Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers.

BACKGROUND: Cefotetan is highly stable to penicillinase and cephalosporin produced by gram-negative bacteria, and it has strong antimicrobial activity against most gram-negative bacteria, some anaerobic bacteria and streptococcus. The objective of this study was to evaluate the pharmacokinetic profile and tolerability of single and multiple intravenous doses of cefotetan disodium in healthy Chinese volunteers. METHODS: In this single-center, open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1 h intravenous infusion. After completion of the single-dose phase, subjects continued into the multiple-dose phase, in which they received 1.0 g cefotetan disodium BID for 7 consecutive days. Plasma samples were assayed by a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Tolerability was assessed based on physical examinations, vital signs, laboratory tests, and subject interviews. RESULTS: After intravenous administration of single doses of 0.5, 1.0, and 2.0 g cefotetan disodium, the pharmacokinetics of cefotetan were as follows: Cmax was 69.49±12.10 µg·mL-1, 132.03±22.56 µg·mL-1 and 237.75±42.12 µg·mL-1, respectively; AUClast was 278.29±51.13 µg·mL-1·h, 543.25±92.44 µg·mL-1·h and 1003.8±172.39 µg·mL-1·h, respectively; AUC∞ was 284.42±50.76 µg·mL-1·h, 551.38±95.83 µg·mL-1·h and 1020.18±181.19 µg·mL-1·h, respectively; t1/2 was 4.21±0.83 h, 4.39±0.53 h and 4.27±0.74 h, respectively; CL was 1.81±0.33 L·h-1, 1.86±0.32 L·h-1 and 2.02±0.38 L·h-1, respectively; Vd was 10.80±1.89L, 11.78±2.20L and 12.25±1.99L, respectively. In the multiple-dose study, the pharmacokinetics of cefotetan were as follows: Cmax,ss was 147.58±22.71 µg·mL-1; Cmin,ss was 12.92±3.70 µg·mL-1; Cavg was 45.10±7.78 µg·mL-1; AUCτ,ss was 541.15±93.36 µg·mL-1·h; AUC∞ was 612.06±114.23 µg·mL-1·h; t1/2 was 4.30±0.63 h; CL was 1.90±0.35L·h-1; Vd was 8.91±1.57L; DF was 300.92±33.28%; Accumulation Index was 1.17±0.05. No serious adverse events were reported. Adverse events were generally mild. CONCLUSION: Cefotetan disodium showed favorable tolerability in this study. The Cmax and AUCs of cefotetan disodium demonstrated dose-dependent pharmacokinetic characteristics after single dose over a dose range (0.5-2.0 g) in healthy subjects, whereas the t1/2 was independent of dose. Except for Vd, there was no difference in other pharmacokinetic parameters between multiple and single administration.

A simple and sensitive liquid chromatographic technique for the determination of cefotetan disodium in human plasma and its application in a pharmacokinetic study.

A simple and sensitive liquid chromatographic method was developed for quantification of cefotetan disodium (CTT), a semi-synthetic cephamycin antibiotic, in human plasma. CTT and the internal standard chloramphenicol were extracted from plasma by a simple one-step protein precipitation with 35% (v/v) perchloric acid. Separation was carried out on a reverse-phase C18 column with a mobile phase of acetonitile-water containing 0.5% (v/v) phosphoric acids (20:80, v/v) at a flow rate of 1.0 mL/min. The column effluent was monitored by UV detection at 300 nm. The column temperature was maintained at 40°C. This method demonstrated good linearity in the range of 0.525-300.0 µg/mL, with correlation coefficients greater than 0.99. The limit of quantification (LOQ) was 0.525 µg/mL in human plasma. Intra- and inter-day precisions were less than 6.63% in terms of relative standard deviation (RSD). The accuracy, when expressed by the bias, ranged from 0.57% to 4.04%. The mean extraction recovery of CTT was higher than 40.94%. The method was found to be precise, accurate, and specific for CTT quantitative analysis, and was successfully applied for a pharmacokinetic study of CTT after a single intravenous dose of 1.0 g of CTT in healthy Chinese subjects.

