"The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.
Aspergillosis is a f"...
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.)
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.
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:
Staphylococcus aureus ( methicillin-susceptible isolates only)
Streptococcus pyogenes (Group A beta-hemolytic streptococci)
Streptococcus spp. (Viridans group streptococci)
Citrobacter spp. b
Enterobacter spp. b
Klebsiella spp. (including Klebsiella pneumoniae) b
Neisseria gonorrhoeae (including beta-lactamase-positive and negative strains)
aEnterococcus species may be intrinsically
resistant to cefotaxime.
bMost extended spectrum beta-lactamase (ESBL)-producing and carbapenemase-producing isolates are resistant to cefotaxime.
Bacteroides spp., including some isolates of Bacteroides
Clostridium spp. (most isolates of Clostridium difficile are resistant)
Fusobacterium spp. (including Fusobacterium nucleatum).
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.
Salmonella spp. (including Salmonella typhi)
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.
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.
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 method2,3. 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.
For anaerobic bacteria, the susceptibility to cefotaxime as MICs can be determined by a standardized agar test method3,4. The MIC values obtained should be interpreted according to the criteria provided in Table 1.
Table 1: Susceptibility Test Interpretive Criteria for
|Pathogen||Minimum Inhibitory Concentrations (mcg/mL)||Disk Diffusion Zone Diameters (mm)|
|(S) Susceptible||(I) Intermediate||(R) Resistant||(S) Susceptible||(I) Intermediate||(R) Resistant|
|Acinetobacter spp.||≤ 8||16-32||≥ 64||≥ 23||15-22||≤ 14|
|Enterobacteriaceae||≤ 1||2||≥ 4||≥ 26||23-25||≤ 22|
|Haemophilus spp. *a||≤ 2||-||-||≥ 26||-||-|
|Neisseria gonorrhoeae*||≤ 0.5||-||-||≥ 31||-||-|
|Neisseria meningitidis*||≤ 0.12||-||-||≥ 34||-||-|
|Streptococcus pneumoniae† 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‡||≤ 8||16-32||≥ 64||-||-||-|
|Anaerobic bacteria (agar method)||≤ 16||32||≥ 64||-||-||-|
|Susceptibility of staphylococci
to cefotaxime may be deduced from testing only penicillin and either cefoxitin
aHaemophilus spp includes only isolates of H. influenzae and H. parainfluenzae.
*The current absence of data on resistant isolates precludes defining any category other than “Susceptible”. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing.
†Disc diffusion interpretive criteria for cefotaxime discs against Streptococcus pneumoniae are not available, however, isolates of pneumococci with oxacillin zone diameters of > 20 mm are susceptible (MIC ≤ 0.06 mcg/mL) to penicillin and can be considered susceptible to cefotaxime. S. pneumoniae isolates should not be reported as penicillin (cefotaxime) resistant or intermediate based solely on an oxacillin zone diameter of ≤ 19 mm. The cefotaxime MIC should be determined for those isolates with oxacillin zone diameters ≤ 19 mm.
‡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.
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 infection 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.
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 test1,2,3,4. 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*Using the
Reference Agar Dilution procedure.
|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* ATCC 25285||8-32||-|
|Bacteroides thetaiotaomicron* ATCC 29741||16-64||-|
|Eubacterium lantem* ATCC 43055||64-256||-|
1 Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobials Susceptibility Tests; Twenty-Third Informational Supplement. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -Eleventh Edition. CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard -Eight Edition. CLSI document M11-A8, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.
Last reviewed on RxList: 3/10/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Claforan Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.