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Fundamental and clinical evaluations were made on cefoxitin, a new cephamycin antibiotic, and the following results were obtained. 1) MIC of the drug to clinical isolates was determined and was higher than that of cefazolin to Gram-positive bacilli. Among Gram-negative rods, the drug showed a sufficient antibacterial activity even to cefazolin-resistant strains. However, the MIC of cefoxitin to cefazolin-sensitive strains tended to be higher than that of cefazolin. 2) As to the passage of cefoxitin in experimental staphylococcal meningitis in rabbits, a percentage of CSF/serum ratio of AUC was 10.7% up to 3 hours and CSF/serum ratio of T1/2 was 1.78 of which value was an intermediate between those of ampicillin and cefazolin. There were, however, larger individual differences. 3) Blood concentrations and urinary recovery rates were determined in 2 children. In 1 patient, in whom the drug was given intravenously at a dose of 25 mg/kg, a blood concentration after 30 minutes was 50 microgram/ml, T1/2 was 57.2 minutes. This patient, however, showed a slight renal dysfunction. In another patient, who received an intravenous injection of 12.5 mg/kg, a 30 minutes blood concentration was 14.6 microgram/ml and T1/2 was 31.8 minutes. Urinary recovery rates up to 6 hours were 85.8% and 73.5%, respectively. 4) Thirty patients with the following bacterial infections were treated with cefoxitin, i.e., urinary tract infection (24 cases), respiratory tract infection (4 cases), each one case of peritonitis and suspected sepsis. An overall efficacy rate was 93.3%, i.e., excellent in 13 cases, good in 15, and failure in 2. Disappearance rate of the causative organism of the 23 clinical isolates was 87.0%, i.e., that the causative organism disappeared in 20 strains, reduced in 1 and persisted in 2. 5) Based on the above results, it was concluded that cefoxitin is a potent new antibiotic in bacterial infections in children, particularly respiratory and urinary tract infections. The optimal recommended dose will be about 25 mg/kg which should be given 3-4 times daily intravenously or by drip infusion.

The authors have carried out the laboratory and clinical studies of cefoxitin. The results were as follows: The sensitivity was estimated by plate dilution method on 26 strains of S. aureus, 25 strains of E. coli, 24 strains of K. pneumoniae, 27 strains of Serratia and 17 strains of Salmonella isolated from patients. The distribution of sensitivity of S. aureus was 1.56-3.13 microgram/ml and the peak of distribution was 3.13 microgram/ml. The strains of 76.0% of E. coli was inhibited at concentration of less than 3.13 microgram/ml. The strains of 91.7% of K. pneumoniae was inhibited at concentration of less than 3.13 microgram/ml. The distribution of sensitivity of Serratia was 6.25-more than 100 microgram/ml and the peak of distribution was 100 microgram/ml. The all strains of Salmonella were inhibited at concentration of less than 3.13 microgram/ml. Cefoxitin was given by intravenous administration for 5 minutes at a single dose of 25 mg/kg of cefoxitin to 2 children, and by drip infusion for 60 minutes at a single dose of 25 mg/kg of cefoxitin to 4 children. After intravenous administration of cefoxitin, the mean peak of serum level was 67.3 +/- 6.3 microgram/ml at 15 minutes, and at 4 and 6 hours after administration was not detected. Half-life time was 22 minutes. And after drip infusion of cefoxitin for 60 minutes, the mean peak of serum level was 35.7 +/- 5.3 microgram/ml at 1 hour, and at 4 and 6 hours after administration was not detected. Half-life time was 20 minutes. The mean urinary recovery rate was 82.4 +/- 3.0% and 90.2 +/- 6.8% up to 6 hours after intravenous administration and drip infusion respectively. Cefoxitin was effective in all of 15 cases with bacterial infections. No side effects was observed.

Using a new cephamycin antibiotic, cefoxitin, clinical studies were carried out, and the following results were obtained: (1) Cefoxitin was administered to 52 children with 38 respiratory tract infections, 2 urinary tract infections, 1 acute otitis media and others, who ranged in age from 2 months to 11 years old. (2) Cefoxitin was given intravenously at a daily dose of 27.3 mg/kg to 110.5 mg/kg. (3) The overall efficacy rate was 80% in 46 cases, i.e., excellent in 10, good in 27, fair in 7 and poor in 2. (4) Clinical side effects were not seen except exanthema in 1 patient. Elevation of GOT and GPT was seen in 2 patients, elevation of A1-P in 1 and eosinophilia in 2 by laboratory tests. However, these findings were alleviated rapidly following the cessation of therapy.

