Cefoxitin

CEFOXITIN — cefoxitin sodium injection, powder, for solution
APOTEX CORP.

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

DESCRIPTION

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 molecular formula is C16 H16 N3 NaO7 S2 , and the structural formula is:

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Cefoxitin for injection contains approximately 53.8 mg (2.3 milliequivalents) of sodium per gram of cefoxitin activity. Solutions of cefoxitin for injection range from colorless to light amber in color. The pH of freshly constituted solutions usually ranges from 4.2 to 7.

Each Pharmacy Bulk Package is supplied as a dry powder in vials containing sterile cefoxitin sodium, equivalent to 10 g cefoxitin and is intended for intravenous infusion only.

A Pharmacy Bulk Package is a container of a 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.

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 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 aureus 1 (including penicillinase-producing strains)

Staphylococcus epidermidis 1

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

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


1
Staphylococci resistant to methicillin/oxacillin should be considered resistant to cefoxitin.

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 mcg/mL or less for aerobic microorganisms and 16 mcg/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-β-lactamase producers]

Klebsiella oxytoca

Anaerobic gram-positive microorganisms

Clostridium perfringens

Anaerobic gram-negative microorganisms

Prevotella bivia (formerly Bacteroides 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 2 (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 3, 4, 5 other than Neisseria gonorrhoeae:

MIC (mcg/mL) Interpretation
≤ 8 Susceptible (S)
16 Intermediate (I)
≥32 Resistant (R)

For testing Neisseria gonorrhoeae 6:

MIC (mcg/mL) Interpretation
≤ 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 (mcg/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% CO2 (See Reference 1).
Escherichia coli ATCC 25922 1-4
Neisseria gonorrhoea e * ATCC 49226 0.5-2
Staphylococcus aureus ATCC 29213 1-4

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