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PubMed1983

Pharmacokinetics of cefoxitin in patients at term gestation: lavage versus intravenous administration.

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.

Cefoxitin↗
PubMedDate not supplied

Differences in the in vitro inhibitory and bactericidal activity of ceftizoxime, cefoxitin, cefotetan, and penicillin G against Bacteroides fragilis group isolates. Comparison of time-kill kinetic studies with MIC values.

Nineteen strains of the Bacteroides fragilis group were used to determine the bactericidal activity of ceftizoxime, cefoxitin, cefotetan, and penicillin G with time-kill kinetics studies. Each antimicrobial agent was tested at subinhibitory (1/2 X MIC), inhibitory (1 X MIC), and suprainhibitory (4 X MIC) concentrations. Penicillin G exhibited virtually no sustained bactericidal activity at any of the antimicrobial concentrations tested. At subinhibitory concentrations, ceftizoxime was considerably more bactericidal than cefoxitin or cefotetan: At 12 hr, ceftizoxime killed 89% of the inoculum, whereas cefoxitin and cefotetan killed 35% and 33% of the inoculum, respectively. At inhibitory concentrations, ceftizoxime was again more bactericidal than cefoxitin and cefotetan: At 12 hr, ceftizoxime killed 90% of the inoculum, whereas cefoxitin and cefotetan killed 78% and 73%, respectively. At suprainhibitory concentrations, all three antimicrobial agents showed comparable bactericidal activity at 12 and 24 hr. Ceftizoxime and cefoxitin had somewhat lower killing rates overall against test strains with high MICs (greater than or equal to 32) versus low MICs (less than or equal to 16). However, at subinhibitory concentrations, ceftizoxime killed the B. fragilis group strains with high or low MIC values more effectively than cefotetan killed strains with low MICs. At the highest antibiotic concentrations tested (4 X MIC), only slight differences were seen in the bactericidal activity of the three compounds, regardless of MICs.

Bacteroides↗
PubMed1988

Comparative effectiveness and safety of cefotetan and cefoxitin as prophylactic agents in patients undergoing abdominal or vaginal hysterectomy.

In a multicenter, randomized clinical trial, 282 women who underwent abdominal or vaginal hysterectomy were given a single preoperative 2 g dose of cefotetan (171 evaluable patients) or three perioperative 2 g doses of cefoxitin (84 evaluable patients) as antibiotic prophylaxis. A successful clinical response occurred in 92 percent of those receiving cefotetan and 90 percent of those receiving cefoxitin who underwent abdominal hysterectomy, and in 94 percent of those receiving cefotetan and 93 percent of those receiving cefoxitin who underwent vaginal hysterectomy. The incidence of vaginal cuff cellulitis was 3.4 percent and 5 percent for cefotetan and cefoxitin patients, respectively, who underwent abdominal hysterectomy, and 4.8 percent and 4.5 percent, respectively, for those who underwent vaginal hysterectomy. The incidence of major wound infection was 3.4 percent and 2.5 percent for cefotetan and cefoxitin, respectively, in the abdominal hysterectomy group. Postoperative changes in oral body temperature, duration of hospitalization, and postoperative grading of surgical wounds were similar. Both drugs were well tolerated. These results suggest that a single dose of cefotetan is equally effective and as safe as multiple-dose cefoxitin for prophylaxis in patients undergoing hysterectomy.

Adult↗
PubMed1992

Enhanced bioavailability of cefoxitin using palmitoyl L-carnitine. I. Enhancer activity in different intestinal regions.

The conditions under which the absorption enhancer palmitoyl L-carnitine chloride (PCC) improved the bioavailability of the poorly absorbed antibiotic cefoxitin throughout the rat intestine has been studied. Cefoxitin alone was appreciably absorbed only in the duodenum (31% vs less than 7% elsewhere). PCC solutions (3 mg/rat, pH 4.0) enhanced cefoxitin bioavailability (F) by 0-, 22-, 16-, and greater than 32-fold in the duodenum, jejunum, ileum, and colon regions, respectively. The inability of PCC to improve F in the duodenum could not likely be attributed to enzymatic degradation of the enhancer, since coadministration with protease and esterase inhibitors produced similar results (F = 30%). Coadministration of PCC solution with cefoxitin in the unligated or ligated colon, increased F to 33 and 76%, respectively. Qualitatively similar results were seen with PCC suspensions (3 mg/rat, pH 6.0). Maintaining a high concentration of cefoxitin and PCC in a restricted region (i.e., by ligating a 2- to 3-cm section of the colon) afforded a two- to threefold advantage over an unligated colon section. The difference in cefoxitin bioavailability between ligated and unligated colon was probably due to sample spreading and subsequent/simultaneous dilution.

