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The in vitro activity of cefoxitin, 3-carbamolyloxymethyl-7-alpha-methoxy-7[2-(2-thienyl)acetamido]-3-cephem-4-carboyxlic acid, was investigated. Activity against gram-positive organisms was less than that of cephalothin and cephloridine. It was highly active against gram-negative bacilli, with activity against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae equal to that of currently available cephalosporins. In addition, it was active against certain Enterobacter strains, Serratia marcescens, indole-positive Proteae and Herellea. The strains of these latter bacteria were strains susceptible to carbenicillin and ticarcillin. Pseudomonas aeruginosa and other Pseudomonas species were resistant. Changes in pH, inoculum size, and type of growth medium had no significant effect on the activity of the antibiotic. Cefoxitin was highly resistant to hydrolysis by various types of gram-negative beta-lactamases. The precise role of resistance to beta-lactamase hydrolysis varied from strain to strain. Bacterial resistance to cefoxitin was not necessarily related to hydrolysis of the antibiotic. However, the resistance of cefoxitin to hydrolysis did contribute to its activity. Cefoxitin could function as an inducer of beta-lactamase activity and effectively bound to purified beta-lactamases.

To characterize the effect of orally administered probenecid on the pharmacokinetics of cefoxitin in healthy male volunteers, we administered to one group of six subjects 2 g of cefoxitin by intravenous (i.v.) bolus either alone, with 1 g of probenecid concomitantly, or when 1 g of probenecid was administered 1 h previously by using a crossover design. Likewise, we administered to a second group of six subjects 2 g of cefoxitin intramuscularly (i.m.) together with 1 and 2 g of probenecid. Probenecid increased the mean terminal half-life and the area under the serum cefoxitin concentration-time curve (AUC0-24) and decreased renal clearance, but did not alter the volume of the central compartment or the total urinary recovery of i.v.-administered cefoxitin; pretreatment with probenecid produced a greater increase in cefoxitin AUC0-24 and a constant decrease in renal clearance compared to concomitant probenecid. The AUC0-24 after i.m.-administered cefoxitin was greater after 2 g than 1 g of probenecid; the AUC0-24 after i.v.-and i.m.-administered cefoxitin was similar after 1 g of probenecid was given concomitantly. Cefoxitin AUC0-24 was increased further when 1 g of probenecid was given before i.v.-administered cefoxitin or when 2 g of probenecid was given with i.m.-administered cefoxitin. The effect of probenecid was related to both timing and dose.

Intravenous doses of 0.5, 1, and 2 g cephalothin and cefoxitin, a semi-synthetic cephamycin antibiotic highly resistant to bacterial cephalosporinase, were infused over a period of 3 minutes into 18 normal adult males by a randomized, crossover design. Serum and urine data on cefoxitin best fit a two-compartment open model. Serum concentrations following cefoxitin were higher and more prolonged and urine recoveries higher than those following equal doses of cephalothin. The terminal serum half-life of cefoxitin was longer at all dose levels. Renal clearance of cephalothin-like activity exceeded that of cefoxitin, which may possess dose-dependent kinetics. Whereas cephalothin has been reported to metabolize by greater than 35% to the less active desacetyl form, cefoxitin was metabolized by 0.1 to 6% to the descarbamyl form in individual subjects.

We determined the intraoperative serum and wound-muscle concentrations of cefazolin and cefoxitin in 40 patients who were undergoing cholecystectomies. The study employed an open-label design in which all of the patients randomly received cefazolin sodium (20 mg/kg) or cefoxitin sodium (30 mg/kg) intravenously while the patient was in the ward ("on call") or with the induction of anesthesia. Multiple blood and wound-muscle samples were collected intraoperatively and assayed for their cephalosporin concentrations. Considerable differences in intraoperative serum and tissue concentrations between antibiotics were apparent; there were usually higher levels of cefazolin. In all of the patients who received cefazolin sodium, the antimicrobial was detectable in wound tissue at wound closure, while it was detectable in 86% and 38% of patients who received cefoxitin sodium with anesthesia and on call, respectively. Because cefoxitin has a much shorter elimination half-life than cefazolin it seems prudent to administer the agent as close to the start of the operation as possible, and readminister the agent every two to three hours until the wound is closed. For cefazolin, on-call administration appears to be acceptable, with readministration not required for at least four hours.

