FK037 is an oxime-type cephem antibiotic possessing1-hydroxyethyl-5-amino-pyrazole moiety at the 3 position.MIC₈₀s of FK037 against clinical isolates of methicillin-sensitive Staphylococcus aureus (MSSA)(19strains), low-level methicillin-resistant S. aureus (MRSA)(47), high-level MRSA (64), coagulase-negative staphylococci (CNS)(44), Streptococcus pyogenes (50), Streptococcus pneumoniae (24), Escherichia coli CS2 (R+)(51), Klebsiella pneumoniae (50), Proteus mirabilis (48), Proteus vulgaris (54), Providencia rettgeri (51), Morganella morganii (50), Serratia marcescens (50), Enterobacter cloacae (50), Citrobacter freundii (50), Pseudomonas aeruginosa (50), Pseudomonas cepacia (33), Xanthomonas maltophilia (48), Acinetobacter calcoaceticus (49), ampicillin-resistant Haemophilus influenzae (18), Bacteroides fragilis (38) were 0.78, 25, 25, 12.5, 0.013, 0.025, 0.05, 0.39, 0.05, 0.2, 6.25, 0.1, 1.56, 12.5, 3.13, 25, 25, > 100, 25, 0.1, >100pg/ml, respectively. FK037 provided almost the same activity for MSSA as cefpirome (CPR) and flomoxef (FMOX). However, the drug had 2 to 8 times stronger anti-MRSA activity for both low-level and high-level strains than CPR and FMOX.
FK037 had the same binding affinity to PBPs 1, 2 and 3 of S. aureus 209P as CPR, but showed higher affinity to PBP 2' of low-and high-level MRSA strains than CPR. The binding affinity of FK037 to PBPs of E. coli NIHJ JC2 and P. aeruginosaPAO1 was the same level as that of CPR.
FK037 exhibited a strong synergy of bactericidal effect with the complement on E. coli NIHJ JC2 at rather low concentrations. Cultured mouse macrophages engulfed well and easily digested E. coli cells in the presence of higher concentrations than 1/4 MIC of FK037.
FK037 is a useful chemotherapeutic for infections by gram-positive and gram-negative bacteria including some strains of MRSA, if its pharmacokinetics in humans are good.

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The in vitro activity of FK037, a new cephalosporin, was examined in comparison with that of ceftazidime (CAZ), ceftizoxime (CZX), flomoxef (FMOX), cefuzonam (CZON), imipenem (IPM), piperacillin (PIPC) and ampicillin (ABPC). FK037 had a strong activity against a broad spectrum of gram-positive and gram-negative standard strains. The activity of FK037 against gram-positive cocci was one-second to one-fourth that of CZON, FMOX and IPM. However, FK037 showed higher activity against methicillin-resistant staphylococci than CZON, FMOX and IPM did.
FK037 showed a strong activity against Enterobacteriaceae. FK037 also provided a potent activity against cephem-resistant strains of Klebsiella pneumoniae, Enterobacter cloacae and Serratia marcescens, indicating that the activity of FK037 is less affected by cephalosporinase-production than that of CAZ and CZX. FK037 was not hydrolyzed by typical cephalosporinase and penicillinase but was weakly hydrolyzed by OXA-type enzyme. From these results, FK037 is likely to be stable to the enzymes at the low concentrations expected in the bacterial cells and, therefore, the stability contributes to the antibacterial activity of FK037 against cephalosporinase-producing bacteria.

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We studied the antibacterial activity of FK037 against 440 strains of 19 species clinically isolated in Chiba University hospital between January and December in 1993. The MICs of FK037 and 7 reference antibiotics such as ceftazidime (CAZ), cefazolin (CEZ), piperacillin (PIPC), imipenem (IPM), gentamicin (GM), astromicin (ASTM) and ofloxacin (OFLX) were measured by a microbroth dilution method.
1) FK037 had the strongest antimicrobial activity against Escherichia coli, Klebsiellapneumoniae, Klebsiella oxytoca, Citrobacter freundii, Acinetobacter calcoaceticus, Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus agalactiae.
2) The MICs of FK037 against Pseudomonas aeruginosa were slightly higher than those of CAZ.
3) The MICs of FK037 against methicillin-resistant Staphylococcus aureus were 32 μg/ml or lower.
4) FK037 had a weak antibacterial activity against Xanthomonas maltophilia, Enterococcus faecalis, Enterococcus avium and Enterococcus faecium.

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We investigated the antimicrobial activity of FK037 in human urine and the influence of FK037 on superoxide generation by polymorphonuclear leukocytes.
1) Antimicrobial activity of FK037 in human urine: MBCs of FK037 were not influenced by urine pH, urinary magnesium concentration, or urinary calcium concentration; MBCs of FK037 against Escherichia coli were ≤0.1, μg/ml, and those against Pseudomonas aeruginosa ranged between 3.13 and 6.25 μg/ml.
2) Influence of FK037 on superoxide generation by polymorphonuclear leukocytes (PMNs): Superoxide generation by PMNs stimulated with phorbol myristate acetate was not influenced in the presence of 10 μg/ml of FK037. However, it was significantly reduced in the presence of 100 μg/ml of FK037. Superoxide generation by PMNs stimulated with bacterial cells in the presence of sublethal dose of FK037 were not different from those in the absence of FK037.
These results indicate that FK037 does not enhance the bactericidal activity of PMNs.

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The in vitro activity of FK037, a new parenteral cephalosporin, was compared with that of cefpirome (CPR), ceftazidime (CAZ) and flomoxef (FMOX) against anaerobic bacterium. A fastidious facultative anaerobic bacteria, Gardnerella vaginalis was also studied. FK037 had broad spectrum against reference strains of anaerobes, inhibiting many anaerobic bacterial strains at 3.13μg/ml or less. However, FK037 had weak activity against Eubacterium lentum ATCC 25559, Clostridium difficile GAI 10029, the Bacteroides fragilis group, Prevotella bivia ATCC 29303, and Fusobacterium varium ATCC 8501, with the MICs of 50μg/ml or more. FK037 was active against fresh clinical isolates of Peptostreptococcus anaerobius, Peptostreptococcus asaccharolyticus, Clostridium perfringens, Mobiluncus spp, Porphyromonas gingivalis, and G. vaginalis, a fastidious facultative anaerobic bacteria; 90% of each bacteria were inhibited by 0.78μg/ml or less of FK037. FK037 inhibited 50% of B. fragilis at 25μg/ml. The activity of FK037 was comparable to that of CPR and CAZ but less than that of FMOX. The activity of FK037 against Fusobacterium nucleatum and F. varium decreased when inoculum size was increased from 10⁶ to 10⁸ CFU/ml. Little influence of inoculum size on the activity of FK037 was observed for the other strains tested. Medium pH affected the activity of FK037 against F. varium and Bacteroides gracilis but not against the other organisms tested. FK037 was bactericidal at 4 times the MIC against B. fragilis. FK037 was more stable than CPR but less stable than CAZ against hydrolysis by β-lactamases, cefuroximase type I, derived from B. fragilis. A 5-day dosing of FK037 induced emergence of C. difficile in higher number than that of CAZ and FMOX in mouse ceca on 7-day after finishing administration of the compounds.

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The relationship between the plasma concentration of FK037 and its MIC against phathogens on the therapeutic efficacy was investigated, using the experimental mouse model with constant plasma concentrations of the drug on the thigh infection caused by methicillin-resistant Staphylococcus aureus (MRSA). FK037 was dose-dependently effective against two strains of MRSA even at the sub MIC, but markedly efficacious against two strains of methicillin-susceptible S. aureus only at the MIC orhigher. Against MRSA, the efficacy of FK037 at the MIC for 3 hours followed by the 1/4 MIC for 3 hours was similar to that at the MIC for 6 hours. Moreover, the postantibiotic effect of FK037 against MRSA may be extremely prolonged because bacterial regrowth after the therapy at various plasma concentrations for 6 hours was markedly suppressed for 18 hours so that the viable counts were significantly less than the initial counts. These results suggest that FK037 is effective against MRSA infections in patients even though its MIC₈₀ is 25 μg/ml.