Pharmacokinetic differences between the epimers of cefotetan disodium after single intravenous injection in healthy Chinese volunteers.

The pharmacokinetic behaviors of the epimers of cefotetan disodium (R-CTT, S-CTT) after a single intravenous injection dose in healthy Chinese volunteers were explored in this study. In an open-label, randomized, three-way, cross-over study, 12 volunteers (6 females and 6 males) received a cross-over fashion doses of 0.5, 1.0, and 2.0 g of cefotetan disodium, separated by washout periods of 7 days. The plasma concentrations of both epimers were measured by validated high-performance liquid chromatography assays. Pharmacokinetic parameters of R-CTT, S-CTT, and total-CTT (R + S mixture) were calculated using a noncompartmental analysis. Generally, the R and S epimers showed different pharmacokinetic behaviors. Following 0.5, 1.0, and 2.0 g doses of cefotetan disodium, values of the total area under the plasma concentration-time curve (AUC(0-∞)) were 124.23 ± 19.54, 231.34 ± 39.34, and 459.09 ± 80.65 for R-CTT; 100.95 ± 14.19, 193.80 ± 30.42, and 372.66 ± 67.32 for S-CTT, respectively. Total body clearance values were 4.13, 4.43, and 4.46 L/h for R-CTT and 5.05, 5.28, and 5.50 L/h for S-CTT, respectively. Mean plasma elimination half-life (t (1/2)) values of R-CTT were 4.16, 4.13, and 4.01 h for 0.5, 1.0, and 2.0 g doses, respectively, and those of S-CTT were 3.15, 3.25, and 3.21 h. There were significant differences in t (1/2) between the two epimers (P < 0.05). The t (1/2) of R-CTT was 28% longer than that of S-CTT, which indicated that the elimination of the S-CTT was greater than that of the R-CTT. All treatments were well tolerated.

Pharmacokinetics and tolerability of intravenous cefotetan disodium for injection in healthy Chinese volunteers: A randomized, open-label, single- and multiple-dose study.

BACKGROUND: Cefotetan disodium for injection is a semisynthetic cephamycin antibiotic that exerts its bactericidal effects by inhibition of cell-wall synthesis. Despite being widely used in the treatment of various infections, little information is available on the pharmacokinetic properties of cefotetan disodium in Chinese subjects. OBJECTIVES: This study evaluated the pharmacokinetics of single and multiple intravenous doses of a generic formulation of cefotetan disodium in healthy Chinese volunteers. The effect of sex on the pharmacokinetics of cefotetan disodium was evaluated as a secondary objective. METHODS: In this open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1-hour intravenous infusion. Those allocated to the 1.0-g dose continued into the multiple-dose phase, in which they received 1.0 g BID for 7 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 15 hours after drug administration and were analyzed using a validated HPLC method. During the multiple-dose phase, blood samples were obtained before drug administration on days 5, 6, and 7 to determine the C(min) at steady state; on day 7, blood samples were also collected from 0 to 15 hours after drug administration. Tolerability was assessed based on physical examinations, vital signs, laboratory tests (hematology, biochemistry, hepatic and renal function, and urinalysis), and subject interviews. RESULTS: Three groups, each consisting of 5 men and 5 women, were enrolled in the single-dose phase. The mean (SD) age of subjects was 23.2 (2.2) years (range, 19-30 years). Their mean weight was 57.0 (6.3) kg (range, 46.4-72.0 kg), and their mean height was 1.66 (0.08) m (range, 1.48-1.81 m). After intravenous administration of single doses of 0.5, 1.0, and 2.0 g, the cefotetan disodium C(max) was 35.01 (6.98), 76.67 (10.52), and 154.33 (27.17) mg/L, respectively; the AUC0₋15(h) was 145.35 (18.36), 307.45 (33.07), and 746.09 (103.07) mg · h/L; the AUC0₋(∞) was 171.51 (20.61), 347.25 (44.20), and 843.84 (131.13) mg · h/L; the t(1/2) was 5.80 (1.29), 4.91 (1.15), and 5.04 (1.26) hours; the CL was 2.96 (0.41), 2.92 (0.39), and 2.42 (0.39) L/h; and the V(d) was 24.55 (5.19), 20.37 (3.66), and 17.30 (3.52) L. After administration of multiple doses, the cefotetan disodium C(max,ss) was 80.53 (10.04) mg/L; the C(mix,ss) was 11.00 (4.04) mg/L; the AUC(ss) was 347.92 (50.04) mg · h/L; the steady-state plasma concentration was 28.99 (4.17) mg/L; the t(1/2) was 6.24 (2.52) hours; the CL was 2.32 (0.64) L/h; and the Vd was 19.19 (4.58) L. No significant differences in pharmacokinetic parameters were noted by sex in the multiple-dose phase. Cefotetan disodium appeared to be well tolerated. CONCLUSIONS: In these healthy Chinese subjects, the cefotetan disodium AUC and C(max) increased in a dose-proportional manner, whereas the t(1/2) was independent of dose. The pharmacokinetic properties of cefotetan disodium were linear at doses of 0.5 to 2.0 g. After multiple doses, the pharmacokinetic parameters of cefotetan disodium were consistent with those after single doses. At the doses studied, cefotetan disodium appeared to be well tolerated in these healthy volunteers.

