High plasma levels of cefotetan are attained after intravenous and intramuscular administration of single doses to normal volunteers .
PLASMA CONCENTRATIONS AFTER 1 GRAM INTRAVENOUS a OR INTRAMUSCULAR DOSE Mean Plasma Concentration (mcg/mL)
|Time After Injection
|a 30-minute infusion
PLASMA CONCENTRATIONS AFTER 2 GRAM INTRAVENOUSa OR INTRAMUSCULAR DOSE Mean Plasma Concentration (mcg/mL)
|Time After Injection
|a Injected over 3 minutes
b Concentrations estimated from regression line
Repeated administration of CEFOTAN™ does not result in accumulation of the drug in normal subjects.
Cefotetan is 88% plasma protein bound.
Therapeutic concentrations of cefotetan are achieved in many body tissues and fluids including:
||maxillary sinus mucosa
||umbilical cord serum
Metabolism And Excretion
The plasma eliminatio n half-life of cefotetan is 3 to 4.6 hours after either intravenous or intramuscular administration.
No active metabolites of cefotetan have been detected; however, small amounts (less than 7%) of cefotetan in plasma and urine may be converted to its tautomer, which has antimicrobial activity similar to the parent drug.
In normal patients, from 51% to 81% of an administered dose of CEFOTAN™ is excreted unchanged by the kidneys over a 24-hour period, which results in high and prolonged urinary concentrations. Following intravenous doses of 1 gram and 2 grams, urinary concentrations are highest during the first hour and reach concentrations of approximately 1700 and 3500 mcg/mL, respectively.
Patients With Renal impairment
In volunteers with reduced renal function, the plasma half-life of cefotetan is prolonged. The mean terminal half-life incre ases with declining renal function, from appro ximate ly 4 hours in volunteers with normal renal function to about 10 hours in those with moderate renal impairment. There is a linear correlation between the systemic clearance of cefotetan and creatinine clearance. When renal function is impaired, a reduced dosing schedule based on creatinine clearance must be used (see DOSAGE AND ADMINISTRATION).
In pharmacokinetic studies of eight elderly patients (greater than 65 years) with normal renal function and six healthy volunteers (aged 25 to 28 years), mean±SD) Total Body Clearance (1.8±0.1 vs. 1.8±0.3 L/h) and mean±SD Vo lume of Distribution (10.4±1.2 vs. 10.3±1.6 L) were similar fo llo wing administration of a one gram intravenous bolus dose.
Mechanism Of Action
Cefotetan is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefotetan has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria.
Resistance to cefotetan is primarily through hydrolysis by some beta-lactamases, alteration of penicillin –binding proteins (PBPs) and decreased permeability.
Cefotetan has been shown to be active against most isolates of the following micro organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE).
Klebsiella species (including K. pneumoniae)
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
The following in vitro data are available but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefotetan against isolates of similar genus or organism group. However, the efficacy of cefotetan in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Citrobacter species (including C. koseri and C. freundii)
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in the selection of an appropriate antibacterial drug for treatment.
Quantitative methods are used to determine antibacterial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure (broth or agar)1,4. The MIC values should be interpreted according to criteria provided in Table 1.
Quantitative methods that require me asurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2,4. This procedure uses paper disks impregnated with 30 mcg cefotetan to test the susceptibility of micro organisms to cefotetan. The disc diffusion interpretive criteria are provided in Table 1.
For anaerobic bacteria, the susceptibility to cefotetan as MICs can be determine d by standardized test methods 3,4. The MIC values obtained should be interpreted according to the following criteria:
Table 1: Susceptibility Test Interpretive Criteria for Cefotetan
||Minimum Inhibitory Concentration
|1 Susceptibility interpretive criteria for microorganisms are based on a dosing regimen of 2 g every 12 hours
2 For Staphylococcus spp., susceptibility to cefotetan may be deduced from testing penicillin and either oxacillin or cefoxitin . Staphylococci susceptible oxacillin or cefoxitin can be considered susceptible to cefotetan.
3 For non-meningitis Streptococcus pneumoniae isolates, susceptibility to penicillin (MIC less than 0.06 mcg/mL or oxacillin zone diameter greater than 20 mm ) can predict susceptibility to cefotetan 4For beta-hemolytic streptococci (including S. pyogenes and S. agalactiae) isolates susceptible to penicillin (MIC less than 0.12 mcg/mL) can be considered susceptible to cefotetan
A report of Susceptible indicates that antibacterial is likely to inhibit growth of the pathogen if the antibacterial drug reaches the concentrations usually achievable at the site of infection. A report of Intermediate indicates that the result should be co nsidered equivocal, and if the micro o rg anism is not fully susceptible to alternative, c linically feasible drugs, the test should be repeated. This category implie s possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major disc re panc ies in interpretation. A report of Resistant indicates that the antibacterial drug is not likely to inhibit growth of the pathogen if the antibacterial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard cefotetan powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg disk the criteria in Table 2 should be achieved.
Table 2: Acceptable Quality Control Ranges for Cefotetan
||Minimal Inhibitory Concentration (mcg/mL)
||Zone Diameter (mm)
||Agar Dilution (mcg/mL)
|Escherichia coli ATCC 25922
||0.06 – 0.25
||28 – 34
|Neisseria gonorrhoeae ATCC 49226
||30 – 36
||0.5 – 2
|Staphylococcus aureus ATCC 25923
||17 – 23
|Staphylococcus aureus ATCC 29213
||4 - 16
|Bacterioides fragilis ATCC 25285
||1 – 8
||4 – 16
|Bacterioides thetaiotaomicron ATCC 29741
||16 – 128
||32 – 128
|Eggerthella lenta ATCC 43055
||16 – 64
||32 – 128
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10 , Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests -Fifth Edition. Approved Standard NCCLS Do cument M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993 Clinical and Laboratory Standards Institute (CLSI).
Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12 , Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8 . Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-seventh Informational Supplement, CLSI document M100-S27 , Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.