DESCRIPTION
Cefotetan for Injection, USP, as cefotetan disodium, is a sterile, semisynthetic, broad-spectrum, beta-lactamase resistant, cephalosporin (cephamycin) antibiotic for parenteral administration. It is the disodium salt of [6R-(6α,7α)]-7-[[[4-(2-amino-1-carboxy-2-oxoethylidene)-1,3-dithietan-2-yl]carbonyl]amino]-7-methoxy-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Structural formula:
Cefotetan for Injection, USP is supplied in vials containing 80 mg (3.5 mEq) of sodium per gram of cefotetan activity. It is a white to pale yellow powder which is very soluble in water. Reconstituted solutions of Cefotetan for Injection, USP are intended for intravenous and intramuscular administration. The solution varies from colorless to yellow depending on the concentration. The pH of freshly reconstituted solutions is usually between 4.5 to 6.5.
Cefotetan for Injection, USP is available in two vial strengths. Each 1 gram vial contains cefotetan disodium equivalent to 1 gram cefotetan activity. Each 2 gram vial contains cefotetan disodium equivalent to 2 grams cefotetan activity.
CLINICAL PHARMACOLOGY
High plasma levels of cefotetan are attained after intravenous and intramuscular administration of single doses to normal volunteers.
|
PLASMA CONCENTRATIONS AFTER 1 GRAM IVa OR IM DOSE
Mean Plasma Concentration (mcg/mL)
|
|
Time After Injection |
|
Route
|
15 min
|
30 min
|
1 h
|
2 h
|
4 h
|
8 h
|
12 h
|
|
IV
|
92
|
158
|
103
|
72
|
42
|
18
|
9
|
|
IM
|
34
|
56
|
71
|
68
|
47
|
20
|
9
|
|
a 30-minute infusion
|
|
PLASMA CONCENTRATIONS AFTER 2 GRAM IVa OR IM DOSE
Mean Plasma Concentration (mcg/mL)
|
|
Time After Injection |
|
Route
|
5 min
|
10 min
|
1 h
|
3 h
|
5 h
|
9 h
|
12 h
|
|
IV
|
237
|
223
|
135
|
74
|
48
|
22
|
12b
|
|
IM
|
—
|
20
|
75
|
91
|
69
|
33
|
19
|
|
a Injected over 3 minutes
|
|
b Concentrations estimated from regression line
|
The plasma elimination half-life of cefotetan is 3 to 4.6 hours after either intravenous or intramuscular administration.
Repeated administration of cefotetan does not result in accumulation of the drug in normal subjects.
Cefotetan is 88% plasma protein bound.
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 cefotetan 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.
In volunteers with reduced renal function, the plasma half-life of cefotetan is prolonged. The mean terminal half-life increases with declining renal function, from approximately 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 (± 1 sd) Total Body Clearance (1.8 (0.1) L/h vs. 1.8 (0.3) L/h) and mean Volume of Distribution (10.4 (1.2) L vs. 10.3 (1.6) L) were similar following administration of a one gram intravenous bolus dose.
Therapeutic levels of cefotetan are achieved in many body tissues and fluids including:
|
skin
|
ureter
|
|
muscle
|
bladder
|
|
fat
|
maxillary sinus mucosa
|
|
myometrium
|
tonsil
|
|
endometrium
|
bile
|
|
cervix
|
peritoneal fluid
|
|
ovary
|
umbilical cord serum
|
|
kidney
|
amniotic fluid
|
Microbiology
The bactericidal action of cefotetan results from inhibition of cell wall synthesis. Cefotetan has in vitro activity against a wide range of aerobic and anaerobic gram-positive and gram-negative organisms. The methoxy group in the 7-alpha position provides cefotetan with a high degree of stability in the presence of beta-lactamases including both penicillinases and cephalosporinase of gram-negative bacteria.
Cefotetan has been shown to be active against most strains of the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE).
Gram-Negative Aerobes
Escherichia coli
Haemophilus influenzae (including ampicillin-resistant strains)
Klebsiella species (including K. pneumoniae)
Morganella morganii
Neisseria gonorrhoeae (nonpenicillinase-producing strains)
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Serratia marcescens
NOTE: Approximately one-half of the usually clinically significant strains of Enterobacter species (e.g., E. aerogenes and E. cloacae) areresistant to cefotetan. Most strains of Pseudomonas aeruginosa and Acinetobacter species are resistant to cefotetan.
Gram-Positive Aerobes
Staphylococcus aureus (including penicillinase- and nonpenicillinase-producing strains)
Staphylococcus epidermidis
Streptococcus agalactiae (group B beta-hemolytic streptococcus)
Streptococcus pneumoniae
Streptococcus pyogenes
NOTE: Methicillin-resistant staphylococci are resistant to cephalosporins. Some strains of Staphylococcus epidermidis and most strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis) are resistant to cefotetan.
Anaerobes
Prevotella bivia (formerly Bacteroides bivius)
Prevotella disiens (formerly Bacteroides disiens)
Bacteroides fragilis
Prevotella melaninogenica (formerly Bacteroides melaninogenicus)
Bacteroides vulgatus
Fusobacterium species
Gram-positive bacilli (including Clostridium species; see WARNINGS)
NOTE: Most strains of C. difficile are resistant (see WARNINGS).
Peptococcus niger
Peptostreptococcus species
NOTE: Many strains of B. distasonis, B. ovatus and B. thetaiotaomicron are resistant to cefotetan in vitro. However, the therapeutic utility of cefotetan against these organisms cannot be accurately predicted on the basis of in vitro susceptibility tests alone.
The following in vitro data are available but their clinical significance is unknown. Cefotetan has been shown to be active in vitro against most strains of the following organisms:
Gram-Negative Aerobes
Citrobacter species (including C. diversus and C. freundii)
Klebsiella oxytoca
Moraxella (Branhamella) catarrhalis
Neisseria gonorrhoeae (penicillinase-producing strains)
Salmonella species
Serratia species
Shigella species
Yersinia enterocolitica
Anaerobes
Porphyromonas asaccharolytica (formerly Bacteroides asaccharolyticus)
Prevotella oralis (formerly Bacteroides oralis)
Bacteroides splanchnicus
Clostridium difficile (see WARNINGS)
Propionibacterium species
Veillonella species
Susceptibility Tests
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefotetan powder. The MIC values should be interpreted according to the following criteria:
|
MIC (mcg/mL)
|
Interpretation
|
|
≤ 16
|
Susceptible (S)
|
|
32
|
Intermediate (I)
|
|
≥ 64
|
Resistant (R)
|
A report of 'Susceptible' indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of 'Intermediate' indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies 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 which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of 'Resistant' indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefotetan powder should provide the following MIC values:
|
Microorganism
|
MIC (mcg/mL)
|
|
E. coli ATCC 25922
|
0.06 to 0.25
|
|
S. aureus ATCC 29213
|
4 to 16
|
Diffusion Techniques
Q
