A Comprehensive Monograph on Ceftriaxone (DB01212)

1.0 Abstract and Key Characteristics

Ceftriaxone is a parenteral, small-molecule, third-generation cephalosporin antibiotic renowned for its broad-spectrum bactericidal activity and distinct pharmacokinetic profile.[1] It is classified as a beta-lactam antibiotic, exerting its effect through the irreversible inhibition of bacterial cell wall synthesis by binding to essential penicillin-binding proteins (PBPs).[2] A defining clinical feature of ceftriaxone is its exceptionally long elimination half-life, which averages between 5.8 and 8.7 hours in healthy adults, a characteristic that facilitates convenient once or twice-daily dosing regimens and enhances its suitability for outpatient parenteral antibiotic therapy (OPAT).[1]

The drug's disposition in the body is characterized by a unique dual elimination pathway; approximately 33-67% of an administered dose is excreted unchanged in the urine via glomerular filtration, with the remainder secreted into the bile and subsequently eliminated through the feces as inactive metabolites.[3] This balanced clearance mechanism provides a degree of safety in patients with isolated renal impairment, as the biliary route can compensate. This property, combined with its excellent penetration into a wide range of tissues, body fluids, and, most notably, the cerebrospinal fluid (CSF), establishes ceftriaxone as a cornerstone therapy for a multitude of severe infections, including bacterial meningitis, sepsis, pneumonia, and complicated urinary tract infections.[1]

However, the clinical application of ceftriaxone is governed by critical safety considerations that are directly linked to its physicochemical and pharmacokinetic properties. Its use is absolutely contraindicated in neonates (≤ 28 days) who are receiving or are expected to receive intravenous calcium-containing solutions, due to the risk of fatal ceftriaxone-calcium precipitation in the lungs and kidneys. It is also contraindicated in hyperbilirubinemic neonates because of its potential to displace bilirubin from albumin, leading to a risk of bilirubin encephalopathy (kernicterus).[9] Furthermore, the same high biliary concentration that contributes to its elimination pathway is also the direct cause of its most characteristic adverse effects: reversible biliary pseudolithiasis (sludge) and, in rare instances, pancreatitis secondary to biliary obstruction.[1] Therefore, a nuanced understanding of ceftriaxone requires an appreciation of how its therapeutic advantages and specific risk profile are fundamentally interconnected.

2.0 Chemical Identity and Physicochemical Properties

The precise identification and characterization of ceftriaxone's chemical and physical properties are fundamental to understanding its formulation, stability, and biological activity.

2.1 Nomenclature and Identifiers

Ceftriaxone is identified across various chemical and pharmacological databases by a consistent set of nomenclature and unique codes, ensuring unambiguous reference in clinical and research settings.

• Drug Name: Ceftriaxone [1]
• DrugBank Accession Number: DB01212 [1]
• CAS Number: The primary identifier for the free acid form is 73384-59-5.[1] Related CAS numbers for its common salt forms include 74578-69-1 (disodium salt) and 104376-79-6 (di-hydrochloride salt).[1]
• Systematic (IUPAC) Name: (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.[1]
• Additional Identifiers: A comprehensive list of identifiers is provided in Table 2.1 for cross-referencing purposes.

2.2 Chemical Structure and Formula

Ceftriaxone's structure is that of a third-generation cephalosporin, featuring a core beta-lactam ring fused to a dihydrothiazine ring, which is essential for its antibacterial activity. Its unique properties are conferred by two complex side chains attached to this core.[1]

• Molecular Formula: C18​H18​N8​O7​S3​.[1]
• Molecular Weight: The average mass of the free acid is 554.58 g/mol.[12] The commercially available form is typically the disodium salt sesquaterhydrate ( C18​H16​N8​Na2​O7​S3​⋅3.5H2​O), which has a calculated molecular weight of approximately 661.60 g/mol.[2]
• Structural Description: The molecule possesses two critical side chains. At position C-7 of the cephalosporin nucleus, it has a 2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetylamino group. This moiety is common to several third-generation cephalosporins and is largely responsible for the drug's broad spectrum of activity and stability against many beta-lactamase enzymes.[1] The side chain at position C-3 is a distinctive thiotriazinedione group. Unlike the metabolically labile acetyl group found at the C-3 position of earlier cephalosporins like cefotaxime, this thiotriazinedione moiety is metabolically stable.[14] This structural feature is a primary determinant of ceftriaxone's pharmacological profile; its resistance to metabolic degradation directly contributes to the drug's prolonged presence in the body and its exceptionally long elimination half-life, which is a key clinical advantage.[3] This C-3 side chain is also sufficiently acidic to form a stable enolic sodium salt, leading to the commercial product being formulated as a disodium salt.[14]

2.3 Physical and Chemical Properties

Ceftriaxone is formulated as a sterile product for parenteral administration, and its physical properties are consistent with this use.

• Appearance: It is a white to yellowish-orange crystalline powder.[2]
• Solubility: The sodium salt is readily soluble in water, sparingly soluble in methanol, and very slightly soluble in ethanol.[2] It also shows slight solubility in DMSO.[12]
• Stability and Formulation: The drug is hygroscopic.[14] Aqueous solutions of ceftriaxone are light yellow to amber in color. A progressive darkening of the solution to a deeper amber or reddish hue suggests hydrolysis of the beta-lactam ring, which compromises the drug's antimicrobial activity and indicates degradation.[3] It is supplied either as a sterile powder for reconstitution or as a premixed, frozen iso-osmotic solution in a dextrose diluent for intravenous use.[8] Each gram of ceftriaxone activity contains approximately 83 mg (3.6 mEq) of sodium, a factor to consider in patients on sodium-restricted diets.[2] The pH of a 1% aqueous solution is approximately 6.7.[2]

Table 2.1: Chemical and Physical Properties of Ceftriaxone

Property	Value	Source(s)
IUPAC Name	(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-5,6-dioxo-1H-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid	1
CAS Number	73384-59-5 (free acid)	1
Molecular Formula	C18​H18​N8​O7​S3​	1
Molecular Weight	554.58 g/mol (free acid, average)	12
Appearance	White to yellowish-orange crystalline powder	2
Solubility (Sodium Salt)	Readily soluble in water; sparingly in methanol; very slightly in ethanol	2
pKa	Multiple predicted values, including ~2.6, ~2.9, and ~8.0	14
LogP	-1.7	12
Stability	Hygroscopic; solutions may darken upon storage, indicating degradation	3
InChIKey	VAAUVRVFOQPIGI-SPQHTLEESA-N	1
FDA UNII	75J73V1629	1

3.0 Clinical Pharmacology

The clinical efficacy of ceftriaxone is rooted in its potent pharmacodynamic action against susceptible bacteria and the mechanisms by which bacteria attempt to subvert this activity.

