Recurrent Amoxicillin-Induced Aseptic Meningitis

Drug-induced aseptic meningitis (DIAM) is a rare adverse effect (AE), most commonly associated with nonsteroidal antiinflammatory drugs (NSAIDs), intravenous immunoglobulin (IVIG), monoclonal antibodies, vaccines, and antibiotics. Amoxicillin-induced aseptic meningitis (AIAM) has been reported, but to our knowledge only 13 cases exist in the literature. Amoxicillin-induced aseptic meningitis is not currently listed as a potential AE on amoxicillin’s product monograph. We present a 14th case of AIAM and suggest that AIAM be added to the list of amoxicillin’s potential AEs. A 73-year-old male with no known allergies presented with 2 days of confusion, headache, nausea, and fever. Four days prior, he developed symptoms of otitis media. Two days later, he was prescribed amoxicillin 500mg PO BID and had taken four doses before presentation. He did not take any NSAIDs. He denied sick contacts or recent travel. His past medical history included another episode of aseptic meningitis, multiple vascular risk factors, chronic obstructive pulmonary disorder, and chronic kidney disease. These were being treated appropriately, with no new or recently adjusted medications. On examination, he had a low-grade fever. His vital signs were otherwise stable. He was alert but disoriented and confused. Passive neck flexion was painful, but there was no objective nuchal rigidity, Kernig’s sign, or Brudzinski’s sign. The remainder of his examination was normal. A lumbar puncture was performed, then empiric treatment with vancomycin, ceftriaxone, and acyclovir was started. Amoxicillin was discontinued immediately. CSF analysis revealed mild lymphocytosis, elevated protein, and normal glucose (Table 1). Gram stain, cultures, and viral polymerase chain reaction were negative. CT of his head was normal. He improved to baseline within 3 days. Antibiotics were discontinued after 1 week. A review of his pharmacy records revealed that he had taken four doses of amoxicillin 500mg PO BID for an upper respiratory tract infection two days before his first episode of aseptic meningitis. He had similar symptoms, including headache, nausea, and confusion. CSF analysis showed lymphocytosis, elevated protein, and normal glucose (Table 1). A CT head and electroencephalography were normal. Amoxicillin was discontinued on admission and he was treated empirically with vancomycin, ceftriaxone, and acyclovir after the lumbar puncture. His symptoms resolved within 3 days. He had not taken any amoxicillin in between these two episodes. Further workup including HIV and syphilis screening, autoimmune serology, thyroid function tests, and MRI of the brain were normal or negative. Given the temporal relationship of his symptoms with amoxicillin, CSF analysis, and negative infectious, autoimmune, and imaging investigations, he was diagnosed with AIAM and advised to avoid amoxicillin in the future. Drug-induced aseptic meningitis is an uncommon adverse reaction characterized by meningeal inflammation with negative microbiology. Causative drugs include NSAIDs, IVIG, monoclonal antibodies, vaccinations, and antibiotics. Of the antibiotics, common culprits are trimethoprim-sulfamethoxazole, ciprofloxacin, cephalexin, metronidazole, penicillin, and isoniazid. AIAM is extremely rare, and have been previously reported only 13 times. As with most cases of DIAM, AIAM is a diagnosis of exclusion. The first episode is not usually attributed to amoxicillin, and many cases likely go undiagnosed. All of the published cases of AIAM, including our own, document a positive rechallenge with amoxicillin. The pathogenesis of DIAM remains elusive. Theories suggest an immune-mediated hypersensitivity reaction or direct meningeal irritation. The former has been supported by the detection of serum immune complexes in the CSF of some patients with DIAM caused by drugs other than amoxicillin. However, one report of AIAM tested serum and CSF for immunoglobulin E to amoxicillin and immune complexes interacting with C1q and did not provide any evidence supporting a type 1 or 3 hypersensitivity reaction. No other cases and similar studies of AIAM have been reported. Further investigations are required to understand its underlying mechanisms. The clinical manifestations of AIAM are typical for meningoencephalitis, including fever, headache, neck stiffness with or without objective meningismus, cognitive changes, and related neurological signs. Our patient’s presentation was therefore similar to previous reports. Given the nonspecific signs and symptoms, the differential diagnosis for recurrent meningitis is