CEFOTAXIME

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 ß-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*, including ß-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 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 gonorrhoeae (including ß-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 (MIC's) 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 ß-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.

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 method¹ (broth or agar) or equivalent with cefotaxime sodium powder. The MIC values obtained should be interpreted according to the following criteria:

When testing organisms ^a other than Haemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp.
When testing Haemophilus spp.^b
When testing Streptococcus ^d
When testing Neisseria gonorrhoeae ^a
a. Staphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime 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.    
e. Interpretive criteria applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.²

 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:
a. Ranges applicable only to tests performed by broth microdilution method using Haemophilus Test Media.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    
c. Ranges applicable only to tests performed by agar dilution method using GC agar base with 1% defined growth supplement.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 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 30mcg cefotaxime sodium disk should be interpreted according to the following criteria:
  
When testing organisms^a other than Haemophilus spp., Neisseria gonorrhoeae, and Streptococcus spp.
When testing Haemophilus spp.^b
When testing Streptococcus other than Streptococcus pneumoniae
When testing Neisseria gonorrhoeae ^d
a. Staphylococci exhibiting resistance to methicillin/oxacillin, should be reported as also resistant to cefotaxime despite apparent in vitro susceptibility.    
b.Interpretive criteria is applicable only to tests performed by disk diffusion method using Haemophilus Test Media.³    
c.The absence of resistant strains precludes defining any interpretations other than susceptible.    
d.Interpretive criteria applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement.³

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:
a. Ranges applicable only to tests performed by disk diffusion method using Haemophilus Test Media.³
b. Ranges applicable only to tests performed by disk diffusion method using GC agar base with 1% defined growth supplement.³
 
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:
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:
a. Ranges applicable only to tests performed by agar dilution method.

Cefotaxime is indicated for the treatment of patients with serious infections caused by susceptible strains of the designated microorganisms in the diseases listed below.

1. Lower respiratory tract infections, including pneumonia, caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae), Streptococcus pyogenes* (Group A streptococci) and other streptococci (excluding enterococci, e.g., Enterococcus faecalis), Staphylococcus aureus (penicillinase and non-penicillinase producing), Escherichia coli, Klebsiella species, Haemophilus influenzae (including ampicillin resistant strains), Haemophilus parainfluenzae, Proteus mirabilis, Serratia marcescens*, Enterobacter species, indole positive Proteus and Pseudomonas species (including P. aeruginosa).
2. Genitourinary infections. Urinary tract infections caused by Enterococcus species, Staphylococcus epidermidis, Staphylococcus aureus*, (penicillinase and non-penicillinase producing), Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella  species, Proteus mirabilis, Proteus vulgaris*, Providencia stuartii, Morganella morganii*, Providencia rettgeri*, Serratia marcescens and Pseudomonas species (including P. aeruginosa). Also, uncomplicated gonorrhea (cervical/urethral and rectal) caused by Neisseria  gonorrhoeae , including penicillinase producing sjtrains.    
3. Gynecologic infections, including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by Staphylococcus epidermidis, Streptococcus species, Enterococcus species, Enterobacter species*, Klebsiella species*, Escherichia coli, Proteus mirabilis, Bacteroides species (including Bacteroides fragilis*), Clostridium species, and anaerobic cocci (including Peptostreptococcus species and Peptococcus species) and Fusobacterium species (including F. Nucleatum*). Cefotaxime, like other cephalosporins, has no activity against Chlamydia trachomatis.
   Therefore, when cephalosporins are used in the treatment of patients with pelvic inflammatory disease and C. trachomatis is one of the suspected pathogens, appropriate anti-chlamydial coverage should be added.    
4. Bacteremia/Septicemia caused by Escherichia coli, Klebsiella species, and Serratia marcescens, Staphylococcus aureus andStreptococcus species (including S. pneumonia).    
5. Skin and skin structure infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing),Staphylococcus epidermidis, Streptococcus pyogenes (Group A streptococci) and other streptococci, Enterococcus species,         Acinetobacter species*, Escherichia coli, Citrobacter species (including C. freundii*), Enterobacter species, Klebsiella species, Proteus mirabilis, Proteus vulgaris*, Morganella morganii, Providencia rettgeri*, Pseudomonas species, Serratia marcescens, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus species).
6. Intra-abdominal infections including peritonitis caused by Streptococcus species*, Escherichia coli, Klebsiella species, Bacteroides species, and anaerobic cocci (including Peptostreptococcus* species and Peptococcus * species) Proteus mirabilis*, and Clostridium species*.    
7. Bone and/or joint infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing strains), Streptococcus species (including S. pyogenes*), Pseudomonas species (including P. aeruginosa*), and Proteus mirabilis*.    
8. Central nervous system infections, e.g., meningitis and ventriculitis, caused by Neisseria meningitidis, Haemophilus influenzae,    Streptococcus pneumoniae, Klebsiella pneumoniae* and Escherichia coli*.   
   

