Cefotax

Cefotaxime sodium.

Each vial contains: Cefotaxime (as Sodium), USP 250 mg, 500 mg, or 1 g.
An off-white, pale yellowish powder 1.05 of monograph substance is approximately equivalent to 1 g of Cefotaxime. Freely soluble in water, particularly insoluble in organic solvents. Cefotaxime is a third generation cephalosporins antibiotic with an extended spectrum of activity and increased potency against Gram-negative bacteria including Enterobacteriaceae, Haemophilus influenza, Moraxella (Branhamella) catarrhalis, and Neisseria spp. But only moderate activity against Pseudomonas spp. Its active metabolite desacetylcefotaxime is given by injection as the sodium salt. Adverse effects are similar to those for all cephalosporins, including hypersensitivity reactions. There is some risk of colonization and superinfection with resistant organisms.

Pharmacology: Pharmacodynamics: Antibacterial action: Cefotaxime is primarily bactericidal; it also may be bacteriostatic. Activity depends on the organism, tissue penetration, dosage, and rate of organism multiplication. It acts by adhering to bacterial penicillin-binding proteins, thereby inhibiting cell walls synthesis. Third-generation cephalosporins appear to be more active against some beta-lactamase-producing gram-negative organisms. Cefotaxime is active against some gram-positive organisms and many enteric gram-negative bacilli, including streptococci (Streptococcus pneumoniae and S. pyogenes), Staphylococcus aureus (penicillinase-and non-penicillinase-producing), Staphylococcus epidermidis, Escherichia coli, Klebsiella species, Haemophilus influenzae, Enterobacter species, Proteus species, Peptostreptococcus species, and some strains of Pseudomonas aeruginosa. Listeria and Acinetobacter are often resistant. The active metabolite of cefotaxime, desacetylcefotaxime may act synergistically with the parent drug against some bacterial strains.
Pharmacokinetics: Cefotaxime is administered by injection as the sodium salt. It is rapidly absorbed after intramuscular injection and mean peak plasma concentration of about 12 and 20 μg per mL have been reported 30 minutes after doses of 0.5 and 1 g of cefotaxime, respectively. Immediately after intravenous injection of 0.5, 1 or 2 g of cefotaxime, mean peak plasma concentration of 38, 102, and 215 μg per mL, respectively, have been achieved with concentrations ranging from about 1 to 3 μg per mL after 4 hours. The plasma half-life of cefotaxime is about 1 hour and that of that active metabolite desacetylcefotaxime is about 1.5 hours; half-lives are increased in neonates and in patients with severe renal impairment, especially those of the metabolite, and a reduction in dosage may be necessary. The effects of liver disease on clearance of cefotaxime and its metabolite have been variable, but in general dosage adjustment has not been considered necessary. About 40% of cefotaxime in the circulation is reported to be bound to plasma proteins. Cefotaxime and desacetylcefotaxime are widely distributed in body tissues and fluids; therapeutic concentrations are achieved in the CSF particularly when the meninges are inflamed. It crosses the placenta and low concentrations have been detected in breast milk.
Following partial metabolism in the liver to desacetylcefotaxime and inactive metabolites, elimination is mainly by the kidneys and about 40 to 60% of a dose has been recovered unchanged in the urine within 24 hours; a further 20% is excreted as the desacetyl metabolite. Relatively high concentrations of cefotaxime and desacetylcefotaxime are achieved in bile and about 20% of a dose has been recovered in the faeces.
Probenecid competes for renal tubular secretions with cefotaxime resulting in higher and prolonged plasma concentrations of cefotaxime and its desacetyl metabolite. Cefotaxime and its metabolite are removed by haemodialysis.

