Claforan (Cefotaxime Sodium) - Description and Clinical Pharmacology

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

DESCRIPTION

Sterile CLAFORAN (cefotaxime sodium) is a semisynthetic, broad spectrum cephalosporin antibiotic for parenteral administration. It is the sodium salt of 7-[2-(2-amino-4-thiazolyl) glyoxylamido]-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate 72 (Z)-(o-methyloxime), acetate (ester). CLAFORAN contains approximately 50.5 mg (2.2 mEq) of sodium per gram of cefotaxime activity. Solutions of CLAFORAN range from very pale yellow to light amber depending on the concentration and the diluent used. The pH of the injectable solutions usually ranges from 5.0 to 7.5. The CAS Registry Number is 64485-93-4.

CLAFORAN is supplied as a dry powder in conventional and ADD-Vantage^® System compatible vials, pharmacy bulk package bottles, and as a frozen, premixed, iso-osmotic injection in a buffered diluent solution in plastic containers. CLAFORAN, equivalent to 1 gram and 2 grams cefotaxime, is supplied as frozen, premixed, iso-osmotic injections in plastic containers. Solutions range from very pale yellow to light amber. Dextrose Hydrous, USP has been added to adjust osmolality (approximately 1.7 g and 700 mg to the 1 g and 2 g cefotaxime dosages, respectively). The injections are buffered with sodium citrate hydrous, USP. The pH is adjusted with hydrochloric acid and may be adjusted with sodium hydroxide.

The plastic container is fabricated from a specially designed multilayer plastic (PL 2040). Solutions are in contact with the polyethylene layer of this container and can leach out certain chemical components of the plastic in very small amounts within the expiration period. The suitability of the plastic has been confirmed in tests in animals according to the USP biological tests for plastic containers, as well as by tissue culture toxicity studies.

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.)

Drug Interactions

A single intravenous dose and oral dose of probenecid (500 mg each) followed by two oral doses of probenecid 500 mg at approximately hourly intervals administered to three healthy male subjects receiving a continuous infusion of cefotaxime increased the steady-state plasma concentration of cefotaxime by approximately 80%. In another study, administration of oral probenecid 500 mg every 6 hours to six healthy male subjects with cefotaxime 1 gram infused over 5 minutes decreased the total clearance of cefotaxime by approximately 50%.

Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered CLAFORAN and ethanol.

Microbiology

Mechanism of Action

Cefotaxime sodium is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefotaxime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram-positive bacteria.

Mechanism of Resistance

Resistance to cefotaxime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Susceptibility to cefotaxime will vary geographically and may change over time; local susceptibility data should be consulted, if available. Cefotaxime has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Gram-positive bacteria

Enterococcus spp. [ Enterococcus species may be intrinsically resistant to cefotaxime.]
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis
Streptococcus pneumoniae
Streptococcus pyogenes (Group A beta-hemolytic streptococci)
Streptococcus spp. (Viridans group streptococci)

Gram-negative bacteria

Acinetobacter spp.
Citrobacter spp. [Most extended spectrum beta-lactamase (ESBL)-producing and carbapenemase-producing isolates are resistant to cefotaxime.]
Enterobacter spp.
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella spp. (including Klebsiella pneumoniae)
Morganella morganii
Neisseria gonorrhoeae (including beta-lactamase-positive and negative strains)
Neisseria meningitidis
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Serratia marcescens

Anaerobic bacteria

Bacteroides spp., including some isolates of Bacteroides fragilis
Clostridium spp. (most isolates of Clostridium difficile are resistant)
Fusobacterium spp. (including Fusobacterium nucleatum)
Peptococcus spp.
Peptostreptococcus spp.

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefotaxime. However, the efficacy of cefotaxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-negative bacteria

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

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar) ^1,2. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method^2,3. This procedure uses paper disks impregnated with 30 mcg cefotaxime to test the susceptibility of microorganisms to cefotaxime. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic techniques

For anaerobic bacteria, the susceptibility to cefotaxime as MICs can be determined by a standardized agar test method^3,4. The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Cefotaxime.

	Minimum Inhibitory Concentrations (mcg/mL)			Disk Diffusion Zone Diameters (mm)
Pathogen	(S) Susceptible	(I) Intermediate	(R) Resistant	(S) Susceptible	(I) Intermediate	(R) Resistant
Susceptibility of staphylococci to cefotaxime may be deduced from testing only penicillin and either cefoxitin or oxacillin.
Acinetobacter spp.	≤8	16–32	≥64	≥23	15–22	≤14
Enterobacteriaceae	≤1	2	≥4	≥26	23–25	≤22
Haemophilus spp. 1   2	≤2	-	-	≥26	-	-
Neisseria gonorrhoeae	≤0.5	-	-	≥31	-	-
Neisseria meningitidis	≤0.12	-	-	≥34	-	-
Streptococcus pneumoniae 3   meningitis isolates	≤0.5	1	≥2	-	-	-
Streptococcus pneumoniae   non-meningitis isolates	≤1	2	≥4	-	-	-
Streptococcus spp.   beta-hemolytic group	≤0.5	-	-	≥24	-	-
Viridans group streptococci	≤1	2	≥4	≥28	26–27	≤25
Other Non-Enterobacteriaceae Other Non-Enterobacteriaceae include Pseudomonas spp. and other nonfastidious, glucose-nonfermenting, gram-negative bacilli, but exclude Pseudomonas aeruginosa, Acinetobacter spp., Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, and Stenotrophomonas maltophilia.	≤8	16–32	≥64	-	-	-
Anaerobic bacteria   (agar method)	≤16	32	≥64	-	-	-

A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infections site necessary to inhibit growth of the pathogen. 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 a 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 antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test^1,2,3,4. Standard cefotaxime powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg disk, the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Cefotaxime

QC Strain	Minimum Inhibitory Concentrations (mcg/mL)	Disk Diffusion Zone Diameters (mm)
Escherichia coli ATCC 25922	0.03–0.12	29–35
Staphylococcus aureus ATCC 29213	1–4	-
Staphylococcus aureus ATCC 25923	-	25–31
Pseudomonas aeruginosa ATCC 27853	8–32	18–22
Haemophilus influenzae ATCC 49247	0.12–0.5	31–39
Streptococcus pneumoniae ATCC 49619	0.03–0.12	31–39
Neisseria gonorrhoeae ATCC 49226	0.015–0.06	38–48
Bacteroides fragilis 1 ATCC 25285	8–32	-
Bacteroides thetaiotaomicron ATCC 29741	16–64	-
Eubacterium lantem ATCC 43055	64–256	-