False-positive eluate reactivity due to the low-ionic wash solution used with commercial acid-elution kits.

BACKGROUND: During the use of commercial red cell (RBC) acid-elution kits for adsorption and elution (adsorption/elution) studies with anti-D, unexpected reactive eluates (anti-D) were obtained from D- RBCs. Such results were not obtained with a parallel xylene method or, historically, with heat and ether methods. STUDY DESIGN AND METHODS: Single-donor and commercial polyclonal anti-D samples were incubated with D+ and D- RBCs. Acid eluates were prepared by the manufacturers' directions. Variations in the wash step of the eluate preparation included the use of commercial kit wash solution versus phosphate-buffered saline versus solutions of various ionic strengths. RESULTS: Anti-D was eluted from 20 of 22 samples of D- RBCs after incubation with commercial polyclonal anti-D (titer 512) and from 2 of 3 samples of D- RBCs incubated with single-donor anti-D (titer 256). With a low-titer (16) single-donor anti-D, 0 of 4 eluates from D- RBCs reacted. When phosphate-buffered saline was substituted for the commercial wash solution, 0 of 11 D- RBC eluates reacted, as compared with 9 of 11 D- RBCs that yielded positive 1+(-)2+ eluates with the commercial wash solution. If the recommended initial phosphate-buffered saline wash was omitted before the use of the commercial wash solution, the eluate reactivity was stronger (2+(-)3+). When low-ionic-strength (< 0.03 M) saline was substituted, anti-D was eluted from D- RBCs. All last washes were nonreactive. Antiglobulin tests on all adsorbing D- were negative. CONCLUSION: Commercial wash solutions used for acid elution are at low ionic strength and commonly yield superior eluates, but in the presence of high-titer antibodies, false-positive eluates can result. It is our belief that the low-ionic-strength wash solution caused aggregation of IgG and nonspecific attachment of IgG on RBCs. Aggregates will contain IgG serum antibodies in proportion to the titer of the antibody. It is this nonspecifically bound antibody that is eluted from antigen-negative RBCs.

Cefotetan: a second-generation cephalosporin active against anaerobic bacteria. Committee on Antimicrobial Agents, Canadian Infectious Disease Society.