3.1 Mechanism of Action (Pharmacodynamics)

Ceftriaxone is a bactericidal antibiotic, meaning it actively kills bacteria rather than simply inhibiting their growth.[2] Its mechanism is targeted at a structure unique to bacteria and essential for their survival: the cell wall.

• Primary Action: The fundamental mechanism of action is the inhibition of bacterial cell wall synthesis.[2] The bacterial cell wall is composed of peptidoglycan, a rigid polymer that protects the cell from osmotic lysis.
• Molecular Target: As a member of the beta-lactam class of antibiotics, ceftriaxone's chemical structure contains a beta-lactam ring that functions as a structural analog of the D-alanyl-D-alanine dipeptide, a natural substrate in peptidoglycan synthesis.[4] This mimicry allows ceftriaxone to selectively and irreversibly bind to a group of bacterial enzymes known as penicillin-binding proteins (PBPs), which include transpeptidases, endopeptidases, and carboxypeptidases located in the bacterial cytoplasmic membrane.[3]
• Consequence of Binding: The binding of ceftriaxone to the active site of these PBPs inactivates them. This enzymatic inhibition blocks the final transpeptidation step of peptidoglycan synthesis, which is the crucial cross-linking of peptide chains that gives the cell wall its structural integrity.[3] The arrest of cell wall assembly results in the formation of a defective, weakened wall that is unable to withstand the internal osmotic pressure of the bacterial cell. This ultimately leads to cell swelling, lysis, and bacterial death.[3]
• Beta-Lactamase Stability: A pivotal characteristic of ceftriaxone is its high degree of stability in the presence of many, but not all, beta-lactamase enzymes.[1] These enzymes, which include both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria, are a primary mechanism of resistance to other beta-lactam antibiotics. Ceftriaxone's structural resilience to hydrolysis by these enzymes allows it to maintain activity against many organisms that are resistant to older penicillins and earlier-generation cephalosporins.[5]

3.2 Mechanisms of Resistance

Despite its stability, bacterial resistance to ceftriaxone is a growing clinical concern and can develop through several well-defined mechanisms.[5] The prudent use of this antibiotic is essential to preserve its efficacy.

1. Enzymatic Hydrolysis by Beta-Lactamases: While ceftriaxone is stable against many common beta-lactamases, its efficacy can be compromised by certain potent enzymes. The production of extended-spectrum beta-lactamases (ESBLs) and AmpC-type cephalosporinases are significant mechanisms of resistance, particularly in Gram-negative bacteria like E. coli and Klebsiella spp..[5] These enzymes are capable of hydrolyzing the beta-lactam ring of ceftriaxone, rendering it inactive. Furthermore, some organisms, such as Citrobacter, Providencia, and Serratia species, possess inducible chromosomal AmpC beta-lactamases. Exposure to ceftriaxone can select for derepressed mutants that constitutively overproduce these enzymes, leading to the development of resistance during therapy.[3] The widespread prevalence of international ceftriaxone formulations combined with beta-lactamase inhibitors like sulbactam or tazobactam is a direct clinical and market response to the challenge posed by these resistance enzymes.[20]
2. Alteration of Target Site (PBPs): Resistance can arise from genetic mutations that alter the structure of the penicillin-binding proteins.[5] These modifications reduce the binding affinity of ceftriaxone for its target, preventing effective inhibition of cell wall synthesis. This is the primary mechanism of resistance in methicillin-resistant Staphylococcus aureus (MRSA), which produces a unique PBP (PBP2a) with very low affinity for most beta-lactam antibiotics, including ceftriaxone. It is also a key mechanism in the development of high-level penicillin and cephalosporin resistance in Streptococcus pneumoniae.
3. Decreased Permeability: In Gram-negative bacteria, ceftriaxone must pass through porin channels in the outer membrane to reach the PBPs in the periplasmic space. Mutations that lead to the loss or modification of these porin channels can restrict the antibiotic's entry into the cell, thereby reducing its effective concentration at the target site and conferring a degree of resistance.[5] This mechanism often works in concert with beta-lactamase production to produce higher levels of resistance.

The clinical implication of these resistance mechanisms is profound. It underscores the importance of the recommendation found on drug labels: therapy may be initiated empirically based on likely pathogens, but it should be guided by culture and susceptibility testing whenever possible to ensure optimal treatment and to mitigate the further development of drug-resistant bacteria.[3]

4.0 Pharmacokinetic Profile

The pharmacokinetic profile of ceftriaxone is distinct among cephalosporins and is central to both its therapeutic advantages and its specific safety concerns. Its long half-life, high protein binding, and dual elimination pathway define its clinical utility.

4.1 Absorption

Ceftriaxone is not absorbed orally and requires parenteral administration.[3]

• Administration Routes: It is administered either intravenously (IV) or intramuscularly (IM).[2]
• Bioavailability: Following IM administration, absorption is rapid and complete.[3] Peak plasma concentrations are typically achieved within 2 to 3 hours post-injection.[16]
• Accumulation: With multiple-dose regimens (e.g., 0.5 to 2 g every 12 or 24 hours), a modest and predictable plasma accumulation of 15% to 36% is observed. Importantly, the elimination half-life does not change with multiple dosing, indicating linear and predictable kinetics within the standard therapeutic range.[6]

4.2 Distribution

Ceftriaxone distributes widely throughout the body, achieving therapeutic concentrations in many tissues and body fluids, including sites of infection that are difficult for many other antibiotics to reach.