Thirty-six patients received an intravenous bolus injection of 2 g cefoxitin over 5 min at various times before abdominal or vaginal hysterectomy. Cefoxitin levels in myometrium and salpinges were substantially higher than those in endometrium and almost as high as those in serum during the first two hours following the i. v. administration of the drug. Tissue concentrations of 8 micrograms/g could be maintained for two hours. The cefoxitin tissue concentrations attained in myometrium, endometrium and salpinges justify controlled prospective clinical studies on the prevention of postoperative wound infections with this antibiotic.

The pharmacokinetics of cefoxitin was studied in 6 healthy volunteers and in 5 patients with a pleural effusion after administration of a single dose of 30 mg/kg i.v. infusion. The serum and pleural fluid concentrations of cefoxitin were determined microbiologically. The elimination half-life of the antibiotic from pleural fluid in all cases was 2-3 fold longer than from serum, which shows a difference between the kinetic elimination processes of the antibiotic from the two fluids. The slow elimination of cefoxitin from pleural fluid facilitates its accumulation in this compartment during a multiple dosage regimen.

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.

Intravenous injections of cefoxitin (2-g doses for adults and 40 mg/kg of body weight doses for children) were administered 90 minutes to two hours before surgery. All nine eyes had anterior segment inflammation. Samples of aqueous humor removed during surgery showed a mean cefoxitin concentration of 6.22 micrograms/ml, almost three times the concentration reported in uninflamed eyes. The greater penetration may have been the result of a breakdown in the blood-aqueous barrier. There were no complications.

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.

Cefoxitin was administered parenterally in doses of 2 g, every six hours for two days, to 20 patients undergoing colorectal surgery. Blood and fecal specimens were obtained for five days for analysis of cefoxitin concentrations. Tissue samples from the gut wall were obtained at surgery. The maximum serum concentrations during surgery varied between 25 and 100 microgram/ml, and the cefoxitin concentrations for the fecal samples were 1.5-35 microgram/g and for the tissue samples, 2.0-50 microgram/g. Fecal samples for cultivation of aerobic and anaerobic bacteria were also obtained daily during the first five days, and after 14 day after operation. Pronounced changes in the microflora occurred during the investigation period. Among the aerobic bacteria, cefoxitin-sensitive Escherichia coli and other enterobacteria decreased markedly while cefoxitin-resistant enterococci, Pseudomonas and Enterobacter proliferated during the antibiotic prophylaxis period. Among the anaerobic bacteria, Bacteroides fragilis and other Gram-negative bacteria decreased significantly. However, after the antibiotic administration period, all cefoxitin-resistant strains decreased while the suppressed E. coli and B. fragilis strains increased. In one patient, a minor postoperative infection caused by a cefoxitin-resistant strain of Pseudomonas aeruginosa was observed.

For elective alimentary tract operations in which contamination is moderate, single dose prophylaxis with piperacillin is equivalent to triple dose cefoxitin, a well established and effective regimen. Both methods failed to control infection arising in the perineal wound after abdominoperineal resection. Just as is the case with drain site infection, such infection often evolves from postoperative contamination and, indeed, is in theory and in fact unlikely to be controlled by perioperative prophylaxis. This study is among the first of several examining the issue of single dose prophylaxis and will be the harbinger of other studies from other groups examining whether or not the course of therapeutic antibiotics can be safely shortened in patients with peritoneal contamination.

Forty-eight patients who underwent elective hip or knee surgery were randomly divided into two groups. A total of 22 patients received a single 1-g preoperative bolus of cefoxitin, and 26 patients received a single 1-g preoperative dose of cephalothin. At various time intervals, serum and bone samples were taken during the operative procedure. Our data indicated that whereas serum levels of cefoxitin and cephalothin were maintained for at least 2h at levels capable of inhibiting most gram-positive cocci and many gram-negative rods, bone levels of cefoxitin rather rapid decay over a 2-h period. Moreover, in only 58% of the entire cephalothin-treated group were bone levels detectable and then only at a concentration that would inhibited gram-positive cocci. No significant morbidity was observed in either treatment group.