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Since β-lactams have been reported to induce convulsions, we studied the convulsant activity of FK037, a new cephem, as well as other cephems. We also studied the effect of these agents on the receptor binding of γ-aminobutyric acid (GABA), an inhibitory transmitter in the central nervous system. Intraventricular injection of FK037, cefazolin (CEZ), cephaloridine (CER), and cefmetazole (CMZ) induced convulsions in mice in a dose-dependent manner. Their ED₅₀ values were as follows; 12 nmol for CEZ, 16 nmol for FK037, 50nmol for CER and 340 nmol for CMZ. Cephalexin (CEX) did not induce convulsions up to 500 nmol. These cephems inhibited GABA receptor binding in a concentration-dependent manner in vitro. Their concentrations that inhibited 50% of the binding were; 1.4 mM for CEZ, 2.7 mM for FK037, 3.7 mM for CER, 10 mM for CMZ and>50 mM for CEX.
These results suggest that FK037 induces convulsions through the inhibition of GABA receptor binding, when accumulated in the central nervous system.

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We investigated the influence of FK037 on the intestinal microflora of 5 healthy male volunteers before, during and after 1 hour intravenous infusion of 2g every 12 hours for 5 days. The total anaerobic bacterial counts scarcely changed in all cases. The total aerobic bacterial counts were transiently decreased after dosing of FK037, but these levels quickly recovered at 7 days after dosing. Although Clostridium difficile was detected in 2 of the 5 volunteers, D-1 antigen was not detected in these strains.β-lactamase activity in feces increased in the dosing period. FK037 was not detected in the feces in any of the cases. No diarrhea or other side effects were seen in any of the volunteers.

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The safety and pharmacokinetics of FK037 were examined in healthy male volunteers in singleand multiple-dose studies. In the single-dose study, 27 subjects were given intravenously 5-minute infusion of 125, 250 or 500 mg, or 60-minute infusion of 500, 1, 000 or 2, 000 mg of the drug. In the multiple-dose study, 6 subjects were given intravenously 60-minute infusion of 2, 000 mg twice a day for four days and once on day 5 (q 12 h). The results were as follows:
1) In the single-dose study, one subject, during 5-minute infusion of 500 mg in the morning, had shock-like reactions such as discomfort, nausea and hypotension, so the infusion was stopped. The subject recovered from the shock-like reactions in the evening and returned to healthy condition in the next morning. In the multiple-dose study, one subject had a fever due to cold, and was withdrawn from the study before the second dosing on day 1. One subject had a slight headache on day 2. For clinical laboratory tests, slight increases in GPT and LAP in each one subject from the single-and multiple-dose studies were observed. In addition, a slight increase in GPT in one subject from the multiple-dose study were found. These increases were not clinically significant. No other abnormal findings in subjective symptoms, clinical laboratory tests or physical examinations were observed.
2) In the multiple-dose study, the fecal microflora was investigated. No remarkable changes in a total number of aerobes and anaerobes were observed with FK037.
3) In the single-dose study, C_max and AUC increased in proportion to the dose, suggesting the linear pharmacokinetics of FK037. T112 was 2.30 hours and as much as 95 % of the dose given was excreted in the urine within 24 hours. In the multiple-dose study, C_max remained constant after day 2, T_1/2 was 2.15 hours, and urinary recovery was 89.1 %. The plasma protein binding was 11.4 %. The steady state was attained by day 2 of multiple dosing.
From these results, we consider that it is possible to conduct phase II study by taking care of shocklike reactions as observed in cephalosporins.

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The pharmacokinetics and serum bactericidal titers of FK037, a new cephalosporin antibiotic, were compared with ceftazidime (CAZ) in a 2-way crossover design in 6 healthy volunteers. Single 1 g doses of FK037 and CAZ were given intravenously as a 60-min infusion.
Plasma concentrations of FK037 and CAZ decreased in biexponential manner after the end of infusion. Urinary recoveries of FK037 and CAZ within 24 h were 91.9 and 90.9 %, respectively. Compared with CAZ, FK037 had a significantly longer elimination half-life (2.21 versus 1.62 h, p<0.01), resulting in higher plasma concentrations of FK037 at 12 h after dosing (1.11 versus 0.40 μg/ml). No significant differences were observed in Cmax, AUC, total clearance, renal clearance, volume of distribution at steady state or protein binding.
The mean serum bactericidal titers of FK037 against Staphylococcus aureus, Streptococcus pneumoniae, Klebsiella pneumoniae and Haemophilus influenzae, which lasted more than 8 h after dosing, were higher than 57 at the peak, and against Enterobacter cloacae and Pseudomonas aeruginosa were higher than 18 at the peak. Compared with CAZ, FK037 showed higher serum bactericidal titers against above 5 strains except P. aeruginosa, which reflected both plasma concentrations and MBC of FK037 and CAZ.

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The mechanisms of the renal excretion of FK037, a new cephalosporin antibiotic, were studied in a 2-way crossover design with or without probenecid in 6 healthy volunteers. Single 1 g doses of FK037 were given intravenously as a 60-minute infusion.
Plasma concentrations of FK037 decreased in a biexponential manner after the end of infusion. The elimination half-life of FK037 without probenecid was 2.10 ± 0.21 h, renal clearance was 91.9 ± 22.1 ml/min, and as much as 91.0 ± 5.4 % of the dose was excreted unchanged in the urine. Concomitant administration with probenecid did not affect the pharmacokinetic profile, i.e., the elimination half-life was 2.13 ± 0.30 h, renal clearance was 89.0 ± 19.2 ml/min, and urinary excretion was 92.5 ± 3.0 %. These findings demonstrate that FK037 is eliminated by glomerular filtration.

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We investigated the antibacterial activity and clinical efficacy of FK037, a new parenteral cephem antibiotic.
The MICs of FK037 against 239 clinical isolates of 7 species were measured using a plate dilution method with an inoculum size of 10⁶ CFU/ml, and compared with those of ceftizoxime (CZX), ceftazidime (CAZ) and cefixime (CFIX).
The MIC₉₀ of FK037 was 0.78 μg/ml against methicillin-sensitive Staphylococcus aureus (MSSA) and 12.5 μg/ml against methicillin-resistant S. aureus (MRSA). FK037 showed the strongest activity against S. aureus of antibiotics.
The MICs of FK037 against Escherichia coli and Klebsiella pneumoniae were≤0.1 μg/ml in all strains, and similar or superior to those of other agents. The MIC₉₀ of FK037 was 3.13 μg/ml against Serratia marcescens and 0.2 μg/ml against Proteus mirabilis, and was similar to that of CAZ.
Against Morganella morganii, the MIC₉₀ was 1.56 μg/ml, being superior to other agents. Against Pseudomonas aeruginosa, the MIC₉0 was 100 μg/ml, being inferior to that of CAZ.
Eight patients with respiratory infections (4 with bacterial pneumonia; including complication of mycoplasinal pneumonia, 2 with chronic bronchitis, 1 with secondary infection of silicosis, 1 with relapse of old tuberculosis) were treated with FK037 by 0.5-2.0 g b.i.d. drip infusion for 4-15 days.
The clinical evaluation in 7 patients, excluded old tuberculosis, was excellent in 1 and good in 6.
All strains isolated (2 of Streptococcus pneumoniae, 2 of Haemophilus influenzae, 1 of E. coli) was eradicated.
No side effects were observed, and in laboratory findings, leukopenia and elevation of GPT were seen in one each.