• Volume of Distribution (Vd): In healthy adult subjects, the apparent volume of distribution ranges from 5.8 to 13.5 L.[3] This relatively small Vd suggests that the drug is primarily distributed within the plasma and extracellular fluid. In critically ill septic patients, the Vd can be significantly larger, with a reported range of 6.48 to 35.2 L, reflecting fluid shifts and altered physiology in this population.[5]
• Protein Binding: Ceftriaxone is highly but reversibly bound to human plasma proteins, primarily albumin.[3] This binding is concentration-dependent; the bound fraction decreases as the plasma concentration of the drug increases. At concentrations below 25 mcg/mL, approximately 95% of the drug is protein-bound, whereas at a higher concentration of 300 mcg/mL, the bound fraction drops to 85%.[3] This non-linear binding can slightly affect the drug's pharmacokinetics at different dose levels.
• Tissue and Fluid Penetration: The drug demonstrates excellent penetration into various tissues and body fluids.[3] It is known to achieve high concentrations in the eyes, inner ear, and bile.[1] The elimination half-life in middle ear fluid has been estimated to be as long as 25 hours, contributing to its efficacy in treating otitis media.[5]
• Cerebrospinal Fluid (CSF) Penetration: A hallmark of ceftriaxone is its ability to cross the blood-brain barrier and penetrate the meninges, particularly when they are inflamed during meningitis.[1] In pediatric patients with bacterial meningitis, mean CSF concentrations of 5.6 to 6.4 mcg/mL have been measured, with ranges extending up to 18.5 mcg/mL or higher, well above the minimum inhibitory concentrations (MICs) for common meningeal pathogens.[2] This property establishes ceftriaxone as a first-line agent for treating bacterial meningitis.

4.3 Metabolism

Ceftriaxone undergoes very little metabolism in the body. The majority of the drug that is not eliminated by the kidneys is handled by the biliary system and gut flora.[3]

• Hepatic Metabolism: Systemic metabolism of ceftriaxone is negligible.[5]
• Intestinal Metabolism: The portion of the drug secreted into the bile (up to 67% of the dose) is ultimately broken down into microbiologically inactive compounds by the normal flora of the gut before being excreted in the feces.[3]

4.4 Elimination

Ceftriaxone is distinguished by its exceptionally long elimination half-life and a balanced, dual pathway of excretion.

• Dual Excretion Pathway: The drug is cleared from the body by both renal and biliary routes. Approximately 33-67% of an administered dose is excreted unchanged by the kidneys, primarily through glomerular filtration.[3] The remainder of the dose is secreted into the bile and eliminated via the gastrointestinal tract.[3]
• Elimination Half-Life (t1/2​): Compared to other cephalosporins, which often have half-lives of 1-2 hours, ceftriaxone has a remarkably long elimination half-life. In healthy adults, it typically ranges from 5.8 to 8.7 hours, with some estimates extending up to 10 hours.[1] This prolonged half-life is the basis for its convenient once or twice-daily dosing schedule.
• Clearance: The total plasma clearance in healthy adults ranges from 0.58 to 1.45 L/hour. Renal clearance, which represents the portion eliminated by the kidneys, accounts for 0.32 to 0.73 L/hour of this total.[5]

4.5 Pharmacokinetics in Special Populations

The unique pharmacokinetic profile of ceftriaxone leads to specific considerations in various patient populations. The dual elimination pathway provides a remarkable degree of flexibility and safety in cases of isolated organ dysfunction. However, this compensatory advantage is lost when both major elimination routes are compromised.

• Pediatric Patients: The volume of distribution and plasma clearance of ceftriaxone are approximately threefold higher in pediatric patients compared to adults. Despite these differences, the drug achieves excellent therapeutic concentrations in the CSF of infants and children with bacterial meningitis, establishing its efficacy in this population.[6]
• Geriatric Patients: The pharmacokinetics are only minimally altered in elderly subjects. Consequently, dosage adjustments are generally not necessary for geriatric patients receiving standard doses up to 2 grams per day, provided there is no severe concurrent renal and hepatic impairment.[6]
• Renal Impairment: Because the biliary excretion pathway can compensate for reduced kidney function, dosage adjustments are typically not required for patients with renal failure who are receiving usual doses of ceftriaxone (up to 2 g/day).[6] The body effectively shifts a larger proportion of the drug's elimination to the biliary route. However, the elimination half-life is significantly prolonged in these patients, increasing from a mean of 6.4 hours in those with normal renal function to as long as 11.4–21.4 hours in patients with renal failure.[3] Ceftriaxone is not removed from the body to any significant extent by hemodialysis or peritoneal dialysis.[6]
• Hepatic Impairment: Similarly, in patients with only hepatic dysfunction, the kidneys can compensate by increasing renal excretion of the drug. Therefore, dosage adjustments are generally not necessary in this population either.[9]
• Combined Renal and Hepatic Impairment: The "forgiving" nature of ceftriaxone's pharmacokinetics ceases when both major elimination pathways are significantly impaired. In patients with both severe renal disease (e.g., dialysis patients) and significant hepatic dysfunction, the drug has limited routes of clearance and can accumulate to potentially toxic levels. In this specific and high-risk population, caution is strongly advised, the total daily dosage should not exceed 2 grams, and close clinical monitoring of plasma concentrations for safety and efficacy is recommended.[9]

Table 4.1: Key Pharmacokinetic Parameters of Ceftriaxone in Diverse Patient Populations

