The in vitro antibacterial activity of cefclidin (CFCL), a new parenteral cephalosporin, and interaction of CFCL with various β-lactamases were studied in comparison with those of ceftazidime (CAZ), cefoperazone (CPZ), and cefotaxime (CTX). CFCL showed a broad antibacterial spectrum against Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. The activity of CFCL against Staphylococcus aureus was almost equal to that of CAZ and slightly weaker than CTX and CPZ. Its activity against most species of the Enterobacteriaceae family was nearly comparable to those of CAZ and CTX, and superior to those of CPZ. Against P. aeruginosa (MIC₉₀, 6.25μg/ml), CFCL was 4-to 32-fold more active than CAZ and CPZ. CFCL also showed potent activity, wih the MIC₉₀ of 3.13μg/ml, against CAZ-and CTX-resistant strains (MIC≥25μg/ml) of Enterobacter cloacae and Citrobacter freundii.
The stability of CFCL to various types of β-lactamases from Gram-negative bacteria was similar to those of CAZ and CTX. In an inhibition study, CFCL showed much higher Ki values for, β-lactamases of E. cloacae, C. freundii and P. aeruginosa than did CAZ and CTX. Extremely lower affinity of CFCL for each β-lactamase demonstrated well its on more potent activity against β-lactamase-producing organisms.

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Cefclidin (CFCL) is a unique, parenteral oxime-type cephem antibiotic possessing (4-carbamoy1-1-quinuclidino) methyl side chain on the 3 position.
MICs of CFCL against 24 to 51 fresh clinical isolates of 7 Gram-positive and 15 Gram-negative species of bacteria were measured by the plate dilution method with one-spot inoculum of 10⁶cfu/ml suspensions of the test bacteria. The affinity to bacterial PBPs was examined by the competitive method improved by the authors.
MIC₈₀ to Pseudomonas aeruginosa, Pseudomonas cepacia, Xanthomonas maltophilia, Acinetobacter calcoaceticus, Escherichia coli, carrying various R plasmids, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Haemophilus influenzae, Bacteroides fragilis, Staphylococcus aureus, MRSA, coagulase-negative staphylococci, Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium were 0.78, 12.5, 12.5, 1.56, 0.1, 0.2, 0.39, 0.39, 0.1, 0.78, 0.39, 1.56, 1.56, 0.39, <100, 50, 100, 50, 0.05, 0.39, <100, and 100μg/ml, respectively. CFCL manifested the strongest binding affinity to PBPs lBs and 3 of E.coli, PBPs 1A and 3 of P.aeruginosa, PBPs 1B, 1C and 3 of S.marcescens, and PBPs 1 and 3 of A. calcoaceticus. Since CFCL has a strong affinity to PBPs essential for cell elongation, its strong bactericidal effect is expected.

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Cefclidin (CFCL) is a novel oxyimino-type cephalosporin bearing 4-carbamoyl-1-quinuclidine moiety on the 3-position. CFCL had a widely expanded antibacterial spectrum including glucosenonfermentative bacteria. CFCL was markedly superior to ceftazidime (CAZ) against Pseudomonas aeruginosa.
Furthermore, CFCL manifested a strong activity against both Enterobacter cloacae and Citrobacter freundii as compared with CAZ. CFCL exhibited an excellent therapeutic effect against systemic infection with various species of Gram-negative and Gram-positive bacteria in mice. The efficacy of CFCL against P. aeruginosa infection was distinctly superior to that of CAZ. In addition, CFCL was more effective against infections caused by E. cloacae, C. freundii, and Acinetobacter calcoaceticus than CAZ.

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The activity of a new parenteral cephalosporin, cefclidin (CFCL), was compared with those of ceftazidime (CAZ), cefotaxime (CTX), cefpiramide (CPM), and cefotiam (CTM) against anaerobic bacteria and Gardnerella vaginalis. In general, CFCL showed a broad spectrum against Gram-positive and-negative reference strains of anaerobic bacteria although weak activity of this compound was seen against Bacteroides fragilis group organisms. Against recent clinical isolates, CFCL revealed moderate or weak activity against members of the B. fragilis group as did other antimicrobials tested. CFCL showed poor activity against Prevotella bivia and Clostridium difficile as well. Against most of other members of anaerobic bacteria, CFCL showed good activity, especially against Mobiluncus spp. and G. vaginalis. Enzymatically, CFCL was more stable than CPM, CTX, and CTM, but less stable than CAZ to hydrolysis by oxyiminocephalosporinases type I derived from B. fragilis. Time-kill study demonstrated bactericidal activity without regrowth at concentrations of two times or more the MIC of CFCL for B. fragilis. Although CFCL had bactericidal potency in rat pouch infection with B. fragilis, regrowth was seen 48h after starting administration of this compound. CFCL seemed to cause little overgrowth of C. difficile in a mouse model.

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The in vitro and in vivo antibacterial activities of cefclidin (CFCL), a new parenteral cephem antibiotic, were compared with those of cefoperazone (CPZ), cefmenoxime (CMX), ceftazidime (CAZ) and cefzonam (CZON). The following results were obtained.
CFCL had a broad antimicrobial spectrum against Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa, and it's antibacterial activity against clinical isolates of Enterobacter cloacae, Enterobacter aerogenes, Providencia rettgeri, and Morganella morganii were superior to those of CPZ, CMX, CAZ, CZON. The activities of CFCL against Gram-positive cocci were comparable to those of CAZ, but it was less active than CPZ, CMX, and CZON. Against P. aeruginosa, CFCL was the most potent compound of all the cephem antibiotics tested. In the sensitivity distribution of clinically isolated strains, the MIC₅₀ values (μg/ml) of CFCL were 6.25 for Staphylococcus aureus, 3.13 for Staphylococcus epidermidis, 0.10 for Streptococcus pyogenes, 0.10 for Streptococcus pneumoniae, 0.10 for Escherichia coli, 0.20 for Klebsiella pneumoniae, 0.20 for Proteus vulgaris, 0.20 for M. morganii, 0.10 for E. cloacae, 0.20 for E. aerogenes, 0.78 for Serratia marcescens, 0.10 for Haemophilus influenzae, 1.56 for Branhamella catarrhalis, 0.78 for Acinetobacter calcoaceticus, and 0.78 for P. aeruginosa. The in vitro activity of CFCL was well sustained in vivo as shown by results obtained in experimental infections in mice. In particular, CFCL was the most active drug against P. aeruginosa including gentamicin-resistant and β-lactamase-overproducing strains. Morphological studies using a scanning electron microscope and a phase-contrast microscope showed that CFCL caused spheroplast and bulge formation in P. aeruginosa at low concentration.