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The in vitro antimicrobial activities of FK037, a novel parenteral cephalosporin developed in Japan, and its therapeutic efficacy were evaluated in the treatment of respiratory tract infections. The minimum inhibitory concentrations (MICs) of FK037, cefpirome (CPR), ceftazidime (CAZ) and flomoxef (FMOX) against a total of 138 strains consisting of six different species, methicillinsusceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coil, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Pseudomonas aeruginosa were determined by the micro-broth dilution method using the Dynatech MIC 2000 system. As shown in MICs, FK037 was more active than CAZ and FMOX, and as active as CPR against most of the species tested. Growth of all the MRSA strains tested was inhibited by 64 μg/ml or less of FK037.
A dose of 1 g (7 patients), 2 g (6 patients) and 4 g (5 patients), respectively, of FK037 was given daily to a total of 18 patients for 6 to 15 days (mean: 11.2 days): 13 with pneumonia, one with pyothorax, and 2 each with secondary infection in association with bronchiectasis and chronic bronchitis. The clinical effects were excellent in 9 and good in 8 (efficacy rate: 100%). One patient with eosinophilic pneumonia was excluded from clinical evaluation. Seven strains were identified as causative organisms: 4 strains of Streptococcus pneumoniae, 2 strains of Heamophilus influenzae, and one strain of Moraxella catarrhalis. FK037 eradicated all of them.
No clinical adverse effects were observed during treatment with FK037. A transient elevation of γ- GTP and leucocytopenia was observed in one patient each.
From the above results, we conclude that FK037 is a useful antibiotic for parenteral use as a first choice in the treatment of respiratory tract infections.

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We evaluated a dosing plan in elderly patients and clinical efficacy of FK037, a new injectable cephem antibiotic. Bile, blood, urine and sputum samples were collected serially from 2 elderly patients after 1 g i.v. 60 min infusion of FK037. The peak concentrations of FK037 in plasma were 53.5-82.1μg/ml and T 1/2 β were 3.12-8.01 hrs. Urinary recovery rate up to 8 hrs were 49.0-58.7%. Sputum concentration pointed 0.67 μg/ml at 3 hrs after administration. Bile concentrations kept 12.3-16.1 μg/ml for 8 hrs.
The clinical evaluation was carried out in 13 patients (pneumonia 6, chronic bronchitis 2, infected bronchiectasis 1, otitis media 1, cholecystitis, cholangitis 1, acute cholecystitis 1, cholangitis (suspicion) 1). The clinical efficacy was available in 10 cases which were excellent in 5 and good in 5. No adverse reactions or abnormal laboratory findings were observed on this trial.

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We performed laboratory and clinical studies on FK037, a new cephem antibiotic.
The in vitro antibacterial activity of FK037 against clinically isolated strains was determined and compared with that of flomoxef (FMOX), cefpirome (CPR), ceftazidime (CAZ), imipenem (IPM) and vancomycin (VCM). The MICs of FK037 against methicillin-sensitive Staphylococcus aureus (9 strains) ranged from 0.39 to 1.56 μg/ml, which was inferior to IPM but equal to or slightly inferior to FMOX, CPR and VCM. The MICs against methicillin-resistant S. aureus (6 strains) ranged from 3.13 to 12.5μg/ml, showing that FK037 was 2 dilution less active than VCM but more active than FMOX, CPR and CAZ. Against Escherichia coli (14 strains), the MICs of FK037 were 0.05 μg/ml or less, which was the most active of all of the antibiotics. Against Klebsiella pneumoniae (14 strains), the MICs were 0.2μg/ml or less, which were almost equal to those of CPR and larger than those of the other reference drugs. The MICs against Enterobacter cloacae (10 strains) ranged 0.1 to 25μg/ml, which were less than those of CPR and IPM. The MICs against Pseudornonas aeruginosa (12 strains) ranged 1.56 to 25μg/ml, showing that FK037 was 1 or 2 dilutions less active than CAZ and IPM but one more dilution active than CPR.
The peak FK037 concentration in the sputum after intravenous administration of 1.0 g of FK037 was 11.0μg/ml in one case. The extent of transfer of FK037 to sputum proved to be satisfactory.
FK037 was administered to 5 patients with respiratory tract infections (sepsis with pneumonia in 1 case, pneumonia in 2 and lung abscess in 2) in doses of 0.5 to 1.0 g twice a day by drip infusion for 5 to 12 days. The clinical efficacy was excellent in 2 cases, good in 2 and poor in 1. The causative organisms were isolated in 3 cases and eradicated in all of them. No side effects were observed in the study. However, laboratory findings showed an elevation of GOT, GPT, ALP and γ-GTP in one, which returned to normal after the therapy.

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We performed studies on absorption- excretion and clinical efficacy of FK037, a new parenteral cephem antibiotic. We obtained the following results:
1) Absorption-excretion study
One gram of FK037 was administered to 5 patients for 45-60min by drip infusion. The plasma and urinary concentrations of FK037, were measured. The maximum plasma concentrations (C_max) of 49.6 to 78.6μg/ml were observed just after the termination of infusion, followed by a reduction in plasma at half-lifes (T_1/2) of 1.63-4.55hrs. T_1/2 was prolonged in the aged patients with low renal function. The urinary excretion rates were 64.4-79.6%.
2) Clinical results
Twenty-one patients (12 with bacterial pneumonia, 7 with chronic respiratory tract infection, 1 with pyothorax and 1 with mycoplasma pneumonia) were given 0.5-2.0g of FK037 twice a day by drip infusion. Clinical efficacy of 20 patients except 1 with mycoplasma pneumonia, were “excellent” in 8, “good” in 8, “fair” in 3 and “poor” in 1, with the efficacy rate of 80.0%.
No side effects were observed. As for the abnormal changes in laboratory findings, slight elevations 0f GOT and GOT·GPT·ALP·LAP·γ-GTP were noted in l patient each.

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We studied the pharmacokinetics of FK037, a newly developed cephalosporin antibiotic, in 12 patients with renal dysfunction.
The drug was injected intravenously at a dose of 0.5g by drip infusion for 60 minutes, and its concentrations in the plasma and urine were determined by HPLC. The patients were classified according to Ccr values into group I (50≤Cr<70, n=3), group II (30≤Ccr<50, n=3), group III (Ccr<30, n=4) and group IV (uremic patients, n=2).
The plasma concentration of FK037 decreased more slowly in patients with severely impaired renal function than in those with slight or moderate renal dysfunction. T_1/2β of FK037 in the plasma were 3.80 hour in group I, 4.87 hour in group II, 8.15 hour in group III and 39.93 hour in group IV. With hemodialysis (group IV), T_1/2β was shortend to 3.54 hour. This demonstrated that FK037 had a good dialytic property. The urinary excretion rates (0-24 hours) of FK037 were 73.7% in group I, 66.0% in group II, and 53.8% in group III, showing a tendency toward a decline in relation to increasing degrees of renal dysfunction.
The clinical efficacy and safety of FK037 were assessed in 24 patients with respiratory tract infections. The clinical efficacies were excellent in 4, good in 18, poor in 1 and unknown in 1, with an efficacy rate of 95.7%. No side effects were observed, and abnormal laboratory findings were observed in 8; a neutropenia in 1, an elevation of GOT in 2, an elevation of GOT and GPT in 1, and decline of prothronbin activity in 4.

