Cefotaxime for Injection

BEFORE THERAPY WITH CEFOTAXIME (cefotaxime for injection) FOR INJECTION USP AND DEXTROSE INJECTION IS INSTITUTED, CAREFUL INQUIRY SHOULD BE MADE TO DETERMINE WHETHER THE PATIENT HAS HAD PREVIOUS HYPERSENSITIVITY REACTIONS TO CEFOTAXIME (cefotaxime for injection) SODIUM, CEPHALOSPORINS, PENICILLINS, OR OTHER DRUGS. THIS PRODUCT SHOULD BE GIVEN WITH CAUTION TO PATIENTS WITH TYPE I HYPERSENSITIVITY REACTIONS TO PENICILLIN. ANTIBIOTICS SHOULD BE ADMINISTERED WITH CAUTION TO ANY PATIENT WHO HAS DEMONSTRATED SOME FORM OF ALLERGY, PARTICULARLY TO DRUGS. IF AN ALLERGIC REACTION TO CEFOTAXIME (cefotaxime for injection) FOR INJECTION USP AND DEXTROSE INJECTION OCCURS, DISCONTINUE TREATMENT WITH THE DRUG. SERIOUS HYPERSENSITIVITY REACTIONS MAY REQUIRE EPINEPHRINE AND OTHER EMERGENCY MEASURES.

During post-marketing surveillance, a potentially life-threatening arrhythmia was reported in each of six patients who received a rapid (less than 60 seconds) bolus injection of cefotaxime (cefotaxime for injection) through a central venous catheter. Therefore, cefotaxime (cefotaxime for injection) should only be administered as instructed in the DOSAGE AND ADMINISTRATION section.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Cefotaxime (cefotaxime for injection) for Injection USP and Dextrose Injection, 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 evaluation should be instituted as clinically indicated.

The acute toxicity of cefotaxime (cefotaxime for injection) was evaluated in neonatal and adult mice and rats. Significant mortality was seen at parenteral doses in excess of 6000 mg/kg/day in all groups. Common toxic signs in animals that died were a decrease in spontaneous activity, tonic and clonic convulsions, dyspnea, hypothermia, and cyanosis.

Cefotaxime (cefotaxime for injection) sodium overdosage has occurred in patients. Most cases have shown no overt toxicity. The most frequent reactions were elevations of BUN and creatinine. Patients who receive an acute overdosage should be carefully observed and given supportive treatment.

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 µg/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 µg/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

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.

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:

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 µg 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 µg cefotaxime (cefotaxime for injection) sodium disk should be interpreted according to the following criteria:

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

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

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:

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:

REFERENCES

1) Richmond, M. H. and Sykes R. B.: The ß-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.

Cefotaxime (cefotaxime for injection) is generally well tolerated. The most common adverse reactions have been local reactions following IV injection. Other adverse reactions have been encountered infrequently.

The most frequent adverse reactions (greater than 1%) are:

Local (4.3%)— Injection site inflammation with IV administration.

Hypersensitivity (2.4%)—Rash, pruritus, fever, eosinophilia and less frequently urticaria and anaphylaxis.

Gastrointestinal (1.4%)—Colitis, diarrhea, nausea, and vomiting.

Symptoms of pseudomembranous colitis can appear during or after antibiotic treatment.

Nausea and vomiting have been reported rarely.

Less frequent adverse reactions (less than 1%) are:

Cardiovascular System—Potentially life-threatening arrhythmias following rapid (less than 60 seconds) bolus administration via central venous catheter have been observed.

Hematologic System—Neutropenia, transient leukopenia, eosinophilia, thrombocytopenia and agranulocytosis have been reported. Some individuals have developed positive direct Coombs Tests during treatment with cefotaxime (cefotaxime for injection) and other cephalosporin antibiotics. Rare cases of hemolytic anemia have been reported.

Genitourinary System—Moniliasis, vaginitis.

Central Nervous System—Headache, encephalopathy.

Liver—Transient elevations in SGOT, SGPT, serum LDH, and serum alkaline phosphatase levels have been reported.

Kidney—As with some other cephalosporins, interstitial nephritis and transient elevations of BUN and creatinine have been occasionally observed with cefotaxime (cefotaxime for injection) .

Cutaneous—As with other cephalosporins, isolated cases of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported.

Cephalosporin Class Labeling

In addition to the adverse reactions listed above which have been observed in patients treated with cefotaxime (cefotaxime for injection) sodium, the following adverse reactions and altered laboratory tests have been reported for cephalosporin class antibiotics: allergic reactions, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and false-positive test for urinary glucose.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Read the entire FDA prescribing information for Cefotaxime (Cefotaxime for Injection)