Ceftriaxone

Ceftriaxone belongs to the pharmacological class of Third-generation cephalosporin antibiotics.

Ceftriaxone has been approved to relieve symptoms and also for the treatment and maintenance of Actinomycosis, severe or extensive, Bite wound infection, treatment, Bloodstream infection, Chronic obstructive pulmonary disease, acute exacerbation, Diabetic foot infection, moderate to severe, Endocarditis, Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure., Intracranial abscess or spinal epidural abscess, Lyme disease, meningitis, bacterial, Meningococcal disease, chemoprophylaxis after close contact with high-risk patient, neuro brucellosis, Odontogenic soft tissue infection, pyogenic, Osteomyelitis and/or discitis, Otitis media, acute, Pneumonia, community-acquired, Prosthetic joint infection, Rat bite fever, Salmonella species infection, Septic arthritis, Sexually transmitted infections, Skin, and soft tissue infection, Spontaneous bacterial peritonitis, Surgical prophylaxis, Toxic shock syndrome, Urinary tract infection.

Ceftriaxone has a pharmacokinetic profile characterized by high plasma protein binding, a long half-life, and renal and biliary excretion. Following intravenous injection, ceftriaxone is rapidly and completely absorbed, with peak plasma concentrations attained within 2 to 3 hours. The drug is found to be highly bound to plasma proteins, with a binding rate of 85% to 95%. Ceftriaxone is primarily excreted via the kidneys, with approximately 50% to 60% of the drug excreted unchanged in the urine and the remaining 40% to 50% excreted via the biliary system. The drug has a long elimination half-life, ranging from 5.8 to 8.7 hours in adults and up to 15 hours in neonates.

The common side effects of Ceftriaxone are nausea, vomiting, gas, weakness, tiredness, itching, diarrhea, headache, upset stomach, etc.

Ceftriaxone is available in the form of an Injectable solution, Powder for injection.

Ceftriaxone is approved in Germany, Japan, Malaysia, India, China, Canada, the U.S., U.K.

Ceftriaxone belongs to the pharmacological class of Third-generation cephalosporin antibiotics.

Ceftriaxone involves the inhibition of mucopeptide synthesis in the bacterial cell wall. This is achieved through the binding of the beta-lactam moiety of ceftriaxone to carboxypeptidases, endopeptidases, and transpeptidases in the bacterial cytoplasmic membrane. These enzymes are essential for cell wall synthesis and division. Upon binding to these enzymes, ceftriaxone causes a loss of activity, leading to the production of defective cell walls and, ultimately, bacterial cell death.

Ceftriaxone has been approved to relieve symptoms and also for the treatment and maintenance of Actinomycosis, severe or extensive, Bite wound infection, treatment, Bloodstream infection, Chronic obstructive pulmonary disease, acute exacerbation, Diabetic foot infection, moderate to severe, Endocarditis, Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure., Intracranial abscess or spinal epidural abscess, Lyme disease, meningitis, bacterial, Meningococcal disease, chemoprophylaxis after close contact with high-risk patient, neuro brucellosis, Odontogenic soft tissue infection, pyogenic, Osteomyelitis and/or discitis, Otitis media, acute, Pneumonia, community-acquired, Prosthetic joint infection, Rat bite fever, Salmonella species infection, Septic arthritis, Sexually transmitted infections, Skin, and soft tissue infection, Spontaneous bacterial peritonitis, Surgical prophylaxis, Toxic shock syndrome, Urinary tract infection.

The CMAX (maximum plasma concentration) of ceftriaxone occurs within 2 to 3 hours after intravenous administration and within 2.5 to 3 hours after intramuscular administration. The TMAX (time to maximum plasma concentration) is reached at these time points. The onset of action varies depending on the condition being treated, but in general, ceftriaxone exhibits a rapid bactericidal effect. The duration of action ranges from 12 to 24 hours, depending on the dose and severity of the infection. The elimination half-life is approximately 7.5 hours in adults with normal renal function.

Ceftriaxone is found to be available in the form of an Injectable solution, Powder for injection.

