1% (25/48) in the cervical mucus, 7.3% (9/124) in the uterine cavity and 0% (0/47) in the ovarian surface.
2. Numbers of microorganisms isolated in each regions were 99 strains in the vagina and portio vaginalis, 28 in the cervical mucus, 10 in the uterine cavity and none in the ovarian surface. Isolation of aerobic Gram-positive bacteria (60-89.3%) and anaerobic Gram-positive bacteria (7.1-30%) were varied in each regions. Lactobacillus spp.(38 strains), Staphylococcus epidermidis (20 strains) and Propionibacterium acnes (10 strains) were isolated from vagina and portio vaginalis, and Lactobacillus spp.(17 strains) were the most often isolated bacteria from the cervical mucus.
3. The preventive effect of CMZ against postoperative infections (abdominal total hysterectomy, n=336, and abdominal cesarean section, n= 143) was confirmed in 98.5% (472/479) of the subjects with subjective or objective side effects at 1.3%.
Localization of various microorganisms in the lower genital region has extensively been studied, while roles of the cervical canal and cervical mucus have been suggested as one of the local defense mechanisms against ascending infections. From the viewpoint of the local and systemic defense mechanisms at non-pregnancy and during pregnancy, it is very interesting to clarify the localization of microorganisms in the lower genital region, and in uterus to where those microorganisms locate by ascending through the cervical canal and pelvis.
We have reported1) the antibacterial activity of cervical mucus at non-pregnancy and at pregnancy, while relations between intravaginal bacteria and bacterial flora in the cervical mucus, in uterine cavity and in intraperitoneal region have not been clarified so far.
In order to clarify those points, bacterial flora in each regions was compared in patients undergone abdominal total hysterectomy. In addition, the preventive effects of cefmetazole (CMZ) which has been used for those 7 years against postoperative infections were analyzed.

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