OBJECTIVE: To offer guidelines for the use of cefotetan, a cephamycin antibiotic, in order to minimize its overprescription. OPTIONS: Clinical practice options considered were treatment of infections with the use of second- and third-generation cephalosporins, carbapenems such as imipenem as well as combination regimens of agents active against anaerobic bacteria, such as metronidazole or clindamycin with an aminoglycoside. OUTCOMES: In order of importance: efficacy, side effects and cost. EVIDENCE: A MEDLINE search of articles published between January 1982 and December 1993. In-vitro and pharmacokinetic studies published in recognized peer-reviewed journals that used recognized standard methods with appropriate controls were reviewed. For results of clinical trials, the reviewers emphasized randomized double-blind trials with appropriate controls. VALUES: The Antimicrobial Agents Committee of the Canadian Infectious Disease Society (CIDS) and a recognized expert (M.J.G.) recommended use of cefotetan to prevent and treat infections against which it has proved effective in randomized controlled trials. BENEFITS, HARMS AND COSTS: These guidelines should lead to less inappropriate prescribing of cefotetan, with its attendant costs and risk of development of resistant bacteria. RECOMMENDATIONS: Cefotetan could be considered an alternative single agent for prophylaxis of infection in patients undergoing elective bowel surgery. It may be used to treat patients with acute pelvic inflammatory disease and endometritis. VALIDATION: This article was prepared, reviewed and revised by the Committee on Antimicrobial Agents of the CIDS. It was then reviewed by the Council of the CIDS, and any further necessary revisions were made by the chairman of the committee.

Penetration of cefotetan into suction skin blister fluid and tissue homogenates in patients undergoing abdominal surgery.

The penetration of cefotetan (2-g intravenous bolus) into the suction blister fluid and tissue homogenates of 11 patients was investigated. Mean concentrations in tissue were significantly lower than contemporary suction blister fluid levels. These data show that the determination of beta-lactam concentrations by the tissue homogenate method may seriously underestimate the actual antibiotic levels in extracellular fluid.

Clinical pharmacokinetics of cefotetan.

Cefotetan is a 7-alpha-methoxy beta-lactam. A long serum half-life and resistance to beta-lactamase hydrolysis have made cefotetan an attractive chemotherapeutic agent, and the results of clinical trials worldwide have demonstrated its efficacy in a wide variety of clinical situations. Cefotetan can be administered intravenously (bolus or infusion) or intramuscularly with lidocaine (lignocaine) 0.5%. Mean peak plasma concentrations are almost linearly related to dose. The volume of distribution is between 8 and 13L and is not different from other cephalosporins. No accumulation is seen after repeated doses and no metabolite has been detected in either plasma or urine. Total body clearance is 1.8 to 2.9 L/h. Renal clearance accounts for about 64 to 84% of a dose, and 75% of a dose is excreted in the urine within 24 hours. The plasma elimination half-life is between 3 and 4 hours after intravenous and intramuscular doses. Half-life is considerably prolonged in patients with renal impairment (up to 10 hours). Cefotetan concentrations are likely to be active against susceptible bacteria in most tissues and body fluids. Breast milk and cerebrospinal fluid concentrations are low. The recommended dosage is 1g every 12 hours, increasing to 2g in severe infections and 3g in life-threatening infections. In surgical prophylaxis, a single dose of 2g is given with the induction of anaesthesia; an additional dose of 2g may be administered 12 hours later. In children over 6 months, the recommended dosage is 30 mg/kg given 12-hourly. In patients with a creatinine clearance of 10 to 40 ml/min (0.6 to 2.4 L/h), the dose is halved or the dosage interval is doubled. When creatinine clearance is less than 10 ml/min (0.6 L/h), the dose is quartered or the dosage interval quadrupled.

In vitro antibacterial activity of cefoxitin and cefotetan and pharmacokinetics in dogs.

