Forgram

Antibacterial.
Pharmacology: After 500 mg and 1.5 b bolus IV injection in healthy subjects, mean peak plasma concentrations were 0.15 and 0.28 mg/mL, respectively.
Following IM injection, mean peak plasma concentrations were about half those achieved after IV administration of an equivalent dose. After 2 hrs, mean plasma concentrations by the 2 routes were similar.
In surgical patients and those with bacterial infections, mean plasma concentrations 24 hrs after the first dose of 2 g ceftriaxone were between 0.012 and 0.02 mg/mL. Peak plasma concentrations ranged from 0.18 and 0.25 mg/mL. Steady-state mean plasma concentration following repeated administration of 2g every 24 hrs was 0.015 mg/mL.
In neonates with bacterial meningitis given 50 mg/kg IV boluses, mean plasma concentrations after 1-2 hrs were 0.12 mg/mL in those less than 1 week of age, and 0.1 mg/mL if >1 week.
Repeated 12-hrly IV dosing (eg, 1 g every 12 hrs) causes accumulation with peak trough levels up to 50% higher than after the 1st dose. Repeated dosing at 24-hr intervals (eg, 2 g every 24 hrs) results in mean maximum plasma concentrations at 8% higher and grade tissue penetration than the twice-daily dosing schedule.
In studies which have examined the kinetics of both total and free ceftriaxone, apparent volume of distribution of total ceftriaxone during the terminal elimination phase increased with increasing dose, but the volume of distribution of the free ceftriaxone remained relatively constant. Volume of distribution of infants >1 month old compared with adults is 3-fold larger, as is the plasma clearance. Elimination half-life in healthy adults is about 6-9 hrs.
Ceftriaxone penetrates well into most tissues and body fluids including cerebrospinal fluid (inflamed and non-inflamed meninges), sputum, pleural, peritoneal, blister and ascitic fluids; tears, bile, gallbladder tissue, bone, myometrium, endometrium and salpinges tissues, synovial fluid, prostate, nasal mucosa, tonsil and middle ear mucosa. Ceftriaxone is the first systemic cephalosporins to adequately penetrate into the vitreous humor. Ceftriaxone is highly protein bound (95%).
Ceftriaxone is eliminated unchanged by the kidneys and liver, 56% of a dose of ¹⁴C-labeled ceftriaxone appeared in the urine, and 14% as microbiologically inactive, material in the feces. Structure of the metabolites have not been identified.
The percentage of ceftriaxone recovered in the bile during constant infusion varied from 11-65%. Renal clearance is governed mainly by glomerular filtration of unchanged drug. In neonates, 70% of a dose is eliminated in the urine compared with 40-50% in adults.
Microbiology: Mechanism of Action: Ceftriaxone sodium, a semisynthetic broad-spectrum "third generation" cephalosporin antibiotic, exert its bactericidal activity by interfering with the synthesis of the bacterial cell wall. It binds to penicillin-binding protein 3 responsible for the synthesis of peptidoglycan, a heteropolymeric structure that gives the cell wall its mechanical stability.
The 1st 2 steps in cell wall synthesis (ie, formation of an acetylmuranyl pentapeptide followed by alternating linkage to acetylglucosamine to form peptidoglycan chains) are unaffected by penicillins or cephalosporins. It is the final step in this process, in which strands of peptidoglycan are cross-linked by peptide side chains, that is inhibited by ceftriaxone. This transpeptidation reaction is mediated by the transpeptidase enzyme and occurs at the surface of the cell membrane. Ceftriaxone, because of its similarity to the terminal D-alanine-D-alanine of the pentapeptide, binds covalently to the active site of the transpeptidase enzyme and inhibits it, causing spheroplast formation and eventual lysis of the bacterial cell membrane resulting bacterial death.
Spectrum of Activity: Ceftriaxone is active in vitroagainst the following organisms:
Gram-Positive Aerobes: Staphylococcus aureus (including penicillinase-producing strains), Streptococcus pneumoniae, Streptococcus pyogenes, Viridians group Streptococci.
Gram-Negative Aerobes: Acinetobacter calcoaceticus, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae (including ampicillin resistant and β-lactamase producing strains), Morganella morganii, Neisseria meningitidis, Proteus mirabilis, Proteus vulgaris, Serratia marcescens, Salmonella spp (including Salmonella typhi).
Anaerobes: Bacteroides fragilis, Clostridium spp, Peptostreptococcus spp.
Note: Methicillin-resistant Staphylococci are resistant to cephalosporins, including ceftriaxone. Most strains of Group D Streptococci and Enterococci are resistant. Most strains of Clostridium difficile are resistant.
The following microorganisms are sensitive to ceftriaxone in vitro but the clinical significance is unknown:
Gram-Positive Aerobes: Streptococcus agalactiae.
Gram-Negative Aerobes: Citrobacter diversus, Citrobacter freundii, Providencia spp (including Providencia rettgerri), Shigella spp.
Anaerobes: Bacteroides bivius, Bacteroides melaninogenicus.

