Cefepime (BMY-28142, CFPM), a new parenteral cephalosporin was evaluated for itsin vitroandin vivoantibacterial activity and compared it with ceftazidime (CAZ), cefuzonam (CZON), cefotaxime (CTX)and cefmenoxime (CMX). CFPM showed a wellbalanced, broad spectrum of activity against a number of clinical isolates. The activity of CFPM against Gram-positive bacteria was several times greater than that of CAZ, nearly comparable to CTX and CMX, and slightly weaker than CZON. Enterobacteriaceae, CFPM showed superior activity to the reference cephalosporins againstProvidencia stuartii, Providencia rettgeri, Morganella morganii, Citrobacter freundiiandEnterobacter cloacae. The activity of CFPM againstPseudomonas aeruginosawas comparable to that of CAZ. CFPM was more stable than CZON, CTX and CMX to various types of β-lactamases from Gram-negative bacteria. The bactericidal activity of CFPM was demonstrated by a time-kill curve withEscherichia coliandP. aeruginosa. CFPM resulted in a time-kill curve similar to that of CAZ. The highin vitroactivity of CFPM was reflected in itsin vivoefficacy against experimental infections in normal and immuno-suppressed mice. CFPM was the most effective among the cephalosporins tested against Gram-negative bacteria infections.

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The antibacterial activity of cefepime (CFPM, BMY-28142) againstEnterobacter cloacaeandCitrobacter freundiiand interactions of CFPM with these bacteria's cephalosporinases were studied in comparison with cefotaxime (CTX) and ceftazidime (CAZ). CFPM showed superior activity against CTX-resistant (MIC≤25μg/ml) strains ofE. cloacaeandC. freundiito those of CAZ and CTX:more than 90 % of these strains were inhibited by CFPM at 1.56μg/ml. In the presence of an inducer for cephalosporinase, the antibacterial activities of CTX and CAZ against susceptible strains were reduced much more than that of CFPM, indicating that the activity of CFPM is less affected by cephalosporinase-production than those of the other two agents. On the other hand, the ability of CFPM to induce cephalosporinase activity ofE. cloacaeandC. freundiistrains was equal to or somewhat lower than that of CTX and higher than that of CAZ. In hydrolysis and inhibition studies, CFPM showed much higher Km and Ki values for cephalosporinases ofE. cloacaeGN 7471 andC. freundiiGN 7391 than did CTX and CAZ. This low affinity of CFPM for cephalosporinases is likely to confer stability against the enzymes at the low concentrations expected in the bacterial cells and, therefore, contribute to the antibacterial activity of CFPM against cephalosporinase-producing bacteria.

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Cefepime (BMY-28142, CFPM) is a broad spectrum cephem antibiotic effective against both Gram-positive and Gram-negative bacteria including staphylococci andPseudomonas aeruginosa. The MIC₉₀of CFPM to methicillin-sensitiveStaphylococcus aureus (MSSA), methicillin-resistantS. aureus (MRSA), coagulase negative staphylococci, Streptococcus pyogenes, other β-streptococci, Streptococcus pneumoniae, Enterococcus faecium, Enterococcus faecalis, Escherichia coli, Klebsiellaspp., Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, Providencia rettgeri, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Pseudomonas aeruginosa, Pseudomonas cepacia, Acinetobacter calcoaceticus, ampicillin-resistantHaemophilus influenzaeandBacteroides fragiliswere 6.25, >100, 50, 0.025, 0.1, 0.05, >100, >100, 0.1, 0.2, 0.1, 0.2, 0.05, 0.05, 0.05, 0.39, 0.78, 0.39, 6.25, 6.25, 25, 0.2 and>100μg/ml, respectively, using 15 to 51 clinical isolates. CFPM manifested stronger binding affinities to PBP_s1 and 2 ofS. aureus, PBP_s1B_sand 2 ofE. coli, and PBPS 1B and 1C ofS. marcescensthan ceftazidime (CAZ). CFPM possesses the same binding affinity to the PBP_sofP. aeruginosaas CAZ. Synergy with complement in producing its bactericidal effect was clearly demonstrated on the cells ofE. coli. The cells ofE. coliwere well phagocytosed and rapidly digested by mouse cultured macrophages in the presence of a higher than 1/4 MIC of CFPM.

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Cefepime (CFPM, BMY-28142) is a newly developed parenteral cephem antibiotic. Thein vitroandin vivoantibacterial activity of CFPM was evaluated and compared with ceftazidime (CAZ), cefoperazone (CPZ), cefuroxime (CXM), cefuzonam (CZON) and cefsulodin (CFS). Thein vitroantibacterial activity of CFPM againstStaphylococcus aureus (methicillin-sensitiveS. aureus: MSSA), coagulase negative staphylococci, andStreptococcus pyogeneswas more active than CAZ. Its activity againstStreptococcus pneumoniaewas comparable to that of CAZ. Enterococci andClostridium difficilewere more resistant to the cephalosporins tested. CFPM was more active than CAZ and CPZ against family Enterobacteriaceae. CFPM was equivalent to CAZ againstPseudomonas aeruginosaandAcinetobacter calcoaceticus.Against Haemophilus influenzaeandBordetella pertussis, CFPM was comparable to CPZ but more active than CAZ. The cephalosporins tested were very potent againstNeisseria gonorrhoeae (non-PPNG and PPNG). CFPM had excellent activity against a broad spectrum of clinical important pathogens, including staphylococci and streptococci to a wide variety of opportunistic Gram-negative rods. CFPM was stable to Richmond types and cefuroximase in β-lactamase. In systemic infections withS. aureus, Escherichia coli, Klebsiella pneumoniaeandP. aeruginosa. CFPM was more effective than CAZ and CPZ. AgainstSerratia marcescens, CFPM was more active than CPZ but inferior to CAZ. In respiratory tract infection withK. pneumoniaein normal mice, the therapeutic effect of CFPM was more effective than that of CAZ. In the case of respiratory tract infection withS. pneumoniaein neutropenic mice, the therapeutic effect of CFPM was more effective than that of CAZ. In urinary tract infection withE. coli, the therapeutic effect of CFPM was more effective than CAZ. In the case of urinary tract infection withP. aeruginosa, CFPM was more effective than CAZ and CFS. Serum, lung tissue and kidney tissue levels of CFPM showed similar pharmacokinetic patterns in CAZ. These findings suggest that CFPM is clinically useful as a parenteral cephalosporin antibacterial agent.

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The antibacterial activity of cefepime (BMY-28142, CFPM) against anaerobic bacteria was evaluated. CFPM was relatively active against the genusBacteroideswith the exception ofBacteroides fragilisgroup organisms, the genusFusobacteriumwith the exception ofFusobacterium varium, Gram-positive anaerobic cocci, and the genusClostridiumwith the exception ofClostridium difficileandClostridium septicum. The activity was almost the same as that of ceftazidime. CFPM was less stable to β-lactamase derived fromB. fragilisthan ceftazidime, but more stable than cefpiramide, cefotiam, cefotaxime and cefazolin. Although overgrowth ofC. difficilewas observed in 40% of mouse caecum one day after the last dosing of CFPM, C. difficilewas not detected 7 days after.

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Alteration of fecal flora was studied in six healthy male volunteers receiving cefepime (CFPM), a new cephalosporin, at a dose of one gram twice a day for five days. The treatment caused little change in fecal flora except pronounced decrease or elimination inEscherichia coliandLactobacillusspp.; these organisms were normalized after cessation of cefepime administration. Overgrowth ofCandidaspp. andPseudomonasspp. was not seen in all volunteers. A small number ofClostridium difficilewere detected temporarily in only one of six volunteers, who developed no loose feces nor diarrhea.

