Can Ceftriaxone Cause Fever?
Yes, ceftriaxone can cause drug-induced fever as a hypersensitivity reaction, though this is relatively uncommon compared to its therapeutic use in treating infections that themselves cause fever.
Mechanism and Incidence of Drug Fever
Cephalosporins, including ceftriaxone, are among the antibiotic classes most commonly associated with drug-induced fever, typically occurring as a hypersensitivity reaction 1.
Drug fever from antibiotics most commonly appears after 7-10 days of administration, persists as long as the drug is continued, disappears soon after stopping the drug, and will rapidly reappear if the drug is restarted 1.
In a clinical study of parenteral antibiotics, beta-lactams frequently induced drug fever, though specific data for ceftriaxone showed lower rates than some other cephalosporins: cefotaxime induced drug fever in 15% of patients, ceftizoxime in 14%, while older agents like cefazolin caused drug fever in 0% 2.
The FDA drug label lists drug fever as a recognized adverse reaction to ceftriaxone, though reported at less than 1% frequency 3.
Clinical Presentation of Ceftriaxone-Induced Fever
The typical pattern begins with low-grade fever at onset, followed by high and remittent fever, with the highest diurnal body temperature rising gradually 2.
The fever subsides promptly after cessation of the causative antibiotic—this pattern accounted for 70% of all drug fever cases in one study 2.
Associated laboratory findings may include transient elevation of serum lactate dehydrogenase (occurring in 51% of drug fever cases) and transient slight decreases in neutrophil counts (23%) and platelet counts (8%) 2.
Critical Distinction: Persistent Fever During Treatment vs. Drug Fever
When evaluating fever in patients receiving ceftriaxone, the clinical context is paramount. In neutropenic cancer patients, persistent fever after 3-5 days of antibiotic therapy may indicate drug fever, but also suggests nonbacterial infection, resistant bacterial infection, emergence of secondary infection, inadequate drug levels, or infection at an avascular site 4.
Even patients with documented bacterial infections adequately treated with ceftriaxone may require 4-5 days of therapy before defervescence occurs 5, 6.
In typhoid fever specifically, the mean period of defervescence with ceftriaxone is 4 days when medical complications are excluded 6.
Special Populations
Immunocompromised Patients
In febrile episodes among HIV-infected or hematooncological patients treated with ceftriaxone, the drug achieved defervescence in 87.5% of cases with a mean treatment duration of 7.1 days 7.
The high success rate of ceftriaxone in treating fever in these immunocompromised populations suggests that when fever resolves on ceftriaxone, it is treating the underlying infection rather than causing drug fever 7.
Cancer Patients
- In neutropenic cancer patients, the median time to defervescence ranges from 2 days in low-risk patients to 5-7 days in high-risk patients when treated with appropriate antibiotics including cephalosporins 4.
Practical Approach to Suspected Ceftriaxone-Induced Fever
If fever persists beyond 5 days of ceftriaxone therapy without identified source, consider drug fever in the differential diagnosis along with resistant infection, fungal infection, and non-infectious causes 4.
Reassessment should include review of all culture results, meticulous physical examination, chest radiography, vascular catheter evaluation, and additional cultures 4.
The definitive diagnostic test is discontinuation of ceftriaxone: drug fever should resolve within 24-48 hours of stopping the medication 1.
Important Caveats
Do not prematurely attribute persistent fever to drug reaction in the first 3-5 days of therapy, as many bacterial infections require this duration for clinical response 4, 6.
The newer beta-lactam derivatives may have higher incidence of drug fever, possibly related to their side chain structures 2.
Ceftriaxone can cause other adverse reactions that may present with fever, including pancreatitis (possibly secondary to biliary obstruction), hemolytic anemia, and allergic reactions including anaphylaxis 3.