1) Serum concentrations of cefoxitin (CFX) was lower than that of cefazolin (CEZ), but the tissue concentrations of CFX were higher in ovary, oviduct and uterus compared with CEZ. 2) CFX was administered to 15 patients with moderate intrapelvic or urinary tract infections at a dose of 4 g per day for 5 to 7 days. The overall results obtained were as follows; excellent in 6 cases, good in 6 cases. The CFX treatment was effective in all patients, 8 cases, with intrapelvic infections. 3) The majority of organisms detected were E. coli (12 strains), and the antimicrobial activity of CFX against them was superior to those of CEZ and CET. 4) No side effects and abnormal laboratory findings were observed. 5) It is considered that CFX will be a useful drug in the field of obstetrics and gynecology.

Cefoxitin (CFX) was evaluated for its safety and efficacy in children. Fifteen patients were treated with 73-125 mg/kg per day of CFX by intravenous administrations. The diagnosis of the patients were acute pharyngitis (4), pneumonia (2), pertussis and pneumonia (1), urinary tract infection (3); and the remaining 5 patients were esteemed to have nonbacterial infections. All the 10 patients of bacterial infections were cured after the CFX therapy. The pathogens recovered were Streptococcus pyogenes (1), Streptococcus pneumoniae (3), Haemophilus influenzae (2), Escherichia coli (2), enteropathogenic Escherichia coli (1), and Klebsiella pneumoniae (1). All the strains isolated were susceptible to CFX, but the 2 isolates of Haemophilus influenzae had relatively high MIC values (12.5 mcg/ml). Diarrhea (3 cases) and transient neutropenia (1 case) were found to be associated with the CFX therapy. However, no severe adverse reactions were encountered. Half-life of the serum level was short (24.1 minutes) and excretion into the urine was rapid. CSF concentration obtained 30 minutes after an intravenous injection of 50 mg/kg of CFX in 1 case with inflamed meninges was considerably high (8.3 mcg/ml). CFX appears to be a safe and effective antibiotic when used in children with susceptible bacterial infections.

The antimicrobial activity of cefoxitin against clinical isolated organisms was measured: Cefoxitin was more active than cefazolin and cephalothin against Escherichia coli. The serum concentrations of cefoxitin following intravenous injection of 25 mg/kg were 267.7, 38.8, 8.3 microgram/ml at 5, 30, 120 minutes after injection, respectively. Cefoxitin was excreted 90.5% in urine within 6 hours after injection. Cefoxitin was administered clinically to 22 pediatric patients with various infections (urinary tract infection 9, respiratory tract infection 10, S.S.S.S. 1, Salmonella enteritis 1, and cervical lymphadenitis 1) at the dose of 45-98 mg/kg/day for 4-10 days, and the following satisfactory results were obtained; excellent in 16, good in 5, and poor in 1. The rate of satisfactory clinical response was 95.5%. Slight elevation of transaminase and A1-P were observed in 4 patients, but no other serious side effects were observed.

We studied cefoxitin (CFX) concentration of oro-maxillary tissues in rats and in 18 patients by means of bioassay method. In rats, the highest peak concentrations were observed in the gingiva and buccal mucosa followed by the tongue, submaxillary gland, lower jaw bone and the masseter muscle in the order listed. In patients, the highest peak concentrations were observed in the maxillary sinus mucosa and peak concentrations in oro-maxillary tissues were from 1/5 to 2/3 of the corresponding serum concentrations. Further study is needed to elucidate the reason for the high peak CFX concentration in the maxillary sinus mucosa and the apparent delayed peak concentration in the salivary gland.

Laboratory and clinical studies were performed on a newly introduced antibiotic of the cephamycin series, cefoxitin (CFX), and the results obtained were as follows: 1. Employing clinical isolates, MICs were determined and comparisons made with those of cephalosporins. The MICs of CFX against S. aureus and S. pyogenes slightly inferior to those of the cephalosporins, while the MICs of CFX against Gram-negative bacilli such as E. coli, Proteus sp. and Klebsiella sp. were considerably superior to those of CER and CET, and slightly superior to those of CEZ. 2. The peak serum concentrations were 34.7 mcg/ml and 67.6 mcg/ml at 30 minutes after an intravenous injection in doses of 12.5 mg/kg and 25 mg/kg, respectively. The peak serum concentration was 40.8 mcg/ml at the end of 60 minutes intravenous drip infusion when it was given in a dose of 25 mg/kg. In these cases, the serum half life were 25.8-51.2 minutes, and their urinary recovery were 67-90%. 3. Clinically, CFX was given to the 29 children with a total of 31 of varying bacterial infections: 6 cases of urinary tract infection (U.T.I.), 19 of respiratory tract infection (R.T.I.), 2 of staphylococcal scalded skin syndrome (S.S.S.S.), 2 of purulent lymphadenitis and 2 cases of soft tissue dermatological infections. Overall efficacy rate was 83.9% (26 cases). No significant adverse reaction was noted except for 1 case of rash. Abnormal laboratory findings observed were elevation of GOT and GPT in 1 patient and of GPT in 1 patient.