Adjuvants, Pharmaceutic↗
PubMed1990

Effects of propofol and of thiopentone anaesthesia on the renal clearance of cefoxitin in the sheep.

We have examined the renal extraction ratios and clearances of cefoxitin in three groups of adult merino ewes. One group (n = 3) was studied for 12 h without perturbation; these were designated control studies. The other two groups (n = 4 each) were studied before (baseline values), during and after the induction and 70-min maintenance of anaesthesia with propofol or thiopentone. In the control studies, mean renal extraction ratio and clearance for cefoxitin were, respectively, 0.67-0.92 and 0.66-0.91 litre min-1 and were consistent throughout the entire study period in individual animals. Comparable values were obtained as baseline values in the anaesthesia groups. Compared with individual baseline values, blood concentrations of cefoxitin doubled during anaesthesia with each agent. At the same time, renal extraction ratio and clearance for cefoxitin each decreased significantly to about 50-60% of their control values. Recovery to control values of arterial blood concentrations and renal extraction ratio of cefoxitin took at least 5 h, but recovery of renal clearance was more rapid. The results indicate that renal elimination of an organic anion such as cefoxitin may be affected by changes in renal blood flow and in renal function produced by propofol and thiopentone; these effects may last for several hours after recovery of renal blood flow.

Anesthesia, Intravenous↗
PubMedDate not supplied

Penetration of cephalothin and cefoxitin into experimental infections with Bacteroides fragilis.

The in vitro activities of cephalothin and cefoxitin against Bacteroides fragilis were studied by time-kill curves and measurement of residual drugs in culture supernatants. Cefoxitin was bactericidal, causing a decrease of 10(7) in viable counts over 24 hr. Cephalothin caused an initial decrease of 10(2) B. fragilis at 2 hr; this change was followed by growth of the organism within 24 hr back to the number present before addition of cephalothin. The concentration of cephalothin in broth decreased rapidly within 2 hr and was undetectable within 24 hr, whereas the level of cefoxitin decreased only 25% over the 24-hr period. Penetration of these drugs into perforated ping pong balls implanted intraperitoneally in rabbits was studied. Three weeks after implantation the reservoirs were infected with B. fragilis. After intramuscular administration of five doses of antibiotic, the penetration of cephalothin, as measured by bioassay, in uninfected and infected capsules was 16% and 2%, respectively, of the peak serum concentration; similar findings were noted with cefoxitin. For determination of the rate of breakdown within the infected site, radiolabeled antibiotic was injected into the capsule, and the concentrations of bioactive and radioactive drug were determined. With radiolabeled cephalothin there was a rapid decrease in bioactivity during the initial 60 min, and no active drug was measurable after 2 hr. In contrast, only 40% of cefoxitin was inactivated at the end of 6 hr. The results indicate that levels of cephalothin and cefoxitin are reduced significantly in sites infected with B. fragilis. The decrease appears to be mediated by both a decrease in penetration and inactivation at the site of infection.

Animals↗
PubMedDate not supplied

Treatment of septicemic patients with cefoxitin: pharmacokinetics in renal insufficiency.

Experience with cefoxitin in the treatment of septicemia of diverse etiologies in 11 patients is reviewed. Results of a small study of the pharmacokinetics of cefoxitin in patients with renal insufficiency, which was used as a guideline for determining the dosage of cefoxitin for severely ill patients with renal insufficiency, are included. In addition, a summary of data on file at Merck Sharp and Dohme Research Laboratories (Rahway, New Jersey) that concern 135 bacteremic patients who were treated with cefoxitin and evaluated is presented. Although information derived from septicemic patients is among the most difficult to interpret in regard to the efficacy of an investigational antibiotic, both our experience and the summary of data confirm that cefoxitin is a potent antibiotic suitable for use in septicemic patients when the etiologic agent is susceptible; the data also demonstrate that cefoxitin has a significantly expanded spectrum of activity as compared with that of cephalothin.

Cefoxitin↗
PubMedDate not supplied

Cefoxitin: an overview of clinical studies in the United States.