Treatment of the Following Infections due to Ceftriaxone-Sensitive Organisms:
Lower respiratory tract infections including pneumonia; acute bacterial otitis media; skin and skin structure infections; urinary tract infections; uncomplicated gonorrhea; pelvic inflammatory disease; bacterial septicemia, bone and joint infections; intra-abdominal infections; meningitis.

Ceftriaxone may be administered IV or IM.
Usual Adult Dose: 1-2 g given once daily depending on the type and severity of infection. Maximum Dose: 4g/day. Treatment of Uncomplicated Nongonococcal Infections: Single IM dose of 250 mg is recommended. Surgical Prophylaxis: Single IV dose of 1 g is recommended ½-2 hrs before surgery.
Usual Pediatric Dose: Infants and Children <12 years: Mild to Moderate Infections: 50-75 mg/kg body weight/day given once daily. Maximum Dose: 2 g/day. Severe Infections (ie, meningitis, septicemia, sepsis neonaforum): 100 mg/kg body weight given once daily. Maximum Dose: 4 g/day.

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Patient Information: Usual duration of ceftriaxone therapy is 4-14 days, but complicated infections may require prolonged treatment. For most infections, except gonorrhea, continue therapy for at least 48 hrs after the patient become asymptomatic or evidence of bacterial eradication has been obtained. When treating infections caused by Streptococcus pyogenes, continue therapy for at least 10 days.
Renal Impairment: No dosage adjustment is required in patients with impaired renal function. However, monitor blood levels in patients with severe renal impairment and in patients with both renal and hepatic dysfunctions.
Administrations: IM: Dissolve 250-mg or 500-mg powder for injection in 2 mL, and 1g in 3.5 mL of 1% lidocaine solution and administer by deep intragluteal injection. Ceftriaxone and lidocaine solution must never be administered IV.
IV: Dissolve 250-mg powder for injection in 2 mL, and 500 mg and 1 g in 5 mL water for injection. Administer by IV injection for 2-4 min.
IV Infusion: Ceftriaxone should be administered by IV infusion over a period of 30 min. Dissolve 1-g powder for injection in 40 mL in one of the following calcium-free infusion solutions: 0.9% Sodium Chloride Solution; 0.45% Sodium Chloride + Dextrose 2.5% Solution; Dextrose 5%; Dextrose 10% Solution; Levulose 5% Solution; Dextran 6% Dextrose Solution, Sterile Water for Injections.

Known allergy to the cephalosporin group of antibiotics. Hypersensitivity to lidocaine solution (in case of IM injection).

Make a careful inquiry about previous hypersensitivity reactions to cephalosporins and penicillins before instituting ceftriaxone therapy. Generally, cephalosporins may be given safely to patient who are hypersensitive to penicillins, although cross-reactions have been reported. Any patient who has demonstrated some form of allergy, particularly to drugs, should receive antibiotics, eg ceftriaxone cautiously. Discontinue ceftriaxone if an allergic reaction occurs. Serious hypersensitivity reactions may require epinephrine and other measures.
Like most broad-spectrum antibiotics, prolonged use may give rise to pseudomembranous colitis due to overgrowth of Clostridium difficile. Mild cases usually respond to drug discontinuation. Moderate to severe cases may need fluid and electrolyte supplementation.