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Cefclidin (CFCL) is a new parenteral cephalosporin with a broad antibacterial spectrum and potent antipseudomonal activity. CFCL was 8 to 16 times more active than ceftazidime (CAZ) and cefsulodin against Pseudomonas aeruginosa (MIC₉₀, 3.13μg/ml). The activity of CFCL against most species of the Enterobacteriaceae family was roughly comparable to those of CAZ and cefmenoxime (CMX) and exceeded that of cefotiam. The activities of CFCL against Citrobacter freundii (MIC₉₀, 0.78μg/ml), Enterobacter cloacae (MIC₉₀, 3.13μg/ml), and Enterobacter aerogenes (MIC₉₀, 0.2μg/ml) were 16 to 256 times greater than those of CAZ and CMX. The activities of CFCL against Gram-positive cocci and anaerobes were comparable to those of CAZ, but CFCL was less active against those types of organisms than CMX. CFCL showed potent antibacterial activity against β-lactamase-producing strains of Enterobacteriaceae and Pseudomonas spp. Its activity was little affected by the levels of β-lactamase production, compared with the other compounds. CFCL was highly stable to hydrolysis by various β-lactamases, except for R plasmid-mediated type II (OXA 1) penicillinase. The susceptiblity profile of CFCL to β-lactamase was almost the same as that of CAZ, but CFCL was more stable than CMX. CFCL also showed an extremely low affinity for β-lactamases from strains of E. cloacae, C. freundii, and P. aeruginosa, as compared with CAZ and CMX. The ability of CFCL to induce β-lactamase was about equal to that of CAZ. CFCL showed high affinities for PBP 3 of E. coli and P. aeruginosa. CFCL caused filamentation at its lowest effective concentrations, as reflected by the affinities of CFCL for PBP 3.

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The in vivo antibacterial activity of cefclidin (CFCL), a new parenteral cephalosporin, was evaluated in comparison with ceftazidime (CAZ), cefmenoxime, cefotiam, cefazolin, cefoperazon, and cefsulodin. In systemic infection in mice caused by Pseudomonas aeruginosa, CFCL (ED₅₀=4.43mg/kg) was superior to CAZ (ED₅₀=27.3 mg/kg). CFCL was also 3 to 30 times more effective than CAZ against Acinetobacter calcoaceticus and β-lactamase-producing strains of Enterobacter cloacae and Citrobacter freundii. Against Enterobacteriaceae and Gram-positive cocci, CFCL was as effective as CAZ.
In urinary tract infections in mice or intrauterine infections in rats caused by P. aeruginosa, CFCL was more effective than CAZ in reducing viable bacterial counts. In respiratory tract infections caused by Klebsiella pneumoniae in mice or granuloma pouch infections caused by P. aeruginosa or Escherichia coli in rats, CFCL was as effective as CAZ.

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We studied the antibacterial activity of cefclidin (CFCL) against 411 strains of 20 species clinically isolated in Chiba University Hospital in 1988.
The MICs of CFCL and other β-lactams including ceftazidime (CAZ) and imipenem (IPM) were measured by micro dilution broth method.
1. CFCL showed the strongest antibacterial activity of the/Madams tested against Escherichia coli, Citrobacter freundii, Pseudomonas aeruginosa, and Xanthomonas maltophilia.
2. The MICs of CFCL were smaller than those of CAZ against Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, and Morganella morganii, but IPM or aztreonam (AZT) showed lower MICs than CFCL.
3. The MICs of CFCL were equal to those of CAZ against Streptococcus pyogenes and Streptococcus pneumoniae, but MICs of IPM and piperacillin (PIPC) against those species were lower than those of CFCL.
4. CFCL showed weak antibacterial activity against Staphylococcus aureus and Enterococcus faecalis, as well as other β-lactams except for IPM.
5. No cross resistance was observed between CFCL and CAZ or IPM against P. aeruginosa.

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The antibacterial activity of cefclidin (CFCL) and reference antibiotics against recent clinical isolates between 1991. 1 and 1991. 7 was evaluated and the following results were obtained.
1. CFCL showed potent activity against Enterobacteriaceae resistant to an oxime type cephem and aztreonam (AZT). Furthermore, CFCL manifested powerful action against Pseudomonas aeruginosa which is resistant to AZT and ceftazidime (CAZ). These results might be attributable to the high stability of CFCL to β-lactamase and also the extremely low binding affinity to β-lactamase.
2. CFCL exhibited a characteristic antibacterial activity showing the prominent action to nonhydrolytic type resistant strains which are increasing in the recent year, resulting from the improved stability of CFCL to β-lactamase and also the markedly lowered binding affinity to β-lactamase as compared with the already launched oxime type cephems.
3. Many high resistant strains to new-quinolones were included in the present examination, and the MICs of CFCL against these strains were relatively higher.

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We carried out single administration toxicity studies with cefclidin (CFCL), a new injectable cephalosporin, in mice, rats and beagles, and obtained the following results.
1) The LD₅₀ values of CFCL were more than 10, 000mg/kg for mice and rats with oral and subcutaneous administration, and more than 5, 000mg/kg for both species with intramuscular injection. The LDso values in intravenous injection were more than 10, 000mg/kg for mice, 2, 236mg/kg for male rats, and 2, 147mg/kg for females. Two dogs given 3, 000mg/kg did not die but one of two treated with 8, 000mg/kg died on day 2 after intravenous injection.
2) Mucous or loose stool was observed after oral, subcutaneous and intramuscular administration in rats. Clonic convulsion was observed in one male after intramuscular administration in mice. Local injuries at injection sites such as alopecia or crust were observed in rats treated subcutaneously or intramuscularly. In intravenously treated groups, prone position and hypoactivity were observed in mice and rats. Additionally, mice showed cyanosis of limb, swelling of perirhinal portion or limbs and ptosis, and rats showed clonic convulsion. Licking and vomiting were toxic signs observed in surviving dogs.
3) Histopathologically, degeneration, necrosis and regeneration of tubular epithelium and dilatation of tubular lumenin kidneys were detected in the animals which recieved intravenous administration and showed abnormalities in kidneys in macroscopic examinations.

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A study on subacute toxicity of cefclidin (CFCL) was carried out in SD rats. CFCL was administered to rats through the tail vein at the dosages of 30, 100, 300 and 1, 000 mg/kg for 4 weeks. The results obtained from the present study were as follows:
1. CFCL caused neither death nor changes in body weight and water consumption throughout the experimental period. Transient decrease in food consumption was recorded at the dosage of 1, 000 mg/kg at the commencement of treatment. Swelling, scab and blackish purple discoloration in the tail (injection sites) and shedding of the tip of the tail were observed in some rats receiving 1, 000mg/kg No abnormality was found in ophthalmological examinations.
2. Hematological examinations revealed a decrease in hematocrit and an increase in reticulocytes at the dosages of 300 mg/kg and above, and decreases in red blood cell count, hemoglobin, hematocrit and mean corpuscular hemoglobin concentration (MCHC) in rats receiving 1, 000 mg/kg.
3. Biochemical examinations revealed a slight decrease in plasma potassium level at the dosages of 300 mg/kg and above and increases in a2-globulin and plasma sodium level and decreases in plasma triglyceride level, and al-globulin at the dosage of 1, 000 mg/kg.
4. In urinalysis, an increase in protein excretion was noted at the dosages of 300 mg/kg and above.
5. At autopsy, swelling of kidneys was noted at the dosages of 300 mg/kg and above. Increased cecum and kidney weights at the dosages of 300 mg/kg and above and increased lung weight at the dosage of 1, 000 mg/kg appeared.
6. Histopathological examinations revealed hypertrophy of white pulp in spleen at the dosages of 300 mg/kg and above. Slight vacuolar degeneration of proximal tubular epithelium in kidneys, macrophage infiltration in alveolus and edema of alveolar septum in lung, extramedullary hematopoiesis in spleens and the findings exhibiting local damages in the tail (injection sites) also appeared at the dosage of 1, 000 mg/kg.
7. The above-mentioned changes at the end of treatment period disappeared or attenuated after 4 weeks of the recovery period.
The non toxic dose of CFCL for rats was concluded to be 100 mg/kg.