Cefoxitin, a new cephamycin antibiotic that is active against aerobic and anaerobic bacteria, was studied by 35 investigators in the United States. Of 657 patients eligible for evaluation of efficacy of the compound, 69% were cured and 92% were cured or improved on clinical grounds. Bacteriologic response to therapy with cefoxitin was equally good for infections due to gram-positive cocci (94% cured), gram-negative bacilli (87% cured), and anaerobes (95% cured). Cefoxitin was effective clinically and bacteriologically in the eradication of infections due to organisms resistant to ampicillin, cephalothin, chloramphenicol, tetracycline, and aminoglycosides. Overall rates of favorable response to cefoxitin therapy by disease were: lower respiratory tract infections, 90%; urinary tract infections, 87%; intraabdominal infections, 90%; gynecologic infections, 94%; and septicemia, 84%. Cefoxitin was tolerated well, and major abnormalities of hematologic, hepatic, renal, or central nervous system function were encountered rarely. Resistance to cefoxitin did not develop among gram-negative cocci, anaerobes, or gram-negative bacilli in the medical centers in which the antibiotic was used.

Bacterial Infections↗
PubMedDate not supplied

Cefoxitin and cephamycins: microbiological studies.

The cephamycins are a family of beta-lactam antibiotics that are produced by actinomycetes and are structurally similar to the cephalosporins. They are characterized by the presence of a 7-alpha-methoxyl group, which confers unusually high resistance to beta-lactamases. Cefoxitin, the first semisynthetic cephamycin, is resistant to almost all beta-lactamases. Cefoxitin retains the 3-carbamoyl group of cephamycin C and thus has excellent metabolic stability. Cefoxitin is bactericidal and almost devoid of any inoculum effect. Active against many cephalothin-resistant gram-negative bacteria, cefoxitin demonstrates a very broad spectrum that includes indole-positive Proteus and many strains of Serratia. In contrast to that of the cephalosporins, cefoxitin's spectrum of activity against anaerobic pathogens includes Bacteroides fragilis. The therapeutic effectiveness of cefoxitin in experimental infections in mice confirms the excellent characteristics of this semisynthetic cephamycin and indicates that it should be a very valuable agent for treatment of bacterial infections.

Animals↗
PubMedDate not supplied

Comparative studies of multiple-dose cefoxitin vs. single-dose cefonicid for surgical prophylaxis in patients undergoing biliary tract operations or hysterectomy.

Three hundred one patients were studied in ongoing, double-blinded, randomized clinical trials of the efficacy and safety of multiple-dose cefoxitin and single-dose cefonicid for the prevention of postoperative surgical infection in patients undergoing elective biliary tract operations or hysterectomy. In the biliary surgery trial, one patient (1.5%) of 66 assessable patients given cefoxitin and three (4.7%) of 64 given cefonicid developed incisional infection of the abdominal wound (P = not significant [NS] ). Two (6%) of 31 patients undergoing vaginal hysterectomy who were given cefoxitin and four (14%) of 29 given cefonicid developed vaginal cuff cellulitis (P = NS); three (6%) of 49 patients undergoing abdominal hysterectomy who were given cefoxitin and none of 37 given cefonicid developed pelvic cellulitis (P = NS). Adverse effects ascribable to one of the study drugs were infrequent and minor in both groups. Levels of cefonicid in serum and the uterus or gallbladder wall 2-3 hr after the preoperative dose--before wound closure--were high (mean, 30-40 micrograms/ml), values five to six times higher than those for cefoxitin. The duration of postoperative hospitalization and the costs of hospital care for the two treatment groups were similar in both trials. These studies suggest that a single preoperative dose of cefonicid provides protection against surgical infection following biliary tract operations and hysterectomy that is comparable to that provided by cefoxitin given both preoperatively and 24 hr postoperatively.

Biliary Tract Diseases↗
PubMed1987

Cefoxitin resistance in Bacteroides species: evidence indicating two mechanisms causing decreased susceptibility.

Clinical isolates of Bacteroides species resistant to cefoxitin (not due to beta-lactamase) were obtained from two sources and examined for PBP affinity (to cefoxitin) and outer membrane proteins. Mutants of Bacteroides fragilis with decreased susceptibility to cefoxitin were obtained in the laboratory with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine. No spontaneous mutants resistant to cefoxitin could be selected. Changes in the affinity of PBP 1 or PBP 2 were correlated with a decrease in susceptibility to cefoxitin. Two clinical isolates showing decreased affinity of PBPs for cefoxitin also showed outer membrane protein changes with a protein of 49-50,000 daltons apparently absent. Three strains did not have altered PBP affinity or altered outer membrane protein profile, one strain being a laboratory mutant.