The susceptibility of 50 clinical Escherichia coli isolates to various antibacterials, including cefoxitin and cefotetan was ascertained, and the minimal inhibitory concentration (MIC) of cefoxitin and cefotetan for each of these isolates was determined. The pharmacokinetics of cefoxitin and cefotetan after a single i.v. or SC injection (30 mg/kg of body weight) were determined in 4 dogs. Of the 50 E coli isolates, 98% were susceptible in vitro to cefotetan, 90% were susceptible to cefoxitin, and 88% were susceptible to gentamicin. The MIC that would inhibit the growth of 90% of the E coli isolates (MIC90) was 0.25 microgram/ml for cefotetan and 4 micrograms/ml for cefoxitin. Plasma cefotetan concentrations remained above MIC90 for (mean +/- SD) 8.2 +/- 1.72 hours and 13.52 +/- 0.28 hours after i.v. and SC administration, respectively. Plasma cefoxitin concentrations remained above MIC90 for (mean +/- SD) 5.37 +/- 1.18 hours and 7.95 +/- 0.71 hours after i.v. and SC administration, respectively. We concluded that cefotetan was superior to cefoxitin in activity against E coli in vitro. We recommend that cefotetan be given at a dosage of 30 mg/kg, i.v., every 8 hours, or SC, every 12 hours.

Penetration of intravenous antibiotics into brain abscesses.

INTRA-ABSCESS CONCENTRATIONS OF the intravenously administered latamoxef (LMOX, moxalactam in the United States) and cefotetan (CTT), were studied in 11 patients with intracranial abscess. None of these patients underwent surgical ablation of the abscess. In all cases, the abscess was aspirated, and multiple aspirations were required in five patients. Antibiotic concentrations in 18 aspirates were, therefore, determined by the agar well method. LMOX concentrations in 16 aspirates drawn from nine brain abscess cases ranged from 0 to 10.9 micrograms/ml, with a mean (standard deviation) of 4.18 (3.04) micrograms/ml. The CTT concentration in one patient with a brain abscess was 8.51 micrograms/ml, and the LMOX concentration in the one remaining patient with subdural empyema was 5.20 micrograms/ml. In one patient, the serum-to-pus penetration rate of LMOX was estimated to be 0.11 against the peak value of the concentration in serum or 0.44 against the simultaneously obtained level in serum. Significantly higher concentrations of LMOX were produced in abscess cavities with multiple-dose administration or by prior drainage of pus. More-advanced stages of local inflammation, as demonstrated by computed tomography, correlated with higher concentrations. However, the routine indexes of systemic inflammation, such as body temperature, white blood cell count, and level of C-reactive protein in serum, cannot be used to predict the concentration present in intracerebral pus. A tendency for LMOX concentrations in pus obtained after single dose-administration to decrease with increasing duration from symptom onset to sampling was observed but was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and clinical study of cefotetan in bile: prophylactic use in biliary tract surgery.

The excretion of cefotetan, a 7 alpha-methoxy-cephalosporin, was studied in 27 patients undergoing biliary surgery. Pharmacokinetic parameters were determined after a single intravenous bolus dose of 1 g (10 patients) or 2 g (17 patients). Rapidly excreted in bile, cefotetan concentrations were considerably higher in bile [range: 92-2,594 mg.l-1 (1 g); 35-4,610 mg.l-1 (2 g)] than in plasma despite the presence of gall stones. Bile bactericidal activities against Staphylococcus aureus (MIC 8 mg.l-1) and Bacteroides fragilis (MIC 2 mg.l-1) correlated well with gall bladder cefotetan levels [r = 0.888 (1 g); r = 0.971 (2 g)]. No cefotetan was detected in the bile of 3 patients with nonfunctioning gall bladders. One other patient with very low activity and these three aside, the inhibitory quotients (cefotetan concentration/MIC) were > 4 for both doses against both bacteria.

Cefotetan-induced immune hemolytic anemia.