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Thein vitroandin vivoantibacterial activities of cefepime (CFPM, BMY-28142), a new parenteral cephem antibiotic, were compared with those of cefoperazone (CPZ), cefmenoxime (CMX), ceftazidime (CAZ) and cefuzonam (CZON). The following results were obtained. CFPM had a broad antimicrobial spectrum against Gram-positive and Gram-negative bacteria, and it's antibacterial activity was almost equal to those of CPZ and CMX againstStaphylococcus aureusandStaphylococcus epidermidisamong Gram-positive bacteria and similar to that of CMX againstStreptococcusspp. All the cephem antibiotics tested were inactive againstEnterococcus faecalis. On the other hand, its activity against Gram-negative bacteria, like those of CMX and CZON, was very high. Activity was also similar to that of CAZ againstPseudomonas aeruginosa. In the sensitivity distribution of clinically isolated strains, the MIC₅₀values (μg/ml) of CFPM were 1.56 forS. aureus, 0.78 forS. epidermidis, 0.025 forStreptococcus pyogenes, <0.006 forStreptococcus pneumoniae, 0.05 forEscherichia coli, 0.05 forKlebsiella pneumoniae, 0.05 forProteus vulgaris, 0.025 forMorganella morganii, 0.10 forEnterobacter aerogenes, 0.39 forSerratia marcescens, 0.10 forHaemophilus influenzae, 0.39 forBranhamella catarrhalis, 3.13 forAcinetobacter calcoaceticusand 1.56 forP. aeruginosa. CFPM showed concentration-dependent bactericidal action againstE. coli, A. calcoaceticusandP. aeruginosa. In a morphological examination by phase-contrast microscope, CFPM induced the formation of filamentous cells, spheroplast-like structures and lysis ofE. coli, S. marcescensandP. aeruginosa.The therapeutic efficacy of CFPM against experimental intraperitoneal infections in mice was comparable to those of CPZ and CZON againstS. aureusand inferior to that of CPZ and superior to those of CAZ and CMX againstS. pneumoniae. On the other hand, the therapeutic efficacy of CFPM was superior to those of reference cephem antibiotics againstE. coli, K. pneumoniaeandS. marcescens, and similar or inferior to that of CAZ and superior to those of CPZ and piperacillin againstP. aeruginosa.

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The antibacterial activity (MIC) of cefepime (CFPM) and other antibiotics against bacteria isolated from clinical cases in 1988 was evaluated and the results were as follows.
1. The activity of CFPM against coagulase-negative staphylococci (CNS) andStreptococcus pneumoniaewas greater than ceftazidime (CAZ), and almost equal to cefotaxime (CTX).
2. CFPM showed strong activity against CTX-resistantCitrobacter freundiiandEnterobacterspp., This result suggests that CFPM has low binding affinity to β-lactamase.
3. MIC₅₀ of CFPM against norfloxacin-resistantSerratia marcescensandPseudomonas aeruginosawas high. Denaturation of the protein structure of the outer membrane of strains which are highly resistant to new-quinolone drugs results in low permeability and CFPM's high MIC₅₀ value.
4. CFPM has a new antibacterial profile; i. e. strong antibacterial activity (related to low β-lactamase binding affinity) in strains resistant to oxime type cephems.

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Thein vitroandin vivoantibacterial activity of cefepime (BMY-28142, CFPM), a new parenteral cephalosporin, was evaluated in comparison with ceftazidime (CAZ), cefmenoxime(CMX) and cefoperazone (CPZ). CFPM showed a well-balanced broad spectrum of activity against Grampositive and-negative bacteria isolated clinical speciments. Its activity against Enterobacteriaceae, such asEscherichia coli, Klebsiellaspp., Proteus mirabilis, Providencia rettgeri, Citrobacter diversuswas almost equal to that of CAZ, CMX and CPZ. CFPM demonstrated superior activity to CAZ, CMX and CPZ againstMorganella morganii, Providencia stuartii, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Serratia marcescens. The activity of CFPM againstPseudomonas aeruginosa, Pseudomonas cepaciaandAcinetobacter calcoaceticuswas very comparable to that of CAZ. CFPM showed potent activity against various types of β-lactamase-producing organisms. The MIC values ranging from 0.025 to 1.56μg/ml for CFPM indicate good stability against β-lactamases. The antibacterial activity of CFPM was slightly affected by the addition of serum or culture media or by the pH of the medium. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of CFPM were similar to a variety of bacteria. The remarkablein vitroantibacterial activity of CFPM was reflected in itsin vivoefficacy against various type of experimental infections in mice. CFPM was eight times more effective than CAZ againstS. aureus, E. coli, M. morganiiandE. cloacae infections, and as effective as CAZ againstS. pyogenes, K. pneumoniae, P. aeruginosainfections.

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In studies with infected mice, cefepime (CFPM) was found to be more effective when administered as multiple injections than as a single injection againstStaphylococcus aureusSmith, Escherichia coliJuhl andPseudomonas aeruginosaA9843A. On switching from single to triple administrations, the PD₅₀s(protective dose 50%) of CFPM improved from 1.1, 0.09 and 6.8 mg/kg to 0.60, 0.06 and 2.04 mg/kg againstS. aureusSmith, E. coliJuhl andP. aeruginosaA9843A, respectively. Such an effect was not observed with ceftazidime (CAZ).In vitrobactericidal activity was studied by model systems simulating the blood levels of CFPM and CAZ in mice after single (20 mg/kg) and triple (6.7 mg/kg×3) intramuscular injections, respectively. Thein vitrobactericidal activity of CFPM was approximately equal to that of CAZ in model systems simulating the blood levels of these compounds in mice. Thein vitrobactericidal activity of CFPM was higher than that of CAZ whenE. coliJuhl was exposed to CFPM or CAZ for 60 min. Inin vivoexperiments, the bactericidal activity of CFPM was as high as that of CAZ, and CFPM inhibited re-growth ofP. aeruginosaA9843A long term in mice.

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A microbiological assay (bioassay) and HPLC methods for quantitative determination of cefepime (CFPM) in body fluids were investigated. The drug was studied by agar-diffusion microbiological assay using Morganella morganii IFO 3848 as the test organism and Modified Antibiotic Medium 2 as the test medium. The minimum detectable concentrations of CFPM in human serum were 0.02μg/ml for the cup-plate and agar-well methods and 0.16μg/ml for the disc-plate method. The lowest detectable concentrations of CFPM in the buffer were 0.02μg/ml for the cup-plate and agar-well methods and 0.04μg/ml for the disc-plate method. Standard solutions prepared with human serum and 1% phosphate buffer (pH 6.0) should be used for the assay of serum and urine samples. The concentrations of CFPM in serum and urine determined by bioassay correlated well with those determined by HPLC. No bioactive metabolites of CFPM were observed in human urine samples. CFPM in human plasma and urine was stable at-20°C for at least 30 days.

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The comparative phamacokinetics of cefepime (CFPM) and ceftazidime (CAZ) were studied in rats after intravenous administration of 20mg/kg. The C_max, T_1/2 and area under the curve (AUC) of CFPM, 5 minutes after an intravenous administration of 20mg/kg, were 51μg/ml, 18 minutes and 23.8μg·h/ml, respectively. Both CFPM and CAZ showed similar phamacokinetics, although the AUC of CAZ was slightly greater than that of CFPM. Tissue levels of CFPM were higher than CAZ in kidney, lung, muscle, skin, stomach, small intestines, cecum and eye. Both compounds demonstrated appreciable brain tissue levels. The urinary recovery of CFPM was higher than that of CAZ, whereas biliary recovery of both compounds was very low. No bioactive metabolites were observed in the feces, urine and bile of rats given CFPM and CAZ. The serum-protein binding rate of CFPM was slightly higher than that of CAZ in all sera tested.

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A phase I clinical study of cefepime (CFPM), a new parenteral cephem was performed in 21 healthy male volunteers in order to evaluate its safety and pharmacokinetic profile. Initially, 5 fasted subjects were administered a single 0.5g dose of CFPM intravenously over 30 minutes. After confirmation of safety at the 0.5g dose, a single dose of 1g was given to 5 subjects, and then a dose of 2g to 5 subjects. In the multiple dose study, 6 subjects received 1g of CFPM twice a day (every 12h) for 5 consecutive days (total 9 doses). The following results were obtained.
1. No symptoms were reported during the single dose study except in 1 subject recieving the 1g dose, who developed urinary retention 6 hours after administration. One subject in the multiple dose study complained of transient headache on the 9th administration which disappeared without any treatment. Otherwise, no abnormalities were observed in clinical symptoms and signs or laboratory tests.
2. The blood concentration after single doses of 0.5g, 1g and 2g demonstrated dose proportionality. The half-lives of the 3 treatment groups were 1.75, 1.76 and 1.94h, respectively. The cumulative urinary excretion in the form of unchanged CFPM in the single dose study within 24h was about 79.8-89.0% of the administered dose.
3. The half-life in the multiple dose study was 1.90 h and 73.7-83.5% of the administered dose was excreted in the urine within 12h. There was no evidence of accumulation in serum or urine.

