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 a Pharmacy Bulk Package 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 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.
Each Pharmacy Bulk Package is supplied as a dry powder containing sterile cefotetan disodium equivalent to 10 grams cefotetan and is intended for intravenous use only. Cefotetan for Injection, USP contains 80 mg (3.5 mEq) of sodium per gram of cefotetan activity.
A Pharmacy Bulk Package is a container of sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion. FURTHER DILUTION IS REQUIRED BEFORE USE (see DOSAGE AND ADMINISTRATION, and DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).
CLINICAL PHARMACOLOGY
High plasma levels of cefotetan are attained after intravenous administration of single doses to normal volunteers.
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PLASMA CONCENTRATIONS AFTER 1 GRAM IVa OR IM DOSE
Mean Plasma Concentration (mcg/mL)
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Time After Injection |
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Route
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15 min
|
30 min
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1 h
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2 h
|
4 h
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8 h
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12 h
|
|
IV
|
92
|
158
|
103
|
72
|
42
|
18
|
9
|
|
IM
|
34
|
56
|
71
|
68
|
47
|
20
|
9
|
|
a 30-minute infusion
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PLASMA CONCENTRATIONS AFTER 2 GRAM IVa OR IM DOSE
Mean Plasma Concentration (mcg/mL)
|
|
Time After Injection |
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Route
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5 min
|
10 min
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1 h
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3 h
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5 h
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9 h
|
12 h
|
|
IV
|
237
|
223
|
135
|
74
|
48
|
22
|
12b
|
|
IM
|
—
|
20
|
75
|
91
|
69
|
33
|
19
|
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a Injected over 3 minutes
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b Concentrations estimated from regression line
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The plasma elimination half-life of cefotetan is 3 to 4.6 hours after intravenous 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:
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skin
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ureter
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muscle
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bladder
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fat
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maxillary sinus mucosa
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myometrium
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tonsil
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endometrium
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bile
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cervix
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peritoneal fluid
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ovary
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umbilical cord serum
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kidney
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amniotic fluid
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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
