Description of Ceftriaxone
Ceftriaxone is a third generation cephalosporin antibiotic used in the treatment of wide ranges of bacterial infections. It has a broad spectrum of activity especially against gram negative bacteria and has relatively long half-life. This allows for its convenient once or twice daily dosing. Ceftriaxone is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, and cephalosporinases and extended-spectrum beta-lactamases. However, resistance to ceftriaxone usually occurs through beta-lactamase hydrolysis, altered PBPs, or reduced bacterial cell permeability. Addition of β-lactamase inhibitors such as Sulbactam and tazobactam to ceftriaxone increases its bactericidal properties and reduces the probability of resistance development to it.
Mode of action of Ceftriaxone
How does ceftriaxone work?
Ceftriaxone has bactericidal activity resulting from the inhibition of bacterial cell wall synthesis ultimately leading to cell death. Ceftriaxone is stable to a broad range of bacterial B-lactamases.
Mechanism of resistance of Ceftriaxone
Ceftriaxone is stable to a wide range of both Gram-positive and Gram-negative beta-lactamases, including those which are able to hydrolyse advanced generation penicillin derivatives and other cephalosporins. Resistance to ceftriaxone is encoded mainly by the production of some beta-lactam hydrolysing enzymes (including carbapenemases and some ESBLS) especially in Gram-negative organisms. For Gram-positive organisms such as S. aureus and S. pneumoniae, acquired resistance is mainly encoded by cell wall target site alterations. Outside of the advanced generation parenteral cephalosporins cross-resistance to other drug classes is generally not encountered.
Pharmacodynamic Properties of Ceftriaxone
Ceftriaxone Injection has a broad spectrum activity in vitro which includes Gram-positive and Gram-negative aerobic and some anaerobic bacteria. The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. It has a high degree d stability in the presence of beta-lactamases, both penicilinases and cephalosporinases of Gram-negative and Gram positive bacteria.
Ceftriaxone has been shown to be acive aganst most strains of the following microorganisms, both in viro and in clinical infections
Aerobic Gram-negative microorganisms:
- Acinetobacter calcoaceticus
- Enterobacter aerogenes
- Enterobacter cloacae
- Escherichia coli
- Haemophilus influenzae (including ampicillin-resistant and beta-lactamase producing strains)
- Haemophilus parainfluenzae
- Klebsiella oxytoca
- Klebsiella pneumoniae
- Moraxella catarrhalis (indluding beta-lactamase producing strains)
- Morganella morgari
- Neisseria gonorrhoeae (including penicillinase and nonpenicillinase producing strains)
- Neisseria meningitidis
- Proteus mirabilis
- Proteus vulgaris
- Serratia marcescens,
- Many strains of Pseudomonas aeruginosa
Aerobic Gram-positive microorganisms:
- Staphylococcus aureus (including penicillinase producing strains),
- Staphylococcus epidermidis
- Streptococcus pneumoniae
- Streptococcus pyogenes
- Viridans group streptococci
- Bacteroides fragilis
- Clostridium species
- Peptostreptococcus species.
Pharmacokinetic Properties of Ceftriaxone
The pharmacokinetics of ceftriaxone are largely determined by its concentration-dependent binding to plasma albumin. The plasma free (unbound) fraction of the drug in man is approximately 5% over most of the therapeutic concentration range, increasing to 15% at concentrations of 300 mg/. Owing to the lower albumin content, the proportion of free ceftriaxone in interstitial fluid is correspondingly higher than in plasma. Bioavailability after intramuscular injection is 100%.
Ceftriaxone is eliminated mainly as unchanged drug, approximately 60% of the dose being excreted in the urine (almost exclusively by glomerular filtration) and the remainder via the biliary and intestinal tracts. The total plasma clearance is 10-22 ml/min. The renal clearance is 5-12 ml/min.