Immune hemolytic anemia due to a drug-adsorption mechanism has been described primarily in patients receiving penicillins and first-generation cephalosporins. We describe a patient who developed anemia while receiving intravenous cefotetan. Cefotetan-dependent antibodies were detected in the patient's serum and in an eluate prepared from his red blood cells. The eluate also reacted weakly with red blood cells in the absence of cefotetan, suggesting the concomitant formation of warm-reactive autoantibodies. These observations, in conjunction with clinical and laboratory evidence of extravascular hemolysis, are consistent with drug-induced hemolytic anemia, possibly involving both drug-adsorption and autoantibody formation mechanisms. This case emphasizes the need for increased awareness of hemolytic reactions to all cephalosporins.

Pharmacokinetics and tissue penetration of single-dose cefotetan used for antimicrobial prophylaxis in patients undergoing colorectal surgery.

The pharmacokinetics and tissue penetration of cefotetan were studied after a single injection of 2 g given intravenously for antimicrobial prophylaxis to 16 consecutive patients undergoing colorectal surgery. Concentrations in tissue greater than or equal to the MIC for 90% of the main pathogens tested were considered adequate. The elimination half-life at beta phase was 4.6 +/- 1.4 h, the total body clearance was 0.75 +/- 0.19 ml/kg/min, and the volume of distribution was 260 +/- 71 ml/kg. At the time of incision (33 +/- 16 min after the injection), cefotetan concentrations were 14.2 +/- 7 micrograms/g in abdominal-wall fat, 16.4 +/- 1 micrograms/g in epiploic fat, and 163 +/- 62 mg/liter in serum. At the time of surgical anastomosis (151 +/- 54 min), cefotetan concentrations were 33.3 +/- 6 micrograms/g in the colonic wall and 73 +/- 34 mg/liter in serum. Upon closure of the abdomen (216 +/- 76 min), cefotetan concentrations were 6.3 +/- 3 micrograms/g in abdominal-wall fat, 6.1 +/- 4 micrograms/g in epiploic fat, and 64 +/- 38 mg/liter in serum. Cefotetan tissue penetration was 10% into abdominal and epiploic fat and 46% into the colonic wall. Levels in tissue were compared with the MIC for 90% of the most frequently encountered pathogenic germs (Staphylococcus aureus, Bacteroides fragilis, and Escherichia coli). Adequate concentrations in tissue were obtained up to anastomosis but not upon closure. The authors therefore recommend the injection of an additional dose of 1 g before closure in order to ensure optimal efficacy throughout the surgical procedure.

[Free concentration and protein binding of ceftriaxone].

UNLABELLED: Ceftriaxone (CTRX) was administered in dose of 1 g 30 minutes intravenous drip infusion to 5 healthy volunteers. Cefpiramide (CPM) and cefotetan (CTT) were administered as control antibiotics. The serum concentrations of total and free drugs, using ultrafiltration, were assayed by bioassay and HPLC. Protein binding rates and pharmacokinetic parameters were calculated. Free concentration of antibiotics were following orders in each sampling time: CTRX greater than CTT greater than CPM. Mean free concentrations of CTRX at 0 hour and at 8 hours after intravenous drip infusion was more than 20 micrograms/ml and more than 2 micrograms/ml. Even at 24 hours after intravenous drip infusion free concentrations of CTRX were detectable. Mean half life in beta phase by HPLC was following orders: CTRX (7.5 hours) greater than CPM (5.4 hours) greater than CTT (4.7 hours). Mean protein binding rates were following orders: CPM (98%) greater than CTT (94%) greater than CTRX (92%). CONCLUSIONS: Characteristic of CTRX is high free drug concentration and long half life.

Evaluation of cephalosporins/cephamycins with antianaerobic activity by integrating microbiologic and pharmacokinetic properties.

