Antibiotics

Ceftriaxone: Indications, Mechanism of action, Dosage, Interactions and, Side Effects,

  • Pharmacology
  • Antibiotics
  • 2020-09-03 12:51:41
  • 11 minutes, 21 seconds

Ceftriaxone: Indications, Mechanism of action, Dosage, Interactions and, Side Effects,

Ceftriaxone is a third generation cephalosporin antibiotic that is used in the treatment of bacterial infections caused by susceptible, usually gram-positive organisms.

Ceftriaxone has an invitro activity against gram positive and gram negative aerobic and anaerobic bacteria.

Mechanism of action of ceftriaxone

Ceftriaxone works by inhibiting mucopeptide synthesis in the bacterial cell wall.

Ceftriaxone has a broad-spectrum gram-negative activity and a lower efficacy against gram-positive organisms but higher efficacy against resistant organisms.

Ceftriaxone is stable against hydrolysis by a variety of beta lactamases including penicillinases and cephalosporinases and extended spectrum beta lactamases of gram-negative and gram-positive bacteria.

The bactericidal activity of ceftriaxone results from inhibiting cell-wall synthesis that is mediated by binding to 1 or more penicillin-binding proteins (PBPs) and exerting antimicrobial effect by interfering and interrupting the biosynthesis of peptidoglycan (major structural component of bacterial cell wall.

The beta lactam moiety of ceftriaxone binds to cerboxypeptidases, endopeptidases and transpeptidases in the bacterial cytoplasmic membrane. These enzymes are involved in the cell wall synthesis and cell division.

By binding to these enzymes, ceftriaxone results in the formation of defective cell walls and cell death of the susceptible bacteria because activity of cell-wall autolytic enzymes continues while cell-wall assembly is arrested

Resistance

Bacterial resistance to ceftriaxone may develop as a result of the following mechanisms:

  • Hydrolysis by beta-lactamases that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species.
  • Bacterial efflux pumps.
  • Outer membrane impermeability in Gram-negative organisms.
  • Reduced affinity of penicillin-binding proteins for ceftriaxone.

Pharmacodynamics

Ceftriaxone is stable in a wide range of both gram-positive and gram-negative beta lactamases, including those which are able to hydrolyze advanced generation penicillin derivatives and other cephalosporins.

Resistance to ceftriaxone is encoded mainly in the production of the beta lactam hydrolyzing enzymes including carbapenemases and some ESBLs especially in Gram-negative organisms.

For gram positive organisms such as staphylococcus aureus and S pneumonia, acquired resistance is mainly encoded by cell wall target site allowances.

Pharmacokinetics

Ceftriaxone demonstrates nonlinear dose-dependent pharmacokinetics because its protein binding about 85% - 95% is bound to plasma protein depending on the concentration of ceftriaxone.

Mean peak plasma concentrations of about 40 to 80 micrograms/Ml have been reported 2-3 hours after administration of 0.5 to 1 gram intramuscularly.

Ceftriaxone has a VD of 6-14 L

The plasma half-life of ceftriaxone is not dependent on the dose and varies between 6 to 9 hours; it may be prolonged in neonates.

The half-life does not change more especially in patients with moderate renal impairment but it may be prolonged in severe renal failure especially when there is also hepatic impairment.

Ceftriaxone is widely distributed in body fluids and tissues.

It crosses both inflamed and non-inflamed meninges generally achieving therapeutic concentration in the CSF.

The excretion of ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency.

It crosses the placenta and low concentration has been detected in breast milk. High concentration is achieved in bile.

About 40% to 65% 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 the feaces as unchanged drug and microbiologically inactive compounds.

Indications of ceftriaxone

Ceftriaxone is indicated in the management of the following infections in adults and children including neonates from birth

  1. Bacterial meningitis
  2. Community acquired pneumonia
  3. Hospital acquired pneumonia
  4. Acute otitis media
  5. Intraabdominal infections
  6. Complicated unrinary tract infections including pyelonephritis
  7. Bone and joint infection
  8. Complicated skin and soft tissue infection
  9. Gornorrhea
  10. Syphilis
  11. Bacterial endocarditis
  12. Ceftriaxone can also be used I the treatment ofacute exacebations of chronic obstructive pulmonary disease in adults
  13. Disseminated lyme borreliosis (early stage ii) and late stage iii in adults and children including neonates from 15 days of age.
  14. Preoperative prophylaxis of surgical site infections,
  15. Management of neutropenic patients with ever that is suspected to be due to bacterial infections,

Ceftriaxone is used for treatment of meningitis, including meningitis caused by  pneumococci, meningococci, H influenzae, and susceptible enteric gram-negative rods, but not by L monocytogenes.

Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin non-susceptible strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these
strains.

