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Mefoxin Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefoxitin

Mefoxin Pharmacology, Pharmacokinetics, Studies, Metabolism - Cefoxitin

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.

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 7 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^a (including penicillinase-producing strains)

Staphylococcus epidermidis^a

Streptococcus agalactiae

Streptococcus pneumoniae Streptococcus pyogenes

^a Staphylococci resistant to methicillin/oxacillin should be considered resistant to cefoxitin.

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

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 g/mL or less for aerobic microorganisms and 16 m g/mL or less for anaerobic microorganisms against most (³ 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-b-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 method¹ (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^a,b,c other than Neisseria gonorrhoeae:

MIC (m g/mL)	Interpretation
£ 8	Susceptible (S)
16	Intermediate (I)
³ 32	Resistant (R)

^a Staphylococci exhibiting resistance to methicillin/oxacillin should be reported as also resistant to cefoxitin despite apparent in vitro susceptibility.

^b For testing Haemophilus influenzae these interpretative criteria applicable only to tests performed by broth microdilution method using Haemophilus Test Medium (HTM)¹.

^c 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 blood¹.

For testing Neisseria gonorrhoeae^d

MIC (m g/mL)	Interpretation
£ 2	Susceptible (S)
4	Intermediate (I)
³ 8	Resistant (R)

^d Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base ¹. A report of "Susceptible" indicates that the with 1% defined growth supplement and incubated in 5% CO² 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 cefoxitin powder should provide the following MIC values:

Microorganism		MIC ( g/mL)
Escherichia coli	ATCC 25922	1-4
Neisseria gonorrhoeaea	ATCC 49226	0.5-2
Staphylococcus aureus	ATCC 29213	1-4

^a Interpretative criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement and incubated in 5% CO₂¹.

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 standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-m g 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- g cefoxitin disk should be interpreted according to the following criteria: For testing aerobic microorganisms^a,b,c other than Neisseria gonorrhoeae:

Zone Diameter (mm)	Interpretation
³ 18	Susceptible (S)
15-17	Intermediate (I)
£ 14	Resistant (R)

^a Staphylococci exhibiting resistance to methicillin/oxacillin should be reported as also resistant to cefoxitin despite apparent in vitro susceptibility.

^b For testing Haemophilus influenzae these interpretative criteria applicable only to tests performed by disk diffusion method using Haemophilus Test Medium (HTM)¹.

^c 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% CO₂².

For testing Neisseria gonorrhoeae^d:

Zone Diameter (mm)	Interpretation
³ 28	Susceptible (S)
24-27	Intermediate (I)
£ 23	Resistant (R)

^d Interpretative criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement and incubated in 5% CO₂².

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

Microorganism		Zone Diameter (mm)
Escherichia coli	ATCC 25922	23-29
Neisseria gonorrhoeaea	ATCC 49226	33-41
Staphylococcus aureus	ATCC 25923	23-29

^a Interpretative criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement and incubated in 5% CO₂².

Anaerobic Techniques

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

MIC (m g/mL)	Interpretation
£ 16	Susceptible (S)
32	Intermediate (I)
³ 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^a or Using a Broth^b Microdilution Method:

Microorganism		MIC ( g/mL)
Bacteroides fragilis	ATCC 25285	4-16
Bacteroides thetaiotaomicron	ATCC 29741	8-32

^a Range applicable only to tests performed using either Brucella blood or Wilkins-Chalgren agar. ^b Range applicable only to tests performed in the broth formulation of Wilkins-Chalgren agar³.

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