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The antimicrobial activity of FK037 against major pathogenic bacteria of respiratory tract infections was investigated and compared with that of other injectable β-lactam antibiotics. Eleven patients with respiratory tract infections were treated with FK037, and its efficacy and safety were evaluated.
1) The in vitro activity of FK037 against methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae was inferior to that of imipenem but almost the same or superior to that of ceftazidime, cefoperazone and cefmenoxime. The potency of FK037 against methicillin-resistant S.aureus was superior to that of the other drugs. The MICs of FK037 against various gram-negative bacteria, except Moraxella catarrhalis, were also excellent and almost equal to those of other injectable cephems.
2) The clinical efficacy of FK037 at daily doses of 1.0-4.0 g for 5-15 days in 10 of 11 cases was evaluated as excellent in 2 cases, good in 7 cases and poor in one case. No clinical side effects were observed in any of the 11 cases, but 7 abnormal changes in laboratory values were observed after treatment in 5 patients. All of the changes were slight and transient.
Based on these findings, FK037 was concluded to be a useful agent in the treatment of respiratory tract infections.

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The clinical efficacy, bacteriological efficacy and safety of FK037 were studied in 5 patients with respiratory tract infections (pneumonia 3, chronic bronchitis 1, acute bronchitis 1). FK037 was administered to the 5 patients in a daily dose of 1.0 or 2.0 g for 13 or 14 days by drip intravenous infusion. The clinical efficacy was excellent in 1 patient and good in 4.
Two strains of isolated bacteria (Staphylococcus aureus and Streptococcus pneumoniae) were eradicated. None of adverse reactions was noted. Slight and transient abnormal laboratory finding of leucocytopenia was noted in only 1 patient.
In penetration of FK037 into the pleural fluid, C_max P/S ratio and AUC P/S ratio were 38.2% and 99.5%, respectively. High pleural fluid levels were maintained for 8 hours after administration.
According to the above results, it is considered that FK037 penetrates well into the pleural fluid among cephem antimicrobial agents.

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We performed bacteriological and clinical studies on FK037, a new parenteral cephalosporin antibiotic, with the following results.
1) Antimicrobial activity
The MIC₉₀ of FK037 against various clinical isolates (10 species, 238 strains) was as follows: 3.13μg/ml against methicillin-sensitive Staphylococcus aureus, 50 μg/ml against methicillin-resistant S.aureus (MRSA), > 100 μg/ml against Enterococcus faecalis, 0.10μg/ml against Escherichia coli, ≤ 0.05 μg/ml against Klebsiella pneumoniae, 3.13 μg/ml against Enterobacter cloacae, 1.56 μg/ml against Enterobacter aerogenes, 3.13 μg/ml against Citrobacter freundii, ≤0.05 μg/ml against Proteus mirabilis, 0.10 μg/ml against Proteus vulgaris, 25μg/ml against Pseudomonas aeruginosa. Its activity against these bacterial species including MRSA was more potent than that of control drugs; ceftazidime (CAZ), flomoxef (FM0X), ceftizoxime (CZX) and cefotiam (CTM). The activity against P. aeruginosa was almost as potent as that of CAZ. The activity against E. faecalis was less active as well as that of the control drugs.
2) Clinical efficacy
Four patients with pneumonia were treated with FK037 at daily doses of 1.0 or 4.0 g for 7-14 days. Clinical response was excellent in 3 patients and good in 1. No adverse reactions or abnormal laboratory findings were observed.

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FK037, the newly developed injectable cephem, was evaluated in vitro and in vivo. The results were as follows.
1) Antimicrobial activity: Minimal inhibitory concentrations (MICs) against 513 clinical isolates including 16 different species were determined by the microbroth dilution method and were compared with those of ceftazidime (CAZ), cefpirome, and cefuzonam (CZON). FK037 showed excellent antimicrobial activity at the same level as CZON against gram-positive bacteria including methicillinresistant Staphylococcus aureus, although the MICs were superior to that of CAZ. The MIC values of FK037 for gram-negative bacteria were equivalent to those of other cephems tested.
2) Clinical efficacy and adverse reactions: Seventeen patients with respiratory tract infections were treated with FK037, and the overall efficacy rate was 75%(excellent in 4, good in 8, fair in 1, poor in 3 and not evaluable in 1). Side effects of FK037 were not observed. As for abnormal laboratory findings, the elevation of GOT, GPT and ALP was observed in 1 case, the elevation of GOT in 1, the elevation of GPT in 1, leukopenia in 1, an increase in the number of eosinophils in 3, and mild elevation of serum potassium in 1. These abnormalities were all mild and transient, suggesting that FK037 is a useful and safe antibacterial agent.

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FK037 is a new cephalosporin antibiotic. We performed laboratory and clinical studies on the drug to evaluate its usefulness in respiratory tract infections. The antibacterial activity of FK037 against respiratory pathogenic bacteria was: potent: The MIC₅₀ of FK037 at 10⁶ CFU/ml was 0.05 μg/ml against Haemophilus influenzae, 0.025μg/ml against Streptococcus pneumoniae, 1.56μg/ml against Branhamella catarrhalis, and 6.25 μg/ml against Pseudomonas aeruginosa.
The maximal sputum levels of FK037 ranged from 0.04 μg/ml to 1.9 μg/ml in 3 patients with respiratory tract infections and rates of maximal sputum levels to peak serum levels were 0.07%, 0.2%, and 7.1% in 3 patients treated with FK037.
Eleven patients with respiratory tract infections were examined for clinical evaluation of FK037, which were administered in 0.5 g/0.5 g, 1.0 g/1.0 g or 2.0 g/2.0 g daily for 1 to 13 days. Causative organisms were S. pneumoniae (4), P. aeruginosa (1), Corynebacterium pseudodiphtheriticum (2), Escherichia coli (1), B. catarrhalis (1). The bacteriological effect was 9/9, and the: clinical therapeutic efficacy was 100%.
From these results, we concluded that FK037 was an effective and useful antibiotic for the treatment of respiratory tract infections.

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We examined FK037, a new developed cephem antibiotic, for its pharmacokinetics in the plasma and sputum, and for its clinical efficacy in respiratory tract infection. The results were as follows.
1) Antibacterial activity
The MICs of FK037 against 714 strains isolated from clinical materials (170 strains of Grampositive cocci, 49 of Moraxella catarrhalis, 51 of Haemophilus influenzae, 322 of enterobacteria, 122 of nonglucose-fermentable Gram-negative rods) were measured and compared with those of ceftazidime (CAZ), cefuzonam (CZON) and flomoxef (FMOX) according to the standard method authorized by the Japanese Society of Chemotherapy. Against methicillin-resistant Staphylococcus aureus, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Morganella morganii, FK037 showed excellent antibacterial activity. FK037 showed lower activity against Pseudomonas aeruginosathan CAZ, but higher than CZON, FMOX. Against other species of bacteria, it was equally or more powerful than CZON, FMOX.
2) Plasma and sputum levels
Plasma and sputum concentration of FK037 were studied in 2 patients with chronic bronchitis after drip infusion of 0.5g or 1.0g. The maximum sputum levels were 1.00μg/ml, 0.75μg/ml in the two.
3) Clinical results
FK037 was administered to 3 patients with chronic bronchitis at 0.5-1g in 2 divided doses for 14 days. The clinical efficacy was rated as good in 3 cases. There were no adverse reactions or abnormal laboratory-findings.

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We performed basic and clinical studies on FK037, a new parenteral cephalosporin antibiotic, and the following results were obtained.
1) Antimicrobial activity:
The minimum inhibitory concentrations (MIC) of FK037 against a total of 302 clinically isolated strains of 13 species were measured and compared with those of five cephalosporins (ceftazidime, flomoxef, ceftizoxime, cefpirome, cefepime) and one carbapenem (imipenem) using the MIC 2000 System (Dynatech Laboratories).
FK037 provided a stronger bactericidal activity than ceftazidime, ceftizoxime and cefepime, and equaled to or was stronger than flomoxef and cefpirome in bactericidal activity against grampositive bacteria, and had stronger bactericidal activity than imipenem, and was equal to or stronger than five cephalosporin antibiotics in bactericidal activity against gram-negative bacteria.
FK037 had wide bactericidal activity against these clinical isolated strains except methicillin -resistant Staphylococcus aureus.
2) Clinical study results:
FK037 was administered to 4 patients with pneumonia in daily doses of 1.0g to 4.0g for 7-15 days by drip infusion. Clinical response was excellent in one, good in one and fair in one except unknown in one patient.
No objective or subjective side effects related to the antibiotic were noted. Abnormal laboratory changes were observed in 2 cases, but were transient.

