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Protein binding, serum kinetics and minimum inhibitory concentrations (MICs) for Staphylococcus aureus were determined for cefoxitin, cefazolin, ceftazidime and ceftriaxone in the rabbit. MICs of cefazolin and cefoxitin were also measured for Escherichia coli. Varying concentrations of the bacteria were administered intradermally to create areas of cellulitis, which were quantified as mean erythematous areas (EAs). Despite large differences in protein binding of the antibiotics (range 12-88%) and antibiotic dosing to allow serum concentrations to drop below the respective MICs, there was no statistical difference in the mean EAs of the animals after bacterial challenge. Antibiotic protein binding did not alter the course of cellulitis nor correlate with bacterial MIC in this model.

The penetration of four cephalosporins into tissue fluid obtained with a skinabrasion technique was studied. Two oral antibiotics, cephalexin and CGP 9000, had similar pharmacology and penetrated the fluid in equivalent amounts. Cefuroxime (33% protein-bound) and cefoxitin (65-79% proteinbound) attained levels in tissue fluid which were very similar to their blood levels. The level of antibiotic in the tissues seems to be closely related to the blood level and is not adversely affected by protein binding.

To prevent infection in 40 patients who underwent vaginal or abdominal hysterectomy, each patient received a single 15-mg/kg dose of either cefoxitin or cefamandole by rapid (5-minute) intravenous injection before the operation. Samples of serum, myometrium, endometrium, ovaries, and tubes were obtained at various intervals after injection of the antibiotic and were assayed for cephalosporin concentration. Maximum tissue concentrations of 30 micrograms/g of both drugs were detected approximately 30 minutes after the dose, with levels dropping below 3 micrograms/g in approximately 2 hours. Although both antibiotics achieved closely similar concentrations in serum and tissues, the ratios of these levels to their usual mean minimum inhibitory concentrations for Bacteroides fragilis were appreciably higher for cefoxitin than for cefamandole. These pharmacokinetic observations support the current dosage recommendations for the use of cefoxitin in treating and preventing gynecologic infections, as well as the recommendation that it be administered shortly before the operation to maximize tissue levels during the perioperative period.

The ability of ceftizoxime to penetrate the outer membrane was compared with those of five other new cephalosporins: cefotiam, cefuroxime, cefotaxime, cefmetazole and cefoxitin, using a clinical isolate of Enterobacter cloacae as a test strain. Estimation of permeability was performed by a method utilizing the inhibitory activities of the cephalosporins against beta-lactamase located in the periplasm. Of the cephalosporins tested, both ceftizoxime and cefmetazole gave remarkably high concentrations in the periplasm, several times higher than those of cefotaxime and cefoxitin and ten or more times higher than those of cefuroxime and cefotiam. The approximate permeability coefficient of ceftizoxime was also several times higher than those of cefotiam and cefmetazole and over ten times higher than those of cefoxitin, cefuroxime and cefotaxime.

The diffusion of cefotaxime compared with that of cefazolin, cefoxitin and cefamandole in the interstitial fluid has been studied in rabbits. The different antibiotics were administered intramuscularly at a dose of 30 mg/kg by injection. Serum concentrations were determined at 30 minutes, 2, 4, 8 and 12 hours following the injection.

Cefoxitin (Mefoxitin), Cephaloridin, Cephalothin and Cefazolin were tested in vitro against 380 clinical isolates of Staph. aureus and Enterobacteriaceae using the tube dilution procedure. Of the gramnegative microorganisms a selection of 150 strains was examined regarding susceptibility to the antibiotic combinations cefoxitin/gentamicin and cefoxitin/sisomicin in comparison to cephalothin/gentamicin and cephalothin/sisomicin. Cefoxitin has a broad antimicrobial spectrum and a high beta-lactamase-resistance. Cefoxitin was more active than the other antibiotics tested against E. coli, Klebsiella, Serratia, Enterobacter, indole-negative and -positive Proteus species. The high effectiveness of cefoxitin against anaerobic bacteria such as Bacteroides fragilis and Clostridium perfringens is discussed. Cefoxitin has an excellent bactericidal potency. Among the combinations tested cefoxitin/sisomicin was most active and obtained synergistic effects in most species. The resistance rate of cefoxitin of 8.7% was reduced to 0.7% with cefoxitin/sisomicin.