When evaluating antimicrobial agents, in vitro microbiologic activity and pharmacokinetics are important factors, but these data are usually not assessed simultaneously. The purpose of the study was to compare cefoxitin, cefotetan, ceftizoxime, cefotaxime (CT), desacetylcefotaxime (DACT), and CT/DACT (1:1 ratio) by integrating their microbiologic activity against clinical isolates of Bacteroides fragilis with their pharmacokinetic properties. Minimal inhibitory concentrations (MIC) were determined by the agar dilution method. Steady-state serum concentration--time profiles were simulated for 2-gm doses in a 70-kg patient using ADAPT software and pharmacokinetic data from published studies. Serum protein binding (%) of each agent was also obtained from published studies and used to calculate the unbound serum concentration--time profiles. As estimates of pharmacodynamic activity, time below the MIC (T less than MIC) and percentage of the dosing interval below the MIC (% INT less than MIC) were calculated for individual isolates using total and unbound serum concentrations. Data analysis included MIC50, MIC90, range, breakpoint susceptibility, and analysis of variance for T less than MIC and % INT less than MIC (Scheffé post-hoc test, P less than 0.05). The MIC90 of cefotetan was at least a twofold dilution lower than the other agents. However, using unbound (pharmacologically active) serum concentrations, T less than MIC and % INT less than MIC for ceftizoxime (at a simulated eight-hour dosing interval) were significantly smaller than with the other antibiotic regimens. Integration of in vitro and pharmacokinetic data may provide additional information to assist in the evaluation of antimicrobials. For B fragilis from our institution, the pharmacodynamic profile of unbound ceftizoxime is superior to the other antianaerobic cephalosporins/cephamycins tested.

Tissue distribution of cefotetan in patients with Crohn's disease.

Concentrations of cefotetan in the intestinal wall of patients with Crohn's disease were investigated with the method of tissue homogenates with the aim to evaluate the effects of inflammation on tissue distribution. Twenty-four patients who underwent surgery were treated with a 2-gram single dose of cefotetan intravenously before the operation. The mean tissue levels in inflamed intestinal wall were constantly higher than in normal wall, but the difference was statistically significant only in samples taken more than 2 h after cefotetan administration (31.0 +/- 17.8 vs 14.7 +/- 11.4 mg/kg; p less than 0.05). The mean residence time was 284.3 min for inflamed tissue and 123.9 min for normal. The areas under the curve were significantly higher in inflamed wall than in normal, with mean values of 4,789 and 3,020.2 mg/l.h, respectively (p less than 0.05). Inflammation seems to facilitate the penetration of cefotetan into the intestinal wall of patients with Crohn's disease but above all, it increases the mean residence time in inflamed tissue.

Comparative evaluation of the pharmacokinetics of N-methylthiotetrazole following administration of cefoperazone, cefotetan, and cefmetazole.

The comparative pharmacokinetics and in vivo production of N-methylthiotetrazole (NMTT) were evaluated following administration of cefoperazone, cefotetan, and cefmetazole. In a randomized-crossover manner, 11 healthy male volunteers received single 2-g intravenous doses of each agent and serial blood and urine samples were collected. Concentrations of NMTT and the parent compound in plasma, urine, and the reconstituted antibiotic solution were determined by high-pressure liquid chromatography. The amounts of NMTT administered were 6.06 +/- 0.46, 14.4 +/- 0.87, and 17.4 +/- 1.06 mg for cefoperazone, cefotetan, and cefmetazole, respectively (P less than 0.05). The mean NMTT plasma concentration-time profiles following administration of each cephalosporin were markedly different. Six hours after dosing, NMTT concentrations in plasma following cefoperazone administration were higher than those following administration of cefmetazole and cefotetan. Urinary recoveries of NMTT averaged 137.0 +/- 37.1, 38.3 +/- 6.98, and 25.2 +/- 5.95 mg following administration of cefoperazone, cefotetan, and cefmetazole, respectively (P less than 0.01). The apparent amount of NMTT produced in vivo, calculated by subtracting the amount of NMTT administered from the amount of NMTT excreted in urine, was significantly lower following cefmetazole administration than after administration of cefoperazone and cefotetan (P less than 0.01). The discrepancy between in vitro NMTT production (cefmetazole greater than cefotetan greater than cefoperazone) and the amount of NMTT formed in vivo and excreted unchanged (cefoperazone greater than cefotetan greater than cefmetazole) suggests that in vivo production of NMTT is dependent on the disposition of the parent cephalosporin. These results further suggest that cephalosporins which undergo extensive biliary excretion, such as cefoperazone, are associated with the greatest amount of in vivo NMTT release, whereas cephalosporins which are primarily renally excreted, such as cefmetazole, are associated with the lowest in vivo production of NMTT.

