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Cefotaxime

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Cefotaxime

CLINICAL PHARMACOLOGY

There was a dose-dependent increase in serum levels after the IV administration of 500 mg, 1 g, and 2 g of cefotaxime (cefotaxime for injection) (38.9, 101.7, and 214.4 g/mL respectively) without alteration in the elimination half-life. There is no evidence of accumulation following repetitive IV infusion of 1 g doses every 6 hours for 14 days as there are no alterations of serum or renal clearance. About 60% of the administered dose was recovered from urine during the first 6 hours following the start of the infusion.

Approximately 20-36% of an intravenously administered dose of 14C-cefotaxime (cefotaxime for injection) is excreted by the kidney as unchanged cefotaxime (cefotaxime for injection) and 15-25% as the desacetyl derivative, the major metabolite. The desacetyl metabolite has been shown to contribute to the bactericidal activity. Two other urinary metabolites (M2 and M3) account for about 20-25%. They lack bactericidal activity.

A single 50 mg/kg dose of cefotaxime (cefotaxime for injection) was administered as an intravenous infusion over a 10- to 15-minute period to 29 newborn infants grouped according to birth weight and age. The mean half-life of cefotaxime (cefotaxime for injection) in infants with lower birth weights ( ≤ 1500 grams), regardless of age, was longer (4.6 hours) than the mean half-life (3.4 hours) in infants whose birth weight was greater than 1500 grams. Mean serum clearance was also smaller in the lower birth weight infants. Although the differences in mean half-life values are statistically significant for weight, they are not clinically important. Therefore, dosage should be based solely on age. (See DOSAGE AND ADMINISTRATION section.)

Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered cefotaxime (cefotaxime for injection) and ethanol.

Microbiology

The bactericidal activity of cefotaxime (cefotaxime for injection) sodium results from inhibition of cell wall synthesis. Cefotaxime (cefotaxime for injection) sodium has in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime (cefotaxime for injection) sodium has a high degree of stability in the presence of β-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. Cefotaxime (cefotaxime for injection) sodium 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.

Aerobes, Gram-positive:

Enterococcus spp.
Staphylococcus aureus*
, including β-lactamase-positive and negative strains
Staphylococcus epidermidis

Streptococcus pneumoniae
Streptococcus pyogenes (Group A beta-hemolytic streptococci)
Streptococcus
spp.

*Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to cefotaxime (cefotaxime for injection) sodium.

Aerobes, Gram-negative:

Acinetobacter spp.
Citrobacter spp.
Enterobacter
spp.
Escherichia coli
Haemophilus influenzae
(including ampicillin-resistant strains)
Haemophilus parainfluenzae

Klebsiella
spp. (including Klebsiella pneumoniae)
Morganella morganii

Neisseria meningitidis

Proteus mirabilis
Proteus vulgaris
Providencia rettgeri

Providencia stuartii

Serratia marcescens

NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics, e.g. penicillins, cephalosporins, and aminoglycosides, are susceptible to cefotaxime (cefotaxime for injection) sodium. Cefotaxime (cefotaxime for injection) sodium is active against some strains of Pseudomonas aeruginosa.

Anaerobes:

Bacteroides spp., including some strains of Bacteroides fragilis
Clostridium
spp. (Note: Most strains of Clostridium difficile are resistant.)
Fusobacterium spp. (including Fusobacterium nucleatum).
Peptococcus
spp.
Peptostreptococcus spp.

Cefotaxime (cefotaxime for injection) sodium also demonstrates in vitro activity against the following microorganisms but the clinical significance is unknown. Cefotaxime (cefotaxime for injection) sodium exhibits in vitro minimal inhibitory concentrations (MIC's) of 8 g/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefotaxime (cefotaxime for injection) sodium in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:

Aerobes, Gram-negative:

Providencia spp.
Salmonella spp. (including Salmonella typhi)
Shigella spp.

Cefotaxime (cefotaxime for injection) sodium is highly stable in vitro to four of the five major classes of β-lactamases described by Richmond et al.1, including type IIIa (TEM) which is produced by many gram-negative bacteria. The drug is also stable to β-lactamase (penicillinase) produced by staphylococci. In addition, cefotaxime (cefotaxime for injection) sodium shows high affinity for penicillin-binding proteins in the cell wall, including PBP: Ib and III.

Cefotaxime (cefotaxime for injection) sodium and aminoglycosides have been shown to be synergistic in vitro against some strains of Pseudomonas aeruginosa but the clinical significance is unknown.

Susceptibility Tests

Dilution techniques

Quantitative methods that are used to determine minimum inhibitory concentrations (MIC's) provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method2 (broth or agar) or equivalent with cefotaxime (cefotaxime for injection) sodium powder. The MIC values obtained should be interpreted according to the following criteria:

When testing organismsa other than Haemophilus spp. and Streptococcus spp.