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The pharmacokinetics, susceptibility and clinical efficacy of cefepime (CFPM), a new parenteral cephem antibiotic, were investigated.
1. Pharmacokinetics: CFPM was intravenously administered in single doses of 250mg, 500mg and 1000mg (nominal potency) to 6 healthy male adult volunteers with intervals of one week between injections. The blood levels of CFPM at 5 minutes after administration were 36.8μg/ml, 68.5μg/ml, and 119.2μg/ml for the 250mg, 500mg and 1000mg doses respectively. T_1/2β were 1.60, 1.59 and 1.66 h, respectively. The urinary recovery rates within 8h were 73.5, 74.5 and 75.2%, respectively.
2. Susceptibility: The susceptibility of CFPM against 180 clinical isolates of 7 species with an inoculum size of 106 cells/ml was studied. Cefotaxime (CTX) and ceftazidime (CAZ) were used as controlled drugs. The MIC₉₀ of CFPM against Escherichia coli, Klebsiella sp., Proteus mirabilis and Morganella morganii were all 0.1μg/ml with good susceptibility. The MIC₉₀ were superior to those of CTX and CAZ.
3. Clinical efficacy: Eleven patients with infections (respiratory tract infections 3, and urinary tract infections 8) were treated with excellent responses in 5 and good responses in 6. The efficacy rate was 100%. No adverse reactions or abnormal laboratory findings were observed.

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Cefepime (CFPM), a new cephem, was given to 10 patients with respiratory tract infection and the clinical response was examined. Diagnosis were as follows; 2 cases of acute bronchitis, 2 chronic pulmonary emphysema, 1 chronic obstructive lung disease (COLD), 1 chronic bronchitis, 1 pneumonia, 1 pulmonary fibrosis, 1 bronchiectasis and 1 bronchial asthma. One gram of the drug was dissolved in 100 ml of saline, and patients received 2 g daily via i.v. drip infusion. The duration of dosing ranged from 4-7.5 days. Clinical efficacy was excellent in 3 patients, good in 5, fair in 1 and poor in 1. The efficacy rate was 80%. The causative organisms isolated were Haemophilus influenzae; 4 strains, Branhamella catarrhalis; 2, Streptococcus pneumoniae; 3, Pseudomonas aeruginosa; 1, Serratia marcescens; 1, Acinetobacter calcoaceticus; 1 and Flavobacterium sp.; 1. All organisms isolated were eliminated. Concentrations of CFPM in serum and sputum were measured in three patients with respiratory tract infection, who were given the drug as a single intravenous dose of 1.0g. Peak serum levels were 56.9-84.4μg/ml and half-life was 1.5-2h. Peak sputum levels ranged from 0.79-33μg/mL after 1-2h. In all patients side effects were not observed. As to laboratory examination, a transient slight elevation of GOT and GPT was noted in 2 patients.

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Thein vitro antimicrobial activity of cefepime (CFPM), a new cephalosporin agent for parenteral use was measured and its therapeutic efficacy in respiratory infection was evaluated. The minimum inhibitory concentrations (MICs) of CFPM, ceftazidime (CAZ) and latamoxef (LMOX=moxalactam) against 20 strains each of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterbacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined by a microbroth dilution method using the Dynatech MIC 2000 system. As shown by MICs, CFPM was the most active of the 3 agents tested against S. aureus and Enterobacteriaceae. On the other hand, CFPM was somewhat less active against P.aeruginosa than CAZ. A daily dose of 2 gram of CFPM was given intravenously for 4-15 days (mean: 10.3 days) to 12 patients: 7 with acute pneumonia, 1 with lung abscess, 1 with infection supervening on old pulmonary tuberculosis and 3 with infection supervening lung cancer. The clinical efficacy were good in 6 and poor in 4. Two cases with Mycoplasma pneumoniae pneumonia were excluded from clinical evaluation. Two strains of Streptococcus pneumoniae and 3 strains of Haemophilus influenzae were identified as causative organisms and all them were eradicated by an administration of CFPM. Drug exanthema and eosinophilia were each observed in one patient. These adverse reactions disappeared after completion of the therapy. From the above results, we conclude that CFPM is one of the most useful cephalosporin agents for parenteral use as a first choice in the treatment of respiratory infection.

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Bacteriological and clinical studies on cefepime (CFPM), a new injectable cephalosporin, were carried out and the following results were obtained. The MICs of CFPM for 429 clinical isolates of 22 species were compared with those of the other antibiotics, cefuzonam (CZON), latamoxef (LMOX), cefmenoxime (CMX), cefoperazone (CPZ), ceftazidime (CAZ), imipenem/cilastatin sodium (IPM/CS), sulbactam/CPZ (SBT/CPZ). Among Gram-positive cocci, the MICs of CFPM were superior to those of CZON, CMX, IPM/CS against Staphylococcus aureus and Streptococcus pneumoniae. Among Gram-negative bacilli, CFPM was more effective against Enterococcus cloacae and Morganella morganii than any other antibiotics tested. The MICs of CFPM were also superior or equal to those of CAZ, CMX and IPM/CS against Escherichia coli, Proteus mirabilis and Pseudomonas aeruginosa. In a clinical trial, CFPM was administered to 13 patients with respiratory tract infections (pneumonia 11, bronchiectasis 2) by intravenous drip infusion at a dose of 2.0g/day. The duration of treatment ranged from 10 to 15 days. Clinical response was excellent in 3 cases, good in 8 with an overall efficacy rate of 84.6%. No side effects were observed. As for abnormal laboratory findings, a slight elevation of GOT and GPT were observed in one case, respectively.

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Cefepime (CFPM), a new cephem antibiotic, was studied clinically.
1. The influence of probenecid was investigated, 6 healthy volunteers were administratedintravenously 1.0g of CFPM with or without probenecid according to a cross-over study design.Probenecid was given 1.0g,
2 hours before and 0.5g, 4 hours after the administration of CFPM. There was no difference between pharmacokinetic parameters with or without probenecid.
2. CFPM was administerted to a patient with chronic bronchitis. The clinical efficacy was good. No side effects or abnormal laboratory findings were observed.

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Minimum inhibitory concentration (MIC) of cefepime (CFPM), a newly developed antibiotic. against 29 strains of Escherichia coli, 19 of Klebsiella pneumoniae, 10 of Enterobacter cloacae. and 17 of Pseudomonas aeruginosa isolated from blood of patients admitted to Keio University Hospital between 1987 and 1988 were determined by the agar plate two fold dilution method. The MICs of ceftazidime (CAZ) and imipenem (IPM) were also determined against these strains. The MIC of CFPM ranged from≤0.01μg/mI to 0.1μg/ml against E. coli, 0.02μg/ml to 3.13μg/ml against K. pneumoniae, 0.02μg/ml to 3.13μg/ml against E. cloacae and 0.78μg/ml to 25μg/ml against P.aeruginosa, respectively. The MIC₉₀ of CFPM against E. coli and K. pneumoniae were 0.05μg/ml and 0.1μg/ml. The MIC₉₀ of CFPM was 0.78μg/ml against E. cloacae and 25μg/ml against P.aeruginosa. The antibacterial activity of CFPM against these strains was superior to that of CAZ.CFPMM was more active than 1PM against E. coli and K. pneumoniae. CFPM was as active as IPIVI cloacae and P. aeruginosa. These data show that CFPM will be a drug of first choice for the t E. coil and K. pneumoniae septicemia.

