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MEFOXIN（cefoxitin sodium injection, powder, for solution）

2015-09-02 06:45:54 来源: 作者: 【大中小】浏览:311次评论:0条

Registered trademark of Abbott Laboratories, Inc.

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To reduce the development of drug-resistant bacteria and maintain the effectiveness of MEFOXIN1 and other antibacterial drugs, MEFOXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Registered trademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO., Inc., 1985, 1996, 2000 All rights reserved
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DESCRIPTION

MEFOXIN (Cefoxitin for Injection) is a semi-synthetic, broad-spectrum cepha antibiotic sealed under nitrogen for intravenous administration. It is derived from cephamycin C, which is produced by Streptomyces lactamdurans. Its chemical name is sodium (6R,7S)-3-(hydroxymethyl)-7-methoxy-8-oxo-7-[2-(2-thienyl)acetamido]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate carbamate (ester). The empirical formula is C16H16N3NaO7S2, and the structural formula is:

MEFOXIN contains approximately 53.8 mg (2.3 milliequivalents) of sodium per gram of cefoxitin activity. Solutions of MEFOXIN range from colorless to light amber in color. The pH of freshly constituted solutions usually ranges from 4.2 to 7.0.

CLINICAL PHARMACOLOGY

Clinical Pharmacology

Following an intravenous dose of 1 gram, serum concentrations were 110 mcg/mL at 5 minutes, declining to less than 1 mcg/mL at 4 hours. The half-life after an intravenous dose is 41 to 59 minutes. Approximately 85 percent of cefoxitin is excreted unchanged by the kidneys over a 6-hour period, resulting in high urinary concentrations. Probenecid slows tubular excretion and produces higher serum levels and increases the duration of measurable serum concentrations.

Cefoxitin passes into pleural and joint fluids and is detectable in antibacterial concentrations in bile.

In a published study of geriatric patients ranging in age from 64 to 88 years with normal renal function for their age (creatinine clearance ranging from 31.5 to 174.0 mL/min), the half-life for cefoxitin ranged from 51 to 90 minutes, resulting in higher plasma concentrations than in younger adults. These changes were attributed to decreased renal function associated with the aging process.

Microbiology

The bactericidal action of cefoxitin results from inhibition of cell wall synthesis. Cefoxitin has in vitro activity against a wide range of gram-positive and gram-negative organisms. The methoxy group in the 7α position provides cefoxitin with a high degree of stability in the presence of beta-lactamases, both penicillinases and cephalosporinases, of gram-negative bacteria.

Cefoxitin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms

Staphylococcus aureus2 (including penicillinase-producing strains)

Staphylococcus epidermidis2

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Most strains of enterococci, e.g., Enterococcus faecalis , are resistant.

Staphylococci resistant to methicillin/oxacillin should be considered resistant to cefoxitin.
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Aerobic gram-negative microorganisms

Escherichia coli

Haemophilus influenzae

Klebsiella spp. (including K. pneumoniae)

Morganella morganii

Neisseria gonorrhoeae (including penicillinase-producing strains)

Proteus mirabilis

Proteus vulgaris

Providencia spp. (including Providencia rettgeri)

Anaerobic gram-positive microorganisms

Clostridium spp.

Peptococcus niger

Peptostreptococcus spp.

Anaerobic gram-negative microorganisms

Bacteroides distasonis

Bacteroides fragilis

Bacteroides ovatus

Bacteroides thetaiotaomicron

Bacteroides spp.

The following in vitro data are available, but their clinical significance is unknown.

Cefoxitin exhibits in vitro minimum inhibitory concentrations (MIC's) of 8 μg/mL or less for aerobic microorganisms and 16 μg/mL or less for anaerobic microorganisms against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefoxitin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-negative microorganisms

Eikenella corrodens [non-ß-lactamase producers]

Klebsiella oxytoca

Anaerobic gram-positive microorganisms

Clostridium perfringens

Anaerobic gram-negative microorganisms

Prevotella bivia (formerlyBacteroides bivius)

Cefoxitin is inactive in vitro against most strains of Pseudomonas aeruginosa and enterococci and many strains of Enterobacter cloacae.

Susceptibility Tests

Dilution Techniques:

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method (1) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefoxitin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms *, †, ‡ other than Neisseria gonorrhoeae
MIC (μg/mL)	Interpretation
* Staphylococci exhibiting resistance to methicillin/oxacillin should be reported as also resistant to cefoxitin despite apparent in vitro susceptibility. † For testing Haemophilus influenzae these interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM) (1). For testing streptococci these interpretative criteria applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood (1). ‡
≤ 8	Susceptible (S)
16	Intermediate (I)
≥ 32	Resistant (R)

For testing Neisseria gonorrhoeae *:
MIC (μg/mL)	Interpretation
Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement and incubated in 5% CO 2 (1). 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. *
≤ 2	Susceptible (S)
4	Intermediate (I)
≥ 8	Resistant (R)

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefoxitin powder should provide the following MIC values:

Microorganism		MIC (μg/mL)
Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement and incubated in 5% CO 2 (1). *
Escherichia coli	ATCC 25922	1-4
Neisseria gonorrhoeae*	ATCC 49226	0.5-2
Staphylococcus aureus	ATCC 29213	1-4

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 (2) requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-μg cefoxitin to test the susceptibility of microorganisms to cefoxitin.