Ceftriaxone can be used in the following treatment:

• Actinomycosis, severe or extensive
• Bite wound infection, treatment
• Bloodstream infection
• Chronic obstructive pulmonary disease, acute exacerbation
• Diabetic foot infection, moderate to severe
• Endocarditis, prophylaxis
• Endocarditis, treatment
• Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure
• Intracranial abscess or spinal epidural abscess
• Lyme disease
• Meningitis, bacterial
• Meningococcal disease, chemoprophylaxis after close contact with high-risk patient
• Neurobrucellosis
• Odontogenic soft tissue infection, pyogenic
• Osteomyelitis and/or discitis
• Otitis media, acute
• Pneumonia, community-acquired
• Prosthetic joint infection
• Rat bite fever
• Salmonella species infection
• Septic arthritis
• Sexually transmitted infections
• Skin and soft tissue infection
• Spontaneous bacterial peritonitis
• Surgical prophylaxis, colorectal
• Toxic shock syndrome, streptococcal
• Urinary tract infection, complicated

Ceftriaxone can help to relieve symptoms and also for the treatment and maintenance of Actinomycosis, severe or extensive, Bite wound infection, treatment, Bloodstream infection, Chronic obstructive pulmonary disease, acute exacerbation, Diabetic foot infection, moderate to severe, Endocarditis, Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure., Intracranial abscess or spinal epidural abscess, Lyme disease, meningitis, bacterial, Meningococcal disease, chemoprophylaxis after close contact with high-risk patient, neuro brucellosis, Odontogenic soft tissue infection, pyogenic, Osteomyelitis and/or discitis, Otitis media, acute, Pneumonia, community-acquired, Prosthetic joint infection, Rat bite fever, Salmonella species infection, Septic arthritis, Sexually transmitted infections, Skin, and soft tissue infection, Spontaneous bacterial peritonitis, Surgical prophylaxis, Toxic shock syndrome, Urinary tract infection.

Ceftriaxone is approved for use in the following clinical indications:

● Actinomycosis, severe or extensive

● Bite wound infection, treatment

● Bloodstream infection

● Chronic obstructive pulmonary disease, acute exacerbation

● Diabetic foot infection, moderate to severe

● Endocarditis, prophylaxis

● Endocarditis, treatment

● Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure.

● Intracranial abscess or spinal epidural abscess

● Lyme disease

● Meningitis, bacterial

● Meningococcal disease, chemoprophylaxis after close contact with high-risk patient

● Neurobrucellosis

● Odontogenic soft tissue infection, pyogenic

● Osteomyelitis and/or discitis

● Otitis media, acute

● Pneumonia, community-acquired

● Prosthetic joint infection

● Rat bite fever

● Salmonella species infection

● Septic arthritis

● Sexually transmitted infections

● Skin and soft tissue infection

● Spontaneous bacterial peritonitis

● Surgical prophylaxis, colorectal

● Toxic shock syndrome, streptococcal

● Urinary tract infection, complicated

Actinomycosis, severe or extensive: 2 g once daily (IV or IM)

Bite wound infection, treatment: 1 to 2 g once daily (IV or IM)

Bloodstream infection: 2 g once daily (IV or IM)

Chronic obstructive pulmonary disease, acute exacerbation: 1 g once daily (IV or IM)

Diabetic foot infection, moderate to severe: 1 to 2 g once daily (IV or IM)

Endocarditis, prophylaxis: 1 to 2 g once (IV or IM) 30 to 60 minutes before the procedure

Endocarditis, treatment: 2 g once daily (IV)

Intra-abdominal infection, mild to moderate, community-acquired in patients without risk factors for resistance or treatment failure: 1 to 2 g once daily (IV)

Intracranial abscess or spinal epidural abscess: 2 g once daily (IV)

Lyme disease: 2 g once daily (IV or IM)

Meningitis, bacterial: 2 to 4 g once daily (IV)

Meningococcal disease, chemoprophylaxis after close contact with high-risk patient: 250 mg once (IM)

Neurobrucellosis: 2 g once daily (IV)

Odontogenic soft tissue infection, pyogenic: 1 to 2 g once daily (IV or IM)

Osteomyelitis and/or discitis: 2 g once daily (IV or IM)

Otitis media, acute: 50 mg/kg once daily (IV or IM) for three days

Pneumonia, community-acquired: 1 to 2 g once daily (IV)

Prosthetic joint infection: 2 g once daily (IV)

Rat bite fever: 1 to 2 g once daily (IV or IM)

Salmonella species infection: 2 g once daily (IV)

Septic arthritis: 1 to 2 g once daily (IV or IM)

Sexually transmitted infections: 250 mg once (IM)

Skin and soft tissue infection: 1 to 2 g once daily (IV or IM)