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Cefclidin (CFCL) was administered intravenously to beagle dogs daily for 4 weeks at dosage levels of 30, 100, 300 and 1000 mg/kg and 4-week recovery study was performed at dosage levels of 300, 1000 mg/kg.
1. No deaths occurred in all dosage groups. No toxicological changes were found in body weight, food and water consumption and electrocardiographic parameters in all dosage groups.
2. No changes related to the treatment were observed in the 100 mg/kg or less groups.
3. In the 300 and 1000 mg/kg group, urinary NAG and eosinophilic granules of the renal tubular epithelium increased.
4. In the 1000 mg/kg group, vomiting, salivation and licking were exhibited, and platelet, RBC, Ht and Hb decreased, and ESR and urinary γ-GPT increased. Pathological examination showed increases in kidney and thymus weights, and discoloration of the kidneys. Cell infiltration in the renal interstitium, and degeneration and regeneration of the renal tubular epithelium were observed. These changes observed at 1000 mg/kg during treatment were shown to be reversible through the treatment free recovery period. During the recovery period after the 4-week treatment, clinical signs such as relaxed nictitating membrane and myosis appeared in 2 dogs in the 1000 mg/kg group. However, no histopathological findings of the eye ball and optic nerves of the dogs were noted.
The non-toxic dose of CFCL in beagle dogs administered intravenously for 4 weeks was considered to be 300 mg/kg because the only adaptive changes to the drug, the increase in urinary-NAG and eosinophilic granules, were observed at this dose level.

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Cefclidin (CFCL), a new cephalosporin antibiotic, was administered to mated female rats at 7 to day 17 of gestation at dose levels of 100, 300 and 1, 000mg/kg. Two thirds of 36 dams per group were sacrificed on day 20 of gestation to examine their fetuses. The remaining dams were allowed to deliver spontaneously to examine their neonates for postnatal development.
Neither deaths nor dose-related abnormalities in general conditions of dams were noted. During the dosing period, maternal food intake was reduced in the 300 and 1, 000mg/kg groups, and body weight was reduced in the 1, 000mg/kg group.
No effects of CFCL on pregnancy, delivery and nursing ability of dams were noted.
The numbers of corpora lutea and implantation per litter, the incidence of dead and resorbed fetuses, and the male to female sex ratio of live fetuses in each CFCL group were comparable with those in the control. Reduced fetal weight, increases in the incidences of rudimentary 14th rib and asymmetrical sternebrae were noted in the 1, 000mg/kg group. The external, internal and skeletal examinations of fetuses showed no evidence of teratogenicity of CFCL.
Treatment with CFCL did not affect the live birth ratio, survival rate, body weight, physical and functional development of neonates until weaning. Examinations of neonates after weaning showed slight suppression of male body weight in the 1, 000mg/kg group. However, no effects on physiological function, behavioral and reproductive performances were noted.
In conclusion, the no-effect dosage level of CFCL concerning general toxicological effects in dams was 100mg/kg, on reproduction in dams 1, 000mg/kg, and on development of the next generation was 300mg/kg.

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The present study was carried out to evaluate nephrotoxicity by single intravenous administration of cefclidin (CFCL) alone or in combination with furosemide and glycerol to ratss and wake a comparison with those of cefazolin (CEZ) and cephalothin (CET). The rats were treated with cefclidin at the doses of 300, 1, 000 or 2, 000mg/kg or other cephem antibiotics at the dose of 1, 000mg/kg.
CFCL at 2, 000mg/kg was lethal. Neither CFCL at 300 or 1000mg/kg, CEZ at 1, 000mg/kg nor CET at 1, 000mg/kg induced nephrotoxicity by itself. The treatment with furosemide and glycerol significantly increased blood urea nitrogen, reduced PSP excretion and creatinine clearance and induced some pathological changes such as tubular necrosis. All the antibiotics enhanced the nephrotoxicity caused by the treatment with furosemide and glycerol. The latent nephrotoxicity of CEZ was distinct. CFCL was comparable to or slightly less nephrotoxic than CET.

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Nephrotoxicity of cefclidin (CFCL) was studied and compared with those of cefazolin (CEZ), cephalothin (CET) and cephaloridine (CER). The rats were treated intravenously with 300 or 1, 000mg/kg of CFCL, 1, 000mg/kg of CEZ and CET, and 500 mg/kg of CER (CER dosage was changed from 750mg/kg to 500mg/kg on day 6 or 7) for 7, 14 and 21 days. There were deaths in only rats given 750mg/kg of CER. In the CFCL treated groups, eosinophilic granules in the proximal tubular epithelia showed a dose-related increase. Slightly vacuolar degeneration of the proximal tubular epithelia were observed in the rats treated with 1, 000 mg/kg. A significantly decreased Na⁺, and increased protein and ketone body in the urine were detected in the rats treated with 1, 000mg/kg for 21 days. In CEZ and CET treated groups, swelling of the proximal tubular epithelia and dilatation of the renal tubules in the cortex were observed in addition to the CFCL induced changes. Urinary Clwas decreased in CEZ treated rats and urinary Na⁺was increased in CET treated rats. In CER treated group, elevation of plasma urea nitrogen, decrease of urinary creatinine and endogeneous creatine clearance, and degeneration or necrosis of the tubular epithelia in the cortex were observed. These results indicated that the order of nephrotoxic potential of the four cephem was CER>CEZ>CET>CFCL.

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Nephrotoxicity of cefclidin (CFCL), a new cephalosporin antibiotic, was studied in 6 months-old male rabbits, using two reference drugs, cefazolin and cephalothin. Test doses of 500 and 2, 000mg/kg for CFCL, and 2, 000mg/kg for cefazolin and cephalothin, were administered intravenously.
CFCL was non-nephrotoxic at 500mg/kg. CFCL reduced endogenous creatinine clearance and induced some pathological changes such as proximal tubular vacuolization at 2000mg/kg. Cephalothin induced only pathological changes such as proximal tubular vacuolization at 2, 000mg/kg. The nephrotoxicity of cefazolin was most obvious. Cefazolin induced proteinuria, decreased endogenous creatinine clearance and PSP excretion rate, increased relative kidney weight, and induced some pathological changes such as proximal tubular vacuolization and necrosis at 2, 000mg/kg.
In conclusion, CFCL was less nephrotoxic than cefazolin, but slightly more nephrotoxic than cephalothin in rabbits.

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The effects ofcefclidin (CFCL), a novel antibacterial agent, on the cardiovascular and autonomic nervous system were examined using a variety of in vivo and in vitro models. The effects of cefazolin (CEZ) were also examinated for comparative purposes.
Neither CFCL nor CEZ caused any notable effects on the cardiovascular or autonomic nervous system when administered intravenously to anaesthetised dogs and cats or in vitro preparations. Some evidence of a possible transient stimulation of the sympathetic nervous system was seen following high doses of both CFCL and CEZ.

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An examination of some general pharmacological effects of cefclidin (CFCL) and (CEZ) cefazolin had been made. A range of standard pharmacological tests were used to investigate effects on the gastrointerstinal tract, secretory function and renal function.
Local anaesthetic activity was also evaluated.
Some increase in the activity of gastrointestinal smooth muscle was observed following both CFCL and CEZ but there was no evidence of an effect on gastrointestinal conduction speed. Secretory function was not affected by CFCL, however, changes in gastric secretion, bile secretion and pancreatic output were observed after CEZ.
The highest does of CFCL caused an increase in urine volume and Na⁺, K⁺, and Cl^- excretion in rats, Whilst an increase in Nat was seen after CEZ no notable change in urine output was recorded. Glomerular filtration rates were not affected.
CFCL and CEZ were devoid of local anaesthetic activity.