Parameter	Healthy Adults	Pediatric Patients	Renal Failure	Hepatic Dysfunction	Combined Severe Renal & Hepatic Impairment
Elimination Half-Life (t1/2​)	5.8–8.7 hours 5	Shorter than adults	11.4–21.4 hours 7	Minimally altered	Significantly prolonged
Volume of Distribution (Vd)	5.8–13.5 L 5	~3x greater than adults 6	Increased (mean 33.5 L) 7	Minimally altered	Altered
Protein Binding (%)	85–95% (concentration-dependent) 3	Similar to adults	Similar to adults	Similar to adults	Similar to adults
Primary Elimination Route(s)	Renal (33-67%) and Biliary 3	Renal and Biliary	Primarily Biliary	Primarily Renal	Both pathways impaired
Dosing Adjustment	Standard dosing	Weight-based dosing	No adjustment for usual doses (≤2 g/day) 9	No adjustment for usual doses 9	Caution advised; do not exceed 2 g/day; monitor levels 9

5.0 Antimicrobial Spectrum of Activity

Ceftriaxone is a broad-spectrum antibiotic, but its clinical utility is defined by its specific pattern of activity, including its key strengths against certain pathogens and notable gaps in its coverage.

5.1 General Spectrum

Ceftriaxone exhibits potent bactericidal activity against a wide array of Gram-positive and Gram-negative bacteria.[1] Its spectrum is characterized by enhanced activity against Gram-negative organisms compared to first and second-generation cephalosporins, while retaining useful activity against many important Gram-positive pathogens.[1]

5.2 Gram-Positive Aerobes

• Streptococci: Ceftriaxone demonstrates excellent activity against Streptococcus pneumoniae, including many strains that are non-susceptible to penicillin, making it a cornerstone for treating pneumococcal infections like pneumonia and meningitis.[1] It is also highly active against Streptococcus pyogenes (Group A beta-hemolytic streptococci).[1]
• Staphylococci: The drug is active against coagulase-negative staphylococci and methicillin-susceptible Staphylococcus aureus (MSSA).[1] However, its in vitro activity against MSSA is generally considered less potent than that of first or second-generation cephalosporins.[1] For serious MSSA infections like endocarditis, higher doses (e.g., 2 g IV every 12 hours) are sometimes employed to ensure adequate therapeutic concentrations.[3] It is critically important to note that ceftriaxone has no clinically useful activity against methicillin-resistant S. aureus (MRSA).

5.3 Gram-Negative Aerobes

Ceftriaxone's strength lies in its extensive coverage of Gram-negative pathogens.

• Neisseria species: It is highly potent against Neisseria gonorrhoeae, establishing it as a first-line therapy for gonococcal infections.[1] It is also a drug of choice for treating meningitis caused by Neisseria meningitidis.[3]
• Haemophilus influenzae: It has excellent activity against H. influenzae, including strains that produce beta-lactamase enzymes and are resistant to ampicillin.[1]
• Enterobacteriaceae: Ceftriaxone provides reliable coverage for a wide range of Enterobacteriaceae, including common pathogens like Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.[1] It is also active against Serratia marcescens, Citrobacter species, and Enterobacter species, and is often effective against strains that are multi-drug resistant.[1]
• Pseudomonas aeruginosa: This represents a major and clinically significant gap in ceftriaxone's spectrum. Ceftriaxone lacks useful activity against P. aeruginosa.[3] This is a key feature that distinguishes it from other third-generation cephalosporins like ceftazidime or the fourth-generation cefepime, which are specifically designed for anti-pseudomonal coverage.

5.4 Anaerobes and Other Organisms

• Anaerobes: Ceftriaxone has activity against some oral anaerobes.[1] While in vitro data shows some activity against organisms like Bacteroides fragilis, the minimum inhibitory concentrations can be high, and its anaerobic coverage is not considered as robust or reliable as dedicated anti-anaerobic agents.[16]
• Spirochetes: It is an effective treatment for infections caused by the spirochete Borrelia burgdorferi, the causative agent of Lyme disease, particularly in cases of disseminated or neurological disease.[1]
• Organisms Not Covered: In addition to MRSA and P. aeruginosa, ceftriaxone is not active against several other clinically important pathogens. These include Listeria monocytogenes, Enterococci (e.g., Enterococcus faecalis, E. faecium), and atypical bacteria such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila. The lack of coverage for Listeria is particularly important in the context of empiric therapy for meningitis. While ceftriaxone is a drug of choice for meningitis caused by common pathogens, its ineffectiveness against Listeria necessitates the addition of ampicillin to the empiric regimen for patients at risk for listerial meningitis (e.g., neonates, adults over 50, and immunocompromised individuals) to ensure adequate coverage.[3]

5.5 In Vitro Susceptibility Data

Standardized in vitro susceptibility testing provides quantitative data on ceftriaxone's potency against key bacterial isolates. The following data is derived from quality control (QC) ranges specified in FDA-approved labeling.

Table 5.1: In-Vitro Susceptibility Data for Ceftriaxone Against QC Strains

Organism	ATCC Strain	MIC Range (mcg/mL)	Disk Diffusion Zone Diameters (mm)
Escherichia coli	ATCC 25922	0.03 - 0.12	29 - 35
Staphylococcus aureus	ATCC 25923	---------	22 - 28
Staphylococcus aureus	ATCC 29213	1 – 8	---------
Haemophilus influenzae	ATCC 49247	0.06 - 0.25	31 - 39
Neisseria gonorrhoeae	ATCC 49226	0.004 - 0.015	39 - 51
Pseudomonas aeruginosa	ATCC 27853	8 - 64	17 - 23
Streptococcus pneumoniae	ATCC 49619	0.03 - 0.12	30 - 35
Bacteroides fragilis	ATCC 25285	32 – 128	---------
Source: 16

6.0 Clinical Indications and Therapeutic Use

Ceftriaxone is a widely used antibiotic indicated for the treatment of a broad range of moderate to severe bacterial infections. Its use is guided by its spectrum of activity, favorable pharmacokinetics, and extensive clinical experience.