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The antibacterial activity, absorption, excretion and clinical efficacy of a new cephem, cefepime, were studied with the following results.
1) Antibacterial activity: MICs₅₀ of cefepime for 25 strains each of clinically isolated StaPhylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa and methicillin-resistant S. aureus were 1.56, 0.025, 0.025, 0.025, 3.13, 12.5μg/ml respectively.
2) Absorption and excretion: The blood level and urinary excretion of cefepime were investigated in 2 healthy volunteers after single drip infusion of 1.0g dose. Peak serum concentrations of 79.6 and 86.2μg/ml were achieved at the end of the drip infusion, decreasing to 0.52 and 0.42 At eml at 12 hours after administration. The urinary excretion rates within 12 hours were 72.4 and 76.5%.
3) Clinical efficacy: The clinical efficacy of cefepime were studied in a total of 11 patients (5 with acute bronchitis, 2 with bacterial pneumonia, 1 with acute pyelonephritis, 1 with cystitis, 2 with cholecystitis). Cefepime was administered at a dose of 1.0g once or twice a day. Clinical efficacy was assessed as good in 4 out of 5 cases of acute bronchitis and in all cases of bacterial pneumonia, acute pyelonephritis, cystitis and cholecystitis. No adverse reactions attributable to the drug were observed.

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Laboratory and clinical studies were carried out with cefepime (CFPM), a new injectable cephem, yielding the following results.
1. Antibacterial activity: The antibacterial activity in 365 strains of 10 species (clinical isolates) was compared with that of ceftazidime (CAZ), piperacillin (PIPC) and cefoperazone (CPZ). The antibacterial activity of CFPM against methicillin-sensitive Staphylococcus aureus (MSSA) equaled those of PIPC and CPZ. In particular, against Gram-negative bacteria (including Escherichia coil, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens) CFPM had the highest activity among these antibiotics. CFPM was also close in efficacy to CAZ against Pseudomonas aeruginosa.
2. Clinical efficacy: CFPM was administered to 8 patients with various infections ; pneumonia 5, l ower respiratory tract infection 1, acute cholecystitis 1, decubitus infection 1. No side effects were observed. Laboratory investigation revealed transient rise of transaminases levels in 2 cases, transient rise of LDH in 1 case, neutropenia in 1 case and monocytosis in 1 case.

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Bacteriological and clinical studies with cefepime (CFPM), a new parenteral cephalosporin antibiotic were performed, yielding the following results.
1. Antimicrobial activity
The MICs of CFPM against various clinical isolates were determined with an inoculum size of 10⁶ cells/ml. The MIC₈₀ was 3.13μg/ml for Staphylococcus aureus, 25 for Enterococcus faecalis, ≤0.05 for Escherichia coli, 0.20 for Klebsiella pneumoniae, 0.39 for Enterobacter spp. and Serratia marcescens, 0.10 for Proteus spp., 0.78 for Citrobacter freundii, 6.25 for Acinetobacter calcoaceticus and 12.5 for Pseudomonas aeruginosa. Its activity against Gram-positive cocci was less than cefuzonam and cefmenoxime, but against Gram-negative rods, it was more active than ceftazidime, cefotaxime, cefmenoxime and cefuzonam.
2. Clinical efficacy
One patient with pneumonia, 2 with purulent meningitis, 1 with sepsis, 1 with perianal abscess and 1 with ankylosing spondylitis were treated with CFPM at a daily dose of 2.0-4.0g for 3-17 days. Clinical response was excellent in 1, good in 1, fair in 1, poor in 2 and unknown in 1 patient. S. aureus, E. faecalis, Streptococcus milleri, Streptococcus mitis were eradicated by CFPM. No adverse reactions and no abnormal changes of laboratory investigations were observed.

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The antimicrobial activity against species isolated in our department and the sputum levels of cefepime (CFPM), a new parenteral cephem, were studied with the following results.
1. Antimicrobial activity: The MIC's of 766 strains [241 of Gram-positive cocci (GPC), 34 of Branhamella catarrhalis, 361 of Enterobacteriaceae, 130 of glucose non-fermentative Gram-negative rods (NF-GNR)] of 17 species isolated from clinical samples were measured according to the criteria of the Japan Society of Chemotherapy. Those of CFPM were compared with ceftazidime (CAZ), cefotaxime (CTX), imipenem (IPM) and aztreonam (AZT). CFPM had broad antimicrobial activity against GPC and GNR including Staphylococcus aureus and Pseudomonas aeruginosa and was not less potent than CAZ, CTX, IPM and AZT.
2. Sputum levels: 1g of CFPM was administered to 3 patients by drip infusion and sputum levels were measured. The sputum peak levels were 0.56, 2.0, 2.7μg/ml 1 or 2 hours after completion of drip infusion.

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The new developed broad-spectrum cephalosporin, cefepime (CFPM), was evaluated in vitro and in vivo in comparison with ceftazidime (CAZ), cefoperazone (CPZ), cefotaxime (CTX), piperacillin (PIPC) and gentamicin (GM). The results were as follows;
1. Antimicrobial activity: Minimal inhibitory concentration (MICs) against 210 clinical isolates including 7 different species were determined by microbroth dilution method. CFPM showed excellent antimicrobial activity against Gram-positive and -negative bacteria except methicillin-resistant Staphylococcus aureus. MICs of CFPM were the same or greater than those of the other 3rd generation cephems, PIPC and GM even against Pseudomonas aeruginosa.
2. CFPM concentration in serum and sputum: A patient with diffuse panbronchiolitis was given 1g of CFPM intravenously and its concentration in serum and sputum were measured at intervals using HPLC. A peak serum concentration of 30μg/ml was achieved at the end of the 60 minutes infusion, and peak sputum level of 2.0μg/ml was observed 3-4 hours after the infusion. This suggests that CFPM has rapid and good penetration into the lung.
3. Clinical efficacy and adverse reactions: Twenty one patients with respiratory tract infections were treated with CFPM with an overall efficacy rate of 84.2 %(excellent in 3 cases, good in 13, fair in 1, poor in 2, not evaluable in 2). As to side effects, skin eruption in 1 case, ill feeling in 1 and abdominal pain with loosen stool in 1 were observed. Elevation of LDH in 1 case, GPT and γ-GTP in 1, GPT in 1, and decrease of leukocyte, monocyte, platelets and elevation of GOT, LDH, totalbilirubin, urobilinogen in 1 were observed as abnormal laboratory findings. Most of these were mild and improved rapidly after completion of CFPM. However, slight elevation of GPT in 1 case and a positive reaction in the direct Coombs test in another case have not been followed up.

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Cefepime (CFPM) is a new aminothiazole-methoxyimino cephalosporin which bears a quaternized 1-methylpyrrolidine attached to the 3-position methylene. The usefulness of CFPM in the treatment of bacterial respiratory tract infection was evaluated. The antimicrobial activity (50% minimum inhibitory concentration: MIC₅₀) of CFPM against major respiratory pathogenic organisms was 0.05μg/ml against Streptococcus pneumoniae, 0.2μg/ml against Haemophilus influenzae, 0.39μg/ml against Branhamella catarrhalis, 6.25μg/ml against Staphylococcus aureus, and 6.25μg/m; against Pseudomonas aeruginosa. The concentrations in serum, sputum and bronchial secretion were determined by bioassay using Morganella morganii IFO 3848 as a test organism in patients with respiratory infection receiving i.v. drip infusion of CFPM (1g b.i.d.). The maximal concentrations of CFPM in serum (n=2) were 74.3 and 85.2 μg/ml. Serum half-lives (n=3) ranged from 2.3 2.9 h. The sputum levels (n=2) ranged from 0.25-1.48 μg/ml and the bronchial secretion level (n=1) was 4.3 genii. The ratio of maximal sputum level to maximal serum level as a percentage in one case was 1.74%. Nineteen cases of respiratory infection were subjected to clinical evaluation with CFPM, and received i.v. drip infusion of CFPM (1g b.i.d.). Bacteriological eradication rate was 100% for all S. pneumoniae (8), H. influenzae (3), B. catarrhalis (1), Klebsiella sp.(2) and Escherichia coli (1), isolates. Two strains of P. aeruginosa, one strain each of S. aureus and Xanthomonas maltophilia were not eradicated. The overall eradication rate and clinical efficacy for CFPM were 78.9%(15/19 strains) and 84.2%(16/19 cases), respectively. No adverse drug side effects or abnormalities of laboratory findings were seen in these cases. In summary, CFPM is a most effective cephalosporin antibiotic in the treatment of bacterial respiratory infection.