(*) Efficacy for this organism, in this organ system, has been studied in fewer than 10 infections.
Although many strains of enterococci (e.g., S. faecalis) and Pseudomonas species are resistant to cefotaxime sodium in vitro, Cefotaxime has been used successfully in treating patients with infections caused by susceptible organisms.

Specimens for bacteriologic culture should be obtained prior to therapy in order to isolate and identify causative organisms and to determine their susceptibilities to Cefotaxime. Therapy may be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly.

In certain cases of confirmed or suspected gram-positive or gram-negative sepsis or in patients with other serious infections in which the causative organism has not been identified, Cefotaxime may be used concomitantly with an aminoglycoside. The dosage recommended in the labeling of both antibiotics may be given and depends on the severity of the infection and the patient's condition. Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. It is possible that nephrotoxicity may be potentiated if Cefotaxime is used concomitantly with an aminoglycoside.
(*) Efficacy for this organism, in this organ system, has been studied in fewer than 10 infections.

The administration of Cefotaxime preoperatively reduces the incidence of certain infections in patients undergoing surgical procedures (e.g., abdominal or vaginal hysterectomy, gastrointestinal and genitourinary tract surgery) that may be classified as contaminated or potentially contaminated.
In patients undergoing cesarean section, intraoperative (after clamping the umbilical cord) and postoperative use of Cefotaxime may also reduce the incidence of certain postoperative infections. See DOSAGE AND ADMINISTRATION section.
Effective use for elective surgery depends on the time of administration. To achieve effective tissue levels, Cefotaxime should be given 1/2 or 1 1/2 hours before surgery. See DOSAGE AND ADMINISTRATION section.
For patients undergoing gastrointestinal surgery, preoperative bowel preparation by mechanical cleansing as well as with a non-absorbable antibiotic (e.g., neomycin) is recommended.
If there are signs of infection, specimens for culture should be obtained for identification of the causative organism so that appropriate therapy may be instituted.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefotaxime and other antibacterial drugs, cefotaxime should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Prescribing cefotaxime for injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Cefotaxime should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.
Because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when Cefotaxime is administered to such patients. Continued dosage should be determined by degree of renal impairment, severity of infection, and susceptibility of the causative organism.
Although there is no clinical evidence supporting the necessity of changing the dosage of cefotaxime sodium in patients with even profound renal dysfunction, it is suggested that, until further data are obtained, the dose of cefotaxime sodium be halved in patients with estimated creatinine clearances of less than 20 mL/min/1.73 m².
When only serum creatinine is available, the following formula⁵ (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

                                                                                       Weight (kg) x (140 - age)
                                                                  Males:                                                         72 x serum creatinine
                                                                  Females:                                                      0.85 x above value   

As with other antibiotics, prolonged use of Cefotaxime may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.
As with other beta-lactam antibiotics, granulocytopenia and, more rarely, agranulocytosis may develop during treatment with Cefotaxime, articularly if given over long periods. For courses of treatment lasting longer than 10 days, blood counts should therefore be monitored.
Cefotaxime, like other parenteral anti-infective drugs, may be locally irritating to tissues. In most cases, perivascular extravasation of Cefotaxime responds to changing of the infusion site. In rare instances, extensive perivascular extravasation of Cefotaxime may result in tissue damage and require surgical treatment. To minimize the potential for tissue inflammation, infusion sites should be monitored regularly and changed when appropriate.

Patients should be counseled that antibacterial drugs including cefotaxime for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefotaxime for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefotaxime for injection or other bacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Increased nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics.

Probenecid interferes with the renal tubular transfer of cephalosporins, thereby delaying their excretion and increasing their plasma concentrations.

As with other cephalosporins, cefotaxime may potentiate the renal toxicity of nephrotoxic drugs. See INDICATIONS AND USAGE section.

Cephalosporins, including cefotaxime sodium, are known to occasionally induce a positive direct Coombs' test.

Urinary glucose testing with non-specific reducing agents may yield a false-positive reaction in patients treated with cefotaxime. This phenomenon is not seen when a glucose-oxidase specific method is used.

Lifetime studies in animals to evaluate carcinogenic potential have not been conducted. Cefotaxime was not mutagenic in the mouse micronucleus test or in the Ames' test. Cefotaxime did not impair fertility to rats when administered subcutaneously at doses up to 250 mg/kg/day (0.2 times the maximum recommended human dose based on mg/m²) or in mice when administered intravenously at doses up to 2000 mg/kg/day (0.7 times the recommended human dose based on mg/m²).

Reproduction studies have been performed in pregnant mice given cefotaxime intravenously at doses up to 1200 mg/kg/day (0.4 times the recommended human dose based on mg/m²) or in pregnant rats when administered intravenously at doses up to 1200 mg/kg/day (0.8 times the recommended human dose based on mg/m²). No evidence of embryotoxicity or teratogenicity was seen in these studies. Although cefotaxime has been reported to cross the placental barrier and appear in cord blood, the effect on the human fetus is not known. There are no well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Use of the drug in women of child-bearing potential requires that the anticipated benefit be weighed against the possible risks.
In perinatal and postnatal studies with rats, the pups in the group given 1200 mg/kg/day of Cefotaxime were significantly lighter in weight at birth and remained smaller than pups in the control group during the 21 days of nursing.

