What medications can cause fever?

Medications That Can Cause Fever

Many medications can cause fever through various mechanisms, with the most common being hypersensitivity reactions, but also through direct pharmacological effects, immune responses, or tissue damage. 1, 2

Common Medications Associated with Drug Fever

Antimicrobials

• Beta-lactams (penicillins and cephalosporins) are among the most common causes of drug-induced fever 1, 3
• Sulfonamides are frequently implicated in drug-induced fevers 3
• Vancomycin can cause fever through immunologic reactions, sometimes accompanied by rash and neutropenia 4
• Antimicrobial-induced fever may persist as long as the drug is continued and typically resolves within 1-3 days after discontinuation 1

Antipsychotics and Neuroleptics

• Antipsychotic medications, particularly phenothiazines, thioxanthenes, and butyrophenones (like haloperidol) can cause fever through neuroleptic malignant syndrome 1
• Amisulpride can induce fever either through simple hypersensitivity reactions or as part of neuroleptic malignant syndrome 5
• Neuroleptic malignant syndrome presents with muscle rigidity, hyperthermia, and elevated creatinine phosphokinase concentrations 1, 5

Other Medications

• Anticonvulsants like carbamazepine and phenytoin can cause fever as part of hypersensitivity reactions 6, 2
• Cardiovascular drugs including quinidine and procainamide 2
• Antihypertensives like methyldopa 2
• Serotonin reuptake inhibitors can cause fever through serotonin syndrome, which may be exacerbated by concomitant use of linezolid 1

Mechanisms of Drug-Induced Fever

• Hypersensitivity reactions (most common mechanism) 1, 2
• Altered thermoregulation 2
• Direct pharmacological effects on heat production or dissipation 2
• Tissue damage 2
• Drug withdrawal (alcohol, opiates, barbiturates, benzodiazepines) can cause fever with associated tachycardia, diaphoresis, and hyperreflexia 1

Clinical Characteristics of Drug Fever

• Typically occurs after 7-10 days of drug administration (mean 21 days, median 8 days) 1, 2
• Fever persists as long as the drug is continued 2
• Resolves within 1-3 days after drug discontinuation, though can take up to 7 days 1, 5
• Rapid recurrence if the drug is restarted 2
• Rash and eosinophilia are uncommon accompaniments 1, 5

Management Approaches

• The primary management is discontinuation of the suspected medication 1, 5
• Supportive care with antipyretics (paracetamol/acetaminophen or NSAIDs) and hydration while waiting for resolution 5, 7, 8
• For neuroleptic malignant syndrome: immediate discontinuation of the antipsychotic, intensive supportive care, benzodiazepines for agitation, external cooling, and IV fluids 5
• Patients who experienced anaphylaxis or toxic epidermal necrolysis should never be rechallenged with the offending drug 1
• For pregnant women with fever, acetaminophen is recommended for treatment of fever 1

Important Considerations

• Drug fever is a diagnosis of exclusion after ruling out infectious and other causes 4
• When evaluating persistent fever in patients on antibiotics, consider drug fever as a potential cause, especially after 3-5 days of treatment 1
• In critically ill patients, non-infectious causes of fever including drug fever should be considered in the differential diagnosis 1
• Most adverse events related to antimicrobials are rapidly reversible upon discontinuation of the medication 3

Specific Patient Populations

• In neutropenic cancer patients, drug fever should be considered when fever persists despite appropriate antibiotic therapy 1
• In pregnant women, acetaminophen is preferred for fever management 1
• In children, aspirin should not be used for fever management due to the risk of Reye's syndrome 1