Spontaneous bacterial peritonitis: 2 g once daily (IV)

Surgical prophylaxis, colorectal: 1 g once (IV) before surgery, then every 12 hours for up to 48 hours after surgery

Toxic shock syndrome, streptococcal: 2 g once daily (IV)

Urinary tract infection, complicated: 1 to 2 g once daily (IV)

Injectable solution: 1g/50mL, 2g/50mL

Powder for injection: 250mg, 500mg, 1g, 2g, 10g, 100g

Injectable solution, Powder for injection

• Dosage Adjustments in Pediatric Patients:

For infants, children, and adolescents, the recommended dosage for IM and IV administration is 50 to 75 mg/kg/dose every 24 hours, with a maximum dose of 1,000 mg/dose. In certain infections, higher doses may be recommended.

• Dosage Adjustments in Kidney Patients:

If a patient has altered kidney function, the dosing of the medication may need to be adjusted. For patients with a creatinine clearance (CrCl) greater than 15 mL/minute, no adjustment is necessary. For those with a CrCl less than 15 mL/minute, no adjustment is needed but doses greater than two g/day should be used with caution and close monitoring in patients with hepatic dysfunction.

Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients with normal serum creatinine levels. Young patients admitted post-trauma or major surgery, as well as those with sepsis, burns, or hematological malignancies, are at the highest risk for ARC. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients. Monte Carlo simulation can be used to determine to dose for these patients.

For patients with a CrCl ≥150 mL/minute or an organism with a minimum inhibitory concentration (MIC) of 2, a dose of 2 g twice daily is recommended. No adjustment is necessary for patients undergoing hemodialysis thrice weekly, but quantities greater than two g/day should be used with caution and close monitoring in patients with hepatic dysfunction. Alternatively, a dose of 2 g thrice weekly post-dialysis is recommended for achieving pharmacodynamic goals when the MIC ≤1 mcg/mL. For patients undergoing peritoneal dialysis, no adjustment is necessary but doses greater than two g/day should be used with caution and close monitoring in patients with hepatic dysfunction.

There are no specific dietary restrictions related to the use of ceftriaxone, a type of antibiotic medication used to treat various bacterial infections. However, it is important to follow the instructions of a healthcare professional when taking ceftriaxone, as certain foods or drinks may interact with the medication and affect its absorption, efficacy, or side effects. For example, ceftriaxone should not be mixed with calcium-containing solutions or administered simultaneously with intravenous calcium-containing products. This may cause ceftriaxone-calcium precipitation and increase the risk of adverse effects such as lung and kidney damage.

Ceftriaxone may be contraindicated under the following conditions:

• Individuals with a known allergy to this medication or any of its ingredients, as well as other cephalosporins or penicillin.
• Hyperbilirubinemia neonates as well as preterm neonates should not be given ceftriaxone treatment. In vitro studies have indicated that ceftriaxone may displace bilirubin from serum albumin, which could lead to bilirubin encephalopathy in these patients.
• Neonates who are 28 days old or younger and require (or are expected to require) treatment with a calcium-containing Intravenous solutions, including continuous calcium-containing infusions like parenteral nutrition, due to the risk of ceftriaxone-calcium precipitation.

The physician should closely monitor the patients as well as keep pharmacovigilance as follows:

General-Severe Cutaneous Adverse Reactions:

Severe cutaneous adverse reactions (SCAR) have been reported with beta-lactam treatment, including Ceftriaxone Sodium for Injection, and may include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). If SCAR is suspected, the use of Ceftriaxone should be discontinued, and appropriate therapy should be administered.

Clostridium difficile-associated disease:

The use of antibacterial agents, including Ceftriaxone, has been associated with Clostridium difficile-associated disease (CDAD), which may cause mild diarrhea to fatal colitis. CDAD should be considered in patients who present with diarrhea, colitis symptoms, pseudomembranous colitis, toxic megacolon, or colon perforation after antibacterial treatment. If CDAD is suspected or confirmed, appropriate measures should be taken, including discontinuing antibacterial agents and possible surgical intervention.

Hypersensitivity:

Ceftriaxone should be cautiously administered to patients with hypersensitivity reactions to ceftriaxone, other cephalosporins, penicillins, or other allergens. Anaphylactic reactions with fatal outcomes have been reported, even in patients without known allergies or previous exposure. Patients with type I hypersensitivity to penicillin may also have cross-hypersensitivity to β-lactam antibiotics, including Ceftriaxone. In cases of allergic reactions, Ceftriaxone should be discontinued, and appropriate therapy should be initiated.

