Drug fever

• A drug reaction of unclear mechanism that causes isolated fever

Pathophysiology

• Stipulated to involve any of five mechanisms:
  • Altered thermoregulation, including anticholinergics
  • Drug administration-related fever, including amphotericin B, cephalosporins, and vancomycin
  • Expected drug effect, including chemotherapy (tumour lysis) and penicillins (Jarisch-Herxheimer reaction)
  • Idiosyncratic reactions, including primaquine, quinidine, quinine, and sulfonamides
  • Hypersensitivity reaction, including allopurinol, quinidine, quinine, and sulfonamides

Etiology

• Long list of offending medication, mostly based on collections of case reports12
• Antimicrobials are the most common overall class
  • Penicillins are most common, including penicillin, piperacillin, ticarcillin ampicillin, methicillin, carbenicillin, mezlocillin, staphcillin, nafcillin, oxacillin, and cloxacillin
  • Cephalosporins, including cefazolin, cefotaxime, ceftazidime, cephalexin, and cephalothin
  • Tetracycline and minocyline
  • Trimethoprim-sulfamethoxazole
  • Isoniazid
  • Nitrofurantoin
  • Case reports of acyclovir, amphotericin B, aureomycin, colistin, declomycin, erythromycin, furadantin, mebendazole, novobiocin, para-aminosalicylic acid, rifampin, streptomycin, terramycin, and vancomycin
• Cardiovascular
  • Methyldopa
  • Quinidine and quinine
  • Procainamide
  • Dobutamine
  • Case reports with clofibrate, diltiazem, furosemide, heparin, hydralazine, hydrochlorothiazide, nifedipine, oxprenelol, and triameterene
• Neurologic medications
  • Phenytoin is the most common within this class
  • Lysergic acid
  • Carbamazepine
  • Nomifensine
  • Thioradazine
  • Case reports of amphetamine, doxepin, haloperidol, nomifensine, sulfasalazine, triamterene, benztropine, and trifluoperazine
• Chemotherapy and immunomodulators
  • Bleomycin
  • Streptomycin
  • Case reports of 6-mercaptopurine, chlorambucil, cisplatin, cytarabine, cytosine arabinoside, daunorubicin, hydroxyurea, L-asparaginase, procarbazine, streptozocin, and vincristine
• Antiinflammatory or immunomodulatory medications
  • Azathioprine
  • NSAIDs, including ibuprofen, tolmetin, and aspirin
  • Case reports of everolimus, mycophenolate mofetil, and sirolimus
• Other medications, including allopurinol, cimetidine, clofibrate, folate, interferon, iodide, levamisole, metoclopramide, piperazine, propylthiouracil, prostaglandin E2, ritodrine, theeophylline, and thyroxine

Clinical Presentation

• Fever without focus and no other likely causes
• Can occur at any point in administration of the medication, but most often 7 to 10 days after starting
• Fever pattern was mostly unpredictable, but could be intermittent or remittent (high but fluctuating); rarely continuous
• Fever most commonly high, but could be low-grade
• Usually appear well, even when febrile, including a relative bradycardia
• Many have rigors, and may occasionally have other systemic signs or symptoms
• Occasional leukocytosis or eosinophilia

Further Reading

• Drug fever. Pharmacotherapy. 2010;30(1):57-69. doi: 10.1592/phco.30.1.57