Ceftriaxone crosses non-inflamed and inflamed meninges, attaining concentrations 4-17% of the simultaneous plasma concentration
Indications and Uses of Ceftriaxone
Ceftriaxone sodium is a broad-spectrum bactericidal cephalosporin antibiotic. Ceftriaxone is active in vitro against a wide range of Gram-positive and Gram-negative organisms, which include B-lactamase producing strains. Ceftriaxone is indicated in the treatment of the following infections either before the infecting organism has been identified or when known to be caused by bacteria of established sensitivity
- Skin and soft tissue Infections
- Infections in neutropenic patients
- Peri-operative prophylaxis of infections associated with surgery
Ceftriaxone may be administered by deep intramuscular injection, or as a slow intravenous injection
Dosage and Method of Adminstration of Ceftriaxone
The dosage and mode of administration should be delermined by the severity of the infection, susceptibility of the causative organism and the patient’s condition.
Adults and children 12 years and over
- Standard therapeutic dosage. 1g once daily.
- Severe infections: 2 to 4 g daily, normally as a once daily dose.
- Per-operative prophylaxis: Usually one dose of 1 g given in slow intravenous injection.
Children under 12 years:
Standard therapeutic dosage:
20-50 mg/kg body weight once daily.
Up to 80 mg kg body weight daily may be given in severe infections, and also for children with body weights of 50 kg or more
Premature Neonates daily dose is 50 mg/kg, which should not be exceeded.
For any age – whether adults, children or neonates, the dosage and mode of Ceftriaxone administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient’s condition.
Reconstitution of Ceftriaxone Injection
For Intravenous injection
1g ceftriaxone should be dissolved in 9.6 ml of Sterile Water for injection USP. The injection should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion.
For Intramuscular injection
1g ceftriaxone should be dissolved in 3.5ml of 1% Lidocaine Injection. The solution should be administered by deep Intramuscular injection. Doses greater than 1g should be divided and injected at more than one site.
Diluents containing calcium, (eg Ringer’s solution Hartmann’s solution), should not be used to reconstitute ceftriaxone víals or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Therefore, ceftriaxone and calcium-containing solutions must not be mixed or administered simultaneously.
Ceftriaxone should not be mixed in the same syringe with any drug other than 1% Lidocaine Injection BP (for intramuscular injection only). The reconstituted solution should be clear. Do not use if particles are present. Ceftriaxone sodium when dissolved in Water for Injections Ph Eur forms a pale yellow to amber solution. Variations in the intensity of colour of the freshly prepared solutions do not indicate a change in potency or safety
For single use only. Discard any unused contents.
Contraindications of Ceftriaxone
Ceftriaxone is contraindicated in patients with known hypersensitivity to beta-lactam antibiotics. In patients hypersensitive to penicillin, the possibility of allergic cross-reactions should be borne in mind. Hyper-bilirubinaemic newboms and preterm newborns should not be treated with ceftriaxone. In vitro studies have shown that ceftriaxone can displace bilirubin from its binding to serum albumin and bilirubin encephalopathy can possibly develop in these patients.
Ceftriaxone is contraindicated in:
- Premature newborns up to a corrected age of 41 weeks (weeks of gestation + weeks of life).
- Full-term newborns (up to 28 days of age) with jaundice, or who are hypo-albuminaemic or acidotic because these are conditions in which bilirubin binding is likely to be impaired, if they require (or are expected to require) IV calcium treatment, or calcium-containing infusions because of the risk of precipitation of ceftriaxone-calcium.
Warnings and Precautions
This product should be given cautiously to penicilin sensitive patients. Antibiotics should be given cautiously to patients with any kind of allergy particularly to drugs. Serious hypersensitivity reactions may require use of subcutaneous epinephrine and other emergency measures.
Pseudomembranous colitis has been reported with use of cephalosporins and other broad spectrum antibiotics. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with antibiotic use
Ceftriaxone Injection doses should not exceed 2g/day without dose serum monitoring. Rarely, alterations in Prothrombin time have occurred and may require co- administration of vitamin K (10 mg weekly. Administer with caution to patients with history of G.I. diseases, especially colitis. There is no evidence of carcinogenesis, mutagenesis and impairment of fertility for doses upto 20 times the clinical dose
Drug Interactions with Ceftriaxone
- Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form.
- Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line.
- Aminoglycoside antibiotics and diuretics: No impairment of renal function has so far been observed after concurrent administration of large doses of ceftriaxone and potent diuretics (e.g.furosemide).
