CLINICAL PHARMACOLOGY
Following IM administration of a single 500 mg or 1 g dose of CLAFORAN to normal volunteers, mean peak serum concentrations of 11.7 and 20.5 mcg/mL respectively were attained within 30 minutes and declined with an elimination half-life of approximately 1 hour. There was a dose-dependent increase in serum levels after the IV administration of 500 mg, 1 g, and 2 g of CLAFORAN (38.9, 101.7, and 214.4 mcg/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 is excreted by the kidney as unchanged cefotaxime 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 CLAFORAN 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 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 CLAFORAN and ethanol.
Microbiology
The bactericidal activity of cefotaxime sodium results from inhibition of cell wall synthesis. Cefotaxime sodium has in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime 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 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 Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to cefotaxime sodium. , including β-lactamase-positive and negative strains
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes (Group A beta-hemolytic streptococci)
Streptococcus spp.
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 gonorrhoeae (including β-lactamase-positive and negative strains)
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 sodium. Cefotaxime 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 sodium also demonstrates in vitro activity against the following microorganisms but the clinical significance is unknown. Cefotaxime sodium exhibits in vitro minimal inhibitory concentrations (MICs) of 8 mcg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of cefotaxime 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 sodium is highly stable in vitro to four of the five major classes of 5-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 sodium shows high affinity for penicillin-binding proteins in the cell wall, including PBP: Ib and III.
Cefotaxime 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 (MICs) provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method1 (broth or agar) or equivalent with cefotaxime sodium powder. The MIC values obtained should be interpreted according to the following criteria:
When testing organismsStaphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime despite apparent in vitro susceptibility. other than Haemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp.
|
| MIC (mcg/mL) | Interpretation |
| ≤8 | Susceptible (S) |
| 16–32 | Intermediate (I) |
| ≥64 | Resistant (R) |
| When testing Haemophilus spp.Interpretive criteria is applicable only to tests performed by broth microdilution method using Haemophilus Test Media.2 |
| MIC (mcg/mL) | Interpretation
|
| ≤2 | Susceptible (S) |
| When testing Streptococcus Streptococcus pneumoniae must be tested using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood. |
| MIC (mcg/mL) | Interpretation |
| ≤0.5 | Susceptible (S) |
| 1 | Intermediate (I) |
| ≥2 | Resistant (R) |
| When testing Neisseria gonorrhoeae Interpretive criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.2 |
| MIC (mcg/mL) | Interpretation |
| ≤0.5 | Susceptible (S) |
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. Standard cefotaxime sodium powder should provide the following MIC values:
| Microorganism | MIC (mcg/mL) |
| Escherichia coli ATCC 25922 | 0.06–0.25 |
| Staphylococcus aureus ATCC 29213 | 1–4 |
| Pseudomonas aeruginosa ATCC 27853 | 4–16 |
| Haemophilus influenzae Ranges applicable only to tests performed by broth microdilution method using Haemophilus Test Media.2 ATCC 49247 | 0.12–0.5 |
| Streptococcus pneumoniae Ranges applicable only to tests performed by broth microdilution method using cation-adjusted Mueller-Hinton broth with 2–5% lysed horse blood.2 ATCC 49619 | 0.06–0.25 |
| Neisseria gonorrhoeae Ranges applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.2 ATCC 49226 | 0.015–0.06 |
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 procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg cefotaxime sodium to test the susceptibility of microorganisms to cefotaxime sodium. Reports from the laboratory providing results of the standard single-disk susceptibility test using a 30 mcg cefotaxime sodium disk should be interpreted according to the following criteria:
When testing organismsStaphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime despite apparent in vitro susceptibility. other than Haemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp.
|
| MIC (mcg/mL) | Interpretation |
| ≥23 | Susceptible (S) |
| 15–22 | Intermediate (I) |
| ≤14 | Resistant (R) |
| When testing Haemophilus spp.Interpretive criteria is applicable only to tests performed by disk diffusion method using Haemophilus Test Media.3 |
| Zone Diameter (mm) | Interpretation
|
| ≥26 | Susceptible (S) |
| When testing Streptococcus other than Streptococcus pneumoniae |
| Zone Diameter (mm) | Interpretation |
| ≥28 | Susceptible (S) |
| 26–27 | Intermediate (I) |
| ≤25 | Resistant (R) |
| When testing Neisseria gonorrhoeae Interpretive criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement.3 |
| Zone Diameter (mm) | Interpretation |
| ≥31 | Susceptible (S) |
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 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 mcg cefotaxime 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 influenzae Ranges applicable only to tests performed by disk diffusion method using Haemophilus Test Media.3ATCC 49247 | 31–39 |
| Neisseria gonorrhoeae Ranges applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement.3 ATCC 49226 | 38–48 |
Anaerobic Techniques
For anaerobic bacteria, the susceptibility to cefotaxime sodium as MICs can be determined by standardized test methods.4 The MIC values obtained should be interpreted according to the following criteria:
| MIC (mcg/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 sodium powder should provide the following MIC values:
| Microorganism | MIC (mcg/mL) |
| Bacteroides fragilis Ranges applicable only to tests performed by agar dilution method. ATCC 25285 | 8–32 |
| Bacteroides thetaiotaomicron ATCC 29741 | 16–64 |
| Eubacterium lantem ATCC 43055 | 64–256 |
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