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

For testing aerobic microorganisms * † ‡ other than Neisseria gonorrhoeae:
Zone Diameter (mm)	Interpretation
* Staphylococci exhibiting resistance to methicillin/oxacillin should be reported as also resistant to cefoxitin despite apparent in vitro susceptibility. † For testing Haemophilus influenzae these interpretative criteria applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM) (1). For testing streptococci these interpretative criteria applicable only to tests performed by disk diffusion method using Mueller-Hinton agar with 5% defibrinated sheep blood and incubated in 5% CO 2 (2). ‡
≥ 18	Susceptible (S)
15-17	Intermediate (I)
≤ 14	Resistant (R)

For testing Neisseria gonorrhoeae *:
Zone Diameter (mm)	Interpretation
Interpretative criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement and incubated in 5% CO 2 (2). *
≥ 28	Susceptible (S)
24-27	Intermediate (I)
≤ 23	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 cefoxitin.

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 cefoxitin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism		Zone Diameter (mm)
Interpretative criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement and incubated in 5% CO 2 (2). *
Escherichia coli	ATCC 25922	23-29
Neisseria gonorrhoeae*	ATCC 49226	33-41
Staphylococcus aureus	ATCC 25923	23-29

Anaerobic Techniques:

For anaerobic bacteria, the susceptibility to cefoxitin as MIC's can be determined by standardized test methods (3). 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. Standard cefoxitin powder should provide the following MIC values:

Using either an Agar Dilution Method * or Using a Broth † Microdilution Method:
Microorganism		MIC (μg/mL)
* Range applicable only to tests performed using either Brucella blood or Wilkins-Chalgren agar. Range applicable only to tests performed in the broth formulation of Wilkins-Chalgren agar (3) †
Bacteroides fragilis	ATCC 25285	4-16
Bacteroides thetaiotaomicron	ATCC 29741	8-32

INDICATIONS AND USAGE

Treatment

MEFOXIN is indicated for the treatment of serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

Lower respiratory tract infections, including pneumonia and lung abscess, caused by Streptococcus pneumoniae, other streptococci (excluding enterococci, e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, Haemophilus influenzae, and Bacteroides species.
Urinary tract infections caused by Escherichia coli, Klebsiella species, Proteus mirabilis, Morganella morganii, Proteus vulgaris and Providencia species (including P. rettgeri).
Intra-abdominal infections, including peritonitis and intra-abdominal abscess, caused by Escherichia coli, Klebsiella species, Bacteroides species including Bacteroides fragilis, and Clostridium species.
Gynecological infections, including endometritis, pelvic cellulitis, and pelvic inflammatory disease caused by Escherichia coli, Neisseria gonorrhoeae (including penicillinase-producing strains), Bacteroides species including B. fragilis,Clostridium species, Peptococcus niger, Peptostreptococcus species, and Streptococcus agalactiae. MEFOXIN, like cephalosporins, has no activity against Chlamydia trachomatis. Therefore, when MEFOXIN is used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added.
Septicemia caused by Streptococcus pneumoniae, Staphylococcus aureus (including penicillinase-producing strains), Escherichia coli, Klebsiella species, and Bacteroides species including B. fragilis.
Bone and joint infections caused by Staphylococcus aureus (including penicillinase-producing strains).
Skin and skin structure infections caused by Staphylococcus aureus (including penicillinase-producing strains), Staphylococcus epidermidis, Streptococcus pyogenes and other streptococci (excluding enterococci e.g., Enterococcus faecalis [formerly Streptococcus faecalis]), Escherichia coli, Proteus mirabilis, Klebsiella species, Bacteroides species including B. fragilis, Clostridium species, Peptococcus niger, and Peptostreptococcus species.

Appropriate culture and susceptibility studies should be performed to determine the susceptibility of the causative organisms to MEFOXIN. Therapy may be started while awaiting the results of these studies.

In randomized comparative studies, MEFOXIN and cephalothin were comparably safe and effective in the management of infections caused by gram-positive cocci and gram-negative rods susceptible to the cephalosporins. MEFOXIN has a high degree of stability in the presence of bacterial beta-lactamases, both penicillinases and cephalosporinases.

Many infections caused by aerobic and anaerobic gram-negative bacteria resistant to some cephalosporins respond to MEFOXIN. Similarly, many infections caused by aerobic and anaerobic bacteria resistant to some penicillin antibiotics (ampicillin, carbenicillin, penicillin G) respond to treatment with MEFOXIN. Many infections caused by mixtures of susceptible aerobic and anaerobic bacteria respond to treatment with MEFOXIN.