MIC (g/mL) Interpretation
≤ 8 Susceptible (S)
16-32 Intermediate (I)
≥ 64 Resistant (R)
When testing Haemophilus spp.b
MIC (g/mL) Interpretationc
≤ 2 Susceptible (S)
When testing Streptococcusd
MIC (g/mL) Interpretation
≤ 0.5 Susceptible (S)
1 Intermediate (I)
≥ 2 Resistant (R)
a. Staphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime (cefotaxime for injection) despite apparent in vitro susceptibility.
b Interpretive criteria is applicable only to tests performed by broth microdilution method using Haemophilus Test Media.2
c The absence of resistant strains precludes defining any interpretations other than susceptible.
d Streptococcus pneumoniae must be tested using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.

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 that 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 procedure.3 Standard cefotaxime (cefotaxime for injection) sodium powder should provide the following MIC values:


Microorganism MIC (g/mL)
Escherichia coli ATCC 25922 0.03-0.12
Staphylococcus aureus ATCC 29213 1-4
Pseudomonas aeruginosa ATCC 27853 8-12
Haemophilus influenzaea ATCC 49247 0.12-0.5
Streptococcus pneumoniaeb ATCC 49619 0.03-0.12
a Ranges applicable only to tests performed by broth microdilution method using Haemophilus TestMedia.2
b Ranges applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.2
Diffusion Techniques

Quantitative methods that require measurements of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure4 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 g cefotaxime (cefotaxime for injection) sodium to test the susceptibility of microorganisms to cefotaxime (cefotaxime for injection) sodium. Reports from the laboratory providing results of the standard single-disk susceptibility test using a 30 g cefotaxime (cefotaxime for injection) sodium disk should be interpreted according to the following criteria:

When testing organismsa other than Haemophilus spp. and Streptococcus spp.


Zone Diameter (mm) Interpretation
≥ 23 Susceptible (S)
15-22 Intermediate (I)
≤ 14 Resistant (R)
When testing Haemophilus spp.b
Zone Diameter (mm) Interpretationc
≥ 26 Susceptible (S)
When testing Streptococcus other than Streptococcus pneumoniae
Zone Diameter (mm) Interpretation
≥ 28 Susceptible (S)
26-27 Intermediate (I)
≤ 25 Resistant (R)
a Staphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime (cefotaxime for injection) despite apparent in vitro susceptibility.
b Interpretive criteria is applicable only to tests performed by disk diffusion method using Haemophilus Test Media 4.
c The absence of resistant strains precludes defining any interpretations other than susceptible.

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 cefotaxime (cefotaxime for injection) sodium.

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 g cefotaxime (cefotaxime for injection) sodium disk should provide the following zone diameters in these laboratory test quality control strains:


Microorganism Zone Diameter (mm)
Escherichia coli ATCC 25922 29-35
Staphylococcus aureus ATCC 25923 25-31
Pseudomonas aeruginosa ATCC 27853 18-22
Haemophilus influenzaea ATCC 49247 31-39
a Ranges applicable only to tests performed by disk diffusion method using Haemophilus Test Media.4
Anaerobic Techniques

For anaerobic bacteria, the susceptibility to cefotaxime (cefotaxime for injection) sodium as MICs can be determined by standardized test methods.5 The MIC values obtained should be interpreted according to the following criteria:


MIC (g/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 cefotaxime (cefotaxime for injection) sodium powder should provide the following MIC values:


Microorganism MIC ( g/mL)
Bacteroides fragilisa ATCC 25285 8-32
Bacteroides thetaiotaomicron ATCC 29741 16-64
Eubacterium lantem ATCC 43055 64-256
a Ranges applicable only to tests performed by agar dilution method.

REFERENCES

1) Richmond, M. H. and Sykes R. B.: The -Lactamases of Gram-Negative Bacteria and their Possible Physiological Role, Advances in Microbial Physiology 9:31-88, 1973.

2) National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December, 1993.

3) National Committee for Clinical Laboratory Standards. MIC Testing Supplemental Tables NCCLS Document M100-S14, Vol. 24, No. 1. NCCLS, Wayne, PA, January, 2004.

4) National Committee for Clinical Laboratory Standards. Performance Standard for Antimicrobial Disk Susceptibility Tests - Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December, 1993.

5) National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria - Third Edition. Approved Standard NCCLS Document M11-A3, NCCLS, Villanova, PA, December, 1993.

Last reviewed on RxList: 10/3/2007
This monograph has been modified to include the generic and brand name in many instances.

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