Hemolytic Anemia:

Ceftriaxone Sodium for Injection BP is not be used in patients with a history of cephalosporin-associated hemolytic anemia since recurrence can be severe. Hemolytic anemia, including severe cases and fatalities, has been observed in patients receiving cephalosporin-class antibacterials, including ceftriaxone. Patients who receive prolonged or frequent courses of ceftriaxone may benefit from periodic monitoring for signs and symptoms of hemolytic anemia.

Susceptibility/Resistance:

Prescribing Ceftriaxone Sodium for Injection BP in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient as well as risks the development of drug-resistant bacteria. Ceftriaxone sodium is not nephrotoxic, but periodic monitoring of serum ceftriaxone concentrations is recommended in severe renal impairment. If evidence of accumulation is found, dosage should be decreased accordingly.

There are no known interactions between alcohol and ceftriaxone. However, it is generally recommended to avoid consuming alcohol while being treated with antibiotics, as alcohol consumption can weaken the immune system and potentially reduce the effectiveness of the medication. Additionally, alcohol can cause dehydration, exacerbating some common side effects of ceftriaxone, such as diarrhea.

Ceftriaxone is excreted in low concentrations in human milk, so caution should be exercised when administering Ceftriaxone to nursing women.

Pregnancy Category B

Ceftriaxone falls under Pregnancy Category B and has not been found to cause embryotoxicity, fetotoxicity, or teratogenicity in mice, rats, and primates, even when given in doses up to 20 times the usual human dose. However, since there are no adequate and well-controlled studies on pregnant women, this drug should only be used during pregnancy if clearly needed.

There are no specific food warnings for ceftriaxone. However, it is essential to note that ceftriaxone should not be mixed or administered simultaneously with calcium-containing solutions, such as calcium-containing intravenous solutions or oral products, including dairy products like milk. This is because ceftriaxone can form insoluble complexes with calcium, leading to the formation of clots in the lungs and kidneys, which can be fatal.

The adverse reactions related to Ceftriaxone can be categorized as follows:

Common

• Diarrhea
• Nausea and vomiting
• Stomach pain
• Rash
• Headache
• Dizziness
• Swelling, pain, or redness at the injection site

Less common

• High blood pressure
• Low blood pressure
• Decreased white blood cell count
• Increased liver enzymes
• Kidney dysfunction or failure
• Seizures
• Allergic reactions, including anaphylaxis

Rare

• Pseudomembranous colitis
• Pancreatitis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Hemolytic anemia
• Thrombocytopenia
• Agranulocytosis

The clinically relevant drug interactions of Ceftriaxone are briefly summarized here:

The combination of ceftriaxone and calcium-containing products is not recommended as it can result in the formation of a precipitate. This can happen when ceftriaxone is mixed with calcium-containing solutions in the same IV administration line or when diluents containing calcium are used to reconstitute Ceftriaxone Sodium for Injection BP vials to further dilute a reconstituted vial for Intravenous administration. However, in patients other than neonates, ceftriaxone as well as calcium-containing solutions might be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid.

In neonates, there is an increased risk of precipitation of ceftriaxone-calcium, and in vitro studies using adult and neonatal plasma have demonstrated this. Sonographic abnormalities in the gallbladder have been reported in patients treated with ceftriaxone sodium. These abnormalities appear on sonography as an echo without acoustical shadowing, suggesting sludge, or as an echo with acoustic shadowing, which may be misinterpreted as gallstones. It has been determined that the sonographically-detected material is predominantly a ceftriaxone-calcium salt. The condition appears to be transient and also reversible upon discontinuation of ceftriaxone sodium and the institution of conservative management.

Ceftriaxone may cause renal lithiasis through the precipitation of calcium ceftriaxonate, which can be symptomatic and may lead to renal insufficiency, especially in children older than three years and who have been treated with high daily doses or total doses exceeding 10 grams and presenting other risk factors. In such cases, sonography for renal lithiasis is recommended, and treatment with Ceftriaxone Sodium for Injection BP should be withdrawn to allow signs and symptoms to resolve.

Prothrombin time alterations and hypoprothrombinemia had occurred rarely in patients treated with ceftriaxone sodium. Patients with impaired vitamin K synthesis or low vitamin K stores may require hematology and coagulation parameters monitoring during Ceftriaxone Sodium For Injection BP treatment. Vitamin K administration might be necessary if the prothrombin time is being prolonged before or during treatment.