- Alcohol: No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of ceftriaxone. Ceftriaxone does not contain an N-methylthiotetrazole moiety associated with possible ethanol intolerance and bleeding problems of certain other cephalosporins.
- Antibiotics: In an in vitro study, antagonistic effects have been observed with the combination of chloramphenicol and ceftriaxone.
- Anticoagulants: As ceftriaxone has an N-methylthiotriazine side-chain, it might have the potential to cause hypo-prothrombinaemia resulting in an increased risk of bleeding in patients treated with anticoagulants
- Oral Contraceptives: Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment.
- Based on literature reports ceftriaxone is incompatible with amsacrine, vancomycin fluconazole and aminoglycosides
Ceftriaxone Interference with Laboratory Tests:
In patients treated with ceftriaxone, the Coombs’ test may in rare cases be false-positive. Ceftriaxone, like other antibiotics, may result in false-positive tests for galactosaemia. Likewise, non-enzymatic methods such as copper reduction methods (Benedict’s, Fehling’s or Clinitest) for glucose determination in urine may give false-positive results. For this reason, urine-glucose determination during therapy with ceftriaxone should be carried out enzymatically.
Ceftriaxone Use in Pregnancy and Lactation
Is ceftriaxone used or safe in pregnancy and breastfeeding women?
Ceftriaxone crosses the placental barrier. Safety in human pregnancy has not been established. Reproductive studies in animals have shown no evidence of neurotoxicity, ototoxicity. teratogenicity or adverse effects on male or Female fertility, birth or perinatal and postnatal development. In primates, no embryotoxicity and teratogenicity has been observed. Therefore ceftriaxone should not be used in pregnancy unless absolutely indicated.
Low concentrations of ceftriaxone are excreted in human milk. Caution should be exercised when ceftriaxone is administered to a nursing woman
Ceftriaxone Effects on Ability to Drive and Use Machines:
Ceftriaxone has been associated with dizziness, which may affect the ability to drive or operate machinery.
Undesirable Effects of Ceftriaxone
What are side effects of Ceftriaxone?
Ceftriaxone Injection is generally well tolerated. In clinical trials, the following reactions were encountered which may or may not be related to Ceftriaxone Injection therapy. The common reactions observed were eosinophilia, thrombocytosis, leucopenia, SGOT and SGPT level elevation. Reactions observed in very less population were pain, tenderness at site of injection, phlebitis, rash, pruritus, fever, chills, anaemia, neutropenia, lymphopenia, thrombocytopenia, diarrhea, nausea, vomiting, dysgeusia, alkaline phosphatase, bilirubin elevation, BUN elevation, creatinine elevation case in urine, headache, dizziness, moniliasis and vaginitis.
Superinfection caused by microorganisms non-susceptible to ceftriaxone such as yeasts, fungi (mycosis of the genital tract) or other resistant microorganisms may develop.
Pseudomembranous colitis is a rare undesirable effect caused by infection with Clostridium difficile during treatment with ceftriaxone. Therefore, the possibility of the disease should be considered in patients who present with diarrhoea following antibacterial agent use
Overdosage of Ceftriaxone and Its Treatment
What should be done should one be overdosed with Ceftriaxone?
In the case of overdose of Ceftriaxone, nausea, vomiting, diarrhoea, can occur. Ceftriaxone concentration can not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is rather symptomatic.
Are there substances or drugs that are not compatible with Ceftriaxone?
In particular, diluents containing calcium, (e.g. Ringer’s solution, Hartmann’s solution) should not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Ceftriaxone must not be mixed or administered simultaneously with calcium containing solutions. Based on literature reports, ceftriaxone is not compatible with amsacrine, vancomycin, fluconazole, aminoglycosides, pentamidine, clindamycin phosphate and labetalol.
How to Store Ceftriaxone
How should ceftriaxone be stored?
Store below 30°C. Protected from light.
Keep out of reach of children,
For single use only. Discard any unused contents.
Ceftriaxone 1gm powder is usually presented in vial with 3.5 ml Lidocaine Injection & 10 ml water for injection.