What medications can cause fever in patients, particularly those with a history of autoimmune disorders, cancer, or HIV/AIDS?

Medications That Cause Fever

Drug-induced fever is a common but frequently underdiagnosed condition that occurs when fever coincides temporally with drug administration and resolves after discontinuation of the offending agent, with antimicrobial agents—particularly beta-lactam antibiotics—being the most frequently implicated class. 1, 2

Timing and Clinical Presentation

The lag time between initiating a drug and fever onset averages 21 days (median 8 days), though this is highly variable. 1, 3 In nonsensitized individuals receiving a drug for the first time, fever most commonly appears after 7-10 days of administration. 2, 4 Once the offending drug is discontinued, fever typically resolves within 1-3 days but may take up to 7 days to normalize. 1, 3

Key Clinical Features

• There is nothing characteristic about drug-induced fevers—they do not follow a predictable pattern. 1
• Fever may be low-grade initially, progressing to high remittent fever that subsides promptly after drug cessation (this pattern accounts for 70% of cases). 5
• Rash occurs in only a small fraction of cases, and eosinophilia is uncommon. 1
• Most patients have no history of previous drug reactions. 6
• Fever may be well-tolerated or accompanied by general symptoms mimicking sepsis. 7

Most Common Causative Medications

Beta-Lactam Antibiotics (Highest Risk)

Beta-lactam antibiotics are the most frequent cause of drug fever, with newer derivatives showing particularly high incidence rates. 5, 4

• Piperacillin: 17% incidence 5
• Cefotaxime: 15% incidence 5
• Ceftizoxime: 14% incidence 5
• Cefoperazone: 8% incidence 5
• Ampicillin: 3% incidence 5
• Cefazolin: 0% incidence 5

The higher incidence with newer beta-lactam derivatives suggests the side chain attached to their core moiety may be involved in the mechanism. 5

Other Antimicrobial Agents

• Antimicrobial agents other than beta-lactams only rarely induce drug fever. 5
• Penicillins and cephalosporins remain among the most commonly associated agents overall. 4
• Antitubercular medications are frequently implicated. 4
• Linezolid can exacerbate serotonin syndrome when used concomitantly with serotonin reuptake inhibitors. 1

Cardiovascular Medications

• Quinidine 4
• Procainamide 4
• Methyldopa 4

Neuropsychiatric Medications

Antipsychotic neuroleptic medications—phenothiazines, thioxanthenes, and butyrophenones (especially haloperidol in the ICU)—are strongly associated with neuroleptic malignant syndrome, which manifests as muscle rigidity, fever, and elevated creatinine phosphokinase. 1

Serotonin reuptake inhibitors can cause serotonin syndrome through excessive 5-HT1A receptor stimulation, presenting with fever, tachycardia, diaphoresis, and hyperreflexia. 1

• Phenytoin 4
• Trihexyphenidyl (causes anticholinergic syndrome with hyperthermia, hot/dry/erythematous skin, mydriasis, and hypoactive bowel sounds) 3
• Tetrabenazine (simple hypersensitivity fever after several days) 3

Other Medications

• Allopurinol 6
• Amphotericin B (fever is one of the most common adverse reactions, sometimes accompanied by shaking chills within 15-20 minutes of infusion initiation) 8

Life-Threatening Hyperthermic Syndromes

Malignant Hyperthermia

Malignant hyperthermia is caused by succinylcholine and inhalation anesthetics (halothane most frequently), representing a genetically determined dysregulation of cytoplasmic calcium control in skeletal muscle that causes intense muscle contraction, fever, and elevated creatinine phosphokinase. 1 Onset can be delayed up to 24 hours, especially in patients on steroids. 1

Neuroleptic Malignant Syndrome

This syndrome is rare but more often identified in the ICU than malignant hyperthermia, with central initiation of muscle contraction distinguishing it from malignant hyperthermia. 1

Serotonin Syndrome

This is a distinct entity from neuroleptic malignant syndrome that should not be confused with it. 1

Drug Withdrawal-Associated Fever

Withdrawal from alcohol, opiates (including methadone), barbiturates, and benzodiazepines can cause fever with associated tachycardia, diaphoresis, and hyperreflexia. 1 This is particularly important because a history of use may not be available at ICU admission, and withdrawal fever may occur several hours or days after admission. 1

Special Populations

Patients with HIV/AIDS

Cotrimoxazole (TMP-SMX) used for Pneumocystis jiroveci pneumonia causes allergic reactions in up to 60% of HIV-positive patients compared with only 5% of HIV-negative patients. 1 Clinical manifestations include urticaria, macular exanthemas, erythema multiforme, and Stevens-Johnson syndrome/TEN with constitutional symptoms. 1

Risk factors include history of syphilis, higher total plasma protein concentration, and low CD4 count (though this may be related to higher CD4:CD8 ratio). 1

Patients with Cancer

In patients with malignancy receiving antibiotics, respiratory infection is the most frequent cause of fever exceeding 38°C, while in non-malignant disease patients, the antibiotic itself is the most frequent cause of recurrent fever during therapy. 5

Diagnostic Approach

Drug-induced fever is a diagnosis of exclusion established by temporal relationship between starting the drug and fever onset, with fever persisting as long as the drug is continued and resolving within 1-3 days after discontinuation. 1, 3, 2

Laboratory Findings (Non-Specific)

• Transient elevation of serum lactate dehydrogenase (51% of cases) 5
• Transient slight decrease in neutrophil counts (23% of cases) 5
• Transient slight decrease in platelet counts (8% of cases) 5
• Moderate elevation or decrease in white blood cell count 7
• Eosinophilia (uncommon) 1, 7
• Liver cytolysis 7
• Increased C-reactive protein 7

Critical Diagnostic Steps

• Infection must be systematically ruled out before attributing fever to a drug. 7
• Clinical or biological signs of severity should question the diagnosis of drug fever. 7
• Assess temporal relationship between drug initiation and fever onset 3
• Evaluate for other symptoms suggesting specific syndromes (muscle rigidity for NMS, anticholinergic signs) 3

Management

When drug fever is suspected, the involved drug(s) should be stopped after reliable assessment of imputability, with fever disappearance after discontinuation being the cornerstone of diagnosis. 3, 7

Important Caveats

• Rechallenge with the offending drug will usually cause fever recurrence within a few hours, confirming diagnosis, but is controversial and should be performed with extreme caution due to potential for more severe reactions. 2
• Patients who had anaphylaxis or toxic epidermal necrolysis should never be rechallenged. 1
• Rechallenge is rarely done unless the drug is essential and alternatives are unavailable. 1
• Before stopping a suspected drug, perform risk/benefit assessment—it may be complicated to stop an antimicrobial during active infection or an immunosuppressive drug when required. 7

Supportive Measures for Amphotericin B-Related Fever

• Aspirin, acetaminophen, antihistamines, or antiemetics may improve tolerance 8
• Meperidine 25-50 mg IV may decrease duration of shaking chills and fever 8
• Alternate-day administration may decrease anorexia and phlebitis 8
• Small doses of corticosteroids just prior to or during infusion may decrease febrile reactions (keep dosage and duration to minimum) 8

Clinical Pitfalls

• Early diagnosis reduces inappropriate and potentially harmful and expensive diagnostic and therapeutic interventions. 2
• Drug fever is probably more common than recognized because consultations are generally not requested for adverse drug reactions with typical findings like rashes and eosinophilia. 6
• The duration of drug administration before fever appears is highly variable and differs among drug classes. 6
• Most patients present with fever and no other symptoms or signs suggesting drug-induced fever. 6