What is Ceftriaxone (a cephalosporin antibiotic)?

What is Ceftriaxone?

Ceftriaxone is a semisynthetic, broad-spectrum third-generation cephalosporin antibiotic administered exclusively by intravenous (IV) or intramuscular (IM) injection—it has no oral formulation and cannot be absorbed from the gastrointestinal tract. 1, 2

Chemical and Pharmacological Properties

• Ceftriaxone sodium is a sterile, semisynthetic cephalosporin with the chemical formula C18H16N8Na2O7S3∙3.5H2O and molecular weight of 661.60 2
• The drug contains approximately 83 mg (3.6 mEq) of sodium per gram of ceftriaxone activity 2
• It appears as a white to yellowish-orange crystalline powder, with solutions ranging from light yellow to amber depending on storage, concentration, and diluent 2

Pharmacokinetics and Dosing Advantages

• Ceftriaxone has an exceptionally long elimination half-life of 5.8-8.7 hours (mean 6.5 hours), which permits once-daily administration—a distinguishing feature among cephalosporins 1, 2, 3, 4
• The drug is completely absorbed following IM administration, with peak plasma concentrations occurring 2-3 hours post-injection 1, 2
• Multiple IV or IM doses ranging from 0.5 to 2 g at 12- to 24-hour intervals result in 15% to 36% accumulation above single-dose values 1, 2
• Ceftriaxone distributes well throughout all body spaces, including cerebrospinal fluid in the presence of meningeal inflammation 4

Antimicrobial Spectrum

Gram-Positive Coverage:

• Excellent activity against Streptococcus pneumoniae (including strains with reduced beta-lactam susceptibility), methicillin-susceptible Staphylococcus aureus, group B streptococci, and viridans group streptococci 2, 5
• Activity against S. pneumoniae is comparable to second-generation agents but generally less than first-generation cephalosporins against many Gram-positive bacteria 1, 3

Gram-Negative Coverage:

• Outstanding bactericidal action against Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Neisseria meningitidis 2, 5, 4
• Excellent activity against Enterobacteriaceae including Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter species 2, 4
• Ceftriaxone has broader Gram-negative coverage than cefazolin, making it preferred for severe community-acquired infections and intra-abdominal infections (when combined with metronidazole) 1
• Some activity against Pseudomonas aeruginosa exists, but ceftriaxone cannot be recommended as sole therapy for pseudomonal infections 2, 3

Anaerobic Coverage:

• Activity against Bacteroides fragilis, Clostridium species (most strains of C. difficile are resistant), and Peptostreptococcus species 2

Clinical Indications

FDA-Approved Uses (per drug label):

• Lower respiratory tract infections 2
• Acute bacterial otitis media 2
• Skin and skin structure infections 2
• Urinary tract infections (complicated and uncomplicated) 2
• Uncomplicated gonorrhea (cervical/urethral, rectal, and pharyngeal) 2
• Pelvic inflammatory disease (must add antichlamydial coverage as ceftriaxone has no activity against Chlamydia trachomatis) 2
• Bacterial septicemia 2
• Bone and joint infections 2
• Intra-abdominal infections 2
• Meningitis caused by H. influenzae, N. meningitidis, or S. pneumoniae 2
• Surgical prophylaxis (single 1 g preoperative dose) 2

Guideline-Recommended Uses:

• For intra-abdominal infections, ceftriaxone (or cefotaxime) combined with metronidazole is recommended as a first-choice option for severe infections and second-choice for mild-to-moderate infections 1
• Ceftriaxone is listed in combination regimens for mild to moderately severe intra-abdominal infections in adults 1
• The drug has been used successfully in limited cases of meningitis and shunt infections caused by Staphylococcus epidermidis and E. coli 2

Clinical Efficacy

• Clinical cure rates consistently exceed 90% across various serious bacterial infections 6, 4
• In pediatric meningitis, 18 of 20 patients recovered (2 deaths at 36 hours) with mean 6 days hospitalization 7
• Recovery achieved in all 11 cases of severe bronchopneumopathy, generally due to S. pneumoniae 7
• For acute bacterial otitis media, one study showed lower clinical cure rates with single-dose ceftriaxone compared to 10 days of oral therapy, though a second study found comparable cure rates 2

Important Clinical Considerations and Pitfalls

Route of Administration:

• A critical pitfall is confusing ceftriaxone with oral cephalosporins—ceftriaxone has no oral formulation and prescribers must specifically order cefixime or another appropriate oral cephalosporin when oral therapy is intended 8, 9
• Cefixime 400 mg orally is the standard oral substitute recommended by the CDC for conditions like gonorrhea when oral therapy is appropriate 1, 8, 9
• However, cefixime provides lower and less sustained bactericidal levels than ceftriaxone 125 mg IM, with higher failure rates for pharyngeal gonorrhea (5.8% vs 1.8%) 8, 9

Resistance Concerns:

• The spread of derepressed mutants hyperproducing chromosomal beta-lactamases and extended-spectrum beta-lactamases has diminished activity against Enterobacteriaceae, necessitating careful attention to sensitivity studies 5
• The broader spectrum of ceftriaxone compared to cefazolin increases risk of promoting antimicrobial resistance and collateral damage to normal flora 10

Dosage and Special Populations:

• Standard adult dosing: 1-2 g IV/IM once daily or in divided doses 2
• Pediatric dosing: 50-75 mg/kg/day in two divided doses; 100 mg/kg/day for CNS infections 6
• Dosage adjustments are not necessary for elderly patients or those with renal or hepatic impairment alone (up to 2 g/day), but modification is needed with combined hepatic and renal dysfunction 2, 4
• Ceftriaxone is not significantly removed by hemodialysis 2

Adverse Effects:

• Most common: diarrhea, nausea, vomiting, candidiasis, and rash 5
• Reversible biliary pseudolithiasis may occur, particularly at higher dosages (≥2 g/day), though true lithiasis incidence is <0.1% 5
• Injection site discomfort or phlebitis can occur 5
• No unique toxicities or hypoprothrombinemic bleeding identified 4

Drug Interactions:

• In vitro antagonistic effects observed with chloramphenicol combination 2
• Elimination not altered when co-administered with probenecid 2
• Calcium interaction: Ceftriaxone recovery from plasma is reduced at calcium concentrations ≥6 mM (24 mg/dL) in adults or ≥4 mM (16 mg/dL) in neonates, reflecting ceftriaxone-calcium precipitation 2