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We investigated the antibacterial activities and the clinical effects of FK037.
The MIC₉₀ of FK037 against gram-positive cocci was 2.0 μg/ml for methicillin-sensitive Staphylococcus aureus (MSSA) and 32 μg/ml for methicillin-resistant S.aureus (MRSA). In comparison with other antibiotics, that of FK037 for MSSA was higher than those of flomoxef (FMOX) and imipenem (IPM), but antibacterial activity of FK037 for MRSA was superior to other antibiotics.
Against gram-negative rods, the MIC₉₀ of FK037 was 0.063μg/ml for Escherichia coli, 0.25 μg/ml for Klebsiella pneumoniae, 0.25 μg/ml for indole-positive Proteus spp., and activity of FK037 was 1-5 grade superior to other antibiotics.
Against Pseudomonas aeruginosa, the MIC₉₀ of FK037 was higher than that of IPM, equal to CAZ and 5 grades lower than that of FMOX.
In clinical study, FK037 was administered to 9 patients with complicated urinary tract infections, and the clinical effects and side effects were investigated. FK037 was administered at doses of 0.25, 0.5, 1.0 g, twice a day for 5 days.
The general clinical effects were evaluated according to the criteria proposed by the Japanese UTI Committee, and was excellent in 3 patients and good in 4.
Ten strains of causative organisms were eliminated, and no isolates appeared after treatment were observed.
No side effects were observed, and in laboratory findings, a slight elevation of GOT and an elevation of GOT, GPT were seen each 1 patient.

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We studied the antimicrobial activity and the pharmacokinetics of FK037, a new cephem antibiotic, and its clinical value in urinary tract infection (UTI).
1) The MICs of FK037 and control antibiotics (ceftazidime: CAZ, flomoxef. FMOX, imipenem: IPM) were measured using the plate dilution method against reference strains and clinical isolates from urinary tract infections. The MIC₉₀ of FK037 against methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus was 1.56 and 25 μg/ml, respectively. Those against Escherichia coli and Klebsiella pneumoniae were both 0.1 μg/ml. These results revealed that FK037 was superior to the controlled antibiotics in activity. However, FK037 was inferior to CAZ and IPM in activity against Pseudomonas aeruginosa.
2) The blood concentration and urine excretion were measured in a patient with complicated UTI who was treated by intravenous drip infusion of 0.5 g of FK037. The blood concentration was 20.4 μg/ml immediately after the drip infusion and the urine level was 1, 240 μg/ml in the first 2 hours. The urinary recovery rate amounted to 100% within 12 hours.
3) Five patients with complicated UTI were treated with 0.25 g, 0.5 g or 1.0 g of FK037 twice a day for 5 days. Clinical efficacy was excellent in 2 patients, moderate in 2 patients, according to the criteria proposed by the Japanese UTI Committee. All the pretreatment isolates were eliminated. There were no significant clinical or laboratory adverse reactions.
Therefore, this study demonstrated FK037 to be an effective and safe antibiotic in the treatment of complicated UTI.

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We performed basic and clinical studies on FK037, a new injectable cephem antibiotic, and obtained the following results.
1) The in vitro antimicrobial activity of FK037 against 321 clinically isolated strains (13 species) was assessed and compared with that of cefpirome (CPR), ceftazidime (CAZ), ceftizoxime (CZX) and flomoxef (FMOX). FK037 was similar or superior to other drugs in activity against Staphylococcus aureus and Staphylococcus epidermidis. However FK037 as well as other drugs had no activity against Enterococcus faecalis. Against Citrobacter and Enterobacter, FK037, like CPR, was superior to other drugs in activity. Against Pseudomonas aeruginosa, FK037 was superior to CZX and FMOX, similar to CPR and slightly inferior to CAZ in activity.
2) FK037 was administered to 11 patients with complicated urinary tract infection and assessed according to the Japanese UTI committee's criteria. The clinical efficacy rate was 81.8%(excellent in 4 patients, moderate in 5 and poor in 2). In the bacteriological response 19 of 21 isolated strains (90.5%) were eradicated. No side effects were observed, but abnormal laboratory findings on liver function were noted in 2 cases.

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We studied the antibacterial activity and efficacy of FK037, a new injectable cephem antibiotic, in the urological field.
1) Antibacterial activity: The MICs of FK037 were measured against 211 clinically isolated strains of 14 species from urinary tract infections and compared with those of ceftazidime (CAZ), cefoperazone (CPZ) and imipenem (IPM). In general, the antibacterial activities of FK037 were superior to those of CAZ and CPZ, but inferior to those of IPM.
2) Clinical efficacy: According to the criteria of Japanese UTI Committee, the overall clinical efficacy rate was 75.0%(9/12) for chronic complicated UTI. Bacteriologically, 18 of 20 strains (90.0%) isolated were eradicated.
3) Side effect: A mild and transient rash was observed in 1 patient. In 1 patient, eosinophilia was noted, but was not problematic clinically.
Based on the above findings, FK037 might be useful in the treatment of urinary tract infection.

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We investigated the prostatic tissue levels of FK037, a new parenteral cephem, in the patients with benign prostatic hypertrophy. In a clinical study, FK037 was evaluated clinical efficacy on urinary tract infections (UTI) and acute bacterial prostatitis.
Prostatic tissue levels of FK037 were measured at 35 to 70 minutes after lg drip infusion in 5 patients with prostatic hypertrophy, who underwent transurethral resection of prostate or open prostatectomy. The concentration of FK037 was 37.5±14.2 μg/ml in the plasma and 14.6±2.44 μg/g in the prostatic tissue.
The ratio of prostatic tissue level to plasma level was 0.43 ± 0.15.
FK037, at daily doses of 1-2g for 5 days, was given to 9 patients with complicated UTIs, 7 patients indwelling catheters. The overall clinical efficacy rate evaluated by criteria of the Japanese UTI committee was 6/9.
FK037 was given to 3 patients with acute bacterial prostatitis at a daily dose of 2g for 7 days, and the overall clinical efficacy rate was 3/3.
Fifteen (75%) of 20 urinary bacterial strains were eradicated.
No adverse reaction was observed in these 12 cases. As abnormal laboratory findings, a slight elevation of GOT and GPT, and GPT was observed in each one case.

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A research group involving 7 key institutions and their affiliated institutions clinically evaluated the effectiveness of FK037, a newly-developed cephalosporin, on surgical infections.
FK037 was intravenously administered to 98 patients by drip infusion, most of the patients received 2.0 g daily for 4 to 7 days. The clinical efficacy was examined in 90 evaluable patients; 10 with skin and soft tissue infections, 13 with periproctal abscess, 24 with intraabdominal infections, 23 with secondary infections, 20 with biliary tract infections.
The remaining 8 patients dropped out or were excluded. FK037 was effective (good or excellent) in 88.9% of 90 patients, with excellent in 48, good in 32, fair in 7 and poor in 3. The safety was evaluated in 94 patients. As side effects, pruritus and eruption was mild and transitory, and was found only in one. Nine abnormal laboratory test findings were seen in 86 patients: 7 were slight increase in s-GOT, s-GPT or other liver function tests, and 2 were mild eosinophilia. The utility was evaluated in 90, with 88.9% of utility rate. These results suggested that FK037 was effective in surgical infections with good safety.