Meningitis caused by strains of pneumococci with penicillin MICs > 1 mcg/mL may not respond to ceftriaxone and therefore an addition of vancomycin is recommended.

Ceftriaxone should be co-administered with other antibacterial agents whenever the possible range of causative bacteria could not fall within its spectrum.

Administration

For intramuscular administration 1 gram vial of ceftriaxone should be dissolved in 3.5ml of sterile water for injection or 1% Lidocaine Injection BP and the solution should be administered by deep intramuscular injection within the bulk of a relatively large muscle.

More than 1 gram of ceftriaxone should be injected at one site. Therefore dosages greater than 1gram should be divided and injected at more than one site.

As the solvent used is lidocaine, the resulting solution should never be administered intravenously

For intravenous administration,1 gram of ceftriaxone is dissolved in 10 ml of water for injections. The injection should be administered slowly for over 5 minutes, directly into the vein or as an infusion over at least 30 minutes.

An intravenous doses of 50 mg/kg or more in infants and children up to 12 years of age should be given by infusion.

In neonates, intravenous doses should be given over a duration of 60 minutes to reduce the potential risk of bilirubin encephalopathy.

Ceftriaxone is contraindicated in neonates (≤ 28 days) if they require treatment with calcium-containing intravenous solutions, including continuous calcium-containing infusions such as parenteral nutrition, because of the risk of precipitation of ceftriaxone-calcium. This is covered in details in the warning section.

Diluents containing calcium, (e.g. Ringer's solution or 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. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line.

For pre-operative prophylaxis of surgical site infections, ceftriaxone should be administered 30-90 minutes prior to surgery.

IV Incompatibilities

Ringers lactate solution at drug concentrations >10 mg/Ml.

Aminophylline, linezolid, metronidazole (at metronidazole 15 g/L with ceftriaxone 20 g/L; compatible at metronidazole 7.5 g/L with ceftriaxone 10 g/L), clindamycin, theophylline,

Calcium-containing drugs

Dosages

Adults and children above 12 years of age(=50 kgs)

For community acquired pneumonia, acute exacerbations of chronic obstructive pulmonary disease, intra-abdominal infections and complicated urinary tract infections including pyelonephritis the dose is 1-2 grams daily.

For hospital acquired pneumonia, complicated skin infections, soft tissue infections, bone and joint infections the dosage is 6 grams once daily.

Management of acute neutropenic patients with fever that is suspected to be due to bacterial infections, bacterial endocarditis and bacterial meningitis the dosage is 2-4 grams per day.

Acute otitis media a single intramuscular injection of 1-2 grams is given.

Preoperative prophylaxis of surgical site infections 2 grams as a single dose

Gornorrhea 500 mg as a single intramuscular dose

Syphilis 500 to 1 gram once daily dose increased to 2 grams once daily for neurosyphyllis to 10-14 days

Disseminated lyme borreliosis a daily 2 gram dose is given for 10-14 days

Pelvic Inflammatory Disease

250 mg IM as single dose with doxycycline, with or without metronidazole for 14 days

Prosthetic Joint Infection

2 g IV q24hr for 2-6 weeks; continue treatment until clinical improvement observed and patient is afebrile for 48-72 h

The recommended treatment durations vary and national or local guidelines should be taken into consideration

Neonates and infants and children 15 days to 12 years (<50 kgs)

For children with body weight of 50 kilograms and below the usual adult dosage should be given

For community acquired pneumonia, hospital acquired pneumonia, acute exacerbations of chronic obstructive pulmonary disease, intra-abdominal infections and complicated urinary tract infections including pyelonephritis the dose is 50-80mg/kg daily.

For complicated skin infections, soft tissue infections, bone and joint infections dose is 50-100 mg daily to a maximum of 4 grams per day.

Management of acute neutropenic patients with fever that is suspected to be due to bacterial infections the dose is 50-100 mg daily to a maximum of 4 grams per day.

Acute otitis media a single intramuscular injection of 50mg/mg is given. It may be more effective if the intramuscular dose of 50mg/kg is administered for 3 days.

Bacterial endocarditis the dosage is 100 mg/kg per day for a maximum of 4 grams once daily.

Bacterial meningitic dose is 80-100 mg/kg per day

Preoperative prophylaxis of surgical site infections 50-80 mg/kg as a single dose

Gonorrhea 500 mg as a single intramuscular dose

Syphilis 75-100mg/kg, max(4grams) once daily dose for 10-14 days

Disseminated lyme borreliosis a daily 50-80 mg/kg dose is given for 10-14 days

The recommended treatment durations vary and national or local guidelines should be taken into consideration

Patients with renal or hepatic impairment

In patients with renal or hepatic dysfunction, the pharmacokinetics of ceftriaxone are only minimally altered with the half-life slightly increased, even in patients with severely impaired renal function.