Bacterial Outer Membrane Proteins↗
PubMed2026

Cefoxitin versus cefotaxime as empirical treatment of spontaneous bacterial peritonitis in liver cirrhotic patients: randomized controlled clinical trial.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a severe complication of cirrhosis requiring immediate empirical antibiotic therapy. Third-generation cephalosporins are the traditional agents of choice; however, increasing clinical failure rates necessitate the evaluation of alternative antibiotics to ensure optimal therapeutic outcomes. The aim was to investigate the efficacy of cefoxitin versus cefotaxime for SBP treatment. METHODS: A randomized clinical trial was conducted on 140 cirrhotic patients with community-acquired SBP at Al-Rajhy Liver University Hospital, Assiut, Egypt. Patients were randomized to receive either cefotaxime (n = 70) or cefoxitin (n = 70), 2 g every 8 h for 5 days. Polymorphonuclear neutrophil (PMN) counts were measured upon admission, on Day 2 and on Day 5. Clinical response rates at Days 2 and 5, development of hepatorenal syndrome, length of stay and mortality were assessed. RESULTS: According to intention-to-treat analysis, clinical response rates at Day 2 were 74.2% in the cefotaxime group and 80% in the cefoxitin group, while at Day 5, they were 71.4% and 74.3%, respectively (P = 0.704). The PMN counts at Days 0, 2 and 5 showed no significant differences between the cefotaxime and cefoxitin groups (P = 0.889, 0.909 and 0.360, respectively). The incidence of hepatorenal syndrome was 7.1% in the cefotaxime group compared with 8.6% in the cefoxitin group (P = 0.753), and mortality was 15.7% and 12.9%, respectively (P = 0.629). CONCLUSIONS: Cefoxitin showed comparable effectiveness to cefotaxime but may be utilized in selected clinically stable SBP patients.

Humans↗
PubMed1981

Use of peroperative cefoxitin to prevent infection after colonic and rectal surgery.

A double-blind, controlled trial was performed to assess the effect of a short intraoperative course of Cefoxitin, a new broad spectrum cephamycin antibiotic, on the incidence of septic complications following elective colonic and rectal surgery. In addition to a two-day preoperative bowel preparation, patients entered in the study received a short course of either Cefoxitin (three 2g intravenous bolus doses at two-hour intervals, the first before skin incision) or a matching placebo. Thirty-two patients received Cefoxitin and 33 patients received the placebo. Postoperative abdominal wound infections developed in one (3%) of the Cefoxitin-treated patients and nine (27%) of the placebo-treated patients. This difference is statistically significant (p = 0.01). Septic complications remote from the abdominal wound, e.g. intra-abdominal abscesses, occurred in both Cefoxitin-treated and placebo-treated patients, but numbers were too small for meaningful analysis. The study shows that even a very short peroperative course of Cefoxitin is highly effective in reducing postoperative abdominal wound infections after elective colorectal surgery.

Adult↗
PubMed1987

The synergistic effects of concurrent administration to rats of EDTA and sodium salicylate on the rectal absorption of sodium cefoxitin and the effects of inhibitors.

Plasma levels of cefoxitin, as enhanced by rectal coadministration of sodium salicylate, were reduced by concurrent administration of less than 0.5 mg mL-1 N-ethylmaleimide (NEM) or p-chloromercuriphenylsulphonic acid, sodium salt (p-CMP). Concentrations of these inhibitors above 1 mg mL-1 resulted in enhanced peak plasma values of cefoxitin. This did not occur after coadministration with either ethylenediaminetetraacetic acid (EDTA) or polyoxyethylene-23 lauryl ether (POE). Ouabain and 2,4-dinitrophenol (DNP) suppressed plasma cefoxitin levels in the presence of salicylate and the enhancing effects of EDTA and POE when EDTA and POE were administered at low doses. At higher concentrations of EDTA and POE, DNP had little effect, while ouabain had little effect on POE and only partially suppressed the effects of EDTA. Plasma concentrations of cefoxitin after coadministration with salicylate and POE together, or with EDTA and POE together, were about the same as expected from summing the plasma levels resulting from coadministration of each adjuvant individually at the same concentrations. However, combined administration of salicylate and EDTA with cefoxitin yielded plasma cefoxitin concentrations which were much higher than expected from the sum of their individual actions.

2,4-Dinitrophenol↗
PubMed1977

Cefoxitin activity against multiply antibiotic-resistance Klebsiella pneumoniae in vitro.