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As part of a two-part investigation, a pharmacokinetic study was performed with 5 patients after radical mastectomy as the subjects. One gram of FK037, a new semisynthetic parenteral cephem, was administered intravenously over a 60-min period and serial samples of blood and mastectomy wound seromas were taken. The peak levels of FK037 in the plasma were 40.4 - 68.8 μg/ml 1 h after the start of administration, and the levels decreased to 3.2 - 16.1 μg/ml at 7 h, and <0.25 - 0.7 μg/ml at 24 h. The peak levels of FK037 in seroma were 12.2 - 27.4 μg/ml at 2 to 5 h, with a decrease to 6.0 - 14.2 μg/ml at 7 h and to <0.13- 4.5 μg/ml at 24 h. The levels in plasma were simulated well by a two- or one-compartment model and levels in the seroma were simulated well by a one-compartment model. Areas under the curve were almost the same in the plasma and seroma.
In the second part of the study, 25 surgical infections in 24 patients were treated; additional patient could not be treated as planned because of positive results of a skin test for sensitivity to the drug. Clinical efficacy was excellent in 17 infections, good in 4 infections, fair in 2 infections, and poor in 2 infections with an efficacy of 84%. The efficacy rate was low in the 2 serious infections (p=0.02) compared with infections that were not serious. The bacteriological response of 28 strains of 21 bacterial species isolated was evaluated. Twenty-one strains were eradicated and 7 strains persisted, with an eradication rate of 75%. The bacteriological response of the host was evaluated in 13 infections. Bacteria were eradicated in 9 infections, decreased in 2, and persisted in 2. The becteriological response could be evaluated in 23 strains from among the strains isolated of the 27 strains for which the MIC was calculated, and 17 strains (74%) of them were eradicated, but no correlation of the rosponse and the MIC was found. The safety of this drug could be evaluated in 26 infections. Abnormal changes in laboratory test results were found in 11. Two such changes involved eosinophilia and the attending physicians reported the drug as a possible cause.
FK037 seemed to be fairly effective for surgical infections including those with involvement of skin and soft tissue.

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The kinetic profile of FK037, a new cephem antibiotic, which is highly active antimicrobial agent against Gram-positive bacteria including Staphylococcus aureus and Gram-negative bacteria including Pseudomonas aeruginosa was clarified and its clinical efficacy on biliary tract infections, peritonitis and periproctal abscess was investigated.
1) When 1 g of FK037 was intravenously given to patients who were planned to undergo cholecystectomy, the peak level in the gallbladder tissue was 29.5μg/g and that in the gallbladder bile was 14.5μg/ml at 1 hour after administration.
2) The bile concentration was determined in 6 patients with a drainage tube showing the peak level of 2.79-10.6μg/ml, at 2-3.5 hours after administration at a dose of 1 g. In the case of renal failure it kept high level.
3) The concentration in ascitic fluid in a patient with gastric cancer undergoing abdominal drainage showed peak level of 13.0-30.1μg/ml at 2-3.7 hours after administration at a dose of 1 g.
4) The clinical efficacy was excellent in 4 and good in 4 cases. The isolated organisms were S.aureus in 3, Escherichia coli in 3, P.aeruginosa in 1 and Bacteroides fragilis in 1 case. All these organisms but B. fragilis were sensitive to FK037 and eradicated. Abnormal laboratory data consisted of only slight elevation of serum GPT in 1 case.
It concluded that FK037 is a useful antibiotic agent for treatment of surgical infections.

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FK037, a new cephem, was examined for its antibacterial activity and clinical efficacy in the field of surgery, principally gastroenterological surgery. The results of the laboratory and clinical studies were as follows.
1) Antibiotic activity: MICs of FK037 against methicillin-resistant Staphylococcus aureus ranged from 6.25-50μg/ml. MICs of FK037 against all strains of methicillin-sensitive S. aureus were lower than 3.13μg/ml. FK037 had a favorable antibacterial activity against coagulase-negative Staphylococcus, the MIC₉₀ of FK037 was 12.5μg/ml.
FK037 provided high MIC against most strains of Enterococcus spp., and so we considered that FK037 does not have clinical efficacy against the species.
FK037 had a favorable antibacterial activity against Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter freundii, Enterobacter aerogenes, Serratia marcescens, and Acinetobacter calcoaceticus, but showed high MIC for some of Enterobacter cloacae. Against Pseudomonas aeruginosa, resistant to other cephems, FK037 had a favorable antibacterial activity, with 12.5μg/ml inhibiting the growth of 73.8% of strains of the species.
FK037 had high MIC against Xanthomonas maltophilia, and so we considered that FK037 dose not have clinical efficacy against the species.
2) Clinical efficacy: FK037 was administered to 6 patients with infection (2 with panperitonitis due to ulcer, 1 with intraabdominal abscess due to panceratitis, 1 each with peritonitis due to severe obstructive colitis, cholangitis and post operative wound infection). The clinical efficacy was good in 4, fair in 2. None of the patients developed side effects or abnormal changes in laboratory findings that might be attributed to the treatment.

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We carried out a multicenter collaborative trial at 15 institutes to evaluate the clinical efficacy of FK037, a new developed cephem antibiotic, in the treatment of bone and joint infections. FK037 was administered for the treatment of osteomyelitis and arthritis at 1-2g in divided doses for 6-31 days. A total of 46 patients were enrolled in the trial and the number of evaluable cases was 43. The efficacy rate for pyogenic osteomyelitis and arthritis were 68.8% and 100%, respectively. In bacteriological effect against 19 strains, the eradication rate were 68.4%(13/19). The MICs of FK037 were examined against 12 strains isolated in this clinical study. The MICs of FK037 against methicillinsusceptive Staphylococcus aureus were inferior to those of flomoxef (FMOX) and superior to those of ceftazidime (CAZ). However the MIC of FK037 against methicillin-resistant S. aureus was superior to other drugs. In Gram-negative bacteria, the MICs of FK037 were superior to those of CAZ, FMOX against Neisseria sp. and almost the same as those of CAZ against Pseudomonas aeruginosa. Two patients showed diarrhea as side effects. Five patients showed abnormal findings in clinical tests: eosinophilia evaluated in 1, GOT·GPT elevation in 3, GPT·LAP·γ-GTP elevation in 1.
The results suggest that FK037 was highly useful for orthopedics infections.

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We performed basic and clinical studies on FK037, a new injectable cephem antibiotic, in obstetrics and gynecology, and obtained the following results.
1. Antibacterial activity: The MICs of FK037 were examined against 80 strains isolated in this clinical study. The MICs of FK037 against Gram-positive bacteria were superior to those of ceftazidime (CAZ) and the same as or superior to those of flomoxef (FMOX). However, FK037 has no activity against Enterococcus spp. similar to other drugs. In Gram-negative bacteria MICs of FK037 were superior to those of CAZ and FMOX against Escherichia coli and almost the same as those of other drugs against other species. MICs of FK037 against anaerobic bacteria were almost the same as those of CAZ and slightly inferior to those of FMOX.
2. Tissue penetration of genital organs: The concentrations of FK037 in internal genital organs and retroperitoneal fluid after 1.0g 1h d.i.v. administration were examined. The peak levels in the tissue were 32.7-53.1μg/g within 1.5h, and they were declined to 6.13-10.9μg/g at >4-4.6h. The peak levels in retroperitoneal fluid were 24.7μg/ml at 3h, and they were declined to 9.87μg/ml at 7h.
3. Clinical evaluation: 96 patients with obstetric and gynecologic infections were treated with FK037. Clinical efficacy was evaluated in 92 patients and the efficacy rates were 100%(40/40) in intrauterine infection, 94.1%(16/17) in adnexitis, 90.0%(18/20) in pelvic infection, 91.7%(11/12) in external genital infection and others. The overall efficacy rate was 94.6%(87/92). In the bacteriological effect against 97 strains of clinical isolates, the eradication rate was 83.5%(81/97).
Safety was evaluated in 95 patients. Clinical side effects, such as rash and itching, were observed in one patient. As for abnormal laboratory findings, slight elevations of GPT and GOT · GPT were found in two.
It is concluded that FK037 is considered to be one of the useful drugs in the treatment of obstetric and gynecologic infections.