6.1 FDA-Approved and Major Global Indications

Ceftriaxone is indicated for the treatment of the following infections when caused by susceptible organisms [1]:

• Lower Respiratory Tract Infections: Including community-acquired and hospital-acquired pneumonia caused by pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, and methicillin-susceptible Staphylococcus aureus.[16]
• Bacterial Meningitis: A primary indication due to its excellent penetration into the cerebrospinal fluid. It is a drug of choice for meningitis caused by S. pneumoniae, N. meningitidis, and H. influenzae.[3]
• Bacterial Septicemia and Sepsis: Used for the treatment of bloodstream infections caused by susceptible organisms.[3] It is currently being studied in recruiting clinical trials for sepsis.[26]
• Skin and Skin Structure Infections: For infections caused by susceptible Gram-positive and Gram-negative bacteria.[1]
• Urinary Tract Infections (UTIs): Effective for both complicated and uncomplicated UTIs.[1]
• Bone and Joint Infections: Such as osteomyelitis and septic arthritis.[3]
• Intra-abdominal Infections: Often used in combination with an agent that covers anaerobes, such as metronidazole.[3]
• Uncomplicated Gonorrhea: A single-dose regimen is a standard treatment for gonococcal infections of the cervix, urethra, rectum, and pharynx.[3]
• Pelvic Inflammatory Disease (PID): Used as part of a combination regimen for PID.[3]

6.2 Surgical Prophylaxis

Ceftriaxone is frequently administered as a single dose prior to certain surgical procedures to prevent the development of postoperative infections. Its long half-life makes it particularly suitable for this indication, providing sustained antimicrobial coverage throughout the perioperative period.[3] A recruiting clinical trial is currently investigating its use for infection prevention in anterior cruciate ligament (ACL) reconstruction surgery.[27]

6.3 Other and Off-Label Uses

Beyond its primary approved indications, ceftriaxone is used to treat several other conditions based on clinical evidence and guidelines:

• Infective Endocarditis: Used for the treatment of endocarditis caused by susceptible organisms, such as viridans group streptococci and MSSA.[3] A completed Phase 2 clinical trial has evaluated a specific ceftriaxone regimen for treating infective endocarditis caused by Enterococcus faecalis, an organism typically considered resistant to cephalosporins.[28] This investigation into expanding its use against less susceptible organisms highlights ongoing efforts to optimize therapy, likely leveraging its favorable long half-life for outpatient treatment regimens.
• Lyme Disease: It is a standard therapy for disseminated or late-stage Lyme disease, particularly manifestations involving the central nervous system (neuroborreliosis) or heart (Lyme carditis).[1]
• Typhoid Fever: Caused by Salmonella Typhi.[18]
• Other Infections: It is also used for chancroid, relapsing fever, and severe Salmonella or Shigella infections.[8]
• Febrile Neutropenia: It may be used as part of an empiric regimen for patients with fever and a low white blood cell count who are at high risk for infection.[8]

6.4 Antimicrobial Stewardship

Regulatory labels and clinical guidelines strongly emphasize the principles of antimicrobial stewardship in the use of ceftriaxone. To reduce the development of drug-resistant bacteria and maintain its effectiveness, ceftriaxone should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.[9] While empiric therapy may be initiated before susceptibility results are known, treatment should be tailored based on culture and susceptibility information once it becomes available.[3] This approach ensures optimal patient outcomes while preserving the utility of this important antibiotic for future generations.

7.0 Dosage and Administration

The administration of ceftriaxone must be tailored to the patient's age, weight, the severity and site of infection, and renal and hepatic function.

7.1 Routes of Administration

Ceftriaxone is administered parenterally, as it is not absorbed from the gastrointestinal tract.[3]

• Intravenous (IV) Injection/Infusion: Can be administered as a slow IV injection or, more commonly, as an IV infusion over a period of 30 to 60 minutes.[8]
• Intramuscular (IM) Injection: Can be given as a deep IM injection. For larger doses, it is often recommended to divide the dose between two different sites.[2]

7.2 Adult Dosing

• Standard Dose: The usual adult daily dose is 1 to 2 grams administered once a day or in two equally divided doses, depending on the type and severity of the infection. The total daily dose should generally not exceed 4 grams.[18]
• Uncomplicated Gonorrhea: A single intramuscular dose of 250 mg or 500 mg is a standard regimen, though local guidelines should always be consulted.[29]
• Surgical Prophylaxis: A single 1-gram dose administered intravenously 30 minutes to 2 hours before the surgical incision is a typical prophylactic regimen.
• Meningitis: Higher doses are required, typically 2 grams IV every 12 hours.

7.3 Pediatric Dosing

Dosing in pediatric patients is based on body weight and the specific indication.

• General Infections (non-meningitis): The recommended daily dose is 50 to 75 mg/kg, given once daily or in two divided doses every 12 hours. The total daily dose should not exceed 2 grams.
• Bacterial Meningitis: A higher dose of 100 mg/kg/day is recommended, often initiated with a loading dose of 100 mg/kg. The total daily dose should not exceed 4 grams. Treatment duration is typically 7 to 14 days.[18]
• Acute Otitis Media: A single intramuscular dose of 50 mg/kg (not to exceed 1 gram) can be used.
• Skin and Soft Tissue Infections: 50 to 75 mg/kg once daily or in divided doses (not to exceed 2 grams/day).

7.4 Dosage in Special Populations

• Renal and Hepatic Impairment: As detailed in the pharmacokinetics section, no dosage adjustment is typically necessary for patients with either isolated renal impairment or isolated hepatic impairment when receiving doses up to 2 grams per day.[6]
• Combined Severe Renal and Hepatic Impairment: In patients with both significant renal disease (e.g., on dialysis) and severe hepatic dysfunction, the dose should not exceed 2 grams daily, and plasma concentrations of ceftriaxone should be monitored to avoid accumulation.[6]

7.5 Reconstitution and Administration Guidelines

Proper preparation of ceftriaxone is critical to ensure safety and efficacy.