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Pharmacokinetic, bacteriological and clinical studies were performed with cefepime (CFPM), a new i. v. cephem, yielding the following results.
1) CFPM was administered (by intravenous drip infusion 2 g b. i. d. for 5 days) to 6 healthy male volunteers to study its safety and pharmacokinetics. No abnormalities were observed in symptoms, signs or laboratory tests. There was little variation in serum levels between day 1 and day 5, nor any tendency to accumulation.
2) The in vitro antibacterial activity of CFPM against clinical isolates of 14 species was studied and compared with that of other antibiotics. As shown by MICs, CFPM was more active against Gram-positive bacteria than ceftazidime (CAZ) As for Gram-negative bacteria, CFPM was more active than CAZ, except against Pseudomonas aeruginosa and Branhamella catarrhalis.
3) We administered CFPM to 9 patients with respiratory.tract infections at a dose of 1-2 g twice a day for 6-13 days. The clinical efficacy were excellent in 1 case, good in 4 cases, fair in 1 case and poor in 3 cases. No side effects were observed. From laboratory investigation eosinophilia was noted in 1 case and a slight elevation of GOT, GPT, Al-P and LAP was noted in 1 case.

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Antimicrobial activities and clinical studies on cefepime (CFPM), a new injectable cephalosporin, were performed and the following results were obtained.
1. Antimicrobial activity of CFPM
Antimicrobial activity of CFPM against 11 kinds of urinary pathogenic 47-50 isolates from urine were studied and compared to ceftazidime (CAZ), cefuzonam (CZON), cefmetazole (CMZ) and latamoxef (LMOX). The antibacterial activities of CFPM against Escherichia coli and Klebsiella pneumoniae was superior to CAZ. Against Proteus mirabilis and indole (+) Proteus spp., CFPM was superior to CMZ and LMOX. Against Serratia marcescens and Pseudomonas aeruginosa, CFPM was superior to CZON, CMZ and LMOX.
2. Clinical efficacy
CFPM was administered in a daily dose of 1.0 g for ten consecutive days to 12 cases by drip infusion. In 11 cases which were included in the Japanese UTI Committee, excellent results were observed in 4, moderate in 3 and poor in 4 cases, while the overall efficacy rates in terms of bacteriological response were 80.0%(12 out of 15 strains). No adverse reactions were observed. A transient abnormal laboratory change (elevated GPT) was observed in 1 case (8.3%).

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Experimental and clinical investigation of cefepime (CFPM), a newly developed injectable cephem antibiotic, was performed. Experimentally the serum level was studied in rabbits undergoing dehydration and overhydration after a bolus iv. injection of 50 mg of CFPM. Serum concentratiom fell more quickly in dehydrated rabbits than in overhydrated rabbits. Clinically, 19 patients with chronic complicated urinary tract infection, 3 with acute pyelonephritis and one with acute prostatitis wcre treated with CFPM. Of the 16 evaluable cases, response was excellent in 7 patients, modcrate in 4 patients and poor in 5 patients according to the criteria of the UTI Committee. The overall cfficacy rate was 69%. The efficacy rate was excellent in all of acute uncomplicated pyelonephritis and acutc prostatitis patients according to investigator's evaluation. No side effects were noted, but a slight laboratory abnormality in GOT and GPT levels was observed in one case.

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A new cephem antimicrobial agent, cefepime (CFPM), was studied both bacteriologically and clinically in urinary tract infections, and the following results were obtained.
1. The antibacterial activity of CFPM against standard strains and various bacteria isolated from complicated urinary tract infections was compared with those of the controls, ceftazidime (CAZ), cefuzonam (CZON) and ceftizoxime (CZX). Of the standard strains, Gram-negative bacteria were more susceptible to CFPM than to the control drugs. Antimicrobial activity of CFPM against clinical isolates was superior to the controls, especially in the case of Enterobacter cloacae and Citrobacter freundii.
2. One patient with acute uncomplicated pyelonephritis and fifteen patients with complicated urinary tract infection were treated with CFPM at a dose of 2 giday i.v. for 5 days. According to the criteria proposed by the Japanese UTI Committee, the overall efficacy rate was 75%. Elevation of LDH and eosinophilia were noticed in one patient each during CFPM treatment. However, these reactions were mild and transient. It is concluded that CFPM is a effective and safe antibiotic for the treatment of urinary tract infections.

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Twenty patients with complicated urinary tract infection were given cefepime at a daily dose of 2.0g by intravenous drip infusion for five days, and the following results were obtained. Clinical results were excellent in 6 cases, moderate in 10 and poor in 4. The overall clinical efficacy rate was 80%. As to the bacteriological response, 38 strains were eliminated while 4 persisted out of 42. Nine new organisms appeared after treatment. During treatment the only side effect observed was a slight increase in GOT in one case out of total of 20 patients.

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Cefepime (CFPM), a new cephalosporin, was studied bacteriologically, pharmacokintically and the following results were obtained.
1) The antibacterial activity of CFPM against clinically isolated pathogens was compaired with that of ceftazidime (CAZ), cefoperazone (CPZ) and ampicillin (ABPC). Against Staphylococcus epidermidis dis, MIC₅₀ (0.78μg/ml) of CFPM was superior to that of CAZ and was very close to that of CPZ. Against strains of Escherichia coil, Citrobacter freundii, Klebsiella pneumoniac, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, MICs of CFPM were superior to those of CAZ, CPZ and ABPC, and against strains of Pseudomonas aeruginosa, MICs of CFPM was very close to those of CAZ.
2) The pharmacokinetics of CFPM were investigated in 6 healthy male volur and were compared with the results of CAZ in a cross-over test. The mean peak serum concentration 1 hour after i.v. administration measured by HPLC method was 35.9μg/ml for CFPM at a dose of 0.5g 79.7μg/ml for CFPM at a dose of 1.0 g and 74.0μg/ml for CAZ at a dose of 1.0g. The mean value of T_1/2 (β) in serum were 1.92h (CFPM) and 1.54h (CAZ) with 1.0g doses of both drugs and the AUC_0-12 were 156.7μg/·h/ml (CFPM) and 140.8μg·h/ml (CAZ). The urinary excretion rates within 12 h were 82.9% and 89.6% for 0.5 and 1.0g of CFPM respectively and 82.5% for 1.0g of CAZ.
3) CFPM was administrated to 45 patients, including 44 cases of complicated urinary tract infection (UTI) and 1 of prostatitis. The drug was given at a daily dose of 1.0 or 2.0g for 5 days by i.v. drip infusion twice a day. The clinical efficacy of CFPM in 37 cases was excellent in 10 cases and moderate in 14 cases by the UTI Committee's criteria. The overall clinical efficacy was 64.9%. The bacteriological response was 82.4%. No side effects were observed. Abnormal findings in labolatory tests were noted in 6 cases.

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The antibacterial activity, pharmacokinetics and clinical efficacy of cefepime (CFPM), a new cephalosporin antibiotic were studied in the urological field. The results were as follows.
1) Antibacterial activity: The MICs of CFPM against clinical isolates (209 strains of 14 species) from urinary tract infections were determined and compared with those of ceftazidime (CAZ), latamoxef (LMOX) and cefoperazone (CPZ). The overall antibacterial activities of CFPM were excellent and superior to those of other control antibiotics.
2) Pharmacokinetics: The pharmacokinetics were studied using 4 healthy volunteers and 7 patients with impaired renal function. The mean peak serum level and mean serum half-life of CFPM in healthy volunteers were 84.6μg/ml and 1.76 h, respectively. The serum half-lives and urinary excretion rates of CFPM tended to be prolonged in parallel with lower decrease in creatinine clearance.
3) Clinical efficacy: In chronic complicated urinary tract infection, the overall clinical efficacy rate was 73.1% according to the criteria of the Japanese UTI Committee. Bacteriologically 30 of 32 strains (93.8%) were eradicated. Side effects: No symptoms or signs related to side effects were noted. Abnormal laboratory findings were observed in 7 patients, but all of them were mild and transient.

