Ceftriaxone (ceftriaxone sodium)

Dosage of ceftriaxone sodium is expressed in terms of ceftriaxone and is identical for IM or IV administration.

To avoid unintentional overdosage, the commercially available Duplex(R) delivery system containing ceftriaxone and dextrose injection should not be used in patients who require less than the entire 1- or 2-g dose in the container.

Ceftriaxone sodium is administered by IV infusion or deep IM injection.

Ceftriaxone should not be administered intrathecally.

Ceftriaxone has been administered IM or IV to adults or children in outpatient settings, including clinicians' offices, outpatient clinics, infusion centers, skilled nursing facilities, rehabilitation centers, or the patient's home, for the treatment of certain infections suitable for community-based parenteral anti-infective agent therapy (e.g., community-acquired pneumonia, osteomyelitis, endocarditis+). Outpatient parenteral anti-infective therapy often is used to complete a course of ceftriaxone therapy initiated during hospitalization, but ceftriaxone therapy also has been initiated on an outpatient basis. Ceftriaxone usually is administered in the outpatient setting by a healthcare provider; however, the drug has been self-administered in the patients' home by the patient, family member, or other responsible person.

Ceftriaxone should not be reconstituted with or further diluted with diluents containing calcium (e.g., Ringer's/lactated Ringer's solution, Hartmann's solution) because a precipitate can form.

Because precipitation of ceftriaxone-calcium can occur, ceftriaxone must not be admixed with calcium-containing solutions and must not be administered simultaneously with calcium-containing IV solutions, including continuous infusions of calcium-containing solutions such as parenteral nutrition, even via different infusion lines at different sites in any patient (irrespective of age). In adult and pediatric patients older than 28 days of age, ceftriaxone and calcium-containing solutions may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid (e.g., 0.9% sodium chloride injection, 5% dextrose injection).

Ceftriaxone is contraindicated in neonates (28 days of age or younger) if they are receiving (or expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition.

Patients receiving ceftriaxone should be adequately hydrated.

IM injections of ceftriaxone should be made deeply into a large muscle mass, using usual techniques and precautions.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Intravenous Ceftriaxone/Intravenous Calcium Products

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Intravenous ceftriaxone and intravenous calcium may form an insoluble precipitate if administered too closely together.

CLINICAL EFFECTS: Intravenous administration of calcium-containing products with intravenous ceftriaxone may have serious risks in all patients, especially in the neonate population. NEONATES: Intravenous administration of calcium-containing products within 48(1-2) to 120(3) hours of intravenous administration of ceftriaxone may result in damage to the lungs and/or kidneys in neonates. Fatalities in neonates have been reported.(1-7) OLDER CHILDREN and ADULTS: Sequential administration requires proper line flushing. Use within 48 hours may result in the formation of kidney stones in older children(5) and the formation of "sludge" in the gallbladder.(2) Simultaneous administration in patients older than 28 days may result in the formation of an insoluble ceftriaxone-calcium precipitate.(1-7)

PREDISPOSING FACTORS: Neonates, both preterm and term, may be a greatest risk of death from this interaction.(1-4) Young age may predispose patients to formation of ceftriaxone-calcium precipitates in the kidney.(5) High doses of ceftriaxone may also increase the risk of precipitates.(6)

PATIENT MANAGEMENT: The US manufacturer of ceftriaxone, Health Canada, and the US Food and Drug Administration (FDA) state that the concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates less than or equal to 28 days of age. Ceftriaxone should not be used in neonates less than or equal to 28 days of age if they are receiving or are expected to receive calcium-containing intravenous products.(2,3,7) The US manufacturer of ceftriaxone, Health Canada, and the US FDA state that in patients older than 28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid.(2,3,7) The US manufacturer of ceftriaxone, Health Canada, and the US FDA state that ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a Y-site in any age group.(2,3,7)

DISCUSSION: Isolated reports of neonatal (both term and preterm infants) deaths have been associated with ceftriaxone-calcium precipitates in the lungs and kidneys. A total of 7 cases have been reported to the FDA, resulting in 5 deaths. All 5 deaths were in neonates of 3 weeks or less in age. Six of the 7 patients received calcium gluconate, 1 received calcium via hyperalimentation.(6) In some cases, ceftriaxone and the calcium product were administered by different routes,(1) lines,(2) and/or at different times.(1,2) Reports of a ceftriaxone-calcium salt precipitate in the gall-bladder have also been reported.(2) In in vitro studies in adult and neonatal plasma, ceftriaxone recovery was examined with ceftriaxone concentrations up to 1 mM (in excess of concentrations seen with 2 g ceftriaxone infused over 30 minutes) and calcium concentrations up to 12 mM (48 mg/dL). Ceftriaxone recovery was reduced with calcium concentrations of 6 mM (24 mg/dL) in adult plasma and 4 mM (16 mg/dL) in neonatal plasma. This may indicate ceftriaxone-calcium precipitation formation.(2,7) There have been no reports associated with concurrent use of oral calcium products and the US manufacturer of ceftriaxone states that there is no risk with oral calcium products or use of intramuscular ceftriaxone.(4)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Slt Cephalosporins/Slt Anticoagulants (Vit K Antagonists)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but may involve a combination of cephalosporin induced platelet inhibition and alteration of gut flora.

CLINICAL EFFECTS: Concurrent use of some cephalosporins may increase the hypoprothrombinemic effect of the anticoagulant with possible bleeding.