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.

An experimental model, where fibrin clots were inserted subcutaneously in rabbits, was adapted to study the in vivo efficacy of two cephalosporins against Bacteroides fragilis. The respective MIC's of cefamandole and cefoxitin against the microorganism were 16 microgram/ml and 1 microgram/ml. The clots were infected with 10(7) B. fragilis. Groups of seven animals received an intravenous bolus injection (100 mg/kg) of either drug. The serum levels of both drugs were similar to those seen in humans. The peak concentrations of cefamandole (40 microgram/mg) in the clots were found to be ten times higher than those of cefoxitin (4 microgram/mg). The log number of colony forming units in the clots averaged 7.5 at 0 h. At 6 hours, this number reached 8 in the untreated animals, 1.5 after cefoxitin, and 1.7 after cefamandole. The apparent in vitro superiority of cefoxitin against B. fragilis could not be demonstrated in vivo. This discrepancy between in vitro and in vivo data can be explained by the high degree of penetrance of cefamandole into the infected fibrin loci. In this animal system, both cefoxitin and cefamandole had similar in vivo activity against B. fragilis.

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.

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 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.

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.

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.

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.

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 authors present the results of the study of transplacental transfer of 3 recent beta lactam antibiotics: amoxicillin, cephradin and cefoxitin. The experiment was carried out in 37 pregnant women who had a premature rupture of membranes or who were undergoing a cesarean section. In these patients antibiotherapy was indicated in view of a possible superinfection. The results of the study show a worthwhile transplacental penetration of the 3 drugs tested. The concentrations achieved in umbilical cord blood and amniotic fluid increase with time and finally exceed the levels measured in maternal blood, after a period of time varying from 2 to 4 hours according to the drug and the route of administration.

The metabolism of cefoxitin, a new semi-synthetic cephamycin antibiotic, in rats with renal insufficiency was examined in comparison with that in control. Ascending urinary tract infection was produced in rats by intra-cystic inoculation with a virulent strain of Escherichia coli. In rats with severe infection progressed into purulent inflammation in the pelvis and medullar and cortical abscess formation, the urinary excretion of the antibiotic was reduced till the first 2 h after an i.v. dose of 40 mg/kg, while its serum levels and biliary excretion during this period were contrarily higher than those in rats with mild infection limited to pelvic inflammation and in control. On the other hand, in rats with renal arteriarctia produced by constriction of the renal artery with silver clip, blood levels of the antibiotic were higher than those in control. In the former animals, the urinary excretion was reduced to about a half, while the biliary excretion was increased up to twofold of that in control through the whole experimental period. In animals either with severe infection or with renal arteriarctia, the total recovery in the urine and the bile during 6 h of the experimental period was almost equal to those in mild infection or control groups.

Cefoperazone and cefoxitin concentrations were determined in serum and pelvic tissue samples obtained at various intervals after a 2-g intramuscular dose. These levels were determined in 59 women scheduled for elective abdominal hysterectomy. Concentrations were measured by a new high-pressure liquid chromatography method which correlated with the microbiological assay. The mean times (+/- standard deviation) of specimen collection were 188.5 +/- 61 and 185.5 +/- 55 min for cefoperazone and cefoxitin, respectively. The mean serum levels (+/- standard deviation) were 60.8 +/- 18.0 and 14.6 +/- 8.6 micrograms/ml, respectively. For cefoperazone, the mean pelvic tissue concentration was 19.8 micrograms/g. The mean pelvic tissue concentration for cefoxitin was 7.8 micrograms/g. The ratio of tissue concentration to serum concentration varied from 0.220 to 0.469 for cefoperazone and from 0.176 to 1.031 for cefoxitin. Although the serum and tissue concentrations of cefoperazone were much higher than those of cefoxitin, a greater portion of cefoxitin remained in the tissue. The tissue levels of both cefoperazone and cefoxitin were above the minimum inhibitory concentration of most sensitive pathogens several hours after a single prophylactic dose of either antibiotic.