Prolonged treatment with ceftriaxone sodium might result in the overgrowth of non-susceptible organisms and organisms initially sensitive to the drug. The development of resistant organisms during the administration of ceftriaxone sodium in clinical trials had been observed. If superinfection occurs, some appropriate measures should be taken. Ceftriaxone Sodium For Injection BP should be administered cautiously to individuals with a history of allergy, especially to cephalosporins.

The following are the side effects involving "Ceftriaxone":

• Diarrhea
• Nausea
• Vomiting
• Abdominal pain
• Skin rash
• Swelling or redness at the injection site
• Headache
• Dizziness
• Increased liver enzymes

Pregnancy

Pregnancy Category B

Ceftriaxone falls under Pregnancy Category B and has not been found to cause embryotoxicity, fetotoxicity, or teratogenicity in mice, rats, and primates, even when given in doses up to 20 times the usual human dose. However, since there are no adequate and well-controlled studies on pregnant women, this drug should only be used during pregnancy if clearly needed.

Non-teratogenic Effects:

In rats, studies showed that ceftriaxone did not have any adverse effects on reproductive parameters during gestation and also lactation, including postnatal growth, functional behavior, and also reproductive ability of the offspring, when given doses of 586 mg/kg/day or less.

Lactation:

Ceftriaxone is excreted in low concentrations in human milk, so caution should be exercised when administering Ceftriaxone to nursing women.

Pediatric:

Ceftriaxone is safe and effective for neonates, infants, and pediatric patients when given in the recommended dosages. However, like some other cephalosporins, ceftriaxone can displace bilirubin from serum albumin, so it should not be given to hyperbilirubinemia neonates, especially premature ones.

Geriatric:

In clinical studies, 32% of the total number of subjects were 60 and over, and no significant differences in safety or effectiveness were observed between older and younger subjects. Although greater sensitivity in some older individuals cannot be ruled out, dosage adjustments are not necessary for geriatric patients receiving ceftriaxone dosages up to 2 grams per day, as its pharmacokinetics were only minimally altered in this population compared to healthy adult subjects.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of over dosage of "Ceftriaxone."

A patient who received ceftriaxone sodium at a dosage of 10 g/day (2.5 times the maximum recommended dose) exhibited ultrasonography shadows indicative of kidney precipitations and calcium ceftriaxone residue in the urine. There are no reports of other cases of ceftriaxone sodium over dosage. There is no specific information on the symptoms or treatment for this condition. Hemodialysis or peritoneal dialysis cannot decrease the excessive serum concentration of ceftriaxone. Symptomatic treatment is recommended.

Pharmacodynamics

Ceftriaxone is a type of beta-lactam antibiotic from the cephalosporin/cephamycin class, utilized to treat bacterial infections caused by susceptible organisms, mainly gram-positive ones. It is in vitro activity extends to gram-negative aerobic, gram-positive aerobic, and anaerobic bacteria. The bactericidal effect of ceftriaxone is a result of inhibiting cell wall synthesis, accomplished through binding to penicillin-binding proteins (PBPs).Ceftriaxone is resistant to various beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. However, resistance to ceftriaxone typically stems from beta-lactamase hydrolysis, altered PBPs, or decreased bacterial cell permeability. Ceftriaxone should not be administered with or in the same IV line as products containing calcium as it may result in precipitation. Additionally, using ceftriaxone may result in the formation of biliary sludge or gallbladder pseudolithiasis.

Pharmacokinetics

• Absorption:

Ceftriaxone is exclusively administered via injection, either intramuscularly or intravenously, due to its poor oral bioavailability of less than 1%.

• Volume of distribution:

The apparent volume of distribution of an intravenous or intramuscular dose in healthy individuals ranges from 5.78 to 13.5 L, while in septic patients, it ranges from 6.48 to 35.2 L. Ceftriaxone demonstrates adequate penetration into the cerebrospinal fluid, making it an effective treatment for bacterial meningitis.

• Protein binding:

Ceftriaxone is highly protein-bound, with a binding rate of 95%.

• Metabolism:

Ceftriaxone undergoes negligible metabolism.

• Route of elimination:

The primary route of elimination for ceftriaxone is renal excretion, accounting for 33-67% of the administered dose. The remaining amount is excreted through biliary secretion and eliminated from the body via feces.

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