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FK037, the newly developed cephalosporin antibiotic, 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 FK037 for 300 strains of 15 species of clinical isolates were examined. The MIC90 ranged from ≤0.025 to>100μg/ml for Gram-positive cocci, <0.025 to 12.5μg/ml for Gram-negative bacilli and 5≤0.025 to 50μg/ml for anaerobes.
2) Tissue penetration: Good tissue penetration of the drug into intrapelvic genital organs was observed. The level of the drug in uterine arterial serum was similar to that in cubital vein serum and the level in uterine or adnexal tissues ranged from 2.21 to 19.8μg/g after intravenous drip injection of 1.0g.
3) Clinical results: FK037 was given to 25 patients with obstetric and gynecological infections at a daily dose of 2.0g for 4-10days, with the clinical effectiveness of 100%. Bacteriological effect was 81.8% and the eradication rate against isolated organisms was 89.5%. No side effects were observed.
From these findings, FK037 is considered to be a useful antibiotic on obstetric and gynecological infections.

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Fundamental and clinical studies of FK037, a new parenteral cephalosporin, in obstetrics and gynecology were performed, and the following results were obtained.
1) The MICs of FK037 for 90% of the clinical isolates tested were as follows: 0.10μg/ml for Escherichia coli and Klebsiella pneumoniae, 0.20μg/ml for Streptococcus agalactiae, 0.39μg/ml for Gardnerella vaginalis, 0.78μg/ml for Staphylococcus epidermidis, Peptostreptococcus anaerobius and Mobiluncus spp., 1.56μg/ml for Peptostreptococcus magnus, 3.13μg/ml for methicillin-sensitive Staphylococcus aureus (MSSA), 25μg/ml for methicillin-resistant S. aureus (MRSA), Bacteroides fragilis and Prevotella disiens, 100μg/ml for Bacteroides thetaiotaomicron and Prevotella bivia, >100μg/ml for Enterococcus faecalis.
2) Concentrations of FK037 in the blood and female genital organs after 1.0g single intravenous drip infusion of the drug were measured. The maximum serum concentration (C_max) of FK037 was 66.29 μg/ml at 1.00 hour, C_max in the genital organs was 27.41-44.80μg/g at 1.01-1.02 hours, and C_max in the exudate of retroperitoneal fluid was 18.78μg/ml at 3.16 hours.
3) A clinical study, given 1.0 g of FK037 drip infusion twice a day for 3-9 days, was carried out in patients with obstetric and gynecological infections. Clinical efficacy rate was 90.0%(9/10) and bacteriological efficacy rate was 6/9. There were no side effects. As for abnormal laboratory findings, the mild and transient elevation of GOT and GPT was observed.

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We performed basic and clinical studies on FK037, a new injectable cephem antibiotic, and obtained the following results.
1) The concentrations of FK037 in serum, internal genital organs and retroperitoneal fluid after 1 h drip infusion of 1.0 g were measured.
The peripheral serum level was 48.1±10.2μg/ml at 30 min, 55.6±14.8μg/ml at 1 h, decreasing to 3.45±1.30μg/ml at 7 h after administration.
The concentrations in the tissues were 3.24±14.0μg/g at 25 min after administration.
The concentrations in retroperitoneal fluid were 15.4±3.9μg/ml, 27.4±7.5μg/ml and 9.87±4.35μg/ml at 1 h, 2 h and 7 h after administration.
2) In the clinical trial, FK037 was administered to 8 patients with obstetric and gynecologic infections (4 with intrauterine infections, 1 with adnexitis, 2 with pelvic infections, 1 with infectious lymphocele).
The results were as follows: 2 patients were judged as excellent, 4, good and 2, poor. Bacteriologically, 14 organisms were isolated from 7 patients and the eradication rate was 64.3%.
Neither side effects nor abnormal laboratory findings were observed in any of the patients treated with FK037.
It is concluded that FK037 is a very useful antibiotic in obstetric and gynecologic infections.

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FK037, a new parenteral cephalosporin, was evaluated from the dermatological aspects.
1) Minimum inhibitory concentrations (MICs) of FK037, imipenem (IPM) and flomoxef (FMOX) were determined against 32 strains of Staphylococcus aureus isolated from skin infections. The MICH of FK037 against 16 strains of methicillin-sensitive S. aureus was 4μg/ml, being similar to FMOX and slightly inferior to IPM in activity. Against 16 strains of methicillin-resistant S. aureus, the MIC90 of FK037 was 32μg/ml. This was similar to IPM and slightly superior to FMOX in activity.
2) Skin and exudate levels of the drug were 8.0-10.7μg/g and 15.4-23.7μg/ml, 3 hours and 2.4-2.8 hours after the administration of FK037 in a dose of 1.0g by intravenous drip infusion over a period of 1 hour, respectively. The ratios of skin and exudate levels to plasma levels were 0.35-0.46 (n=2) and 1.05-1.27 (n=2), respectively.
3) FK037 was used clinically in 28 patients with skin and skin structure infections. Most patients were treated in a dose of 1.0g twice daily by intravenous drip infusion over a period of 1 hour. The clinical efficacy was evaluated in 27 patients. The overall clinical efficacy was 96.3%. The bacteriological response rate was 72.4%. There were no adverse reactions. Abnormal laboratory findings were observed in 2 cases: elevations of GOT·GPT and GPT ·γ-GTP in each case.

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Bacteriological, pharmacokinetic and clinical studies of FK037 were carried out on FK037 otorhinolaryngological infection. The results were asfollows.
1) The concentrations of FK037 were 3.30 to 24.2μg/g in the tonsil, N. D. to 13.9μg/g in the tympanum mucosa, N. D. to 14.1μg in the granulation in tympanum, 3.93 to 29.4μg/g in the maxillary sinus mucosa, 3.47 to 16.4μg/ml in themaxillary sinus secretion, 9.17μg/g in the granulation maxillary sinus, 2.95μg/g in the parotid gland.
2) Clinically, FK037 was used in 122 patients withotorhinolaryngological infections. The overall efficacy rate of FK037 was 85.2%.
3) The bacterial eradication rates were 90.5% for monomicrobial infection and 86.4% for polymicrobial infections.
4) Side effects were observed in 2 cases (fever, malaise and headache; erythema and itching). Abnormal laboratory findings were noted in 13 cases: 10 cases of elevation of GPT; one case of elevation of GOT and GPT; one case of elevation of GPT and ALP; one case of prolongation of prothronbin time. All were mild in severity.
The results suggest that FK037 is extremely effective and useful for bacterial infections in the otorhinolaryngological field.

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We conducted a basic and clinical evaluation of FK037, a new parenteral cephalosporin, in the ophthalmological field.
1) FK037 like cefpirome, had broad antibacterial activity against gram-positive and gramnegative bacteria. The susceptibility of 20 clinical isolates of Staphylococcus aureus ranged from 0.39 to 3.13μg/ml with a peak level at 1.56μg/ml. The susceptibility of 20 clinical isolates of Pseudomonas aeruginosa ranged from 1.56 to 100μg/ml with a peak at 6.25μg/ml.
2) When FK037 was administered intravenously to matured white rabbits at a dose of 50mg/kg, the aqueous humor level peaked at 6.57μg/ml 60 min after administration. The rate of the peak humor aqueous to the blood level was 8.7%. Thereafter the level gradually decreased to 2.67μg/ml at 6hr after administration. The ocular tissue concentrations at 60 min after administration were 10.8-110.3μg/g in the extraocular tissues and 0.51-31.3μg/g or ml in the intraocular tissues.
3) When FK037 was administered to man at a dose of 1.0 g by i. v. drip infusion for 60 minutes, the aqueous humor levels of FK037 were 0.20-6.69μg/ml at 97-457 min after administration, and the peak tear level of FK037 was 6.4μg/ml at 60 min. after administration, and thereafter the level gradually decreased to 0.2μg/ml at 8hr after administration. The rate of aqueous humor concentration to plasma concentration was 0.52-19.17%, and that of tear to plasma concentration was 5.0-10.7%.
4) 16 patients (lid abscess 3, corneal ulcer 11, orbital cellulitis 2) were treated with FK037 drip infusion at a dose of 0.5-2.0 g two times a day. Clinical responses were excellent in 10, good in 5 and poor in 1, with the efficacy rate of 93.8%. No side effects were observed, and abnormal laboratory findings were observed in 2; an elevation of GPT in 1, an elevation of GOT and GPT in 1.