Pharmacokinetics of cefoxitin, a new injectable semisynthetic-cephamycin, was studied in 12 healthy children and also was studied cerebrospinal fluid levels in 1 patient with bacterial meningitis received 44.5 mg/kg of cefoxitin and thoracic fluid levels in 2 patients were measured. Cefoxitin was administered intravenously to 50 patients with various types of infections an average dose of 130 mg/kg/day for an average of 9 days. The results were as follows: 1. Favorable plasma levels were obtained comparing with those off conventional injectable cephalosporins after 15 mg/kg and 25 mg/kg of cefoxitin for one shot intravenous injection. The half lives of cefoxitin in the plasma were about 15.9 minutes up to 1 hour and 25.5 minutes up to 2 hours after an intravenous administration of cefoxitin at a dose of 15 mg/kg, and while, those were 15.9 minutes and 27.5 minutes after an intravenous administration of cefoxitin at a dose of 25 mg/kg, respectively. 2. Cefoxitin was excreted with high concentration up to 2 hours after the administration and thereafter, urinary concentration of cefoxitin declined rapidly with the lapse of time. The time course urinary concentration reflected those of plasma levels. Approximately 94.7% and 90.6% of dosed cefoxitin were recovered in the urine for 6 hours after the administration at the dose of 15 mg/kg and 25 mg/kg, respectively. 3. The cerebrospinal fluid levels of cefoxitin were only determined in a patient of bacterial meningitis. Therefore, further study should be performed. 4. The thoracic fluid levels with 2 patients were higher than cerebrospinal fluid levels. 5. Among the 50 patients with various infections, cefoxitin was clinically effective in 84% and bacterial response in 87%. 6. As adverse reactions, in total 79 patients included exclusive 29 patients, diarrhea occurred in 1 patient, sweating and cough in 1 patient, rash with fever in 4 patients, vascular pain in 2 patients, and leukopenia was observed in 1 patient, eosinophilia in 1 patient, and increase of GOT and LDH were observed in each 2 patients. The other adverse reactions were not experienced.

The concentration of cefoxitin (CFX, Merxin) in dead space exudate was studied in 14 patients following total extirpation of diffuse uterine cervical cancer. A two-compartment model was used for the analysis. The results obtained were as follows: Calculated maximum concentrations of CFX in the pelvic dead space exudate were 26.55 micrograms/ml at 2.11 hours, 31.07 micrograms/mg at 2.01 hours and 51.51 micrograms/ml at 2.10 hours after 1 hour intravenous drip infusions of CFX 2, 3 and 4 g, respectively. These concentrations were higher than the MIC80 of 12.5 micrograms/ml against E. coli and B. fragilis and were maintained for a sufficient period of time. Based on the results of this study, CFX is considered to be an important and valuable drug in the field of obstetrics and gynecology.

Following are the results obtained from studies made with cefoxitin in the field of pediatrics: (1) The peak serum level observed upon completion of the one hour drip infusion in a dose of 20-25 mg/kg of cefoxitin varied from 66.4 to 93.0 mcg/ml. This fell to a remarkably low level after 2 hours. The serum half-life varied from 18.84 to 27.86 minutes. (2) The cumulative quantity of cefoxitin excreted in the active form in the urine by the end of 6 hours after completion of the drip infusion was 92.9-93.8%. (3) All of the 42 patients with acute pediatric infection (such as various kinds of acute upper or lower respiratory tract infection, urinary tract infection were treated with either cefoxitin by a single shot (23 patients), or by drip infusion (19 patients). The dosage employed was approximately 50-100 mg/kg/day divided into two to three treatments. There was no major difference in the clinical efficacy between administering two times or three times, the efficacy rates being 96% and 89% respectively. The overall efficacy rate was 93%. (4) In either case of intravenous injections by either a single shot or drip infusion, excellent clinical responses were obtained in most patients. These people had a variety of infections, which were considered to be caused by various kinds of Gram-positive cocci, E. coli (including ABPC resistance), P. mirabilis, Kl. oxytoca and Haemophilus. (5) Out of the 42 patients who received cefoxitin in a daily dose of 5-100 mg/kg divided into two or three times either by a single shot or drip infusion, no hepatic or renal function abnormality was observed except for 2 cases of temporary eosinophilia. (6) On the basis of these results, cefoxitin was found to be a highly useful antibiotic in the treatment of acute pediatric infection caused by microorganisms which are sensitive to cefoxitin.