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The spasmolytic effects of cefclidin (CFCL), a novel antibacterial agent and cefazolin (CEZ) were examined in a variety of isolated tissue preparations.
The tissue preparations used comprised guinea-pig ileum, guinea-pig trachea, rat phrenic nerve-diaphragm, rat was deferens, rat uterus and pregnant rat uterus.
In the preparations studied neither CFCL or CEZ caused any notable inhibition of the contractile responses induced by either agonists or electrical stimulation.

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We established a microbiological assay (bioassay) and HPLC methods for determination of cefclidin (CFCL) in biological fluids. The concentration of CFCL was assayed by disc-plate method using Escherichia coli E01174 (clinical isolate) as the test organism and brain heart infusion agar (Difco) as the test medium. The CFCL concentration in plasma was determined with the standard solutions supplemented with 50% of pooled human plasma. For determinations of CFCL in urine and bile specimens, the standard solutions were prepared with M/15 citrate buffer (pH 5.0). The quantitation limits for plasma, urine and bile was 0.12g/ml in all specimens.
Plasma and urine levels of CFCL were determined by HPLC using a reversed-phase column. The quantitation limits of CFCL in plasma and urine were 0.2μg/ml and 1μg/ml, respectively.
CFCL concentrations measured by HPLC were in good agreement with those by the bioassay. CFCL in 2-fold diluted plasma by M/15 citrate buffer (pH 5.0) and urine were stable for at least 30 days and 2 month at-20t, respectively.

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The pharmacokinetics of cefclidin (CFCL), a new parenteral cephalosporin, were compared with those of ceftazidime (CAZ) in experimental animals.
The area under the curves (AUC) of CFCL in plasma were evaluated after intravenous administration with a dose of 20mg/kg; 17.7μg·h/ml in mice, 38.1μg·h/ml in rats, 93.6μg·h/ml in dogs and 99.3μg·h/ml in monkeys. The plasma half-lives were 14, 19, 49, and 63mm in mice, rats, dogs and monkeys, respectively. These parameters of CFCL were similar to those of CAZ.
The kidney levels of CFCL in mice and rats were highest after dosing with 20mg/kg, followed in descending order by plasma, lung, spleen and liver levels.
The urinary recovery of CFCL was 95.4% in mice, 93.3% in rats, 96.2% in dogs and 76.0% in monkeys. The biliary excretion rate of CFCL was extremely low (0.09% within 6hr) in rats.
After pretreatment of probenecid (30 mg/kg, i. v.), the plasma levels and urinary recovery of CFCL were studied in dogs and no significant effect of probenecid was observed.
No antimicrobially active metabolites were observed in urine.
The binding rates of CFCL to serum protein were 9.8% in human, 13.0% in monkeys, 16.5% in dogs, 5.0% in rats and 5.0% in mice.

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Metabolic fate of cefclidin (CFCL) was studied in SD rats after single or repeated intravenous administration of ¹⁴C-CFCL.
1. After single administration of ¹⁴C-CFCL (20mg/kg), the plasma level of radioactivity decreased biphasically (t1/2λ1=38.4min, t1/2λ2=16.3hr). AUC increased in proportion to the increase in dosages (20-820mg/kg). The plasma protein binding rates of CFCL was about 5%.
2. At 5 min after single administration, the tissue level of radioactivity (μg eq./g) was highest in the kidney (379.2-207.3) followed by plasma, lung, trachea, thyroid, bone marrow, aorta and liver, and thereafter decreased rapidly. At 6 day, it decreased below 0.6jig eq./g except kidney cortex (5.1).
3. Within 7 days after single administration, 98.2% and 4.1% of the given radioactivity were excreted into the urine and feces, respectively. About 0.5% of the doses was excreted into the bile within 24hr.
4. After single administration, 95% or more of the radioactivity remained unchanged in plasma and urine.
5. Only a small amount of radioactivity passed through the placenta of pregnant rats on the 19th day of gestation. The milk levels of radioactivity reached peak level at 1 hr after administration, then decreased rapidly.
6. After repeated administration of ¹⁴C-CFCL (20mg/kg, once a day for 7 days), plasma levels, tissue distribution, metabolism and excretion were similar to those after a single administration. There were no effects of CFCL on the hepatic drug-metabolizing enzyme system.

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The pharmacokinetics of cefclidin (CFCL) was investigated and compared to the results of ceftazidime (CAZ) and cefpiramide (CPM) in the same four adult male healthy volunteers.
After constant intravenous infusion of the drug at a dose of lg for 1 hour, the mean peak plasma concentration obtained by the HPLC method was 53.20/μg/ml for CFCL, 59.40μg/ml for CAZ and 105.90μg/ml for CPM. The mean values of t_1/2β in plasma were 0.47 hour 1.54 hour and 3.88 hour, Additionally the AUCs were 127.36μg hr/ml, 137.97μg hr/ml and 588.47μg hr/ml, respectively. The mean urinary excretion rates within 24 hours were 78.8%, 65.5% and 17.2%. The mean plasma protein binding rates were 5.3%, 8.8% and 98.4%.

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In order to propose a dosage regimen of cefclidin (CFCL) in patients with renal insufficiency, CFCL was administered to healthy volunteers or patients with varying degrees of impaired renal function measured by creatinine clearance (Ccr). Plasma concentrations were determined by HPLC and pharmacokinetic parameters were calculated by a two compartment model, demonstrating a significant correlation β and Ccr. Then, we selected β as the parameter which varied in accordance with the degree of impaired renal function. The applicability of this dosage planning was confirmed in subsequent multiple-dose studies using patients. Finally, we proposed a dosage regimen of CFCL for patients with renal insufficiency.

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The pharmacokinetics of cefclidin (CFCL) in elderly patients were evaluated.
The drug was administered at a dose of lg to 5 patients without apparent renal diseases (mean age 76.2 years, mean body weight 45.6kg). Serum and urinary level were determined by HPLC and bioassay methods. Data were analyzed by use of two compartment model. Pharmacokinetic parameters in the elderly patients were compared with those in younger healthy volunteers (mean age 33.2 yrs, mean body weight 65.0kg), which were determined by the same method by Nakashima. The mean half-life of the beta phase of the elderly patients was 3.14 hr and 1.8 times longer than in younger healthy volunteers. The AUC in elderly group was about 1.5 times larger. The distribution volume in steady state per kg body weight was larger. Total clearance and renal clearance were smaller. Using pharmacokinetic parameters obtained, serum levels two doses daily of 1g for two weeks were estimated, and no accumulation seemed to occur in this dosage in the elderly.
These data suggested that the standard dosage of CFCL for elderly patients is a daily 2 time dose of 1g.