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Experimental and clinical studies on FK037, a new cephalosporin antibiotic, were made in the field of oral surgery with the following results.
1) The concentration of FK037 in serum and oral tissues was measured in 11 patients after intravenous drip-infusion of 1.0g during a period of 60min. The concentrations of gingiva, cystwall, granulation and other oral tissues were 1.26-77.3μg/g, 9.33-51.8μg/g, 1.23-72.5μg/g, 5.79-22.7μg/g, respectivery.
2) Prophylactic efficacy of FK037 against post-extraction bacteremia was examined. Doses of 0.5 g or 1.0 g were administered before tooth extraction in 30 patients. There were no bacteremia after tooth extraction in 28 patients.
3) The clinical effect and safety of FK037 were evaluated in 35 patients with odontogenic infection. The clinical effect was excellent in 4, good in 11, poor in 1, with an effectiveness rate of 93.8% in osteitis of jaw, and excellent in 1, good in 16, poor in 2, with an effectiveness rate of 89.5% in cellulitis of perimandibular space. The overall effect was excellent in 5, good in 27, poor in 3, with an effectiveness rate of 91.4%. The bacteriological effect was eradicated in 17, persisted in 3, with eradication rate of 85.0% in 20 patients. Adverse events were observed in one case of diarrhoea, and in the other case of nausea and decrease in blood pressure. As to abnormal findings in laboratory tests, an increase of transaminase was noted in 3 cases. No serious events were seen in any of the patients.

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The in vitro activity of FK037, a newly developed cephalosporin antibiotic in Japan, was studied by determining minimum inhibitory concentration (MIC) using the agar two-fold dilution method. All the strains used for this study were isolated from blood of patients admitted to Keio University Hospital between 1989 and 1992. The range of MIC of FK037 against 36 strains of Staphylococcus aureus with the mecA gene, against which the MIC of methicillin (DMPPC) was 12.5μg/ml or more, was from 6.25 to 50μg/ml. The MIC of FK037 against 16 strains of S. aureus, against which the MIC of DMPPC was 6.25μg/ml or less, was, however, ranged from 0.2 to 6.25μg/ml. Out of these 16 strains, 8 strains had the mecA gene. FK037 was more active than cefclidin (CFCL) and less active than cefpirome (CPR) and cefuzonam (CZON) against these 16 strains. The range of MIC of FK037 against 19 strains of Escherichia coli, 8 of Klebsiella pneumoniae and 28 of Pseudomonas aeruginosa were 0.025 or less to 0.2μg/ml, 0.025 or less to 0.2μg/ml and 0.39 to 100μg/ml or more, respectively. FK037 was more active than not only CZON but also CFCL against E. coli and K. pneumoniae. FK037 was, however, less active than CPR against these organisms. FK037 was more active than CPR and CZON but was less active than CFCL against P. aeruginosa.

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The in vitro antimicrobial activity of FK037, a new parenteral cephalosporin was compared with that of ceftazidime (CAZ), cefpirome (CPR), cefotaxime (CTX), cefepime (CFPM), cefoperazone (CPZ) and ceftizoxime (CZX). The following results were obtained.
FK037 had a broad antibacterial spectrum against gram-positive bacteria including Staphylococcus aureus and gram-negative including Pseudomonas aeruginosa. The antibacterial activity of FK037 against clinical isolates of methicillin-sensitive S. aureus was higher than other antibiotics except for CPR. Against methicillin-resistant S. aureus, FK037 was most potent, and all of the strains were inhibited to grow by less than 50μg/ml of FK037. Against Staphylococcus epidermidis, FK037 was the same in an antibacterial activity as CPR and CPZ. Against Enterococcus faecalis, FK037 was the same in the activity as CZX. FK037 had the most potent activity against Enterococcus faecium and Enterococcus avium. FK037 also showed an extremely potent activity against gram-negative bacteria. The MIC₈₀values of FK037 were less than 1.56μg/ml for Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Citrobacter freundii. Whereas, in the antimicrobial activity against P. aeruginosa, FK037 was the same as CPZ.
FK037 was a new antibacterial agent with a broad spectrum, and was considered to be useful in the treatment of intractable surgical infection.

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The clinical efficacy and safety of FK037 were evaluated in 5 patients with chronic respiratory tract infection. The drug was administered in a daily dose of 2.0g for 8-14 days.
The clinical efficacy was “good” in 4 and “fair” in 1.
Causative organisms were 5 strains, 3 of which were eradicated and the other 2 were persisted.
No side effects were observed and abnormal findings (slight elevation of GOT or Urine RBC) were observed in 1 patient each.

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We evaluated the clinical efficacy and safety of FK037, a new cephem antibiotic. FK037 was administered to 11 patients with infectious disease. They received the drug intravenously for 3 to 15 days in doses of 0.25-2.0g/day. Clinical effects were excellent in 3, good in 6, poor in 1 and unknown in 1. No side effects were noticed. However, as abnormal laboratory findings, leucopenia was observed in 2 cases.

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FK037, a new injectable cephem antibiotic, was evaluated from the view point of its clinical efficacy and adverse reactions in 8 elderly patients with respiratory tract infections. The 8 patients consisted of 7 with pneumonia and 1 with lower respiratory tract infection (bronchiectasis). The drug was administered intravenously at daily dose of 1.0-2.0g for 6-10 days.
The clinical efficacy was good in 8 patients with the overall efficacy rate of 100%. No side effects were observed. Abnormal laboratory findings were seen in 1 case (eosinophilia), which improved after treatment. From the above results, we consider FK037 to be a useful antibiotic for the treatment of respiratory tract infections in elderly patients.

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Efficacy of FK037, a new parenteral cephem antibiotic, was evaluated in 6 patients with respiratory infections: 5 with bronchopneumonia and 1 with chronic bronchitis.
Detection of causative organisms was performed by the transtracheal aspiration (TTA) method. There were 1 case of monomicrobial infection and 3 of polymicrobial infection. Streptococcus pneumoniae, Pseudonionas aeruginosa, glucose non -fermenting gram-negative rod (GNF-GNIZ) and 3 anaerobic bacteria were identified. The dosages were 0.5g twice daily in 3 cases and 1.0g twice daily in 3. The duration of treatment ranged from 4 to 15 days. Clinical effects were good in 3 cases, fair in 1 and poor in 2. No adverse reactions were observed, and laboratory examinations showed a slight elevation of ALP·γ-GTP in 1 case and monocytosis in 1.

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FK037, a new injectable cephem antibiotic, was administered in the treatment of 14 complicated urinary tract infections.
The drug was given at doses of 0.25-1.0g b. i. d. by intravenous drip infusion for 5 days. The clinical efficacy was evaluated as excellent or moderate in 11 cases out of 13, 85% by the Japanese UTI criteria. Bacteriologically, 20 strains out of 22, 91% were eradicated after the therapy. Against strains of Pseudomonas aeruginosa, the response was 1 out of 3 strains. In the safety profile, no side events or abnormal laboratory findings were caused by FK037.

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