Use with caution with history of gastrointestinal disease, especially colitis. Sonographic abnormalities in the gallbladder of patients treated with ceftriaxone have been reported; some of these patients had symptoms of gallbladder disease. These abnormalities appear as an echo without acoustical shadowing suggesting sludge or as an echo with acoustical shadowing which may be misinterpreted as gallstones. Chemical nature of the sonographically detected material has been determined to be predominantly a ceftriaxone salt. Condition appears to be transient and reversible upon discontinuation of ceftriaxone and institution of conservative management. Therefore, discontinue ceftriaxone in patients who develop signs and symptoms suggestive of gallbladder disease and/or sonographic findings.
Superinfecion should always be considered a possibility in patient being treated with a broad-spectrum antimicrobial. Careful observation of the patient is essential. If superinfection occurs during therapy, institute appropriate measures.
Nephrotoxicity has been reported following concomitant administration of aminoglycosides and cephalosporins.
Rarely, alterations in prothrombin time have occurred in patients treated with ceftriaxone. Patients with impaired vitamin K synthesis or low vitamin K administration of 10 mg weekly may be necessary if prothrombin time is prolonged before or during therapy.
Use in pregnancy: Pregnancy Category B. Safely for use during pregnancy has not been established. Use only when clearly needed.
Use in lactation: Since ceftriaxone is excreted in human milk, exercise caution when administered to a nursing woman.
Use in children: In vitro studies show that ceftriaxone can displace bilirubin from serum albumin. Do not administer ceftriaxone to hyperbilirubinemic neonates, especially the premature ones.

Use in pregnancy: Pregnancy Category B. Safely for use during pregnancy has not been established. Use only when clearly needed.
Use in lactation: Since ceftriaxone is excreted in human milk, exercise caution when administered to a nursing woman.

Ceftriaxone is generally well tolerated.
Local Reaction: Pain, induration and tenderness (1%). Phlebitis after IV administration (1%). Incidence of injection site reactions were 17% after 350 mg/mL and 5% after 250 mg/mL, both are IM administration.
Hypersensitivity: Rash (1.7%). Less frequently (<1%), pruritus, fever or chills.
Gastrointestinal: Diarrhea (27%), less frequently (<1%), nausea, vomiting and perversion to the sense of taste. Onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment.
Hematologic: Eosinophilia (6%), thrombocytosis (5.1%), and leukopenia (2.1%). Less frequently (<1%), anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time.
Hepatic: Elevations of AST (3.1%) and ALT (3.3%). Less frequently (<1%), elevations of alkaline phosphatase and bilirubin.
Renal: Elevations of BUN (1.2%). Less frequently (<1%), elevations of creatinine and the presence of casts in the urine.
CNS: Occasionally (<1%), headache or dizziness.
Genitourinary: Occasionally (<1%), moniliasis or vaginitis.
Miscellaneous: Occasionally (<1%), diaphoresis and flushing.
Rarely (<0.1%), adverse events include leukocytosis, lymphocytosis, monocytosis, basophilia, a decrease in prothrombin time, jaundice, gallbladder sludge, glycosuria, hematuria, anaphylaxis, bronchospasm, serum sickness, abnormal pain, colitis, flatulence, dyspepsia, palpitations and epistaxis.

No impairment of renal function or increased nephrotoxicity has been observed in humans after simultaneous administration of ceftriaxone with diuretics, or with aminoglycosides.
A possible disulfiram-like reaction may occur with alcohol.
Ceftriaxone dose not interfere with protein-binding of bilirubin.
Simultaneous administration of probenicid does not alter the elimination of ceftriaxone.

After constitution, solutions retain their physical and chemical stability for 6 hrs at room temperature or 24 hrs at 5°C. Color of solutions ranges from pale yellow to amber, depending on the length of storage, concentration and diluent used.
Due to possible incompatibility, ceftriaxone solutions should not be physically mixed with or piggybacked into solution containing other antimicrobial drugs or into diluent solutions other than those previously mentioned (see Dosage & Administration).
Discard any unused solutions after periods stated.

Store at temperatures not exceeding 30°C. Protect from light.

Cephalosporins

J01DD04 - ceftriaxone ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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