Cefotaxime is excreted in human milk in low concentrations. Caution should be exercised when Cefotaxime is administered to a nursing woman.

See Precautions above regarding perivascular extravasation.

Of the 1409 subjects in clinical studies of cefotaxime, 632 (45%) were 65 and over, while 258 (18%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, General).

Dosage and route of administration should be determined by susceptibility of the causative organisms, severity of the infection, and the condition of the patient (see table for dosage guideline). Cefotaxime for injection may be administered IM or IV after reconstitution. The maximum daily dosage should not exceed 12 grams.

GUIDELINES FOR DOSAGE OF CEFOTAXIME FOR INJECTION    If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefotaxime sodium has no activity against this organism.

To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended dose is a single 1 gram IM or IV administered 30 to 90 minutes prior to start of surgery.

The first dose of 1 gram is administered intravenously as soon as the umbilical cord is clamped. The second and third doses should be given as 1 gram intravenously or intramuscularly at 6 and 12 hours after the first dose.

The following dosage schedule is recommended:

Neonates (birth to 1 month):    
0-1 week of age                        50 mg/kg per dose every 12 hours IV    
1-4 weeks of age                      50 mg/kg per dose every 8 hours IV   

It is not necessary to differentiate between premature and normal-gestational age infants.

Infants and Children (1 month to 12 years):    

For body weights less than 50 kg, the recommended daily dose is 50 to 180 mg/kg IM or IV body weight divided into four to six equal doses. The higher dosages should be used for more severe or serious infections, including meningitis. For body weights 50 kg or more, the usual adult dosage should be used; the maximum daily dosage should not exceed 12 grams.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See PRECAUTIONS, General and PRECAUTIONS, Geriatric Use.)

see PRECAUTIONS, General.

NOTE: As with antibiotic therapy in general, administration of Cefotaxime for injection should be continued for a minimum of 48 to 72 hours after the patient defervesces or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended for infections caused by Group A beta-hemolytic streptococci in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment of several weeks and doses smaller than those indicated above should not be used.

Cefotaxime for injection for IM or IV administration should be reconstituted as follows:

Shake to dissolve; inspect for particulate matter and discoloration prior to use. Solutions of Cefotaxime for injection range from very pale yellow to light amber, depending on concentration, diluent used, and length and condition of storage.

For intramuscular use: Reconstitute VIALS with Sterile Water for Injection or Bacteriostatic Water for Injection as described above.

For intravenous use: Reconstitute VIALS with at least 10 mL of Sterile Water for Injection.

NOTE: Solutions of Cefotaxime for injection must not be admixed with aminoglycoside solutions. If Cefotaxime for injection and aminoglycosides are to be administered to the same patient, they must be administered separately and not as mixed injection.
A SOLUTION OF 1 G CEFOTAXIME FOR INJECTION IN 14 ML OF STERILE WATER FOR INJECTION IS ISOTONIC.

IM Administration: As with all IM preparations, Cefotaxime for injection should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel. Individual IM doses of 2 grams may be given if the dose is divided and is administered in different intramuscular sites.

IV Administration: The IV route is preferable for patients with bacteremia, bacterial septicemia, peritonitis, meningitis, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

For intermittent IV administration, a solution containing 1 gram or 2 grams in 10 mL of Sterile Water for Injection can be injected over a period of three to five minutes. Cefotaxime should not be administered over a period of less than three minutes. (See WARNINGS). With an infusion system, it may also be given over a longer period of time through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing Cefotaxime for injection, it is advisable to discontinue temporarily the administration of other solutions at the same site.

For the administration of higher doses by continuous IV infusion, a solution cefotaxime may be added to IV bottles containing the solutions discussed below.

Solutions of Cefotaxime for injection reconstituted as described above (Preparation of Cefotaxime for injection) remain chemically stable (potency remains above 90%) as follows when stored in original containers and disposable plastic syringes:
Reconstituted solutions stored in original containers and plastic syringes remain stable for 13 weeks frozen.

Reconstituted solutions may be further diluted up to 1000 mL with the following solutions and maintain satisfactory potency for 24 hours at or below 22⁰C, and at least 5 days under refrigeration (at or below 5⁰C): 0.9% Sodium Chloride Injection; 5 or 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.2% Sodium Chloride Injection; Lactated Ringer's Solution; Sodium Lactate Injection (M/6); 10% Invert Sugar Injection, 8.5% TRAVASOL^® (Amino Acid) Injection without Electrolytes.

NOTE: Cefotaxime for injection solutions exhibit maximum stability in the pH 5-7 range. Solutions of Cefotaxime for injection should not be prepared with diluents having a pH above 7.5, such as Sodium Bicarbonate Injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.