Studies on antimicrobial activity, absorption and excretion and clinical use of cefoxitin in pediatric field were performed. 1. MIC of cefoxitin was compared with that of cefazolin and/or ampicillin for clinical isolates of Staphylococcus aureus (36 strains), Escherichia coli (35 strains), Klebsiella pneumoniae (34 strains) and Haemophilus influenzae (80 strains). MIC of cefoxitin against S. aureus was approximately 1-2 tubes higher than that of cefazolin. Many strains of E. coli and K. pneumoniae that showed high MIC to cefazolin were sensitive to cefoxitin. It is presumed that the results are due to the strong resistance of cefoxitin to beta-lactamase degradation. MIC of cefoxitin against H. influenzae was approximately 1-2 tubes lower than that of cefazolin, but approximately 4 tubes higher than that of ampicillin. 2. Serum level and urinary recovery rate of cefoxitin after one shot i.v. injection of 25 mg/kg were examined. The serum mean levels were 33.8 microgram/ml at 1/2 hour, 7.0 microgram/ml at 1 hour and 2.9 microgram/ml at 2 hours after the injection, respectively, and the drug was not detected in serum at 4 and 6 hours after the injection. The mean half-life of serum level was 27.1 minutes. The mean urinary recovery rate within 6 hours after injection was 96.0% and most of the drug were excreted into urine within 2 hours after the injection. 3. In order to evaluate clinical response, bacteriological response and side effects, cefoxitin was applied to 19 cases, i.e., 12 cases of either acute lobar pneumonia or acute bronchopneumonia, 2 cases of acute pyelitis, 1 case each of acute bronchitis, acute purulent tonsillitis, acute purulent arthritis, acute orbital phlegmon and acute buccal abscess. As for clinical response, the overall efficacy rate (the percentage of cases showed excellent and good efficacy) was 88.9%. As for bacteriological response, among the 13 strains which were determined or supposed to be causative organisms, i.e., 6 strains of Streptococcus pneumoniae, 2 strains of H. influenzae and 1 strain each of streptococcus pyogenes, alpha-Streptococcus, Enterococcus, E. coli and Neisseria sp., all strains were disappeared except for Enterococcus which was reduced by the treatment with cefoxitin. No side effect was observed in any case. Abnormalities of laboratory findings were observed in 3 cases, i.e., 1 case each of reduction of RBC and Hb, elevation of GOT and GPT and elevation of GPT, but all of them returned to normal following completion of the dosage term.

Both bacteriological and clinical studies of the effectiveness of cefoxitin (CFX) in the treatment of infections associated with abdominal surgery have been carried out at Tokyo Metropolitan Toshima Hospital from September 1979 through August 1980. The results of these studies are summarized in the following: 1. The clinical isolates from the 29 surgical patients were studied and anaerobes were found in 16 patients (55% of the patients). B. fragilis was found in 11 of the 16 patients (69%) from whom anaerobes were isolated. In all of these patients, aerobes were also isolated--most frequently E. coli or K. pneumoniae. 2. The in vitro antibacterial activity of cefoxitin (CFX) against 83 clinical isolates was compared to that of cephalothin (CET), cefazolin (CEZ) and carbenicillin (CBPC). The activity of CFX against Gram-positive bacteria was generally slightly inferior to that of the other 3 antibiotics. Among the Gram-negative aerobic organisms, CEZ was the most active against E. coli and CFX and CEZ against K. pneumoniae. However, CFX, with MIC's of 0.78-12.5 micrograms/ml, showed the greatest activity against B. fragilis, followed by CBPC, CEZ and CET, in order of decreasing activity. 3. CFX was administered in a 1-hour drip infusion to 3 patients following abdominal surgery, and concentrations of CFX in the serum and the exudate were measured. Peak serum concentrations were obtained at the end of the infusion, with a mean peak level of 97.93 micrograms/ml. Peak concentrations in the exudate were observed 30 to 60 minutes later and varied from 21.10 to 56.25 micrograms/ml. 4. Of the 20 patients administered of CFX, complete clinical and bacteriological data of anaerobic infections were available in 8 patients. The clinical evaluation was 'good' in 7 patients and 'fair' in 1. The bacteriological evaluation was 'eradicated' in 5 patients and 'decreased' in 3. As for side effects, elevations of S-GOT and S-GPT were observed in 4 of the 20 patients received CFX, but these abnormalities might also be attributable to other factors such as underlying disease, surgical intervention etc. No other side effects were found in these patients.