Amoxicillin and risk of aseptic meningitis

Amoxicillin is a narrow-spectrum beta-lactam antibiotic registered in Singapore since 1998 for the treatment of commonly occurring bacterial infections such as respiratory tract, genitourinary and skin and soft tissue infections. It is available as a single ingredient or in combination with clavulanate, a beta-lactamase inhibitor.

About aseptic meningitis

Aseptic meningitis is a condition where the linings of the brain and spinal cord become inflamed without an infectious cause. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), intravenous immunoglobulin and antimicrobials, including amoxicillin, have been identified as potential causes of aseptic meningitis.1 Other causes include neoplasia, autoimmune, or auto-inflammatory systemic diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis) and iatrogenic etiologies such as complications of a lumbar puncture or intrathecal drug adverse effects. The pathogenesis of drug-induced aseptic meningitis remains unclear but an idiosyncratic delayed-type hypersensitivity reaction has been proposed.2

Amoxicillin-induced aseptic meningitis

Very rare cases of aseptic meningitis associated with the use of amoxicillin-containing products have been published in literature.2-5 Patients typically presented with fever and headache which developed a few hours to seven days after amoxicillin exposure. Photophobia, nuchal rigidity, lethargy, myalgia and general malaise were also present in some cases. Notably, most cases demonstrated positive rechallenge, with two to three episodes of amoxicillin-induced aseptic meningitis. Typical cerebrospinal fluid (CSF) findings consisted of pleocytosis (lymphocytic or neutrophilic), which in some cases was accompanied by elevated protein and usually normal glucose levels (unlike low CSF glucose in bacterial meningitis). CSF cultures were consistently negative.

The diagnosis of amoxicillin-induced aseptic meningitis is usually based on a temporal relationship between drug intake and symptom onset, CSF pleocytosis, negative microbiological tests, and rapid resolution, usually within a few days, after drug discontinuation. As it is a diagnosis of exclusion, a thorough drug history can help support a diagnosis of amoxicillin-associated aseptic meningitis after infectious and disease-related (mainly neoplasms and autoimmune disorders) causes of aseptic meningitis have been ruled out.

Health Canada’s review 

In 2021, Health Canada reviewed the potential risk of aseptic meningitis in patients treated with amoxicillin-containing products and concluded that there might be a link between amoxicillin-containing products and the risk of aseptic meningitis.6 Their review took into consideration domestic and international cases of aseptic meningitis associated with amoxicillin use as well as a study of international cases reported to the World Health Organisation (WHO) database, which supported a link between the risk of aseptic meningitis and the use of amoxicillin.

Local situation

To date, HSA has received one report of aseptic meningitis that was possibly associated with the use of amoxicillin/ clavulanic acid.

Currently, aseptic meningitis is a documented adverse event (AE) in the package inserts (PIs) of some amoxicillin-containing products. HSA is working with the product registrants of the remaining products to harmonise this safety information across the local PIs of all amoxicillin-containing products.

HSA’s advisory

Amoxicillin-associated aseptic meningitis is a very rare but reversible AE that can be managed with drug discontinuation. As such, prompt recognition of this AE could prevent aggressive diagnostic procedures and prolonged treatments, as well as the possibility of recurrent episodes related to subsequent amoxicillin use. Healthcare professionals are advised to consider the possibility of this AE in patients prescribed amoxicillin-containing products who present with aseptic meningitis after the exclusion of other infectious or disease-related causes.

References

  1. Fundamental & Clinical Pharmacology 2018;32: 252–260
  2. J Pharm Technol. 2021;37(3):165-166.
  3. Eur J Case Rep Intern Med. 2020;7(6):001543
  4. Pharmacoepidemiol Drug Saf. 2019;28(3):389-395
  5. J Investig Allergol Clin Immunol 2019; 29(3): 239-250
  6. https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00276
Healthcare professional, Industry member, Therapeutic Products
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