30 patients were treated with i.v. cefoxitin (4-8 g/day), of which 20 had documented infections which included endocarditis (5), lung abscess (4), empyema (4), liver and subhepatic abscess (3), osteomyelitis (3), and pancreatic abscess (1). 14 patients had infections caused by anaerobic bacteria and 5 had endocarditis due to aerobic organisms. All but 2 patients with osteomyelitis of the mandible were cured. Adverse reactions were noted in 7 patients, mostly due to drug fever and leukocytosis; one had Coombs'-positive hemolytic anemia. The average serum cefoxitin levels were 24, 16, 12, and 4 microgram/ml at 1, 2, 3 and 4 h, respectively, and the average serum/pleural fluid ratio was 1:0.5 +/- 0.25. All anaerobic and aerobic isolates except one strain of Bacteroides fragilis were susceptible to cefoxitin at less than or equal to 32 microgram/ml. The concentration of cefoxitin in the tissues was measured in 8 rabbits; it was 4 +/- 1 microgram/ml in the heart and 2 +/- 0.5 microgram/ml in the femur and mandibular tissue, suggesting that the lack of response in cases of osteomyelitis could be due to inadequate antibiotic concentration in the bone. Our study suggests that cefoxitin can be used in the treatment of anaerobic infections and endocarditis due to susceptible organisms.

A review is given on the pharmacokinetic characteristics of some cephalosporin antibiotics. The use of the pharmacokinetic parameters serum concentration, serum protein binding, serum half life, and apparent volume of distribution as a basis for the selection of the clinically most effective cephalosporin derivative is discussed. It is concluded that these parameters must be used in conjunction with data on tissue distribution to specialized sites, and with information on antibacterial activity and toxicity.

Pseudomonas aeruginosa K 799/WT and a mutant of this strain, P. aeruginosa K 799/61 ("mutant 61"), that is very sensitive to most beta-lactam antibiotics tested were used to assess the importance of penetration barriers in the resistance of P. aeruginosa to penicillins and cephalosporins. The affinities of various beta-lactams to the penicillin-binding proteins found in membranes prepared from both strains were compared by measuring their competition for the binding of benzyl[14C] penicillin to each of these proteins. Only minor differences between the wild type and the mutant 61 were found. The high sensitivity of the mutant therefore cannot be attributed to drastic alterations of these target proteins, nor can the resistance of the wild type be ascribed to penicillin-binding proteins with low affinities for beta-lactams. Experiments in which the ease of penetration of beta-lactams into the penicillin-binding proteins was measured with exponentially growing intact cells instead of membranes, however, clearly demonstrated an easy access of beta-lactam antibiotics to these proteins in the mutant and an efficient exclusion from the same targets in the wild type.

Three semisynthetic cephamycin antibiotics (7alpha-methoxy-cephalosporins), SK&F 73678, SK&F 83088 (CS-1170) and cefoxitin, have been found to possess favorable biological and chemotherapeutic properties. All three cephamycins are active in vitro against strains of Staphylococcus aureus and a variety of gram-negative bacilli. Beta-lactamase producing organisms including indole-producing Proteus spp., Enterobacter spp. and Serratia strains as well as certain anaerobic bacteria were found to be susceptible to these antibiotics. SK&F 73768 showed somewhat better MIC values than cefoxitin against multiple strains of bacteria. Strains of Pseudomonas aeruginosa and group D streptococci are essentially insensitive to these compounds. Their binding to serum proteins is relatively low. In mice, cefoxitin showed the most favorable pharmacokinetics with respect to peak serum level, serum half-life and urinary recovery. These cephamycins protected mice experimentally infected with a variety of bacterial strains. All three compounds are rapidly bacteriolytic to the logarithmically growing Escherichia coli and belatedly so to Staphylococcus strains with complete sterilizing effect. SK&F 73678 and SK&F 83088 showed activity and potency comparable to or better than cefoxitin and thus can be considered candidates for clinical study.