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We investigated the MICs of cefclidin (CFCL), against 180 clinically isolated strains of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Morganella morganii, Proteus mirabilis and Pseudomonas aeruginosa using a plate dilution method with an inoculum size of 10⁶cells/ml. The MIC₅₀, were 12.5μg/ml for S.aureus, 1.56μg/ml for P.aeruginosa and less than 0.39μg/ml for the others. Its efficacy was superior to that of reference drugs (cefazolin, cefmetazole, cefotaxime and ceftazidime) against gram-negative rods.
Plasma level and urinary excretion of CFCL after intravenous injection (IV) and drip infusion (DI) were compared in 6 healthy male volunteers. The mean plasma level at 5 min was 111.3±7.4μ/ml after IV and 76.3±11. 0μg/ml after DI respectively. The mean value of half life (t1/2β) was 1.61 hour at both of dose routes.
The mean urinary excretion rate within 8 hours was 84.2% and 82.6%, respectively. Twenty patients with bacterial infection were administered CFCL at a daily dose of 1g b.i.d. The clinical effect was excellent in 10 cases, good in 8 cases and fair in 2 cases.
No side effects and laboratory findings were observed.

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The in vitro antimicrobial activity of cefclidin (CFCL), a new cephem antibiotic with a potent antipseudomonal activity for parenteral use, was measured and its therapeutic efficacy especially in respiratory infections was evaluated. The minimum inhibitory concentrations (MIC's) of CFCL, ceftazidime (CAZ), ceftizoxime (CZX) and latamoxef (LMOX=moxalactam) against 20 strains each of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined by a micro-broth dilution method using the Dynatech MIC 2000 system. As shown by MIC's, CFCL was as active as other agents against S.aureus. On the other hand, CFCL was the most active against Enterobacteriaceae and P.aeruginosa of the four agents tested. A daily dose of 2 or 4 grams of CFCL was given intravenously for 6-16 days (mean 12.5 days) to 13 patients: 3 each had acute pneumonia and infected bronchiectasis, 2 with lung abscess and 1 each with chronic bronchitis, diffuse panbronchiolitis, infection super-vening on old pulmonary tuberculosis, secondary infection in association with lung cancer and chronic complicated urinary tract infection. The clinical effects of CFCL were excellent in one, good in 11 and fair in one. Two cases of lung cancer without clinical symptom and signs of infection were excluded from the clinical evaluation. Three strains of P.aeruginosa, two strains of S.marcescens and one strain of Haemophilus influenzae were identified as causative organisms and all of them were eradicated by an administration of CFCL. In 15 patients who received CFCL, drug exanthema was observed in two, and an elevation of serum transaminase and proteinuria were observed in one. These adverse reactions disappeared after completion of the therapy. From the above results, we conclude that CFCL is one of the most useful cephem antibiotics for parenteral use as a first choice in the treatment of respiratory infections.

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We carried out basic and clinical studies on cefclidin (CFCL), a new parenteral cephem antibiotic, and obtained the following results.
1. The in vitro antibacterial activity of CFCL was examined against 400 strains of clinical isolates of 20 species and compared with those of ceftazidime (CAZ), imipenem, latamoxef, cefzonam and cefoperazone. The MIC₉₀ against Pseudomonas aeruginosa was 1.56μg/ml. Furthermore, CFCL also showed excellent activities against CAZ-resistant P.aeruginosa.
2. The clinical evaluation of CFCL was performed in 9 patients: 8 with pneumonia, 1 with bronchiectasis. The clinical effects on pneumonia were excellent in 2 cases and good in 6, and for bronchiectasis good. Four strains were identified as causative organisms and were all eradicated by an administration of CFCL. Each elevation of GOT, GPT, BUN, and creatinine, and two positive responses in direct Coombs' were observed.
Based on the above results, we consider CFCL an effective, safe and useful agent for parenteral use in the treatment of respiratory infections.

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We performed laboratory and clinical studies on cefclidin (CFCL) to evaluate its usefulness in respiratory tract infections, and obtained the following results.
1. Antibacterial activity: The MICs were measured against 27 strains of respiratory pathogenic Pseudomonas aeruginosa, and the observed antibacterial activities were compared with those of 9 reference drugs. As a result, the MIC₅₀ and MIC₉₀ of CFCL was 3.13 and 12.5μg/ml against P. aeruginosa, respectively.
2. Pharmacokinetics in sputum: The time course of serum and sputum concentrations was evaluated after administerring a single dose of 1.0g through intravenous drip infusion to 6 patients with respiratory tract infections. The peak concentration in serum showed 44.6-79.1μg/ml after a single administration of 1.0g. The maximal sputum levels of CFCL ranged 1.37μg/ml to 2.90, μg/ml, and the ratios of maximal sputum levels to peak serum levels ranged 2.22% to 6.50%.
3. Clinical results: Sixteen patients with 14 lower respiratory tract infections and 2 of pneumonia were studied in a clinical evaluation of CFCL, which was administered 2.0 to 4.0g daily twice a day through drip intravenous infusion.
The overall clinical therapeutic efficacy was excellent in 1 patient, good in 9, fair in 1, and poor in 5. The clinical efficacy on 10 of the P.aeruginosa infections was 60%, and the eradication rate was 56%.
Vomiting and venous pain in one patient and two positive responses in direct Coombs' test wereobserved.
From these results, we concluded that CFCL was an effective and useful antibiotics for the treatment of intractable respiratory tract infections, which included P.aeruginosa infections.

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We performed a basic study and clinical evaluation on cefclidin (CFCL), a new parenteral cephalosporin.
The antibacterial activity against Pseudomonas aeruginosa was 3.13μg/ml at MIC₉₀ by MIC₂₀₀₀ system. Organisms were decreased from 1×10⁶CFU/ml to 1×10³ at 3 hr after drip infusion of 1g in an in vitro pharmacokinetic system.
A clinical evaluation was carried out in 35 patients. The efficacy rate was 93.3% in respiratory tract infection, 81.8% in bacterial pneumonia. As for adverse reactions, diarrhea in 2 cases and eruption in 3 cases were observed.

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Cefclidin (CFCL), a new semisynthetic cephalosporin, was studied, yielding the following results.
1) Pharmacokinetics
The plasma concentrations and urinary excretion of CFCL and ceftazidime (CAZ) were compared by i. v. injection of each drug to six healthy adult volunteers in a cross-over method. Five minutes after i.v. injection, the plasma concentration of CFCL and CAZ was 103.3±9.8μg/ml and 112.2±8.5μg/ml, respectively, and the half-life β-phase was 1.75±0.09 hr for CFCL and 1.54±0.12 hr for CAZ.
When probenecid was administered before CFCL dosing, plasma levels and urinary excretions were not affected.
These results suggested that main excretion route of CFCL was glomerular filtration.
With hemodialysis, the half-life (β-phase) was shortened to one seventh, from 18.2 h to 2.4 h r.
2) Clinical results
In six cases of respiratory tract infection, 4 cases of urinary tract infection and 1 case of biliary tract infection, two grams of CFCL daily were given for 4-26 days.
The therapeutic results were 4 excellent, 3 good, 2 fair and 2 poor. One of 3 isolated Pseudomonas aeruginosa, one Haemophilus influenzae and one Escherichia coli were eradicated.
No adverse reactions or abnormal laboratory, test yalues were observed.