The interaction of 6 alpha-(temocillin) and 7 alpha-methoxy substituted (cefoxitin) beta-lactam compounds with various beta-lactamases was studied employing enzyme kinetics and compared to that of unsubstituted compounds. Both chromosomally mediated enzymes from Enterobacter cloacae and Citrobacter freundii were competitively inhibited by the methoxy-substituted compounds. Higher concentrations of cefoxitin caused a competitive inhibition of the plasmid-mediated Tem-1 enzyme, whereas temocillin led to a non-competitive inhibition of the Tem-1 enzyme. These results indicate that the discrepancies in the interaction on the above mentioned compounds have to be attributed to the different molecular structure of the beta-lactam nucleus. Moreover, no predictions can be made on the basis of an analogy between 6 alpha-methoxy-penams and 7 alpha-methoxy cephems.

The absorption of cefoxitin from rat intestine, rectum and small intestine was greater when the powdered form was administered than when an aqueous solution was given. Cefoxitin absorption from the small intestine was significantly increased after its administration in suppository form prepared with a triglyceride base, although rectal absorption from the suppository did not differ from that of the drug in powdered form. The increase in absorption by the small intestine from the suppository form may be due to fatty acids produced from triglyceride by lipase.

The use of lidocaine HCL solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.

The pharmacokinetics of cefonicid in the serum and tissues of patients undergoing open heart surgery, vaginal hysterectomy, and hip replacement was studied and compared with that of cefazolin and cefoxitin. Cefonicid achieved serum and tissue concentrations that were higher and more prolonged than those of cefazolin and cefoxitin. For cefonicid parallelism was observed between the serum and tissue concentration-time curves. Correlations of these properties to clinical efficacy were not attempted.

It has been shown previously that cefoxitin was not detectable in the milk following an intramuscular injection of 1 Gm to mothers. In the present study, using a more sensitive HPLC method, we have shown in five women that low concentrations of cefoxitin (0.25 to 0.65 micrograms/ml) are measured in the milk after the intramuscular injection of 2 Gm.

Hydrolysis kinetics of two cephalosporinases from Citrobacter freundii and Proteus vulgaris having different affinities for cefotaxime and ceftazidime was assessed in studies with cefotaxime, ceftazidime, BMY-28142, and imipenem. The two cephalosporinase genes were cloned into strains of Escherichia coli. The production of these cephalosporinases in strains of E. coli, as well as in the derepressed mutants of C. freundii and P. vulgaris, caused a decrease in susceptibility to the newer cephalosporins. The difference in the rate of hydrolysis at a 0.1 microM concentration of substrate adequately explains the difference in antibacterial activity between cefotaxime and BMY-28142 against E. coli strains with the two cephalosporinases. The results indicate that hydrolysis rate at low substrate concentration, rather than binding with beta-lactams, would be a limiting factor in resistance. The low affinity of cephalosporinases for BMY-28142 means high stability of the agent to the enzymes at low concentration. Furthermore, outer membrane permeability affects the susceptibility of E. coli to cephalosporins synergistically with hydrolysis by cephalosporinases.

Bone and serum concentrations of five cephalosporins were assayed in 92 patients undergoing elective hip or knee prosthetic joint arthroplasty. One hundred twenty-five bone samples were assayed. Although there was no direct relation between serum and bone antibiotic concentrations, a trend toward increased bone antibiotic concentration for drugs with higher serum levels and longer half-lifes (cefazolin and ceforanide) was noted. Bone antibiotic concentrations were maximal within 60 minutes of drug administration. Although bone antibiotic concentrations following 2-g doses were greater than those following 1-g doses, the differences were not statistically significant. A trend toward higher bone antibiotic concentrations at hip surgery was noted, and this difference achieved statistical significance (p less than 0.05) for cefazolin. As a result of analysis of bone antibiotic concentrations, antimicrobial sensitivities, and cost, administration of 2 g of cefazolin immediately prior to operation, followed by 1 g every eight hours for 24 hours, is recommended in elective prosthetic joint surgery.

The pharmacokinetics of cefoxitin was examined in 9 patients undergoing peritoneal dialysis for chronic renal failure. Cefoxitin was administered intraperitoneally in the dialysate fluid every 6 h for 24 h, in two different concentrations, 50 micrograms/ml and 100 micrograms/ml. The plasma half-life of cefoxitin was 20.2 h. The major route of elimination was non-renal, with a clearance of 8.0 ml/min. Peritoneal clearance was 4.1 ml/min. As expected, renal clearance was negligible. The peak plasma concentrations of cefoxitin at the two dose levels used were 7 micrograms/ml and 15 micrograms/ml, respectively, when assayed by HPLC, and 12 micrograms/ml and 24 micrograms/ml when determined by a microbiological assay. The cefoxitin concentration in the dialysate decreased from 50 micrograms/ml to 14 micrograms/ml and from 100 micrograms/ml to 37 micrograms/ml during the 6 h of its retention in the peritoneal cavity.