Subject of the following study was the penetration activity of cefoxitin into different human tissues. The authors obtained material of the cutis, subcutis, fascia, muscle, spongy bone and compact bone during orthopedic surgery on 20 patients. Cefoxitin was administered by means of a continual infusion of a dose of 45 mg per kg body weight per hour. Tissue and serum levels were studied after infusions lasting 15, 60, 90 and 120 minutes. Altogether the results of 215 specimens of serum and 132 specimens of tissue are recorded. The evaluation showed the following mean tissue levels of cefoxitin: 6.6 micrograms/g in compact bone; 14.4 micrograms/g in spongy bone; 23.3 micrograms/g in muscle; 64.2 micrograms/g in fascia, 69.9 micrograms/g in cutis and 21.7 micrograms/g in subcutis.

The role of beta-lactamase and the permeability barrier on the activity of some beta-lactams against 53 strains of the Bacteroides fragilis group was investigated. Minimal inhibitory concentrations of cefamandole, cefoxitin, and cephalothin were determined with or without the addition of clavulanic acid and (or) ethylenediaminetetraacetate using an agar dilution technique. A significant increase of susceptibility with clavulanic acid indicated a role for beta-lactamase, and with ethylenediaminetetraacetate, a role for a permeability barrier. We found that both beta-lactamase and low permeability decreased the activity of the beta-lactams to some extent depending on the bacterial species and the antibiotic. The species-specific exception was B. distasonis which showed only a permeability barrier to all antibiotics tested.

The affinities of cefoxitin, a cephamycin antibiotic, to penicillin-binding proteins of Escherichia coli were reexamined using a recently developed method for separating penicillin-binding proteins. The inhibitions by this antibiotic of four measurable penicillin-sensitive enzymatic reactions, the reactions of D-alanine carboxypeptidases IA and IB, cross-bridge formation and concomitant release of D-alanine, were also measured. An approximate correlation was found between the affinities of cefoxitin to the penicillin-binding proteins responsible for these reactions and its rates of inhibition of the respective penicillin-sensitive reactions.

The present study was undertaken to compare the ability of three cephalosporins--cephalothin, cephaloridine and cefuroxime--and a cephamycin--cefoxitin--to penetrate into extravasal compartments. The study was performed using female adult rabbits with subcutaneously implanted steel net cages. All antibiotics were given in a dose of 50 mg/kg b.w. parenterally as i.v. injections. The concentrations of the different antibiotics were determined simultaneously in serum and in fluid obtained from the cages. The concentrations were followed after single doses as well as after repeated doses using an agar well technique for the assays. To control the experimental conditions electrolyte and protein contents of the fluid in the different cages were followed and were found to be stable during the experimental period. All antibiotics were rapidly eliminated from serum. The concentrations in the cages reached its maximum 1.5-3 hours after administration. The highest concentrations in the extravasal compartments were obtained with cephaloridine and the lowest with cephalothin with the values of the other antibiotics ranging in between.

We have studied cefuroxime, a new beta-lactamase resistant cephalosporin, and cefoxitin, the first cephamycin antibiotic, which is also resistant to many beta-lactamases. Both of these antibiotics have been shown to be microbiologically superior to the "first generation" cephalosporins, cefuroxime having notable activity against Haemophilus influenzae, and cefoxitin against Bacteroides fragilis. Neither antibiotic is absorbed from the gut but, following parenteral administration, serum, urine and bile concentrations are high. Clinical trials have been conducted on both cefoxitin and cefuroxime. The results of these have been satisfactory and untoward side-effects minimal. We suggest that cefoxitin will be particularly valuable in the management of abdominal sepsis and cefuroxime in infections caused by H. influenzae.