Clinical Pharmacokinetics of Cefotetan

Abstract

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.

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

“…S epimer (total-CTT) in plasma was also evaluated and the related PK parameters were calculated (Table 1), allowing a pharmacokinetic comparison to be made with this results. Compared with previous pharmacokinetic reports, the main pharmacokinetic parameters (C max , AUC, t 1/2 , Cl tot , and V) obtained from our study were similar to those in healthy white and Japanese subjects (Martin et al 1994). The pharmacokinetics of cefotetan had also been assessed in healthy Chinese volunteers recently (Shi et al 2010) and the C max (35.01 ± 6.98, 76.67 ± 10.52, and 154.33 ± 27.17 lg/mL for 0.5 g, 1.0 g, and 2.0 g doses, respectively) were lower than those of obtained from our study (67.50 ± 11.26, 125.84 ± 27.49, and 240.22 ± 37.11 lg/ mL).…”

“…Cefotetan (CTT) disodium is a third-generation semisynthetic cephamycin antibiotic with a broad-spectrum of antibacterial activity and a favorable pharmacokinetic activity (Ward and Richards 1985). 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 (Martin et al 1994), especially used as a prophylaxis in abdominal and pelvic surgeries (de Lalla 2009;Mahmoud et al 2009;Jeong et al 2010). The National Surgical Infection Prevention Project (NSIPP) has recommended prophylactic cefotetan administration to prevent infections in colorectal surgery patients, and cefotetan is currently the most commonly prescribed prophylactic antimicrobial agent in the United States (Bratzler et al 2005).…”

Persistence of cefotetan on red blood cells

“…After an intravenous dose of 1 g, the peak serum concentration is approximately 150 mg per L or 242 m mol/L. 5 This is well in excess of the minimal concentration of 1 m mol/L we found for in-vitro RBC binding. Cefotetan appears to remain bound to RBCs for most, if not all, of the life span of the cell.…”

“…3,4 We have previously observed prolonged hemolysis in cefotetan-induced IHA after withdrawal of the drug. Although cefotetan is know to have a plasma t 1/2 of 3 to 4 hours, 5 which is relatively long compared to other cephalosporins, the persistence of IHA for days or weeks is unexplained. We hypothesized that cefotetan may remain bound to RBCs after expected clearance of the drug from plasma.…”

Multiple Pharmacokinetic Parameter Prediction for a Series of Cephalosporins

“…The PK parameters of a series of 20 cephalosporins were collected from the literature,11–32 and compounds were divided into working (training and testing) and validation subsets (Table 1). Data for all compounds were taken from studies using intravenous administration of the drug, with the exception of cefaclor.…”