PREDISPOSING FACTORS: High doses, hepatic and/or renal impairment, and poor nutrition may increase the risk of bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Monitor prothrombin activity and adjust the anticoagulant dosage accordingly. Consider using an alternative antibiotic. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Although the majority of cephalosporins that have been documented to interact with anticoagulants have a NMTT side chain, there are reports of interactions with cefazolin, cefoxitin, ceftaroline, and ceftriaxone as well. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with cephalosporins (OR=1.50; 95% CI 1.21-1.86).

*Known hypersensitivity to ceftriaxone, any other cephalosporin, or any ingredient in the formulation.

*History of anaphylaxis to ceftriaxone, cephalosporins, penicillins, or other beta-lactam anti-infectives.

*Certain neonates (e.g., premature or hyperbilirubinemic, those requiring calcium-containing IV solutions).

*Commercially available premixed (frozen) injection in dextrose may be contraindicated in patients with known allergy to corn or corn products.

• Neonatal hyperbilirubinemia

• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Clostridioides difficile infection
• Disease of liver
• Hemolytic anemia

• Gallbladder disease

Common adverse effects include local reactions at the administration site (warmth, tightness, induration, phlebitis), hematologic effects (eosinophilia, thrombocytosis, leukopenia), and hypersensitivity reactions.

More Frequent

• Thrombocytosis

Less Frequent

• Increased alanine transaminase
• Increased aspartate transaminase
• Skin rash
• Thrombocytopenic disorder

Rare or Very Rare

• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Anaphylaxis
• Angioedema
• Autoimmune hemolytic anemia
• Bronchospastic pulmonary disease
• Choledocholithiasis
• Cholestatic hepatitis
• Clostridioides difficile infection
• Colitis
• DRESS syndrome
• Drug fever
• Encephalopathy
• Erythema multiforme
• Hepatitis
• Hypersensitivity pneumonitis
• Hypoprothrombinemia
• Increased risk of bleeding due to coagulation disorder
• Jaundice
• Kidney stone
• Leukocytosis
• Lymphocytosis
• Lymphopenia
• Myoclonus
• Neutropenic disorder
• Nonconvulsive status epilepticus
• Occlusion of ureter due to calculus
• Pancreatitis
• Pruritus of skin
• Seizure disorder
• Serum sickness
• Stevens-johnson syndrome
• Stomatitis
• Toxic epidermal necrolysis
• Urolithiasis

More Frequent

• Diarrhea
• Eosinophilia
• Leukopenia

Less Frequent

• Abnormal hepatic function tests
• Induration of skin
• Injection site sequelae

Rare or Very Rare

• Acute abdominal pain
• Allergic dermatitis
• Anemia
• Chills
• Dizziness
• Dysgeusia
• Dyspepsia
• Edema
• Epistaxis
• Flatulence
• Flushing
• Glossitis
• Glycosuria
• Headache disorder
• Hematuria
• Hyperhidrosis
• Nausea
• Oliguria
• Palpitations
• Phlebitis after infusion
• Urticaria
• Vomiting
• Vulvovaginal candidiasis

No enhanced messaging available.

Ceftriaxone is contraindicated in premature neonates up to postmenstrual age 41 weeks (i.e., time elapsed since first day of the mother's last menstrual period to birth plus time elapsed after birth).

Ceftriaxone is also contraindicated in hyperbilirubinemic neonates, particularly those who are premature. Ceftriaxone can displace bilirubin from albumin binding sites in vitro. Therefore, there is a possible risk of bilirubin encephalopathy if the drug is used in hyperbilirubinemic neonates.

Ceftriaxone is contraindicated in neonates (28 days of age or younger) if they are receiving (or expected to require) treatment with calcium-containing IV solutions, including continuous infusions of calcium-containing solutions such as parenteral nutrition, because of the risk of precipitation of a ceftriaxone-calcium salt. Fatalities associated with ceftriaxone-calcium precipitates in lungs and kidneys have been reported in neonates who received ceftriaxone and calcium-containing IV solutions.

To reduce the risk of bilirubin encephalopathy, IV infusions of ceftriaxone should be given over 60 minutes in neonates.

Do not use ceftriaxone IM injections prepared using bacteriostatic water for injection containing benzyl alcohol in neonates Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates.

To avoid unintentional overdosage, the commercially available Duplex(R) drug delivery system containing 1 or 2 g of ceftriaxone and 50 mL of dextrose injection in separate chambers should not be used in pediatric patients who require less than the entire 1- or 2-g dose in the container.

Reproduction studies in mice, rats, and primates have not revealed any evidence of embryotoxicity, fetotoxicity, or teratogenicity with ceftriaxone.

Available data from published prospective cohort studies, case series, and case reports over several decades with use of cephalosporins, including ceftriaxone, in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Ceftriaxone crosses the placenta.

No adequate or controlled studies with ceftriaxone have been conducted in pregnant women. Use ceftriaxone during pregnancy only when clearly needed.

Ceftriaxone is distributed into milk in low concentrations; use the drug with caution in breast-feeding women. The effects of ceftriaxone on nursing infants or on milk production are not known. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ceftriaxone and any potential adverse effects on the infant from the drug or the mother's underlying condition.

In clinical studies, safety and efficacy of ceftriaxone in geriatric adults 60 years of age or older have been similar to those observed in younger adults. Although other clinical experience has revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

The pharmacokinetics of ceftriaxone are only minimally altered in geriatric patients compared with healthy younger adults. Dosage adjustments based solely on age are not necessary in geriatric patients receiving ceftriaxone dosages up to 2 g daily, provided they do not have severe renal and hepatic impairment.

Ceftriaxone is substantially eliminated by the kidneys, and the risk of adverse effects may be greater in those with impaired renal function. Because geriatric patients are more likely to have reduced renal function, dosage should be selected with caution and monitoring of renal function should be considered.