We report the results of the study of the bronchial concentrations of several antibiotics. The experiment included 280 patients and the concentrations achieved in bronchial secretions were measured for 11 antibiotics. The samples of bronchial secretions were taken in situ by fibroscopy or through the tracheostomy cannula. The results of the study show that the rate of penetration is variable according to the different drugs; even in the same antibiotic family such as beta-lactam antibiotics the rate of penetration is variable. The bronchial levels of aminoglycosides, macrolides and tetracyclines are worthwhile, and are often superior to the MIC of the infecting organisms; the penetration is also dependant of the inflammatory conditions of the bronchi. Otherwise the sampling conditions were the best possible since samples taken by fibroscopy or by tracheostomy are not contaminated by saliva which is a factor of dilutional error. The methodology used in this study is an approach of pharmacokinetics of antibiotics in respiratory tract.

Cefoxitin is a new semisynthetic cephamycin derivative with broad bactericidal activities. In order to determine the extent of the transplacental transfer of cefoxitin, 35 pregnant women received 1 Gm cefoxitin intramuscularly 15 to 180 minutes before normal or Caesarean delivery. Cefoxitin was measured microbiologically in maternal blood (multiple-time samples), umbilical blood (one-time sample), and amniotic fluid in the cases of Caesarean sections. The mammary excretion of cefoxitin injected at the same dose was investigated by measuring cefoxitin in the milk of 16 nursing mothers. In the maternal blood, a peak plasma level of approximately 25 microgram/ml was reached 30 minutes after the 1-Gm intramuscular injection. A clear-cut passage of cefoxitin in the umbilical cord blood was demonstrated. In the fetal blood, a peak level of 15 microgram/ml was obtained 45 minutes after the injection. No cefoxitin was detectable in any of the milk samples from 30 minutes to 24 hours after the 1-Gm intramuscular injection.

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.

A spectrum of new and commonly used antibiotics was examined with regard to their ability to penetrate into joint fluid in normal and E. coli infected rabbit knee joints. In order to carry out this investigation a new, simple method of measuring antibiotics in very small amounts of synovial fluid was developed. Cephalothin, cefazolin, cefoxitin, carbenicillin, amikacin, and gentamicin all penetrated into synovial fluid effectively achieving peak concentrations within 30 minutes to one hour. Synovial fluid antibiotic concentrations at 2 hours were equal to or higher than simultaneous serum levels. This relationship persisted thereafter. Penetration of antibiotics into infected joints was dependent primarily on serum concentration and was not altered importantly by the presence of acute chronic or previous infection. Antibiotic doses employed were equivalent to clinical usage on a weight basis. Penetration of all antibiotics studied was satisfactory for use against their normally intended pathogens.

In 27 women with fetuses affected by beta-thalassemia major, termination of gestation between 19 and 21 weeks was induced by amniocentesis and intrauterine instillation of prostaglandin F2 alpha. Pharmacokinetics in maternal blood and amniotic fluid were studied after at least three doses of one of the following antibiotics and before prostaglandin F2 alpha infusion: (1) cefoxitin, 2 gm, intravenously, 1/2-hour infusion, three times per day; (2) moxalactam, 2 gm, intravenously, 1/2-hour infusion, three times per day; and (3) ceftazidime, 1 gm, intramuscularly, three times per day. Successful amniotic fluid levels effective against various pathogens implicated in maternal-fetal infections appeared at least 3 hours beyond administration of the drug and ranged between 2.3 and 6.7 micrograms/ml, 1.56 and 15 micrograms/ml, and 1.5 and 5 micrograms/ml for cefoxitin, moxalactam, and ceftazidime, respectively. Beyond the third-hour after infusion a percentage ratio of amniotic fluid to simultaneous maternal serum level of almost greater than or equal to 50 was constantly observed for all studied antibiotics. Cefoxitin serum levels were about the same as those in nonpregnant women, while moxalactam and ceftazidime serum levels were 50% lower than the expected level in normal individuals.