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A pharmacokinetic study of cefepime (CFPM), a recently developed antibiotic, was performed in voluntary patients with various degrees of renal dysfunction and on those undergoing blood purification. They were divided into 5 groups according to creatinine clearance (Ccr)(>50ml/min, 30-50ml/min, 10-30 ml/min, <10ml/min, patients undergoing blood purification). CFPM was given in a single i.v. dose of 0.5g in patients at the same time (1:00 pm) except in those undergoing blood purification: who received the same dose once prior to the hemodialysis. The half-lives (T_1/2β) of CFPM were 1.82±0.06 h (Ccr:>50 ml/min), 5.50±0.80 h (Ccr: 30-50ml/min), 10.01±1.58 h (Ccr: 10-30 ml/min) and 15.63±5.56 h (Ccr:<10ml/mm), respectively. The half-lives during hemodialysis (HD), hemofiltration (HF) and continuous ambulatory peritoneal dialysis (CAPD) were 2.17±0.39 h, 1.74±0.13 h and 15.25±2.76 h, respectively. These findings suggest that CFPM should be administered to patients with Ccr of 10-50ml/min at a dosage of 0.5g twice a day, and to those with Ccr of <10ml/min at a dosage of 0.5g once a day. Furthermore, it should be administered to uremic patients undergoing HD or HF at a dosage of 0.5g before and after termination of blood purification and once on non-dialysis days, and to those undergoing CAPD at a dosage of 0.5g once a day.

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The antimicrobial activity and clinical efficacy of cefepime, a new injectable cephem was investigated. The antimicrobial activities of cefepime against 300 strains isolated from patients with urinary tract infections (UTI) at an inoculum size of 10⁶ CFU/ml were measured by the agar dilution method, and compared with those of ceftazidime (CAZ) and imipenem (IPM). Bacterial isolates consisted of 30 strains each of staphylococci, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Proteus mirabilis, Proteus vulgaris and Pseudomonas aeruginosa. The antibacterial activity of cefepime against staphylococci and E. faecalis was less than that of IPM, but was equally potent to those of CAZ and IPM against other Gram-negative rods except P. aeruginosa. Cefepime was given to 7 patients with complicated UTI at a dose of 2.0 g i.v. per day for 5 days. According to the criteria proposed by the Japanese UTI Committee, the clinical efficacy in 7 cases of complicated UTI was excellent in 2, moderate in 5, with an overall efficacy rate of 100 %. Nine of 10 urinary bacterial strains were eradicated, but one of P. aeruginosa persisted. Two patients suffered from eruption and nausea respectively. These adverse reactions were possibly related to cefepime. No abnormal laboratory findings induced by the drug were observed.

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Bacteriological, pharmacokinetic and clinical studies on cefepime (CFPM), a new cephalosporin, were investigated and the following results were obtained. Antibacterial activities of CFPM against clinical isolates were compared with those of ampicillin, piperacillin, aspoxicillin, cefazolin, cefuroxime, cefoperazone, cefotiam, cefotaxime, ceftizoxime, cefpiramide, ceftazidime, cefoxitin, cefmetazole, cefotetan, latamoxef, ceftriaxone, imipenem, tobramycin and minocycline. Activities against Pseudomonas aeruginosa were also compared with those of cefbuperazone, cefmenoxime, cefuzonam, amikacin. Activities against methicillin-resistant Staphylococcus aureus (MRSA) were compared additionally with those of cloxacillin, amoxicillin, cephalothin, cephaloridine, cefamandole, flomoxef, cefuzonam, ofloxacin, tosufloxacin, amikacin, netilmicin, vancomycin, fosfomycin. MICs of CFPM were studied against clinical isolates such as Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, P. aeruginosa and MRSA. CFPM showed excellent activity against E. coli and K. pneumoniae, and good activity against E. cloacae and P. aeruginosa. However CFPM showed lessactivity against MRSA. In 6 patients given 1.0 g of CFPM, the serum levels (n=2) were 58.35±8.56μg/ml at 5 minutes, 25.40±0.28μg/ml at 1 hour, 16.50±0.85μ/ml at 2 hours and 4.50±0.45μg/ml at 6 hours after administration. The bile levels (n=5) were 16.59±14.34μg/ml at 30 minutes, 16.74±16.26μg/ml at 1 hour, 12.51±10.69μg/ml at 2 hours and 2.12±1.97μg/ml at 6 hours after administration. The pancreatic juice levels (n=1) were 1.29μg/ml at 30 minutes, 1.24μg/ml at 1 hour, 0.87μg/ml at 2 hours and 0.18μg/ml at 6 hours after administration. In the clinical study, CFPM was administered to 11 patients most of whom had intraabdominal infections. Clinical responses were good in all cases. No serious side effects were noted.

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Clinical studies on cefepime (CFPM), a new cephalosporin, were performed in the treatment of surgical infections. CFPM was administered to 25 patients with diagnosis including diffuse peritonitis, localized peritonitis, intraabdominal abscess, cholecystitis, postoperative wound infection, abdominal wall abscess, periproctal abscess, subcutaneous abscess, infected pilonidal sinus and phlegmon. The severity of infection was severe in 3 (12.0%), moderate in 13 (52.0%) and mild in 9 (36.0%). The clinical efficacy-by physicians-in-charge was: excellent in 2, good in 17, fair in 3, poor in 2 and unknown in 1. In the bacteriological examination, the effects were excellent in 1, good in 5, fair in 2 and poor in 1 of 9 strains of Gram-positive bacteria. Against 19 strains of Gram-negative bacteria, the effects were good in 12, fair in 3 and poor in 4, with an overall efficacy rate of 63.2%. Against 14 anaerobic strains, the effects were good in 8, fair in 3 and poor in 3; an efficacy rate of 57.1%. The bacteriological effects on 42 causative bacteria were eradication in 33, persistence in 2 and replacement in 7; i.e. eradication rate of 95.2%. The clinical efficacy in 10 patients who had not responded well to previous antibacterial treatments was excellent or good in 8 cases; an efficacy rate of 80.0%. No side effects were noted. In laboratory tests, abnormal liver function values were observed in 2 of 25 cases (8.0%). The MICs against 26 (68.4%) of the 38 strains of 19 clinically isolated organisms were 12.5μg/ml or lower

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Bacteriological, pharmacokinetic and clinical studies on cefepime, a new injectable cephem derivative, were performed in surgical patients, yielding the following results.
1) Antibacterial activity: MIC₅₀/MIC₉₀ (μg/ml) against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa were 6.3/100, ≤0.05/0.2, ≤0.05/0.1 and 6.3/50. Its antibacterial activity against E. coli and K. pneumoniae was equal or better than ceftizoxime and against S. aureus and P. aeruginosa was better than piperacillin.
2) Concentrations in tissues and body fluids: The peak level of cefepime in bile was 10-20μg/ml, but this was low compared with the plasma level. Concentrations in gallbladder wall, ascites, muscle and fat were judged to be at a sufficient level.
3) Clinical results: Clinical efficacy and safety were evaluated in 36 patients. Clinical efficacy was excellent in 12, good in 19, fair in 3 and poor in 1. One patient was excluded from analysis. The overall efficacy rate was 88.6%. Bacteriologically, the eradication rate was 80.8%; i.e. eradicated in 16, partially eradicated in 2, unchanged in 3 and replaced in 5. As side effects, diarrhea and eruption were each observed in 1 patient. Abnormal laboratory findings were observed in 4 patients, but these were not severe.