Due to the emergence of cephalothin- and gentamicin-resistant Klebsiella pneumoniae at this institution, we investigated the in vitro activity of two new cephalosporin compounds-cefoxitin and cefamandole. Whereas both drugs were active against cephalothin- and gentamicin-susceptible isolates of Klebsiella, only cefoxitin exhibited significant activity against cephalothin- and gentamicin-resistant isolates. Seventeen of 20 (85%) of the cephalothin- and gentamicin-resistant isolates were inhibited by </=12.5 mug of cefoxitin per ml. The minimum bactericidal concentration in broth of representative isolates equaled the agar dilution minimum inhibitory concentration. Kirby-Bauer disk susceptibility testing correlated well with the agar dilution minimum inhibitory concentration. Cephalothin and cefamandole resistance of isolates could be correlated with antibiotic degradation by beta-lactamase. Cephalothin and cefamandole evoked only a transient decrease in viable bacterial cell count with rapid inactivation of antibiotics, and full regrowth of the organisms. Cefoxitin, on the other hand, was quite effective in vitro against multiply resistant Klebsiella. No beta-lactamase degradation of cefoxitin was detected. Growth curves with antibiotics indicated rapid killing of cephalothin- and gentamicin-resistant isolates by cefoxitin.

Cefoxitin↗
PubMed1979

Anaerobic infection in cancer patients: comparative evaluation of clindamycin and cefoxitin.

Clindamycin and cefoxitin with or without gentamicin were administered to cancer patients having localized infections presumably caused by anaerobic pathogens. The rates of favorable response were 89% in patients receiving clindamycine alone and 78% in patients receiving cefoxitin alone. When the total experience is considered (clindamycin or cefoxitin with and without gentamicin), 20 of 24 patients (83%) responded to clindamycin and 18 of 22 (82%) responded to cefoxitin. Both therapies were well tolerated. Clindamycin was found to be more effective than cefoxitin in eradicating the offending anaerobic pathogens from the site of infection. Aerobic pathogens were frequently isolated along with anaerobes from the infectious sites in this series; their susceptibility or resistance to clindamycin or cefoxitin did not influence the therapeutic response.

Anaerobiosis↗
PubMed1981

Evaluation of cefoxitin nephrotoxicity in experimentally induced renal failure.

The nephrotoxicity of cefoxitin was studied in a rat model of impaired renal function. Two levels of renal impairment were produced: "moderate," with blood urea concentrations of 100 to 150 mg/100 ml (16.7 to 25.1 mmol/liter) and glomerular filtration rates 25 to 35% of normal, and "severe," with blood urea concentrations greater than 150 mg/100 ml (greater than 25.1 mmol/liter) and glomerular filtration rates 10 to 20% of normal. Sham-operated animals were used as controls. Three dose schedules of cefoxitin were administered to these controls--500, 1,000, and 2,500 mg/kg per day administered as a divided dose for 5 days. Doses given to the moderately and severely uremic animals were adjusted so that serum levels of cefoxitin were similar to those attained in the sham-operated control animals. Concentrations of urea and creatinine in blood, glomerular filtration rates, and the urinary concentrating capacities of the experimental animals were monitored before and after cefoxitin treatment. There was no evidence of nephrotoxicity in even the most challenging experiment, in which blood serum levels of cefoxitin reached 2,000 microgram/ml in animals, with 15% renal function. These findings support available clinical data, suggesting that cefoxitin can be administered safely to patients with compromised renal function.

Animals↗
PubMed1983

Cefoxitin inactivation by Bacteroides fragilis.

We have surveyed the susceptibility of 1,575 clinical isolates of the Bacteroides fragilis group of organisms to cefoxitin and eight other antimicrobial agents. Eleven isolates, 0.7% of the total, were highly cefoxitin resistant and had minimum inhibitory concentrations of greater than or equal to 64 micrograms/ml. These isolates were also resistant to other beta-lactam antibiotics. Of 11 isolates, 4 were able to inactivate cefoxitin in broth cultures, as measured by microbiological and high-pressure liquid chromatography assays. Two distinct patterns of cefoxitin breakdown products were detected by high-pressure liquid chromatography analysis. The beta-lactamase inhibitors clavulanic acid and sulbactam failed to show synergism with cefoxitin. These data demonstrate that members of the B. fragilis group have acquired a novel resistance mechanism enabling them to inactivate cefoxitin.

Bacteroides fragilis↗