• Reconstitution: The sterile powder is reconstituted with a compatible diluent (e.g., Sterile Water for Injection, Normal Saline, Dextrose 5% in Water) prior to administration.[8]
• Calcium Incompatibility: CRITICAL WARNING: Diluents containing calcium, such as Ringer's solution or Hartmann's solution, must not be used to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration, as a precipitate can form.[9] Ceftriaxone must not be mixed or administered simultaneously with any calcium-containing solutions in the same IV line.[11]
• Intramuscular Administration: To reduce the pain of IM injection, ceftriaxone may be reconstituted with 1% Lidocaine Hydrochloride solution (without epinephrine). However, if lidocaine is used as the diluent, the resulting solution must only be administered intramuscularly and NEVER intravenously. Furthermore, all contraindications to lidocaine must be considered before its use.[9]

8.0 Safety and Tolerability Profile

While generally well-tolerated, ceftriaxone is associated with a range of adverse reactions, from common and mild to rare and life-threatening. A thorough understanding of its safety profile is essential for its appropriate use.

8.1 Overview of Adverse Reactions

The most frequently reported adverse reactions in clinical trials are typically mild and self-limiting [17]:

• Hematologic: Eosinophilia (6%), thrombocytosis (increased platelets, 5.1%), and leukopenia (decreased white blood cells, 2.1%).
• Gastrointestinal: Diarrhea (2.7%).
• Hepatic: Transient elevations of liver enzymes, specifically SGOT (AST, 3.1%) or SGPT (ALT, 3.3%).
• Dermatologic: Rash (1.7%).
• Local Reactions: Pain, induration (hardness), and tenderness at the injection site (1% overall), with phlebitis (vein inflammation) reported in <1% after IV administration.

8.2 Detailed Adverse Reactions by System Organ Class

A more comprehensive list of adverse events, categorized by organ system and including rarer but more severe reactions, is presented in Table 8.1. The following are among the most clinically significant.

• Hypersensitivity Reactions: These can range from mild maculopapular rash, pruritus (itching), and fever to severe, life-threatening reactions such as anaphylaxis.[17] Rare but severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported.[11]
• Gastrointestinal System: Diarrhea is common. A critical and potentially fatal adverse effect is the development of Clostridium difficile-associated diarrhea (CDAD). This condition, caused by the overgrowth of toxin-producing C. difficile in the colon, can manifest as mild diarrhea or severe, life-threatening pseudomembranous colitis. It can occur during therapy or for up to two or more months after treatment has been discontinued.[8] Nausea, vomiting, and pancreatitis (inflammation of the pancreas) have also been reported.[11]
• Hepatic and Biliary System: The most distinctive adverse effect of ceftriaxone relates to its high concentration and excretion in bile. This can lead to the formation of ceftriaxone-calcium precipitates within the gallbladder, which appear as biliary sludge or "pseudolithiasis" on ultrasound. This condition is more common in pediatric patients and is typically asymptomatic and reversible upon discontinuation of the drug. However, it can occasionally become symptomatic, causing biliary colic (gallstone-like pain).[1] The biliary obstruction caused by this sludge is also thought to be a potential trigger for the rare cases of pancreatitis associated with ceftriaxone use.[11]
• Renal and Urinary System: Similar to the biliary effects, the high renal concentration of ceftriaxone can lead to the formation of ceftriaxone-calcium precipitates in the urinary tract. This can result in crystalluria, urolithiasis (kidney stones), and, in rare cases, ureteric obstruction leading to post-renal acute renal failure. This complication is also more frequently observed in children.[3]
• Hematologic System: In addition to the more common effects on blood counts, rare but serious hematologic toxicities can occur. Immune-mediated hemolytic anemia has been reported and can be severe and fatal; if a patient develops anemia during treatment, this diagnosis should be considered and the drug stopped immediately.[11] Alterations in coagulation, specifically hypoprothrombinemia (prolongation of the prothrombin time), can occur, particularly in patients with underlying malnutrition or liver disease, increasing the risk of bleeding.[3]
• Nervous System: Headache and dizziness are reported occasionally.[17] Rare but serious neurological adverse events include seizures, myoclonus, and encephalopathy (characterized by confusion, lethargy, or somnolence). These events have been particularly noted in patients with severe renal impairment who did not receive appropriate dosage adjustments, leading to drug accumulation.[9] In neonates, there is a risk of kernicterus due to bilirubin displacement.[31]

The unique toxicity profile of ceftriaxone can be understood as a "precipitation cascade." The drug's fundamental physicochemical property—its propensity to precipitate with calcium—manifests across multiple organ systems due to its high concentrations in both bile and urine. This single underlying mechanism connects the seemingly disparate adverse events of biliary pseudolithiasis, secondary pancreatitis, and renal urolithiasis, providing a unified framework for understanding its most significant non-allergic risks.