Lower respiratory tract infections: Including pneumonia caused by Streptococcus pneumoniae, S. pyogenes (group A streptococci) and other streptococci (excluding enterococci [e.g. S. faecalis]), Staphylococcus aureus (penicillinase/non-penicillinase-producing), Escherichia coli, Klebsiella sp., Haemophilus influenza (including ampicillin-resistant strains), H. parainfluenzae, Proteus mirabilis, Serratia marcescens and Enterobacter sp., indole-positive Proteus and Pseudomonas sp.
Urinary tract infections: Caused by Enterococcus sp., S. epidermidis, S. aureus (penicillinase/non-penicillinase-producing), Citrobacter sp., Enterobacter species, E. coli, Klebsiella sp., P. mirabilis, P. vulgaris, P. inconstans group B, Morganella morganii, Providencia rettgeri, S. marcescens and Pseudomonas sp. Also, uncomplicated gonorrhea caused by Neisseria gonorrhea, including penicillinase-producing strains.
Gynecological infection: Including pelvic inflammatory disease, endometritis and pelvic cellulitis caused by S. epidermidis, streptococci, enterococcus, Enterobacter sp., Klebsiella sp., E. coli, P. mirabilis, Bacteroides species (including B. fragilis), Clostridium sp., anaerobic cocci (including Peptostreptococcus, Peptostreptococcus) and Fusobacterium sp. (including F. nucleatum).
Bacteremia/Septicemia: Caused by E. coli, Klebsiella sp., S. marcescens, S. aureus and streptococci.
Skin and skin structure infections: Caused by S. aureus (penicillinase/non-penicillinase-producing), S. epidermidis, S. pyogenes (group A streptococci) and other streptococci, enterococcus, Acinetobacter sp., Citrobacter sp., E. coli, Enterobacter, Klebsiella sp., P. mirabilis, M. morganii, P. rettgeri, P. vulgaris, Pseudomonas sp., S. marcescens, Bacteroides sp. and anaerobic cocci (including Peptostreptococcus, Peptococcus).
Intra-abdominal infections: Including peritonitis caused by streptococci, E. coli, Klebsiella spp., Bacteroides sp. and anaerobic cocci, including Peptostreptococcus and Peptococcus sp., P. mirabilis and Clostridium sp.
Bone or joint infection: Caused by S. aureus (penicillinase/non-penicillinase-producing), streptococci, Pseudomonas sp. and P. mirabilis.
CNS infections (e.g. Meningitis and ventriculitis): Caused by N. meningitis, H. influenzae, S. pneumoniae, K. pneumoniae, and E. coli.
Perioperative prophylaxis: This may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures (e.g, abdominal or vaginal hysterectomy, GI and GU surgery) that are classified as contaminated or potentially contaminated. Effective perioperative use depends on the time of administration. For patients undergoing GI surgery, preoperative bowel preparation by mechanical cleansing, as well as with nonabsorbable antibiotic (e.g, neomycin), is recommended.

It is given as the sodium salt by deep intramuscular injection or intravenously by slow injection over 3 to 5 minutes or by infusion over 20 to 60 minutes. Doses are expressed in terms of the equivalent amount of cefotaxime; 1.05 g of cefotaxime is equivalent to about 1 g of cefotaxime. It is usually given in doses of 2 to 6 g daily in to 2 to 4 divided doses to adults. In severe infections up to 12 g may be given daily by intravenous route in up to 6 divided doses; pseudomonal infections usually require more than 6g daily, but a cephalosporin with greater antipseudomonal activity, such as ceftazidime, is preferrable. Children may be given 100 to 150 mg/kg body weight (50 mg/kg for neonates) daily in 2 to 4 divided doses, increased in severe infections to 200 mg/kg (150 to 200 mg/kg for neonates) daily if necessary.
Administration in renal impairment: Doses of Cefotaxime should be reduced in severe renal impairment; after an initial loading dose of 1 g, halving the dose while maintaining the usual frequency of dosing has been suggested.
In the treatment of gonorrhea, a single dose of 0.5 or 1 g of cefotaxime is given.
For surgical infection prophylaxis, 1 g is given 30 to 90 minutes before surgery. At caesarian section, 1 g is given intravenously to the mother as soon as the umbilical cord is clamped and two further doses intramuscularly or intravenously 6 and 12 hours later.

The acute toxicity of Cefotaxime 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 decrease in spontaneous activity, tonic and clonic convulsions, dyspnea, hypothermia, and cyanosis. Cefotaxime sodium overdosage has occurred in patients. Most cases have shown no over 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.

Contraindicated to patients who have history of allergy or hypersensitivity to cephalosporins.

Use with caution in penicillin allergic patients.
Avoid alcohol or alcohol containing medications in patients receiving cefoperazone, cefamandole, moxalactam because of their disulfiram-like effect.

