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Cefotetan

2014-11-09 14:01:37 来源: 作者: 【大中小】浏览:280次评论:0条

Cefotetan for Injection

Rx only

For Intravenous or Intramuscular Use

Cefotetan for Injection, as cefotetan disodium, is a sterile, semisynthetic, broad-spectrum, beta-lactamase resistant, cephalosporin (cephamycin) antibiotic for parenteral administration. It is the disodium salt of [6 R -(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. Structural Formula:

Cefotetan 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 cefotetan 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.

Cefotetan for Injection 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.

USP water test pending.

High plasma levels of cefotetan are attained after intravenous and intramuscular administration of single doses to normal volunteers.

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:

PLASMA CONCENTRATIONS AFTER 1 GRAM IV^a OR IM DOSE Mean Plasma Concentration (mcg/mL)

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 IV^a OR IM DOSE Mean Plasma Concentration (mcg/mL)

Route	5 min	10 min	1 h	3 h	5 h	9 h	12 h
IV	237	223	135	74	48	22	12^b
IM	—	20	75	91	69	33	19
^a Injected over 3 minutes
^b Concentrations estimated from regression line

skin	ureter
muscle	bladder
fat	maxillary sinus mucosa
myometrium	tonsil
endometrium	bile
cervix	peritoneal fluid
ovary	umbilical cord serum
kidney	amniotic fluid

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 ) 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, 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

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 method (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:

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:

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 procedure requires the use of the standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg 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 mcg cefotetan disk should be interpreted according to the following criteria:

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 mcg cefotetan disk should provide the following zone diameters in these laboratory test quality control strains.

Anaerobic Techniques

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

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:

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

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

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

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

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

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

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefotetan and other antibacterial drugs, cefotetan should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Cefotetan for injection is indicated for the therapeutic treatment of the following infections when caused by susceptible strains of the designated organisms:

Urinary Tract Infections caused by E. coli, Klebsiella spp (including K. pneumoniae ), Proteus mirabilis and Proteus spp (which may include the organisms now called Proteus vulgaris , Providencia rettgeri , and Morganella morganii ).

Lower Respiratory Tract Infections caused by Streptococcus pneumoniae , Staphylococcus aureus (penicillinase- and nonpenicillinase-producing strains), Haemophilus influenzae (including ampicillin-resistant strains), Klebsiella species (including K. pneumoniae ), E. coli , Proteus mirabilis , and Serratia marcescens.*

Skin and Skin Structure Infections due to Staphylococcus aureus (penicillinase- and nonpenicillinase-producing strains), Staphylococcus epidermidis , Streptococcus pyogenes , Streptococcus species (excluding enterococci), Escherichia coli , Klebsiella pneumoniae , Peptococcus niger *, Peptostreptococcus species.

Gynecologic Infections caused by Staphylococcus aureus , (including penicillinase- and nonpenicillinase-producing strains), Staphylococcus epidermidis , Streptococcus species (excluding enterococci), Streptococcus agalactiae , E. coli , Proteus mirabilis , Neisseria gonorrhoeae , Bacteroides species (excluding B. distasonis , B. ovatus , B. thetaiotaomicron ), Fusobacterium species*, and gram-positive anaerobic cocci (including Peptococcus niger and Peptostreptococcus species).

Cefotetan, like other cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when cephalosporins are used in the treatment of pelvic inflammatory disease, and C. trachomatis is one of the suspected pathogens, appropriate antichlamydial coverage should be added.

Intra-abdominal lnfections caused by E. coli , Klebsiella species (including K. pneumoniae ), Streptococcus species (excluding enterococci), Bacteroides species (excluding B. distasonis , B. ovatus, B. thetaiotaomicron ) and Clostridium species*.

Bone and Joint Infections caused by Staphylococcus aureus *.

* Efficacy for this organism in this organ system was studied in fewer than ten infections.

Specimens for bacteriological examination should be obtained in order to isolate and identify causative organisms and to determine their susceptibilities to cefotetan. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly.

In cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, it is possible to use cefotetan concomitantly with an aminoglycoside. Cefotetan combinations with aminoglycosides have been shown to be synergistic in vitro against many Enterobacteriaceae and also some other gram-negative bacteria. The dosage recommended in the labeling of both antibiotics may be given and depends on the severity of the infection and the patient's condition.

NOTE : Increases in serum creatinine have occurred when cefotetan was given alone. If cefotetan and an aminoglycoside are used concomitantly, renal function should be carefully monitored, because nephrotoxicity may be potentiated.

The preoperative administration of cefotetan may reduce the incidence of certain post- operative infections in patients undergoing surgical procedures that are classified as clean contaminated or potentially contaminated (e.g., cesarean section, abdominal or vaginal hysterectomy, transurethral surgery, biliary tract surgery, and gastrointestinal surgery).

If there are signs and symptoms of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapeutic measures may be initiated.

Cefotetan is contraindicated in patients with a known allergy to the cephalosporin group of antibiotics and in those individuals who have experienced a cephalosporin associated hemolytic anemia.

BEFORE THERAPY WITH CEFOTETAN IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTETAN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. IF THIS PRODUCT IS TO BE GIVEN TO PENICILLIN-SENSITIVE PATIENTS, CAUTION SHOULD BE EXERCISED BECAUSE CROSS-HYPERSENSITIVITY AMONG BETA-LACTAM ANTIBIOTICS HAS BEEN CLEARLY DOCUMENTED AND MAY OCCUR IN UP TO 10% OF PATIENTS WITH A HISTORY OF PENICILLIN ALLERGY. IF AN ALLERGIC REACTION TO CEFOTETAN OCCURS, DISCONTINUE THE DRUG. SERIOUS ACUTE HYPERSENSITIVITY REACTIONS MAY REQUIRE TREATMENT WITH EPINEPHRINE AND OTHER EMERGENCY MEASURES, INCLUDING OXYGEN, INTRAVENOUS FLUIDS, INTRAVENOUS ANTIHISTAMINES, CORTICOSTEROIDS, PRESSOR AMINES, AND AIRWAY MANAGEMENT, AS CLINICALLY INDICATED.

AN IMMUNE MEDIATED HEMOLYTIC ANEMIA HAS BEEN OBSERVED IN PATIENTS RECEIVING CEPHALOSPORIN CLASS ANTIBIOTICS. SEVERE CASES OF HEMOLYTIC ANEMIA, INCLUDING FATALITIES, HAVE BEEN REPORTED IN ASSOCIATION WITH THE ADMINISTRATION