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We performed laboratory and clinical studies on a new parenteral cephalosporin antibiotic, cefclidin (CFCL).
In vitro antibacterial activity of CFCL was evaluated in comparison to cefoperazone (CPZ), ceftazidime (CAZ), carumonam (CRMN) and imipenem (IPM), using clinically isolated strains of Gram-negative and Gram-positive bacteria.
The antibacterial activity of CFCL was stronger than those of CPZ, CAZ, CRMN, and IPM against Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, but inferior to that of IPM against Staphylococcus aureus. This antibiotic was administered to 6 patients, 2 cases with pneumonia, 2 with acute pyelonephritis, one each with acute cholecystitis and acute bronchitis.
The clinical efficacy of CFCL was excellent in one case and good in 5 cases.
As for side effects, skin eruption and slight elevation of transaminases were observed in each case.
Eosinophilia was observed in 2 cases.

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We studied a newly developed cephalosporin, cefclidin (CFCL), and obtained the following results.
1) The pharmacokinetics of cefclidin were evaluated in 6 patients on continuous ambulatory peritoneal dialysis. Serum, peritoneal dialysate and urine concentrations of the patients on CAPD were determined after a 5 min intravenous infusion of 1.0g CFCL. The elevation of levels and the prolongation of T_1/2β of CFCL in serum were obvious, due to the severe renal dysfunction. The dialysate elimination rates were 2.2-10.2% within the first 24hrs, and these results suggested that the peritoneal loss of this drug was minimal. The urinary recovery rates in the 3 patients were 0.36-5.82% within the first 24hrs.
2) CFCL was used for the treatment of 17 patients with respiratory tract infections and 1 with wound infections. Clinical response was excellent in 1, good in 14, fair in 1, and poor in 2 patients. Laboratory tests revealed liver dysfunctions in 5 cases, a positive direct Coombs' test in 2, a declined prothrombin activity in 2 and an eosinophilia in 1. However, these changes were slight and no severe adverse drug reactions were observed.

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Clinical evaluation of cefclidin (CFCL) was carried out in 20 patients with respiratory infections, 4 with urinary infections and 1 with acute pancreatitis. CFCL was administered lg twice daily in 19 patients by intravenous injection (IV), in 2 patients by drip infusion and 0.5g twice daily in 4 patients by IV. In 22 cases, good effects were observed except 1 case of pneumonia and 2 of pyothorax. Eleven strains were isolated from 9 patients. MICs of CFCL were 0.05-0.2μg/ml against 9 strains of aerobes and 3.13-25μ/ml against 2 strains of anaerobes. Ten organisms except for Fusobacterium which had high MIC values were eradicated.
Anorexia associated with eosinophilia in case and eruption in another 1 case were observed. The leucocyte migration inhibition test was positive to CFCL in both the cases.

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1) Antibacterial activity: The MIC of cefclidin (CFCL) against clinically isolated bacteria was measured and compared with that of ceftizoxime (CZX). Twenty-seven strains of Staphylococcus aureus against CFCL showed a susceptible distribution of 3.13-12.5μg/ml with the peak of 6.25μg/ml, 25 strains of Escherichia coli≤0.05-0.2μg/ml (0.1μg/ml), and 27 strains of Klebsiella pneumoniae≤0.05-0.2μg/ml (0.1μg/ml), exhibiting one fold less activity of CFCL than that of CZX. Twenty-seven strains of Proteus mirabilis showed a distribution of 0.1-0.39μg/ml with the peak of 0.2μg/ml, 27 strains of Proteus vulgaris ≤0.05-0.78μg/ml (0.2μg/ml), and 27 strains of Morganella morganii≤0.05-0.2μg/ml (0.2μg/ml), exhibiting less activity of CFCL than that of CZX. Nineteen strains of Serratia marcescens showed a wide distribution of ≤0.05-12.5μg/ml with the peak of≤0.05μg/ml, exhibiting that the activity of CFCL was superior to that of CZX. Twenty-seven strains of Pseudomonas aeruginosa showed a distribution of 0.2-3.13μ/ml with the peak of 1.5μg/ml, exhibiting that the activity of CFCL was superior to that of CZX.
2) Clinical study: Fourteen cases with 10 of pneumonia, 2 with lung abscess, and one with diffuse panbronchiolitis and pyothorax were studied in a clinical evaluation of CFCL, which was administered at a daily dose of 2g for 4-14 days. Clinical efficacy rates were 78.6%. No adverse reactions were noted and abnormal laboratory changes were observed in one case with eosinophilia, one with elevated GOT and LDH, one case with GOT and GPT and one with positive direct Coombs' test.

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The clinical efficacy and safety of cefclidin (CFCL), a new parenteral cephem antibiotic, were evaluated in 44 patients with respiratory tract infections 22 with pneumonia, 10 with bronchiectasis, 4 with chronic bronchitis, 2 with lung abscess and 2 with diffuse panbronchiolitis. Clinical efficacy was excellent in 9 cases, good in 21, fair in 6, poor in 4, and unevaluable in 4, and the overall clinical efficacy rate was 75%. Seventeen strains out of 23 causative pathogens were eradicated, including 1 polymicrobial infections. Pseudomonas aeruginosa was isolated in 12 cases and the clinical efficacy rate was 50% in P.aeruginosa infected cases. The bacteriological eradication rate was 67% in those cases. Skin eruption was observed only in 1 case. Abnormal laboratory findings were detected in 10 cases, but serious adverse reaction could not be observed.
These results suggest that CFCL is useful for the treatment of respiratory tract infections, especially in infections with P.aeruginosa.

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The clinical usefulness of cefclidin (CFCL) was evaluated in 21 patients with respiratory tract infections: 12 with chronic bronchitis, 5 with acute bronchitis, 2 with bronchiectasis and others. All cases had underlying diseases or complications including 7 cases of chronic sinuitis, 5 cases of lung cancer and 4 cases of old pulmonary tuberculoris.
Thirteen species or 32 strains of causative pathogens were isolated by TTA. Fourteen cases were monomicrobial infections and 8 cases were polymicrobial infections. Isolated pathogens were 10 strains of Haemophilus influenzae, 5 of Pseudomonas aeruginosa, 3 of Streptococcus pneumoniae, 3 of Branhamella catarrhalis and others.
Clinical efficacy was excellent in 2 cases, good in 19 and unevaluable in 1, and the overall efficacy rate was 100%. All causative pathogens were eradicated.
Drug fever was observed in 2 cases, and abnormal laboratory findings were detected in 4 cases: elevation in GOT in 1 case and BUN in 1, and eosinophilia in 2, but all of those changes were slight.
From the above results, we conclude that CFCL is useful for the treatment of respiratory tract infections.

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We performed basic and clinical studies on cefclidin (CFCL), a new parenteral cephalosporin, in respiratory tract infections with the following results.
1. The MICs of CFCL for causative organisms were measured using the plate dilution method with an inoculum size of 10⁶ CFU/ml.
The MIC range for 18 strains of Pseudomonas aeruginosa was 0.1-6.25μg/ml; for 12 strains of Staphylococcus aureus, 6.25-50μ/ml; for 16 strains of Streptococcus pneumoniae, 0.1-0.78μ/ml; for 15 strains of Haemophilus influenzae, 0.1-0.39μg/ml; for 15 strains of Branhamella catarrhalis, 0.78-3.13μg/ml.
2. In clinical evaluation of CFCL in 9 patients, 10 episodes with respiratory tract infections was excellent in 2, good in 7, fair in 1, exhibiting on efficacy rate of 90%.
Causative organisms were P.aeruginosa (3 cases), S.pneumoniae (2 cases), H.influenzae (5 cases) and B.catarrhalis (1 case), and all of them were eradicated.
As for the adverse reactions, facial suffusion in one case was observed.Although the eosinophilia and an elevation in transaminase, BUN, and K⁺ were observed in 7 cases as laboratory abnormal findings, they were mild and transient.

