Cefotan (Cefotetan Disodium) - Description and Clinical Pharmacology

In GALAXY® Plastic Container (PL 2040)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CEFOTAN and other antibacterial drugs, CEFOTAN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

CEFOTAN (cefotetan disodium for injection) and CEFOTAN (cefotetan injection) in Galaxy^® * plastic container (PL 2040) as cefotetan disodium are sterile, semisynthetic, broad-spectrum, beta-lactamase resistant, cephalosporin (cephamycin) antibiotics 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-1 H -tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Its molecular formula is

C₁₇H₁₅N₇Na₂O₈S₄ with a molecular weight of 619.57.

Structural Formula

CEFOTAN (cefotetan disodium for injection) 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 CEFOTAN (cefotetan disodium for injection) 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.

CEFOTAN in the ADD-Vantage Vial† is intended for intravenous use only after dilution with the appropriate volume of ADD-Vantage diluent solution.

CEFOTAN is available in two vial strengths. Each CEFOTAN 1 g vial contains cefotetan disodium equivalent to 1 g cefotetan activity. Each CEFOTAN 2 g vial contains cefotetan disodium equivalent to 2 g cefotetan activity.

CEFOTAN (cefotetan injection) in the Galaxy^® plastic container (PL 2040) is a frozen, iso-osmotic, sterile, nonpyrogenic premixed 50 mL solution containing 1 g or 2 g cefotetan as sterile cefotetan disodium. Dextrose, USP has been added to adjust the osmolality to 300 mOsmol/kg (approximately 1.9 g and 1.1 g to the 1 g and 2 g dosages, respectively); sodium bicarbonate has been added to convert cefotetan free acid to the sodium salt. The pH has been adjusted between 4 and 6.5 with sodium bicarbonate and may have been adjusted with hydrochloric acid. CEFOTAN (cefotetan injection) in the Galaxy^® plastic container (PL 2040) contains 80 mg (3.5 mEq) of sodium per gram of cefotetan activity. After thawing to room temperature, the solution is intended for intravenous use only.

This Galaxy^® container is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration dating period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers as well as by tissue culture toxicity.

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 IV ¹ OR IM DOSE

Mean Plasma Concentration (μg/mL) Time After Injection
Route	15 min	30 min	1h	2h	4h	8h	12h
IV	92	158	103	72	42	18	9
IM	34	56	71	68	47	20	9

PLASMA CONCENTRATIONS AFTER 2 GRAM IV ¹ OR IM DOSE

Mean Plasma Concentration (μg/mL) Time After Injection
Route	5 min	10 min	1h	3h	5h	9h	12h
IV	237	223	135	74	48	22	12 2
IM	--	20	75	91	69	33	19

The plasma elimination half-life of cefotetan is 3 to 4.6 hours after either intravenous or intramuscular administration.

Repeated administration of CEFOTAN 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 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 µg/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 pharmacokinetics studies of eight elderly patients (greater than 65 years) with normal renal function and six healthy volunteers (aged 25 to 28 years), mean (± 1sd) 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 cephalosporinases 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 (eg, E. aerogenes and E. cloacae) are resistant 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, eg, 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 (MIC’s). These MIC’s 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 or cefotetan powder. The MIC values should be interpreted according to the following criteria:

MIC (μg/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 (μg/mL)
E. coli ATCC 25922	0.06-0.25
S. aureus ATCC 29213	4-16

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² requires the use of the standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 μg cefotetan to test the susceptibility of microorganisms to cefotetan.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 µg cefotetan disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥ 16	Susceptible (S)
13-15	Intermediate (I)
≤ 12	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefotetan.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 μg cefotetan disk should provide the following zone diameters in these laboratory test quality control strains.

Microorganism	Zone Diameter (mm)
E. coli ATCC 25922	28-34
S. aureus ATCC 25923	17-23

Anaerobic Techniques: For anaerobic bacteria, the susceptibility to cefotetan as MIC’s can be determined by standardized test methods³. The MIC values obtained should be interpreted according to the following criteria:

MIC (µg/mL)	Interpretation
≤ 16	Susceptible (S)
32	Intermediate (I)
≥ 64	Resistant (R)

Interpretation is identical to that stated above for results using dilution techniques.

As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized cefotetan powder should provide the following MIC values:

Microorganism	MIC (µg/mL)
Bacteroides fragilis ATCC 25285	4-16
Bacteroides thetaiotaomicron ATCC 29741	32-128
Eubacterium lentum ATCC 43055	32-128