Prediction of the pharmacokinetics of cefodizime and cefotetan in humans from pharmacokinetic parameters in animals.

Pharmacokinetic behavior of beta-lactam antibiotics (cefodizime and cefotetan) in humans were predicted from the animal data. Total body clearance (CLp) of these drugs in humans (weighting 65-69 kg) were successfully extrapolated from the allometric relationship between the clearance for the unbound drug in plasma and body weight (r = 0.954-1.000) with a power of 0.948-0.991 for cefodizime and 0.700-0.756 for cefotetan. We also predicted the volume of distribution at steady state (Vdss), the volume of distribution in the central compartment (V1) and the volume of distribution at beta-phase (Vd beta) of these drugs in humans from the observed human plasma unbound fraction, inasmuch as the plasma unbound fraction correlated well (r = 0.913-0.995) with the values of Vdss, V1, and Vd beta among various animal species. Based on these predicted pharmacokinetic parameters, we calculated the plasma concentration profiles of these drugs in humans and found a good agreement between the predicted and observed values. We also report here that the prediction is successful when we consider the plasma protein binding of these drugs.

[Tissue penetration of single-dose cefotetan used for antibiotic prophylaxis in colorectal surgery]. / Pénétration tissulaire du céfotétan utilisé en dose unique pour une antibioprophylaxie en chirurgie colorectale.

Pharmacokinetics and tissue penetration of cefotetan were studied after a single injection of 2 g for antibiotic prophylaxis in colo-rectal surgery. Beta half-life was 4.3 +/- 1 h, total body clearance was 0.74 +/- 0.2 ml/kg/min and volume of distribution was 270 +/- 76 ml/kg. At time of laparotomy, cefotetan concentration was 14.2 +/- 7 micrograms/g in abdominal wall fat and 16.4 +/- 1 micrograms/g in epiploic fat. In the colonic wall, cefotetan concentration was 33.3 +/- 16 micrograms/g. At time of abdominal closure, cefotetan concentrations were 6.3 +/- 3 micrograms/g in the abdominal wall fat and 6.1 +/- 4 micrograms/g in the epiploic fat.

Toxicity and clearance of intravitreal cefotetan.

Direct intravitreal injection of antibiotics plays an important role in the management of bacterial endophthalmitis. In the present study we investigated the toxicity and clearance of intravitreally injected cefotetan in a rabbit model. No toxic ocular side effects could be detected by electroretinography (ERG) or light and electron microscopy up to and including a single intravitreal dose of 1000 micrograms. Intravitreal injection of 2000 micrograms cefotetan resulted in mild degeneration of photoreceptor outer segments and, sporadically, in cataract formation. After intravitreal injection of 4000 micrograms, moderate toxic degeneration of photoreceptors occurred, with displacement and mitochondrial swelling of inner segments. In addition, lysosomal lamellar inclusion bodies could be detected in pigment epithelial cells. After a single intravitreal injection of 1000 micrograms cefotetan, concentrations greater than the minimum necessary for the inhibition of most commonly occurring intraocular pathogens (except Pseudomonas aeruginosa and Staphylococcus epidermidis) were maintained in the vitreous humor for greater than 48 h. Cefotetan may be a potentially important drug for intravitreal injection, especially in cases of gram-negative and suspected anaerobic endophthalmitis.