Prevention

MEFOXIN is indicated for the prophylaxis of infection in patients undergoing uncontaminated gastrointestinal surgery, vaginal hysterectomy, abdominal hysterectomy, or cesarean section.

If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate treatment may be instituted.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of MEFOXIN and other antibacterial drugs, MEFOXIN 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.

CONTRAINDICATIONS

MEFOXIN is contraindicated in patients who have shown hypersensitivity to cefoxitin and the cephalosporin group of antibiotics.

WARNINGS

BEFORE THERAPY WITH 'MEFOXIN' IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOXITIN, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN WITH CAUTION TO PENICILLIN-SENSITIVE PATIENTS. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO 'MEFOXIN' OCCURS, DISCONTINUE THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including MEFOXIN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical eva luation should be instituted as clinically indicated.

PRECAUTIONS

General

The total daily dose should be reduced when MEFOXIN is administered to patients with transient or persistent reduction of urinary output due to renal insufficiency (see DOSAGE AND ADMINISTRATION ), because high and prolonged serum antibiotic concentrations can occur in such individuals from usual doses.

Antibiotics (including cephalosporins) should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

As with other antibiotics, prolonged use of MEFOXIN may result in overgrowth of nonsusceptible organisms. Repeated eva luation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Prescribing MEFOXIN in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Patients should be counseled that antibacterial drugs including MEFOXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When MEFOXIN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may 1. decrease the effectiveness of the immediate treatment and 2. increase the likelihood that bacteria will develop resistance and will not be treatable by MEFOXIN or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued. Sometimes after starting the treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests

As with any potent antibacterial agent, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

Drug Interactions

Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics.

Drug/Laboratory Test Interactions

As with cephalothin, high concentrations of cefoxitin (>100 micrograms/mL) may interfere with measurement of serum and urine creatinine levels by the Jaffé reaction, and produce false increases of modest degree in the levels of creatinine reported. Serum samples from patients treated with cefoxitin should not be analyzed for creatinine if withdrawn within 2 hours of drug administration.

High concentrations of cefoxitin in the urine may interfere with measurement of urinary 17-hydroxy-corticosteroids by the Porter-Silber reaction, and produce false increases of modest degree in the levels reported.

A false-positive reaction for glucose in the urine may occur. This has been observed with CLINITEST3 reagent tablets.

Registered trademark of Ames Company, Division of Miles Laboratories, Inc.
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Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed with cefoxitin to eva luate carcinogenic or mutagenic potential. Studies in rats treated intravenously with 400 mg/kg of cefoxitin (approximately three times the maximum recommended human dose) revealed no effects on fertility or mating ability.

Pregnancy

Pregnancy Category B. Reproduction studies performed in rats and mice at parenteral doses of approximately one to seven and one-half times the maximum recommended human dose did not reveal teratogenic or fetal toxic effects, although a slight decrease in fetal weight was observed.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

In the rabbit, cefoxitin was associated with a high incidence of abortion and maternal death. This was not considered to be a teratogenic effect but an expected consequence of the rabbit's unusual sensitivity to antibiotic-induced changes in the population of the microflora of the intestine.

Nursing Mothers

MEFOXIN is excreted in human milk in low concentrations. Caution should be exercised when MEFOXIN is administered to a nursing woman.

Pediatric Use

Safety and efficacy in pediatric patients from birth to three months of age have not yet been established. In pediatric patients three months of age and older, higher doses of MEFOXIN have been associated with an increased incidence of eosinophilia and elevated SGOT.

Geriatric Use

Of the 1,775 subjects who received cefoxitin in clinical studies, 424 (24%) were 65 and over, while 124 (7%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out (see CLINICAL PHARMACOLOGY).

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION and PRECAUTIONS).

ADVERSE REACTIONS

MEFOXIN is generally well tolerated. The most common adverse reactions have been local reactions following intravenous injection. Other adverse reactions have been encountered infrequently.

Local Reactions

Thrombophlebitis has occurred with intravenous administration.

Allergic Reactions

Rash (including exfoliative dermatitis and toxic epidermal necrolysis), urticaria, flushing, pruritus, eosinophilia, fever, dyspnea, and other allergic reactions including anaphylaxis, interstitial nephritis and angioedema have been noted.

Cardiovascular

Hypotension.

Gastrointestinal

Diarrhea, including documented pseudomembranous colitis which can appear during or after antibiotic treatment. Nausea and vomiting have been reported rarely.

Neuromuscular

Possible exacerbation of myasthenia gravis.

Blood

Eosinophilia, leukopenia including granulocytopenia, neutropenia, anemia, including hemolytic anemia, thrombocytopenia, and bone marrow depression. A positive direct Coombs test may develop in some individuals, especially those with azotemia.

Liver Function

Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase; and jaundice have been reported.

Renal Function

Elevations in serum creatinine and/or blood urea nitrogen levels have been observed. As with the cephalosporins, acute renal failure has been reported rarely. The role of MEFOXIN in changes in renal function tests is difficult to assess, since factors predisposing to prerenal azotemia or to impaired renal functio