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Laboratory and clinical studies were conducted for cefclidin (CFCL), a new injectable cephem, with the following results.
1. Antibacterial activity: The antibacterial activity of 365 strains of 10 species (clinical isolates) were compared with those of piperacillin (PIPC), cefoperazone (CPZ), ceftazidime (CAZ).
Antibacterial activity of CFCL against Gram-negative bacilli was superior or equal to those of PIPC, CPZ, and CAZ. In paticular, CFCL was markedly superior to PIPC, CPZ and more active than CAZ against Pseudomonas aeruginosa.
2. Clinical effects CFCL was administered to 17 patients with respiratory tract infections. The clinical efficacy rate was 68.8%(excellent 1, good 10, poor 5, unevaluable 1). The overall bacteriological response rate was 50%. As for adverse reactions, rash and drug fever were observed in 2 cases and in 1 case, respectively. Abnormal laboratory findings were transient elevation in transaminase and eosinophilia in each case, and leukopenia in 2 cases.

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Basic and clinical studies were conducted on cefclidin (CFCL) which is a newly developed intravenously injectable cephalosporin. The results were as follows.
1) The MICs of CFCL and the control drugs, i: e., cefotaxime (CTX), ceftazidime (CAZ) and cefoperazone (CPZ) against various clinical isolates were determined in accordance with the standard method established by the Japan Society of Chemotherapy.
The MIC₉₀s of CFCL for Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Enterobacter aerogenes, Serratia marcescens, Proteus vulgaris, Proteus mirabilis, Citrobacter spp. and Pseudomonas aeruginosa were 12.5, >100, 0.20, 0.20, 0.78, 0.20 1.56, 0.39, 0.39, 3.13 and 12.5μg/ml, respectively. The antibacterial activity of CFCL against S.aureus was compatible to that of CAZ but inferior to those of CTX and CPZ. The antibacterial activity of CFCL against E. cloacae and Citrobacter spp. was superior to the activities of CTX, CAZ and CPZ. In particular, the antibacterial activity of CFCL against P. aeruginosa was distinctly more potent than those of CTX, CAZ and CPZ.
2) CFCL was used in the treatment of 5 patients (3 patients with pneumonia, 1 with pulmonary abscess, and 1 with acute bronchitis). CFCL was injected i.v. in a daily dosage of 2.0g-4.0g for 9-21 days, and the clinical response was good in 4 cases and poor in 1. P. aeruginosa and Bacteroides intermedius were isolated as causative bacteria and P. aeruginosa was eradicated, but B. intermedius persisted. Neither adverse reactions nor abnormal laboratory change were observed.

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Cefclidin (CFCL), a new cephem antibiotic, was basically and clinically evaluated to provide the following results:
1) Antimicrobial activity: CFCL exhibited excellent activity against not only the gram-positive cocci but the gram-negative rods, especially against Pseudomonas aeruginosa, Enterobacter cloacae and Citrobacter freundii. The activities of CFCL against Streptococcus pyogenes, Escherichia coli and Klebsiella pneumoniae were equal or superior to those of ceftazidime (CAZ) and the other reference drugs, however the activities against Streptococcus pneumoniae and Haemophilus influenzae were slightly inferior to those of other reference drugs.
2) CFCL concentrations in serum and sputum: 1 or 2 grams of CFCL was drip infused for 1 hour to two or one patients with chronic respiratory tract infection to measure its serum and sputum levels by bioassay, respectively. Peak serum levels were 58 and 45μg/ml in the 1 gram group and 137μg/ml in the 2 gram patient at the end of drip infusion. Peak sputum levels were 2.0 and 2.84μg/ml in the 1 gram group and 7.88μg/ml in the 2 gram patient.
3) Clinical evaluation and adverse reactions: 44 patients (20 pneumonia, 1 chlamydia pneumonia, 3 pulmonary abscess, 1 lung cancer, 8 chronic bronchitis, 4 bronchiectasis, 7 diffuse panbronchiolitis) were treated with 2 grams daily of CFCL for 4-33 days. The clinical efficacy rate was 85.4%(pneumonia and pulmonary abscess 91.3%, chronic respiratory infection 77.8%). The bacteriological efficacy rate was 92.9%.
Skin eruption in 2 patients, fever in 1, and squeeze feeling in 1 were observed. Mild aggravation in the liver function test was observed in 8 patients, eosinophilia in 4 (both in 2 patients), elevation of BUN in 1, and anemia in 3 patients. Most of these abnormalities disappeared after cessation of the treatment. We therefore conclude that CFCL is a useful antibiotic agent against bacterial respiratory infections.

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Cefclidin (CFCL) is a new cephalosporin antibiotic, which possesses potent antipseudomonal activity. We performed laboratory and clinical studies on the drug to evaluate its usefulness in respiratory tract infections. The antibacterial activity of CFCL against respiratory pathogenic bacteria was high: its MIC₅₀ (the minimum concentration at which 50% of isolate were inhibited) of CFCL at 10⁶ cfu/ml was 0.2μg/ml against Haemophilus influenzae, 0.2μg/ml against Streptococcus pneumoniae, 1.56μg/ml against Branhamella catarrhalis, 0.1μg/ml against Klebsiella pneumoniae, 25μg/ml against Staphylococcus aureus, and 1.56μg/ml against Pseudomonas aeruginosa. Antipseudomonal activity was superior to those of other β-lactam antibiotics and antimicrobial agents.
The maximal sputum levels of CFCL ranged 0.52μg/ml to 2.9μg/ml in 3 patients with respiratory tract infections and the ratios of maximal sputum levels to peak serum levels were 0.8%, 1.1%, and 4.3% in 3 patients during treatment of CFCL.
Thirty-three patients with respiratory infections were studied for clinical evaluation of CFCL, which were administered 2000mg or 4000mg of CFCL daily for 6 to 19 days. Causative organisms were H.influenzae (7), S.pneumoniae (8), B.catarrhalis (6), K.Pneumoniae (2), S.aureus (1), Pseudomonas fluorescens (1) and P. aeruginosa (11). The bacteriological effect was 88.9%, and the clinical therapeutic efficacy was 90.9%.
From these results, we concluded that CFCL was an effective and useful antibiotic for the treatment of respiratory tract infections.

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We conducted a basic study on cefclidin (CFCL), a new developed cephem antibiotic for injection, and clinically studied its application in the treatment of respiratory infections, with the following results.
1. Antibacterial activity
Against 930 strains of 27 species isolated from clinical materials (193 strains of Gram-positive cocci, 26 of Branhamella catarrhalis, 456 of enterobacteria, 278 of nonglucose-fermentable Gramnegative bacilli, and 23 of Bacteroides fragilis) the minimum growth inhibitory concentration (MIC) of CFCL was measured by the criteria of the Japanese Society of Chemotherapy. A comparison was then made with the antibacterial activity of ceftazidime (CAZ), ceftizoxime (CZX) and latamoxef (LMOX). CFCL proved to be also active against Pseudomonas aeruginosa and Enterobacter spp.Against other species of bacteria, it was equally or more powerful than CAZ, CZX or LMOX.
2. Clinical study results
CFCL was administered to 7 patients with respiratory infections at 2-4g/day b.i.d. for 4-10 days. The clinical efficacy was rated as excellent in 4 cases and good in 3 cases. We noted eruption and fever in one case related to the antibiotic, and a mild elevation in GOT and GPT was observed in the same case. The increased level quickly normalized after withdrawal of the drug.