Reproduction studies have been performed in pregnant mice given Cefotaxime intravenously at does 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 does 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. There are not 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.
Cefotaxime is excreted in human milk in low concentrations. Caution should be exercised when Cefotaxime is administered to a nursing woman.

The adverse effects associated with cephalosporins are broadly similar to those described for penicillins. The most common are hypersensitivity reactions, including skin rashes, urticaria, eosinophilia, fever, reactions resembling serum sickness and anaphylaxis.
There may be positive response to the Coomb's test although hemolytic anemia rarely occurs. Neutropenia and thrombocytopenia have occasionally been reported. Agranulocytosis has been associated rarely with some cephalosporins. Bleeding complications related to hypothrombinaemia and/or platelet dysfunction have occurred especially with cephalosporins and cephamycins having an N-methylthiotetrazole side chain, including cefamandole, cefbuperazone, cefmenoxime, cefmetazole, cefonicid, cefoperazone, ceforanide, cefotetan, cefpiramide and latamoxef. The presence of methylthiadiazolethiol side-chain, as in cefazolin, or an N-methylthiotraizine ring, as in ceftriaxone, might also be associated with such bleeding disorders.
Transient increase in liver enzyme values has been reported. Hepatitis and cholestatic jaundice have occurred rarely with some cephalosporins.
Convulsions and other signs of CNS toxicity have been associated with high doses, especially in patients with severe renal impairment.
Gastrointestinal adverse effects such as nausea, vomiting and diarrhea have been reported rarely. Prolonged use may result in overgrowth of non-susceptible organisms and, as with other broad-spectrum antibiotics, pseudomembranous colitis may develop.
There may be pain at the injection site following intramuscular use, and thrombophlebitis has occurred on intravenous infusion of cephalosporins.

Increased nephrotoxicity with Probenecid, ethacrynic acid, furosemide, gentamicin and Vancomycin.
Disulfiram-like reaction with alcohol ingestion with cephalosporins with methyltetrazole-thiol (MT) side chain, eg. Cefamandole, cefoperazone, moxalactam and cefotetan.
High dose heparin, oral anticoagulants and other drugs that affect hemostasis. May increase the risk of hemorrhage with cephalosporins with MTT side chains.

Direction for Reconstitution: For Intermittent IV Injection: For direct intermittent IV administration, 10 mL of sterile water for injection should be added to a vial containing 500 mg and 1g of cefotaxime to provide a solution containing approximately 50 mg and 95 mg of cefotaxime per mL, respectively. A solution of 1 g of cefotaxime per 14 mL of sterile water for injection is isotonic. The appropriate dose may then be injected directly into a vein over a 3 to 5 minutes period or slowly into the tubing of a freely flowing compatible IV solution. Cefotaxime should not be injected IV over less than 3 minutes since rapid (over less than 1 minute) injection was consistently associated with potentially life-threatening arrhythmias during post marketing surveillance.
Prepared solution must be used immediately.
Discard any unused portion after reconstitution.
Intermittent or Continuous IV infusion: For intermittent or continuous IV infusion, 50 or 100 mL of 0.9% sodium chloride injection or 5% dextrose injection should be added to an infusion bottle labeled as containing 1 or 2 g of cefotaxime or, alternatively, reconstituted solutions of cefotaxime may be further diluted with 50 mL to 1 L of a compatible IV solution. Intermittent IV infusions of Cefotaxime are generally infused over 20-30 minutes; solutions should preferably be infused via butterfly or scalp vein-type needles. Other IV solutions flowing through a common administration tubing or site should be discontinued while cefotaxime is being infused unless the solutions are known to be compatible and the flow-rate is adequately controlled.
IM Injection: IM injections of cefotaxime are prepared by adding 2 mL and 3 mL of sterile water for injection to a vial labeled as containing 500 mg and 1 g of the drug. Resultant solutions contain approximately 230 mg and 300 mg of cefotaxime per mL, respectively. IM injections should be made deeply into a large muscle mass such as the upper outer quadrant of the gluteus maximus; aspiration should be performed to avoid inadvertent injection into a blood vessel.
Prepared solution must be used immediately.
Discard any unused portion after reconstitution.

Store at temperature not exceeding 30°C.

Cephalosporins

J01DD01 - cefotaxime ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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