Table 8.1: Adverse Reactions to Ceftriaxone by System Organ Class and Frequency

System Organ Class	Frequency	Adverse Reaction(s)
Local Reactions	Common (1-10%)	Pain, induration, tenderness at injection site; phlebitis after IV administration 17
Hypersensitivity	Common (1-10%)	Rash 17
	Uncommon (0.1-1%)	Pruritus, fever, chills 17
	Rare (<0.1%) / Postmarketing	Anaphylaxis, bronchospasm, serum sickness, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) 29
Gastrointestinal	Common (1-10%)	Diarrhea 17
	Uncommon (0.1-1%)	Nausea, vomiting, dysgeusia (taste change) 17
	Rare (<0.1%) / Postmarketing	Pseudomembranous colitis (C. difficile-associated diarrhea), pancreatitis, stomatitis, glossitis 29
Hepatic / Biliary	Common (1-10%)	Elevations of SGOT (AST) and SGPT (ALT) 17
	Uncommon (0.1-1%)	Elevations of alkaline phosphatase and bilirubin 17
	Rare (<0.1%) / Postmarketing	Biliary pseudolithiasis (sludge/gallstones), cholestatic jaundice, hepatitis 1
Hematologic	Common (1-10%)	Eosinophilia, thrombocytosis, leukopenia 17
	Uncommon (0.1-1%)	Anemia, neutropenia, lymphopenia, thrombocytopenia, prolongation of prothrombin time 17
	Rare (<0.1%) / Postmarketing	Immune-mediated hemolytic anemia (can be fatal), agranulocytosis, bleeding 29
Renal	Common (1-10%)	Elevations of BUN 17
	Uncommon (0.1-1%)	Elevations of creatinine, presence of urinary casts 17
	Rare (<0.1%) / Postmarketing	Renal precipitations (urolithiasis), ureteric obstruction, post-renal acute renal failure 9
Nervous System	Uncommon (0.1-1%)	Headache, dizziness 17
	Rare (<0.1%) / Postmarketing	Seizures, encephalopathy (confusion, somnolence), myoclonus, vertigo, kernicterus (in neonates) 9

9.0 Contraindications, Warnings, and Drug Interactions

The safe use of ceftriaxone is critically dependent on adherence to its specific contraindications and an awareness of its significant warnings and potential drug interactions.

9.1 Absolute Contraindications

There are several situations in which the use of ceftriaxone is absolutely contraindicated due to the risk of severe or fatal adverse outcomes.

• Hypersensitivity: Ceftriaxone is contraindicated in patients with a known history of hypersensitivity to ceftriaxone or any other cephalosporin antibiotic. Caution is also warranted in patients with a history of severe, immediate-type hypersensitivity reactions (e.g., anaphylaxis) to penicillins or other beta-lactam agents due to the potential for cross-reactivity.[9]
• Neonates (Age ≤ 28 days): The neonatal population has two critical contraindications:

1. Concurrent use with Calcium-Containing IV Solutions: Ceftriaxone is strictly contraindicated in neonates if they require (or are expected to require) treatment with IV calcium-containing solutions, including continuous infusions such as parenteral nutrition. Ceftriaxone and calcium must not be administered simultaneously, even through different infusion lines or at different sites, because of the risk of fatal precipitation of ceftriaxone-calcium salt in the lungs and kidneys. This prohibition extends for a period of 48 hours between the administration of ceftriaxone and any calcium-containing product in this age group.[9]
2. Hyperbilirubinemic Neonates: Ceftriaxone is contraindicated in both premature and term neonates with hyperbilirubinemia (high bilirubin levels). In vitro studies have shown that ceftriaxone can displace bilirubin from its binding sites on serum albumin. This increases the level of free, unbound bilirubin in the blood, which can cross the immature blood-brain barrier and lead to bilirubin encephalopathy, a devastating neurological condition also known as kernicterus.[9]

• Lidocaine Diluent (IV use): When ceftriaxone is reconstituted with lidocaine solution for IM injection to reduce pain, the resulting solution is for IM use only. Intravenous administration of ceftriaxone solutions containing lidocaine is contraindicated.[9]

9.2 Warnings and Precautions

Beyond absolute contraindications, several important warnings require careful consideration and monitoring during therapy.

• Immune-Mediated Hemolytic Anemia: Severe and sometimes fatal cases of immune-mediated hemolytic anemia have been reported. If a patient develops anemia while receiving ceftriaxone, the diagnosis of a cephalosporin-associated anemia should be considered, and the drug must be discontinued until the etiology is determined.[11]
• Clostridium difficile-Associated Diarrhea (CDAD): As with nearly all antibacterial agents, CDAD has been reported with ceftriaxone. It must be considered in any patient who presents with diarrhea following antibiotic use, even months after therapy has ended.[9]
• Alterations in Prothrombin Time: Ceftriaxone can interfere with the vitamin K-dependent clotting cascade, leading to hypoprothrombinemia and an increased risk of bleeding. This is of particular concern in patients with pre-existing risk factors such as chronic hepatic disease, malnutrition, or impaired vitamin K synthesis. Prothrombin time should be monitored in these patients, and vitamin K administration (10 mg weekly) may be necessary if it becomes prolonged.[3]
• Gallbladder Pseudolithiasis and Urolithiasis: Patients should be monitored for signs and symptoms of gallbladder disease or urolithiasis. If symptomatic, discontinuation of ceftriaxone and conservative management are recommended.[9]
• Pancreatitis: Cases of pancreatitis, potentially secondary to biliary obstruction from ceftriaxone-calcium sludge, have been reported.[11]

9.3 Clinically Significant Drug Interactions

• Calcium-Containing Solutions: This is the most critical and well-documented drug interaction. In any patient older than 28 days, ceftriaxone and calcium-containing solutions may be administered sequentially if the infusion lines are thoroughly flushed with a compatible fluid between infusions. However, they must not be mixed in the same container or administered simultaneously via a Y-site in any patient, regardless of age.[11]
• Anticoagulants: Concomitant use with vitamin K antagonists like warfarin may increase the risk of bleeding due to ceftriaxone's potential effect on prothrombin time. Frequent monitoring of coagulation parameters is recommended.[5]
• Aminoglycosides: Although a class warning for all cephalosporins, co-administration with aminoglycosides (e.g., gentamicin) may potentially increase the risk of nephrotoxicity. Monitoring of renal function is advised.[18]
• Chloramphenicol: In vitro studies have demonstrated an antagonistic effect between chloramphenicol and ceftriaxone. This combination should generally be avoided.[16]
• Ethanol: Although extremely infrequent, disulfiram-like reactions between ceftriaxone and ethanol have been described in the literature.[19]
• Probenecid: In a notable departure from its interaction with many other beta-lactam antibiotics like penicillin, probenecid does not affect the elimination of ceftriaxone. This is because ceftriaxone's renal clearance is primarily via glomerular filtration, a process not blocked by probenecid, rather than active tubular secretion.[16]

9.4 Disease-State Interactions

Certain pre-existing conditions can increase the risk of adverse events with ceftriaxone.