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The kinetic profile of cefepime (CFPM), a new cephem antibiotics, which is highly active against Gram-negative bacilli was clarified and its clinical efficacy in biliary tract infections and peritonitis was investigated.
1) When 1g of CFPM was intravenously given to patients, the blood concentration reached 44. 4μg/ml 1 hour after administration. The blood concentrations 2 and 6 hours after administration were 22.7 and 8.7μg/ml, respectively. The half-life was 1.8 hour.
2) The biliary concentration at a dose of 1g was determined in two patients with an indwelling T-tube, showing that the peak level was 17.5μg/ml. The concentration in ascitic fluid in a patient undergoing abdominal drainage showed a peak level of 127μg/ml.
3) The clinical efficacy was excellent in 2 and good in 4 cases. The isolated organisms from biliary tract infections were Escherichia coli, Klebsiella pneumoniae and Citrobacter freundii. The isolated organisms from peritonitis were not only aerobes but also anaerobes such as Bacteroides and Clostridium. All these organisms were sensitive to CFPM. Bacteria were eradicated in 2 cases.
None of the patients given CFPM had side effects or abnormal laboratory data attributable to this antibiotic.

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The clinical usefulness of cefepime (CFPM), a new injectable cephem antibiotic, was evaluated with respect to clinical efficacy and distribution to human body fluids. The drug was administered to 15 cases with surgical infection by bolus or drip intravenous injection at a dose of 0.5-2.0g twice a day. In 7 cases of peritonitis, the clinical efficacy was “excellent” in 2 cases, “good” in 3, “fair” in 1 and “poor” of postoperative abdominal sepsis and ileocecal abscess, “good” efficacy was obtained. Thus, the overall efficacy rate was 80.0%. Bacteriologically, CFPM had high MIC values against several strains such as Enterococcus faecalis, methicillin-resistant Staphylococcus aureus and Enterococcus faecium, but the bacteriological response was not always correlated with the clinical efficacy. No symptoms or signs associated with side effects were observed. Abnormal laboratory findings after CFPM therapy were observed in only 1 case (elevations of GOT and GPT). The drug levels in the serum and bile were evaluated in 3 cases in which a T-tube was inserted into the bile duct. Mean serum concentrations of CFPM were 37.4μg/ml at 30 min after administration, and 28.77μg/ml at 1h, respectively. The levels gradually decreased thereafter to 9.48μg/ml after 4 hours. However, there was considerable case-to-case variation in biliary levels of CFPM with the peak values, reached after 30 min, being 28.3, 17.8 and 5.25μg/ml in the respective three cases.

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Cefepime (CFPM), a new cephem, was studied in terms of its antibacterial activity and clinical efficacy in the field of surgery. The results of those studies were as follows.
1. Antibacterial activity: CFPM showed high MIC against methicillin-resistant (MIC of methicillin ≥12.5μg/ml) Staphylococcus aureus (MRSA), and it had favorable antibacterial activity against methicillin-sensitive (MIC of methicillin <12.5μg/ml) S.aureus (MSSA). In the case of coagulase negative staphylococci (CNS), the MICs of CFPM were in 91% of cases determined to be less than 12.5μg/ml. Most Enterococcus sp. were resistant to CFPM. The peak MIC for Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter freundii and Morganella morganii were equal or less than 0.1μg/ml, and for Enterobacter sp. it was 0.2μg/ml, and the activity was superior to the other drugs tested. The peak MIC for Pseudomonas aeruginosa was 3.13 yg/ml, and activity was judged to be favorable. Some species of Serratia marcescens, Acinetobacter calcoaceticus and Pseudomonas cepacia were resistant to CFPM.
2. Clinical efficacy: CFPM was administered to 11 patients with peritonitis (4), postoperative intraabdominal infection (4), postoperative wound infection (2) and cholangitis (1). The clinical efficacy was good in 8, fair in 2 and unknown in 1, the overall efficacy rate being 80%. No side effects were observed. Three cases of abnormal laboratory findings were noted (elevation of GOT and GPT in 2 cases and decrease of platelets and increase of prothrombin time in 1 case).
From the above results, CFPM was considered to be a useful drug for the treatment of surgical infection, especially infection by Gram-negative rods in the field of gastroenterological surgery.

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The clinical usefulness of cefepime (CFPM), a new cephem antibiotic, was evaluated in the treatment of various otorhinolaryngological infections.
1) Pharmacology
The levels of CFPM of the middle ear mucosa and in serum were determined 90 minutes following the intravenous administration of 1.0g CFPM. The levels of the maxillary mucosa and in serum were examined 60 and 120 minutes following the injection. The levels of CFPM of the middle ear mucosa and in serum at 90 minutes were 25.7 μg/g and 47.5μg/ml respectively. The levels of the maxillar mucosa at 60 and 120 minutes were from 11.2 to 26.2 μg/g. The serum levels at 60 and 120 minutes were from 18.5 to 48.6 μg/ml.
2) Clinical evaluation
CFPM was administered to 17 patients: 3 with otitis media, 7 with paranasal sinusitis, 6 with tonsillitis and 1 with acute pharyngolaryngitis. The clinical efficacy was evaluated in 16 patients and safety assesed in all cases. The clinical response was excellent in 8, good in 6, fair in 1 and poor in 1 patient. The overall efficacy rate was 87.5%. The clinical response classified by disease was excellent, good and poor in 1 patient respectively with otitis media; good in 5 and fair in 1 with paranasal sinusitis; excellent in 6 with tonsillitis and excellent in 1 with acute pharyngolaryngitis. In 12 patients in which organisms were isolated, the bacteriological response was: eradicated in 7, replaced in 1, unknown in 4 patients. No clinical side effects and no abnormal laboratory findings were observed in any of the 17 cases evaluated. From the above results, CFPM was considered to be a useful drug in otorhinolaryngological infections.

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Bacteriological, pharmacokinetic and clinical studies were carried out with cefepime (BMY-28142; CFPM) in otorhinolaryngological infection. The results obtained were as follows.
1. The percentage ratio of CFPM concentration in tissue vs. serum was 80.6% for maxillary sinus mucosa from 7 cases and 33.9% for palatine tonsil from 5 cases after i. v. injection of 1.0g of CFPM (BMY-28142).
2. In the clinical study, patients were given CFPM at a dose of 1.0g, 2 times a day by intravenous infusion. In otorhinolaryngological infection, the overall efficacy rate was 78.3% in 25 cases ; i. e. excellent in 10, good in 8, fair in 3, poor in 2 and unknown in 2. The bacteriological elimination rate was 85.7% and the MIC₅₀ was 0.2 μg/ml. No side effects were noted.

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1) Minimum inhibitory concentrations (MICs)(inoculum 10⁶ cfu/ml) of cefepime (CFPM), cephaloridine (CER) and cefmetazole (CMZ) were determined against 48 isolates of Staphylococcus aureus from skin and skin structure infections. Methicillin-resistant strains of S. aureus (MRSA, 30 isolates) were resistant (12.5μg/ml≅MIC) against CFPM in 14, against CER in 27 and against CMZ in 27.
2) Serum and skin concentrations of CFPM after intravenous administration (20 mg/kg) weredetermined in rats. Mean serum concentrations were 74.33, 18.75, 13.35, 4.86, 0.61 μg/ml, and the corresponding skin concentrations were 18.76, 14.02, 11.78, 3.26, 0.84 μg/g (wet skin) at 5, 15, 30, 60, 120 minutes after the drug administrations.
3) Serum and skin concentrations of CFPM after intravenous administration (0.5 or 1.0g) were determined in patients undergoing skin surgery. The mean ratio of skin/serum concentrations was 0.60 (n=5).
4) CFPM was used clinically in 26 cases of skin and skin structure infections, and the following results were obtained: excellent in 8 cases, good in 12 cases, fair in 4 cases and poor in 2 cases. As side effects, nausea and headache were observed in one case. Abnormal laboratory findings of elevated Al-P and Ω-GTP were observed in one case.

