Microbiology

The bactericidal activity of cefotaxime sodium results from inhibition of cell wall synthesis. Cefotaxime has in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime has a high degree of stability in the presence of β-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. Cefotaxime 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.

Susceptibility Tests

Treatment

Cefotaxime for Injection, USP 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 pyogenes1 (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 marcescens1, Enterobacter species, indole positive Proteus and Pseudomonas species (including P. aeruginosa).

(2) Genitourinary infections. Urinary tract infections caused by Enterococcus species, Staphylococcus epidermidis, Staphylococcus aureus1, (penicillinase and non-penicillinase producing), Citrobacter species, Enterobacter species, Escherichia coli, Klebsiella species, Proteus mirabilis, Proteus vulgaris1, Providencia stuartii, Morganella morganii1, Providencia rettgeri1, Serratia marcescens and Pseudomonas species (including P. aeruginosa). Also, uncomplicated gonorrhea (cervical/urethral and rectal) caused by Neisseria gonorrhoeae, including penicillinase producing strains.

(3) Gynecologic infections, including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by Staphylococcus epidermidis, Streptococcus species, Enterococcus species, Enterobacter species1, Klebsiella species1, Escherichia coli, Proteus mirabilis, Bacteroides species (including Bacteroides fragilis1), Clostridium species, and anaerobic cocci (including Peptostreptococcus species and Peptococcus species) and Fusobacterium species (including F. nucleatum1).
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 and Streptococcus species (including S. pneumoniae).

(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 species1, Escherichia coli, Citrobacter species (including C. freundii1), Enterobacter species, Klebsiella species, Proteus mirabilis, Proteus vulgaris1, Morganella morganii, Providencia rettgeri1, Pseudomonas species, Serratia marcescens, Bacteroides species, and anaerobic cocci (including Peptostreptococcus1 species and Peptococcus species).

(6) Intra-abdominal infections including peritonitis caused by Streptococcus species1, Escherichia coli, Klebsiella species, Bacteroides species, and anaerobic cocci (including Peptostreptococcus1 species and Peptococcus1 species) Proteus mirabilis1, and Clostridium species1.

(7) Bone and/or joint infections caused by Staphylococcus aureus (penicillinase and non-penicillinase producing strains), Streptococcus species (including S. pyogenes1), Pseudomonas species (including P. aeruginosa1), and Proteus mirabilis1.

(8) Central nervous system infections, e.g., meningitis and ventriculitis, caused by Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Klebsiella pneumoniae1 and Escherichia coli1.

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.

1

Efficacy for this organism, in this organ system, has been studied in fewer than 10 infections.

Prevention

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 for Injection, USP and other antibacterial drugs, Cefotaxime for Injection, USP 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.

General

Prescribing Cefotaxime for Injection, USP 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 for Injection, USP 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) × (140 - age)
   Males:              72 × serum creatinine
   Females:           0.85 × 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, particularly 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.

Information for patients

Patients should be counseled that antibacterial drugs including Ceotaxime for Injection, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Cefotaxime for Injection, USP 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, USP or other antibacterial drugs in the future.

Drug Interactions

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

Drug/Laboratory Test Interactions

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

Carcinogenesis, Mutagenesis

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).

Pregnancy

Nursing Mothers

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

Pediatric Use

See Precautions above regarding perivascular extravasation. 

Geriatric Use

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).

Cephalosporin Class Labeling

In addition to the adverse reactions listed above which have been observed in patients treated with cefotaxime 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.

Adults

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, USP may be administered IM or IV after reconstitution. The maximum daily dosage should not exceed 12 grams.

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.

Cesarean Section Patients

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.

Neonates, Infants, and Children

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.

Geriatric Use

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.)

Impaired Renal Function

see PRECAUTIONS, General.

NOTE: As with antibiotic therapy in general, administration of cefotaxime 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.

Preparation of CEFOTAXIME FOR INJECTION (Sterile)

Cefotaxime for Injection, USP for IM or IV administration should be reconstituted as follows:

Strength                       Diluent (mL)      Withdrawable Volume (mL)      Approximate
                                                                                                             Concentration (mg/mL)

500 mg Vial* (IM)                 2                              2.2                                           230
1 g vial* (IM)                        3                              3.4                                           300
2 g vial* (IM)                        5                              6.0                                           330
500 mg vial* (IV)                10                           10.2                                             50
1 g vial* (IV)                       10                           10.4                                             95
2 g vial* (IV)                       10                           11                                               180
1 g infusion                        50-100                    50-100                                      20-10
2 g infusion                        50-100                    50-100                                      40-20

(*) in conventional vials

Shake to dissolve; inspect for particulate matter and discoloration prior to use. Solutions of Cefotaxime for Injection, USP 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. Reconstitute INFUSION BOTTLES with 50 or 100 mL of 0.9% Sodium Chloride Injection or 5 % Dextrose injection. For other diluents, see COMPATIBILITY AND STABILITY section.

NOTE: Solutions of cefotaxime must not be admixed with aminoglycoside solutions. If cefotaxime and aminoglycosides are to be administered to the same patient, they must be administered separately and not as mixed injection.

A SOLUTION OF 1G CEFOTAXIME FOR INJECTION IN 14 ML OF STERILE WATER FOR INJECTION IS ISOTONIC.

Compatibility and Stability

Solutions of cefotaxime 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:

Strength                 Reconstituted              Stability at or         Stability under Refrigeration
                          Concentration mg/mL       below 22°C                    (at or below 5°C)
                                                                                                 Original Containers    Plastic Syringes
500 mg vial IM                  230                          12 hours                      7 days                    5 days
1 g vial IM                         300                          12 hours                      7 days                    5 days
2 g vial IM                         330                          12 hours                      7 days                    5 days
500 mg vial IV                    50                           24 hours                      7 days                   5 days
1 g vial IV                           95                           24 hours                      7 days                   5 days
2 g vial IV                         180                           12 hours                      7 days                   5 days
1 g infusion bottle           10-20                         24 hours                     10 days                      --
2 g infusion bottle           20-40                         24 hours                     10 days                      --

Reconstituted solutions may be further diluted up to 1000 mL with the following solutions and maintain satisfactory potency for 24 hours at or below 22°C, and at least 5 days under refrigeration (at or below 5°C): 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 solutions exhibit maximum stability in the pH 5–7 range. Solutions of cefotaxime 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.