Despite the increasing popularity of antibiotic prophylaxis to reduce febrile morbidity in patients who undergo cesarean delivery, little is known of the pharmacokinetics of antibiotics in the patient at term gestation. This study was designed to elucidate the pharmacokinetics of cefoxitin when administered intravenously or by uterine and peritoneal lavage at cesarean section. Significant differences were found in the values for total body clearance area under the serum concentration-time curve (AUC), and K21 of cefoxitin administered intravenously to pregnant patients at term gestation compared to values for these parameters observed in nonpregnant patients. The concentration of cefoxitin in decidual tissue after uterine and peritoneal lavage with the antibiotic was 92.5 +/- 10.1 micrograms/gm (mean +/- SEM), whereas the concentration of cefoxitin in decidual tissue after intravenous administration of the antibiotic was 36.9 +/- 10.5 micrograms/gm (mean +/- SEM). This difference is statistically significant (p less than 0.05). We conclude that the pharmacokinetics of cefoxitin are altered in the pregnant patient as evidenced by the increased rapidity of clearance of the antibiotic (total body clearance for cefoxitin in pregnant patients, 20.41 L/hr). Moreover, uterine and peritoneal lavage results in significant tissue concentrations of antibiotic, which is of potential importance since the decidua is a presumed site of initiation of bacterial infection after cesarean section.

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.

Cefoxitin is a beta-lactam antibiotic derived from cephamycin C, a naturally occurring substance produced by Streptomyces lactamdurans. Its resistance to destruction by beta-lactamases results in a broad spectrum of antibacterial activity which includes anaerobic as well as Gram-positive and Gram-negative aerobic bacteria, including many resistant to cephalothin and other cephalosporins. Given by intravenous or intramuscular injection, cefoxitin is effective against a wide variety of infections caused by Gram-positive or Gram-negative aerobes as well as by anaerobic bacteria. It is generally well tolerated, thrombophlebitis, skin rash and some degree of discomfort after intramuscular injection, being the most commonly reported side effects. Cefoxitin has not been shown to cause adverse effects on renal function.

Eleven patients about to undergo pulmonary surgery received a bolus injection of 1 g of cefoxitin. The concentrations of cefoxitin in the serum 1 and 2 h after dosage were 38.5 +/- 1.89 and 23.7 +/- 2.56 mug/ml; the lung concentrations at the respective times were 12.6 +/- 0.7 and 10.06 +/- 0.43 mug/ml.

The pharmacokinetics of cefoxitin were studied after the administration of a single intravenous dose of 40 mg/kg to rabbits with normal renal function and rabbits with varying degrees of renal impairment. The plasma and interstitial fluid concentrations of the antibiotic were determined by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. The plasma half-life of slow disposition phase t1/2 beta, increases from 0.26 hour in rabbits with normal renal function to 5.41 hours in rabbits with severe renal impairment. In the interstitial fluid the elimination half-life increases from 1.18 hours in rabbits with normal renal function to 99.00 hours in rabbits with renal impairment. A linear relationship is established between the values that define the elimination of the antibiotic and the serum creatinine concentrations. The constant of the incorporation into the interstitial fluid decreases significantly in rabbits with renal impairment.

A comparative study was carried out on the concentration of cefuroxime, cefoxitin, cefotaxime and cefoperazone in serum and extravascular blister fluid. The results show that cefoperazone (which has the highest protein binding capacity) has a lower and slower extravascular penetration than the other cephalosporins examined.

In an experimental model of peritoneal infection by cephalosporinase- (Ia and Ic) producing bacteria in mice, the reduction of cefoxitin, cefmetazole, and cefazolin concentrations in peritoneal fluid was observed in the mice infected with the Ia enzyme producer, whereas cefbuperazone concentrations were not reduced.