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1. The minimum inhibitory concentrations (MIC_s)(10⁶ cells/ml) of cefepime (CFPM), cefuzonam (CZON), ceftazidime (CAZ) and cefotaxime (CTX) were assayed against 118 strains of Staphylococcus aureus that were isolated from infectious skin lesions. The MIC₅₀ of CFPM, CZON, CAZ and CTX were 3.13, 0.78, 6.25 and 3.13 μg/ml, respectively.
2. Serum levels of CFPM in rats (n=4) at 15 min, 30 min, 1 h and 2 h after intravenous injection (20 mg/kg) were 41.4, 24.5, 10.5 and 0.74μg/ml, respectively. The corresponding CFPM concentrations in the skin were 25.0, 15.1, 6.17 and 1.09 μg/g (wet weight).
3. Human serum levels of CFPM at 10 min (n=1) and 25 min (n=3) after lg intravenous injection were 81.5 μ/ml and 59.4 μg/ml. The corresponding CFPM concentrations in the skin were 38.2μg/g and 17.6 μg/g (wet weight).
4. One gram of CFPM was administered intravenously twice a day for 5-8 days to 5 patients with infectious skin diseases. Excellent improvement was observed in 4 cases and the remaining case was judged to have a good response. Four strains of S. aureus and one strain of Peptostreptococcus prevotii were isolated from the lesions. Every strain was eradicated by CFPM administration. One patient had diarrhea as a side effect.

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The newly developed cephalosporin antibiotic, cefepime, was investigated for its antibacterial activity, tissue penetration, clinical efficacy and bacteriological effect in obstetrics and gynecology patients. The following results were obtained,
1. Antibacterial activity: The MICs of cefepime for 340 strains of 17 species of clinical isolates were examined. The MIC₉₀ ranged from 3.13->100 μg/ml for Gram-positive cocci, 0.025-50 /demi for Gram-negative bacilli, 0.39-0.78μg/ml for anaerobic cocci, and >100μg/ml for anaerobic bacilli.
2. Tissue penetration: Tissue penetration of the drug into intrapelvic genital organs was good. The level in uterine arterial serum was similar to that of cubital vein serum and the peak level in uterine or adnexal tissues ranged from 22.4-36.4μg/g after intravenous injection of 1.0g. The peak level of the drug in pelvic dead space exudate was 27.3μg/ml after 2 hours of administration and 1.05μg/ml at 12 hours.
3. Clinical results: Cefepime was given to 19 cases of obstetric and gynecological infections at a daily dose of 2.0g for 3-10 days, The clinical efficacy was 100%, the bacteriological effect was 81.3% and the eradication rate against isolated organisms was 86.4%. No side effects were observed.
4. From these findings, cefepime is considered to be a useful antibiotic against obstetric and gynecological infections.

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Cefepime (CFPM), a new cephalosporin, was evaluated for its tissue penetration into female genital organs and clinical usefulness in various obstetric and gynecological infections with the following results. After a single intravenous administration of 1.0g, peak serum concentrations in the cubital vein and uterine artery were 20.8 μg/ml, while genital tissue concentrations were 2.02-20.2 μg/g. CFPM was administered to 11 patients with intrauterine infection, uterine adnexitis, pelvic abscess and pelvic peritonitis. The clinical response in 11 patients was excellent in 1 case, good in 9 cases and unknown in 1 case. Loose stools was observed in 1 case as a side effect.

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Pharmacokinetic and clinical studies were performed with cefepime (CFPM), a new cephemantibiotic.
1. The concentration of CFPM was examined in serum, internal genital organs, retroperitoneal fluid and maternal breast milk after 1 hour of drip infusion. The peak levels in tissues were more than 25 μg/g, and that of retroperitoneal fluid was more than 25 μg/ml. But the peak concentration in maternal breast milk was only 1.2 μg/ml.
2. CFPM was administered to 9 patients. In 3 cases of pyometra, clinical response were poor in 2 and unknown in 1. In 6 cases consisting of 1 case of endometritis, 1 case of parametritis, 1 case of inflammation of pelvic retroperitoneal space, 1 case of pelvic peritonitis, 1 case of Douglas abscess and 1 case of vaginal wall abscess, clinical response was good in all cases. No side effects or abnormal laboratory findings due to CFPM were observed.

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Bacteriological, pharmacokinetic and clinical studies on cefepime (CFPM), a new injectable
1. The concentrations of CFPM were examined in serum, internal genital organs and retroperitoneal exudate after a single i. v. administration of 1.0g. The peripheral peak serum level was 29.2μ/ml at 1 h 18 min, decreasing to 11.7μg/ml at 3 h 10 min after the administration. Peak concentrations in the tissues were 11.7-25.8μg/g at 1 h 18 min, 13.4-25.8 μg/g at c. 1 h 30 min, 9.28-20.3 μg/g at c. 2 h, decreasing to 7.01-40.3 μg/g at 3 h 10min after administration. Concentrations in the retroperitoneal exudate after radical hysterectomy were 45.8 ± 15.3 μg/g/ml (mean±SD), 40.3 ± 10.8 μg/ml, 29.3±8.98 μg/ml, 17.3±4.90 μg/ml, or 8.82 ± 4.03 μg/ml at 30 min, at 1, 2, 4, or 6 h, respectively.
2. In a clinical trial, CFPM (2 g dose for days) was given to 7 patients with obstetrical and gynecological infections such as endometritis, pyometra and parametritis. The clinical results were evaluated as excellent in 2 cases, good in 4, and poor in 1. Bacteriologically, 11 organisms were isolated from 7 patients and the eradication rate was 63.6%. No side effects were observed.Eosinophilia was observed in 1 case and transient elevation of GOT, GPT and LDH in 1 case, but with no clear relationship to the drug.cephem antibiotic, were performed and the following results were obtained.

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Pharmacokinetic and clinical trials of a new cephalosporin derivative, cefepime (CFPM) were conducted, and the following results were obtained.
1. CFPM was administered to 5 cases undergoing abdominal simple hysterectomy due to hysteromyoma and endometriosis at a dose level of 1.0g by drip intravenous infusion. The average levels of transfer measured at various locations in the uterine tissue and adnexa at an average of 1.5 hours after administration were studied. The CFPM level was highest in the ovary, 25.3, μg/g (ratio with respect to the uterine arterial blood: 83.7%), followed by the portio vaginalis, cervix uteri, oviductand endometrium and was lowest in the myometrium, 15.3μg/g (50.2%). CFPM concentration were higher than 10.9μg/g in all tissues.
2. To study CFPM transfer to pelvic cavity fluid CFPM was administered to 8 cases undergoing radical hysterectomy due to cervical cancer at a dose of 1.0g by drip intravenous infusion. The drug was transfered at high levels to the pelvic cavity fluid. A level of 25.0μg/ml was observed 3 hours after infusion. The drug level in the pelvic cavity fluid was consistently higher than that of venous blood. These concentration in the uterine tissues and pelvic cavity fluid were higher than the MIC against many strains of Gram-positive and Gram-negative bacteria. Hence they can be considered therapeutically effective concentrations.
3. Ten cases of gynecological infections receiving in total 4.0 to 22.0g of CFPM demonstrated “good” responses in 9 cases, and “poor” in 1 case. Nine strains of organisms were isolated from 7cases.
4. As a side effect Candida vulvovaginitis was observed in 1 case. Abnormality in laboratory tests; elevation of S-GOT and S-GPT was observed in only 1 case out of the 10 cases enrolled in the clinical trial and the 13 cases undergoing pharmacokinetic evaluation.
Based on the results of the studies described above, this drug is considered to have excellent efficacy and safety.

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The clinical efficacy, bacteriological effects and safety of cefepime in the treatment of respiratory infections were evaluated. The drug was given to 20 patients: 7 with pneumonia, 3 with infection secondary to bronchiectasis, 6 with acute exacerbation of chronic bronchitis, 1 with pneumonia+pleuritis, 3 with infection secondary to chronic respiratory disease. Clinical efficacy was excellent in 3 patients, good in 15 patients, fair in 1 patient and poor in 1 patient. The efficacy rate was 90%. As causative organisms, 15 strains were detected and 14 were eliminated by cefepime. As regards safety, out of 20 patients treated, 2 cases of eruption and 1 case of drug fever were observed. Abnormal laboratory values were found in 2 cases: slight elevation of GPT and BUN.

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