CEFTRIAXONE

CLINICAL PHARMACOLOGY

The bactericidal activity of Ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone has a high degree of stability in the absence of betalactamases, both penicillanases and cephalosporinases of gram -negative and positive bacteria. Ceftriaxone is usually active against the following microorganisms in vitro and in clinical infections.

Gram-Negative Aerobes:

Acinetobacter calcoaceticus, Enterobacter serogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including ampicillin resistant and beta-lactamase producing strains), Haemophilus parainfluenzae. Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis (including beta-lactamase producing strains) Morganella morganii, Neissera gonorrhoeae (including penicillases and nonpenicillinase producing strains), Nesseria meniginditis, Proteus mirabilis, Proteus vulgaris and Serratia marcescens.
Ceftriaxone is also active against many strains of Pseudomonas aeruginosa.

NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics e.g. penicillins, cephalosporins and aminoglycosides are susceptible to Ceftriaxone.

Gram-Positive Aerobes:

Staphylococcus aureus (including penicillase-producing strains), Staphylococcus epidermis, Streptococci and enterococci. e/g, Enterococcus (Streptococcus) faecalis are resistant.
Anaerobes: Bacteriodes fragilis, Clostridium species and Peptostreptococcus species.
NOTE: Most strains of C. Difficile are resistant. Ceftriaxone also demonstrates in vitro activity against most strains of the following microorganisms, although the clinical significance is unknown.

Gram-Negative Aerobes:

Citrobacter diversus, Citrobacter freundii, Providencia species (including S.typhi) and Shigella species.

Gram-Positive Aerobes:

Streptococcus agalactiae. Anaerobes: Bacteriodes bivibus and Bacteriodes melaninogenicus.

PHARMAKONETICS:

Ceftriaxone is administered by injection as the sodium salt. After intramuscular injection, mean plasma concentrations of about 43 and 80mcg/ml have been reported about 2 hours after the equivalent of 0.5 and 1gm of Ceftriaxone respectively. Ceftriaxone demonstrates non-linear, dose dependent pharmacokinetics. This is due to the binding to plasma proteins which varies from 85 to 95% in a dose dependent manner. The elimination half-life of Ceftriaxone is not dependent on the dose and varies between 6 and 9 hours: It is prolonged in neonates.

Ceftriaxone is widely distributed in body tissues and fluids; therapeutic concentrations have been achieved in cerebral spinal fluid when the meninges are inflamed. It diffuses across the placenta and is excreted in breast milk in low concentrations.

About 45 to 95% of a dose of ceftriaxone is excreted unchanged in the urine, principally by glomerular filtration: the remainder is excreted in the bile and is ultimately found in faeces as microbiologically inactive compounds.

THERAPEUTIC INDICATIONS

Ceftriaxone is indicated in the following clinical infections caused by microorganisms susceptible to Ceftriaxone:

  • Lower respiratory tract infections such as bronchitis, pneumonia, bronchopneumonia, empyema, lung abscess etc.
  • Acute bacterial otitis media.
  • Skin and soft tissue infections such as abscesses, cellulitis, pyodermas, wound infections e.t.c.
  • Urinary tract infections (complicated and uncomplicated) such as urethritis, cystitis, pyelitis, pyelonephritis, perinephric abscess.
  • Uncomplicates gonorrhea.
  • Pelvic Inflammatory disease.
  • Bacterial septicaemia
  • Intraabdominal infections
  • Meningitis caused by susceptible organisms
  • Prophylaxis- a single dose of Ceftriaxone injection administered pre-operatively may reduce chance of post-operative surgical infections.

DOSAGE AND ADMINISTRATION:

Ceftriaxone injection may be administered by deep intramuscular injection, slow intravenous infusion after reconstitution.
Adults and children 12 years and over.

  1. Standard therapeutic dosage: 1gm once daily
  2. Severe infections: 2-4 gm daily, normally as a single dose every 24 hour. The duration of therapy varies according to the course of the disease. As with other antibiotic therapy in general, administration of Ceftriaxone should be continued for a minimum of 48 to 72 hours after the patient has become a febrile or evidence of bacterial eradication has been obtained.
  3. Acute uncomplicated gonorrhea: A single dose of 250mg intramuscularly should be administered.
  4. Peri-operative prophylaxis: Usually 1 gm as single intramuscular or by slow intravenous injection or slow intravenous infusion, in conjunction with a suitable agent against anaerobic bacteria.

Use in elderly:

These dosages do not require modification in elderly patients provided that renal and hepatic function are satisfactory.

Children under 12 years:

  • Standard therapeutic dosage: 20-50mg/kg body weight once daily.
  • In severe infections up to 80mg/kg body weight daily may be given.
  • Doses of 50mg/kg or over should be given by slow intravenous infusion over at least 30 minutes.