• History of Colitis: Patients with a history of gastrointestinal disease, particularly colitis, should be treated with caution due to the increased risk of developing CDAD.[8]
• Gallbladder Disease: Pre-existing gallbladder disease may be exacerbated by the formation of ceftriaxone-calcium sludge.[23]
• Combined Renal/Liver Disease: As previously noted, patients with severe co-existing renal and hepatic impairment are at risk for drug accumulation and require dosage limitation and careful monitoring.[9]

10.0 Pharmacogenomics

The influence of genetic variations on the safety and efficacy of ceftriaxone is an area of emerging, though not fully established, knowledge. The primary pharmacogenomic concern that has been historically associated with ceftriaxone involves the risk of methemoglobinemia.

• Methemoglobinemia Risk: An older FDA-approved label for the brand name product Rocephin, particularly in the context of co-administration with local anesthetics such as lidocaine, included a warning that individuals with certain genetic conditions may be at an increased risk for developing drug-induced methemoglobinemia. The specific conditions mentioned were glucose-6-phosphate dehydrogenase (G6PD) deficiency and congenital methemoglobinemia (often associated with variants in the CYB5R3 gene).[38]
• Evolving Information and Label Changes: It is significant to note that this information appears to be dynamic. A newer drug label for a generic ceftriaxone product, available through DailyMed, no longer contains this specific warning regarding an increased risk in patients with G6PD deficiency or congenital methemoglobinemia.[38]
• Clinical Implication: This discrepancy between older and newer drug labels suggests that the evidence supporting this specific pharmacogenomic association may have been re-evaluated by regulatory authorities and is perhaps no longer considered strong enough to warrant a specific warning. This highlights the evolving nature of drug safety information. Clinicians should be aware of the theoretical risk but must ultimately refer to the most current prescribing information for the specific ceftriaxone product being used to guide clinical decisions.

11.0 Conclusion: Place in Therapy

Ceftriaxone has secured an enduring position as a cornerstone of modern parenteral antibiotic therapy. Its clinical value is derived from a powerful combination of a broad and potent spectrum of activity against common and serious bacterial pathogens, proven efficacy in life-threatening infections such as meningitis and sepsis, and a uniquely favorable pharmacokinetic profile that permits convenient once or twice-daily dosing. This latter characteristic has made it an invaluable tool for both inpatient care and the expansion of outpatient parenteral antibiotic therapy (OPAT), facilitating earlier hospital discharge and improving patient quality of life.

The therapeutic utility of ceftriaxone is, however, defined by a delicate balance between its efficacy and its distinct risk profile. The very properties that make it advantageous—its long half-life and high concentrations achieved during its dual biliary and renal elimination—are inextricably linked to its most characteristic toxicities. The propensity of ceftriaxone to precipitate with calcium is the unifying mechanism behind a cascade of potential adverse events, from reversible biliary pseudolithiasis to the rarer but more severe complications of pancreatitis and obstructive uropathy.

Safe and effective use of ceftriaxone is therefore contingent upon a deep understanding of this balance. Its clinical application is governed by a set of highly specific and non-negotiable contraindications, particularly in the neonatal population, where the risks of fatal precipitation with calcium and bilirubin-induced encephalopathy are paramount. These prohibitions are not arbitrary rules but are direct consequences of the drug's fundamental physicochemical and pharmacokinetic behavior in a vulnerable patient group.

Looking forward, the greatest threat to the continued utility of this workhorse antibiotic is the relentless emergence of bacterial resistance, especially through the production of extended-spectrum beta-lactamases (ESBLs). This challenge underscores the critical importance of robust antimicrobial stewardship programs. The judicious use of ceftriaxone—reserving it for appropriate indications, guided by susceptibility testing whenever possible, and using appropriate dosing—is essential to preserve its efficacy for future generations. As ongoing clinical trials continue to explore and refine its role in treating complex infections, ceftriaxone remains a powerful and indispensable agent in the global fight against bacterial disease, demanding both respect for its power and wisdom in its application.

Appendix A: Global Brand Names and Identifiers

Ceftriaxone is marketed worldwide under a vast number of brand names. The following table provides a selection of common and representative brand names to aid in the identification of this active ingredient in international clinical practice and research. The list includes both single-agent products and combinations with beta-lactamase inhibitors.

Table A.1: Selected International Brand Names for Ceftriaxone

Brand Name	Manufacturer	Country/Region(s)
Rocephin	Roche	Global (e.g., USA, Germany, Brazil, Japan, UK) 15
Acantex	Investi, Productos Roche	Argentina, Chile 20
Azaran	Hemofarm	Serbia, Russia, Macedonia 20
Biotrakson	Polpharma	Poland, Lithuania, Macedonia 13
Cefaxone	Lupin	India, Peru, Lithuania 20
Cefotrix	T3A, Eberth	Egypt, Germany, Austria 20
Lendacin	Lek, Sandoz	Global (e.g., Poland, Serbia, Hungary, Croatia) 20
Longaceph	Galenika, Max Pharma	Serbia, Croatia, Macedonia 20
Medaxone	Medochemie	Global (e.g., Greece, Romania, Vietnam) 20
Megion	Novartis, Sandoz	Global (e.g., Bangladesh, Mexico, Venezuela) 20
Monocef	Aristo	India, Tanzania 20
Nevakson	Mustafa Nevzat	Turkey, Bosnia & Herzegowina 20
Oframax	Ranbaxy, Sun Pharma	Global (e.g., India, South Africa, Romania, Peru) 20
Tercef	Actavis, Balkanpharma	Global (e.g., Lithuania, Bulgaria, Vietnam) 20
Triaxone	Julphar, Hanmi	UAE, Oman, South Korea 20
Aacef-S	Alpic Biotech	India 20
Abicef-T	ABL Lifecare	India 20
Augtaz	Zuventus	India 20
Cefrine Plus	Macleods	India 20

Source: [20]

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