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We performed a laboratory and clinical evaluation of cefclidin (CFCL), a new parenteral cephalosporin, with the following results.
1) Antimicrobial activity
The minimum inhibitory concentrations (MICs) of CFCL for a total of 307 clinically isolated strains, were determined and compared with those of Piperacillin, ceftazidime, cefuzonam and ceftizoxime, using MIC2000.
CFCL had wide antimicrobial activities to the clinically isolated strains except MSSA, and MRSA. In particular, CFCL had better MICs than another compared antimicrobial agents.
2) Clinical efficacy
CFCL 1g/day or 2g/day was given to 6 patients with bacterial pneumonia, 7 patient with chronic bronchitis, 1 patient with bacterial infection complicated with bronchiectasis, and 1 patient with bacterial infection complicated with lung fibrosis, for 4 to 91 days.
Clinical responses were excellent in 2 patients, good in 9 patients, fair in 1 patient, not effective in 2 patients, and not evaluated in one patient. Clinical efficacy was 79%.
Side effects, including the elevation of intraocular pressure, were not observed in any patients.
Elevation of eosinophile was observed in 1 case.

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Antimicrobial activities and clinical efficacy of cefclidin (CFCL), a new injectable cephalosporin, were studied. The following results were obtained.
1. Antibacterial activity of CFCL
The antibacterial activity of CFCL against 11 species of 45-50 urinary pathogenic isolates from urine were studied and compared to ceftazidime (CAZ), cefsulodin (CFS) and dibekacin (DKB). CFCL was superior to CAZ in antibacterial activities against Escherichia coli and Klebsiella pneumoniae. Against Proteus mirabilis, indole-positive Proteus and Serratia marcescens, CFCL showed weaker activities than CAZ. Antibacterial activity of CFCL was superior to the other drugs against Pseudomonas aeruginosa.
2. Clinical efficacy
CFCL was administered in a daily dose of 1.0g or 2.0g for five or ten consecutive days to 31 cases by i.v. or drip infusion. In 19 cases, which satisfied the criteria of Japanese UTI Committee, excellent results were observed in 3, moderate in 13 and poor in 3 cases, with an overall efficacy rate of 84.2%. The eradication rate in bacteriological response was 96. 4% in 27 out of 28 strains. As for adverse reaction, a skin eruption was observed in 1 case (3.2%).
Slight and transient abnormal laboratory change was observed in 1 case (3.2%).

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Cefclidin (CFCL), a new derivative of injectable cephalosporins, was administered in the treatment of 39 patients with UTI, including 1 acute uncomplicated pyelonephritis (AUP) and 38 chronic complicated cystitis or pyelonephritis (CC-UTI). The results obtained were as follows.
For one AUP caused by Escherichia coli, lg a day of CFCL was given for 3 days, and the efficacy was evaluated as excellent. CC-UTI patients were treated with several dosages such as 0.5g×2, 1g×1, 1g×2, a day for a 5 day course.
The overall efficacy was evaluated as excellent in 5, moderate in 12, and poor in 7, with the rate of efficacy 71% by Japanese UTI criteria. In the bacteriological study, it was notable that 7 strains of Pseudomonas aeruginosa out of 9 were eradicated after the treatment. As for a safety profile, there were no side effects encountered. In laboratory tests there were transient and mild abnormal values which included an elevation of BUN, serum creatinine in one case, and that of S-GOT, S-GPT in another case, however they returned to normal after the discontinuance of the drug. CFCL was considered specially useful in the treatment of UTI caused by stubborn gram negative bacteria, including P. aeruginosa.

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We experimentally and clinically investigated cefclidin (CFCL), a newly developed injectable antibiotic.
The plasma level was studied in rabbits under dehydration and overhydration after a bolus injection 0.1g of CFCL.
The half-life of elimination from plasma under overhydration was identical with that of normal conditions. On the other hand, it was about 1.8 fold longer under dehydration.
In a clinical study, CFCL was given to 25 cases with chronic complicated urinary tract infection and 2 with acute epididymitis and 1 with acute prostatitis. In 20 cases which qualifed criteria of the Japanese UTI Committee, excellent results was observed in 10, moderate in 7 and poor in 3 patients, with an overall efficacy rate of 85.0%. In cases of acute epididymitis, excellent results were observed in one and fair in one case. The effect of acute prostatitis was fair in one case.
No objective and subjective side effects were observed. Abnormal findings in clinical data were shown in 5 cases. No ophthalmologic disorder was observed.

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Cefclidin (CFCL), a newly synthesized cephalosporin for intravenous injection, was evaluated both bacteriologically and clinically for urinary tract infections, and the following results were obtained.
CFCL showed strong antibacterial activity against 8 species of bacteria isolated from the urinary tract. CFCL showed especially stronger antibacterial activity against Citrobacter spp., Enterobacter spp. and Pseudomoruzs aeruginosa than other cephalosporins (ceftazidime, cefuzonam and ceftizoxime).
Twenty-four patients with complicated urinary tract infections were treated with 0.5 or 1.0g of CFCL twice a day for 5 days, and clinical efficacy was evaluated according to the criteria proposed by the Japanese UTI Committee. The overall efficacy rate was 78%.
Adverse reactions were observed in two patients, eruption with eosinophilia in one patient, and aggravation of liver function in another.
These results suggested that CFCL was useful in the treatment of urinary tract infections, especially those caused by Citrobacter spp., Enterobacter spp. and P.aeruginosa.

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We studied the antibacterial activity and clinical efficacy of cefclidin (CFCL), a new injectable cephem antibiotic.
1. Antibacterial activity: We determined the MICs of CFCL against clinical isolates (209 strains of 14 species) from urinary tract infections, and compared them with those of cefoperazone, latamoxef and ceftazidime.
Against Enterococcus faecalis, CFCL had weak antibacterial activity. Against other species, especially Pseudomonas aeruginosa, however, antibacterial activity of CFCL were superior to those of the comparative drugs.
2. Clinical efficacy: Thirty-six patients with complicated urinary tract infection were treated twice a day with 0.5g or 1.0g of CFCL. Out of 36, 28 cases were evaluated according to the criteria of the Japanese UTI Committee, the overall clinical efficacy rate was 53.6%. Bacteriologically, 38 of 46 strains (82.6%) were eradicated. No side effect were observed. In 3 patients, abnormal laboratory findings were noted, but were not problematic clinically.

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Cefclidin (CFCL), a novel parenteral antibiotic was administered to 47 patients with complicated urinary tract infections and the results obtained are given below.
1) In 44 cases which were evaluated according to the criteria of the Japanese UTI Committee, excellent results were observed in 19 and moderate results in 20 cases, with an overall efficacy rate of 88.6%.
2) In the results classified by the types of infection, the efficacy rate was 100% in the cases without indwelling catheter.
3) Bacteriologically, 71 out of 74 strains (95.9%) were eradicated.
4) No side effects of the drug were noticed clinically. Abnormal findings in clinical data were odserved in 2 cases of eosinophilia, 5 cases of elevation of GOT and/or GPT, and one case of elevation in ALP and γ-GTP.

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