In patients with hepatic impairment, the elimination half-life of ceftriaxone is not increased, due to a compensatory increase in renal clearance. This is also due to an increase in plasma free fraction of ceftriaxone contributing to the observed paradoxical increase in total drug clearance, with an increase in volume of distribution paralleling that of total clearance.

Contraindications

Hypersensitivity to ceftriaxone and to other cephalosporins and history of severe hypersensitivity eg anaphylactic reaction.

It is also contraindicated in premature neonates up to a post menstrual age of 41 weeks (gestational age+ chronological age).

Ceftriaxone use is contraindicated in full-term neonates (up to 28 days of age) who have:

  • Hyperbilirubinaemia, jaundice, or who are hypoalbuminaemic or acidotic because of the risk of impaired bilirubin binding that may predispose the neonated to bilirubin encephalopathy.
  • Require intravenous calcium treatment, or calcium-containing infusions due to the risk of precipitation of a ceftriaxone-calcium salt.

Contraindications to lidocaine must be considered before using lidocaine as a diluent for intramuscular injection of ceftriaxone.

Ceftriaxone solutions containing lidocaine should never be administered intravenously

Warnings and precautions

Serious and occasionally fatal anaphylactic reactions have been reported therefore in any case of hypersensitivity reactions, treatment with ceftriaxone must be discontinued immediately.

Cases of fatal reactions with calcium containing products with ceftriaxone, precipitates in the lungs and kidneys in the premature and full term neonates aged less than one month have been reported.

If lidocaine solution used as solvent with ceftriaxone for intramuscular injection, then it should not be administered intravenously.

Some patients with spirochete infections may experience a Jarisch-Herxheimer reaction (JHR) shortly after ceftriaxone treatment is started. Although Jarisch-Herxheimer reaction is usually self - limiting the antibiotic treatment should not be discontinued if such reaction occurs.'

Interaction with calcium containing products

Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in premature and full-term neonates aged less than 1 month have been described.

In vitro studies demonstrated that neonates have an increased risk of precipitation of ceftriaxone-calcium compared to other age groups.

In patients of any age ceftriaxone must not be mixed or administered simultaneously with any calcium-containing intravenous solutions, even via different infusion lines or at different infusion sites. However, in patients older than 28 days of age ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt-solution to avoid precipitation.

In patients requiring continuous infusion with calcium-containing total parenteral nutrition (TPN) solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation.

If the use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites.

Alternatively, infusion of TPN solution could be stopped for the period of ceftriaxone infusion and the infusion lines flushed between solutions

Calcium containing diluents such as Ringers solution should not be used to reconstitute ceftriaxone vials or to further dilute the reconstituted vial for intravenous use because a precipitate may form.

It is known to interact with calcium containing drugs such as;

  • calcium acetate
  • calcium carbonate
  • calcium chloride
  • calcium citrate
  • calcium gluconate

This is because of an increased risk of fatal particulate precipitation in the lungs therefore the doses should be separated by at least 48 hours apart

Concomitant use with oral anticoagulants may increase the risk of anti-vitamin k effect and the risk of bleeding.

Pregnancy and lactation

Ceftriaxone belongs to pregnancy category: B

Ceftriaxone should only be used in pregnancy only in the first trimester if the benefits outweigh the risks.

Ceftriaxone is excreted in breast milk in low concentrations but at therapeutic doses of ceftriaxone there is no effects on the breastfed infants.

Effects on the ability to drive or operate machinery

During the ceftriaxone therapy, some undesired side effects may occur such as dizziness which may influence the ability to drive and use machines.

Patients should be cautious when driving and using machinery

Side effects of ceftriaxone

Ceftriaxone use is usually followed by few side effects

The most common side effects associated with ceftriaxone use are eosinophilia

Leukopenia, thrombocytopenia, diarrhea, rash, increased liver enzymes.

Other less common side effects are rash, pruritis, phlebitis at the injection site, pyrexia and elevated creatinine levels.

Overdose and treatment

In overdose the symptoms of nausea, vomiting and diarrhea may occur.

Ceftriaxone concentration cannot be reduced by hemodialysis or peritoneal dialysis

There is no specific antidote

The treatment for overdose is symptomatic

Availability

Ceftriaxone is available as Generic Name: ceftriaxone (injection)

Brand Name: Rocephin, Rocephin IM Convenience Kit (obsolete), Rocephin ADD-Vantage

Presentation: Parenteral: powder to reconstitute for injection (0.25, 0.5, 1, 2, 10 g per vial)

 


References:
author

Daniel Ogera

Medical educator, passionate about simplifying difficult medical concepts for easier understanding and mastery by nursing and medical students.

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About this article:
  • Topic:Pharmacology
  • Duration:11 minutes, 21 seconds
  • Subtopic:Antibiotics

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