Renal and hepatic impairment:

In patients with impaired renal function, there is no need to reduce the dosage of Ceftriaxone provided liver function is intact. Only in cases of preterminal renal failure (creatinine clearance < 10ml per minute) should the daily dosage be limited to 2 gm or less.

Preparation of solutions for injection and infusion:

The use of freshly prepared solution is recommended.

  • Intramuscular injection: 250mg Ceftriaxone should be dissolved in 2 ml of 1% lignocaine hydrochloride injection or 1 gm in 3.5ml of 1% Lignocaine Hydrochloride injection. The solution should be administered by deep intramuscular injection. Dosages greater than 1 gm should be divided and injected at more than one site. Solutions in lignocaine should not be administered intravenously.
  • Intravenous injection: 250 mg of Ceftriaxone should be dissolved in 5 ml of water for injection or 1 gm in 10ml of water for injections. The injection should be administered over 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.
  • Intravenous infusion: 2mg of Ceftriaxone should be dissolved in 40ml of one of the following calcium free solutions: Dextrose 5 or 10%, sodium chloride injection, sodium chloride and Dextrose injection (0.45% Sodium Chloride and 2.5% dextrose). The infusion should be administered at least over 30 minutes. Solutions containing Ceftriaxone should not be mixed with or added to solutions containing other agents. In particular, Ceftriaxone is not compatible with calcium-containing solutions such as Hartmann’s solution and Ringer’s solution. Reconstituted solutions are stable for 6 hours at room temperature and 24 hours for 24 hours at 5C.

CONTRAINDICATIONS:

Ceftriaxone is contraindicated in patients with known allergy to cephalosporin group of antibiotics, Ceftriaxone is also contraindicated in premature infants and in full-term infants during the first 6 weeks.

UNDESIRABLE EFFECTS:

Ceftriaxone has been generally well tolerated, with adverse reactions being relatively infrequent, usually mild and transient. The most common side effects are;

  • Gastro-intestinal, consisting mainly of loose stools and diarrhoea or, occasionally, nausea, vomiting, stomatitis and glossitis.
  • Cutaneous reactions including maculopapular rash, pruritus, urticaria, oedema and erythema multiforme have occurred.
  • Hematological reactions have included anaemia (all grades), leucopenia, neutropenia, thrombocytopenia, eosinophilia, agranulocytosis and positive Coomb’s test. Regular blood counts should be carried out during treatment. Ceftriaxone has rarely been associated with elongating prothrombin time.
  • Headache and dizziness
  • Drug fever
  • Transient elevation in liver function tests.
  • Other rarely observed adverse reactions include; glycosuria, oliguria, haematuria, anaphylaxis and bronchospasm.
  • Pain or discomfort may ne experienced at the site of injection immediately after administration but is usually well tolerated and transient.
  • Local phlebitis has occurred rarely following intravenous administration but can be minimized by slow injection over 2-4 minutes.

SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE:

  • Care is required when administering Ceftriaxone to patients who have previously shown hypersensitivity (especially anaphylactic reaction) to penicillins or other non-cephalosporin betalactam antibiotics, as occasional instances of allergenicity between cephalosporins and these antibiotics have been recorded. Anaphylactic shock requires immediate counter measures such as intravenous adrenaline injection followed by corticosteroid therapy.
  • In severe renal impairment accompanied by hepatic insufficiency, dosage reduction is required.
  • Pseudomembranous colitis has been reported with the use of cephalosporin group of antibiotics and other broad spectrum antimicrobial agents. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with use of the antibiotic.
  • Ordinary, dosage adjustment is not required in hepatic failure, but in patients of both hepatic failure and significant renal dysfunction, Ceftriaxone dosage should not exceed 2gm/day without close monitoring.
  • Prolonged use may cause overgrowth of non-susceptible organisms and may cause superinfections
  • Administer with caution to patients with a history of G.I diseases especially colitis.

DRUG INTERACTIONS

  • No impairment of renal function has been observed in man after simultaneous administration of Ceftriaxone and diuretics.
  • no interference with the action or increase in nephrotoxicity of aminoglycosides has been observed during simultaneous administration with Ceftriaxone.
  • The Ceftriaxone molecule does not contain the N methylthio-tetrazole substituent which has a disulfiram like effect when alcohol is taken during therapy with certain cephalosporins.

USE IN PREGNANCY AND LACTATION

Ceftriaxone has not been associated with adverse effects on foetal development in laboratory animals but its safety in human pregnancy has not been established. Therefore, it should not be used in pregnancy unless absolutely indicated.
Low concentration of Ceftriaxone is excreted in human milk, caution should be excised when administered to nursing women.

OVERDOSAGE

In the case of overdosage, drug concentrations would not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote, treatment should be symptomatic.