The antimicrobial activity of three 7-alpha-methoxy beta-lactams were compared to cefoperazone and ceftriaxone. All had a similar spectrum of activity against the Enterobacteriaceae, except cefoxitin. Cefotetan was only slightly less active than moxalactam against the Enterobacter spp. Ceftriaxone was most effective on Neisserias, Haemophilus spp, nonenterococcal Streptococcus spp, and Acinetobacter spp. Cefoperazone generally inhibited more pseudomonads while all of the "cephamycins" showed activity against Bacteroides fragilis and B. thetaiotaomicron. Beta-lactamase hydrolysis studies of six substrates having pharmacologic serum half lives of greater than or equal to 2 hrs were performed by bioassay and automated procedures. Excellent correlations were found between methods up to 24 hrs. A "lag-phase" was observed for several drug/enzyme combinations before initiation of significant substrate hydrolysis. The 7-alpha-methoxy beta-lactams were routinely more stable to the six representative enzymes (Richmond-Sykes types I-V) than other "stable" cephalosporins. Substrate hydrolysis rates resulting in greater than 50% drug loss in less than or equal to 1 hr generally produced resistant in vitro test results. Cefotetan, cefoxitin, moxalactam, ceftriaxone, and dicloxacillin were potent inhibitors of Type I (P99) beta-lactamases. Moxalactam demonstrated significant inhibition and affinity for the Type V enzyme while cefoperazone uniquely possesses affinity (so-called inhibition) for all tested beta-lactamases. Cefotetan appears to be a promising, beta-lactam compound with some in vitro characteristics comparable to the 1-oxa-beta-lactams and alpha-methoxyimino cephalosporins.

The pharmacokinetic disposition of 2 g of cefoxitin administered intravenously over 30 min was determined in six patients undergoing continuous ambulatory peritoneal dialysis for chronic renal failure. During the 6-h dialysate dwell time after the drug infusion, the mean apparent volume of distribution for cefoxitin was 0.267 liter/kg (range, 0.201 to 0.325 liter/kg), and the mean elimination t1/2 from plasma was 7.8 h (range, 5.5 to 13.1 h). The peritoneal clearance, averaging 1.51 ml/min (range, 0.58 to 2.35 ml/min), was only 7.4% of the mean plasmas clearance of cefoxitin. Cefoxitin clearance was reduced in patients with renal failure and was not increased by peritoneal dialysis.

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.

An investigation conducted on healthy volunteers showed that cefoxitin quickly reaches high plasma concentrations, and is almost completely excreted via the urine within 6 hours. In a series of 21 cases treated with 2 g i.v. in 100 ml of a 5% glucose solution two or three times a day, a clinical cure was achieved in 20, and marked improvement in the remaining patient.

The interaction of cefoxitin and mezlocillin was studied in rats using the granuloma pouch technique. Proteus morganii strains against which cefoxitin and penicillins exhibited antagonistic antibacterial activity were selected for infection of the pouches. Animals were treated with cefoxitin and/or mezlocillin, and bacterial counts, drug levels and beta-lactamase production in the pouch exudate monitored. A significant decrease in bacterial counts was seen after administration of mezlocillin and cefoxitin in combination but not after the drugs administered alone. Drug concentrations of mezlocillin and/or cefoxitin corresponded directly to the rate of induction of beta-lactamase activity. Although both beta-lactam antibiotics induce beta-lactamase activity, administered in combination in vivo they appear to protect each other from being inactivated thus resulting in synergistic antibacterial activity.

Using several well-characterized beta-lactamases isolated from Gram-negative bacteria, the interactions of cefmenoxime, a new methoxy-imino-amino-2-thiazol cephalosporin were compared with those of cefotaxime, lamoxactam, cefoperazone and ceftazidime. On-line computerized microacidimetry allowed determination of the affinity of these compounds for the enzymes, which was characterized by Ki values. Microacidimetry showed poor interactions of cefmenoxime with penicillinase TEM-1 (low Vm, poor affinity) whereas it showed a high affinity for the cephalosporinases, as is also the case for cefotaxime or lamoxactam. Both cefmenoxime and cefotaxime showed relative susceptibility in Masuda's double disc technique.

beta-Lactamases from five strains of Bacteroides fragilis and two strains of Bacteroides uniformis, all resistant to beta-lactam antibiotics, were compared by means of isoelectric focusing and enzyme kinetic measurements. beta-Lactamases from the five B. fragilis strains were identical, whereas those from the two B. uniformis strains were distinguished from each other and also from the B. fragilis enzymes. The two B. uniformis strains were relatively resistant to cefoxitin (minimal inhibitory concentration, 32 micrograms/ml), but only one of the strains, B. uniformis 2986, was found to rapidly inactivate cefoxitin. This apparently enzymatic inactivation of cefoxitin seemed to be of minor importance, and the main factor for cefoxitin resistance was considered to be a decreased permeability of the drug. Transfer of resistance to beta-lactam antibiotics from these beta-lactamase-producing strains of B. fragilis and B. uniformis to a non-beta-lactamase-producing strain of Bacteroides distasonis was attempted, but with these isolates no transfer of resistance to beta-lactam antibiotics was demonstrated.