Amoxicillin-induced aseptic meningitis: clinical features, diagnosis and management

Meningitis is characterized by diffuse inflammatory changes in the pia mater caused by various biological pathogenic factors, such as bacteria, viruses, fungi or protozoa, tumors, cancers, and autoimmune systemic diseases invading the pia mater and spinal cord membrane [1‐3]. Aseptic meningitis (AM) is defined as the absence of evidence of pathogen infection but the presence of associated neurological symptoms and cytological abnormalities in the cerebrospinal fluid (CSF) [4]. Drugs are an important factor in AM, including nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, intravenous immunoglobulin, antiepileptic drugs, and monoclonal antibodies [5].

The incidence of drug-induced aseptic meningitis (DIAM) remains unreported. Antibiotic-associated DIAM is most often caused by trimethoprim with or without sulfamethoxazole and penicillin-derived antibiotics [5, 6]. Analysis of 329 cases of drug-induced aseptic meningitis showed that 11% of the drugs were antibiotics, of which amoxicillin accounted for 5% [7]. The incidence, pathogenesis, treatment and prevalence of amoxicillin-induced aseptic meningitis (AIAM) are not widely reported. Knowledge of AIAM is limited to individual reports. AIAM has not been labeled as a potential adverse effect in most countries. Assessment of AIAM is still variable today and is a diagnostic and management dilemma for clinicians. Here, we collected case reports of AIAM, explored its clinical features, and provided a reference for clinical diagnosis and treatment.

DIAM is a rare entity, and the onset time is variable, ranging from a few minutes to several months [28, 29]. Moreover, clinical signs and cerebrospinal fluid examination results vary greatly. The clinical manifestations are consistent with meningoencephalitis, including fever, headache, photophobia, neck stiffness, nausea, vomiting, and myalgia [30]. AIAM appeared at 3 h ~ 7 d after administration. DIAM may initially be confused with viral or bacterial meningitis. If other inducements are excluded, the diagnosis of DIAM is based on the time between administration and symptom onset and the rapid disappearance of symptoms after drug withdrawal. Several pathophysiological factors may contribute to DIAM, such as autoimmune disease, migraine, immune dysregulation and genetic predisposition [31]. Meningitis was caused by intravenous penicillin in one woman [32]. Cephalosporins, including cefazolin, ceftriaxone and ceftazidime, are also associated with aseptic meningitis. [7] One woman developed several episodes of aseptic meningitis due to exposure to cefalexin, cefazolin, and ceftazidime [33]. This patient should avoid cephalosporins and consider herself cross-allergic to them. It is not known whether AIAM would show cross sensitivity with other penicillins, and we suggest that it would be advisable to avoid the use of other penicillins in patients who have been diagnosed with AIAM.

The pathophysiology of DIAM is unclear, and two main mechanisms may be involved. One is the direct toxicity of drugs, and the other is related to immune hypersensitivity [30]. The current study suggests that AIAM may be a delayed type 4 hypersensitivity reaction or T-cell-mediated hypersensitivity reaction. Laboratory results in one AIAM patient did not support type I or type III reactions, and no specific IgE or C1q were detected [15]. T-cell activation was detected in another 2 AIAM patients [27]. The occurrence of AIAM independent of amoxicillin dose may indicate that this is an allergic reaction. Men are at higher risk for AIAM than women. A possible explanation is that the immune response differs by sex. [34]

In our study, we found that fever and headache were the most common complaints. Five patients developed symptoms of meningoencephalitis, characterized by neurological symptoms such as disturbances of consciousness and coma. CSF examination results vary in different DIAM cases, usually in terms of CSF cytosis, which is mainly neutrophilic, but some patients have CSF lymphocytosis and eosinophilia with unchanged leucocytes. Protein levels in the CSF are usually high, while glucose levels are normal, although some cases are described as having reduced glucose levels [35]. The typical CSF manifestation of AIAM is neutrophilic lymphocytosis, and the number of white blood cells is tens to hundreds per microliter, with normal glucose levels and variably elevated protein levels. In general, clinical symptoms and cerebrospinal fluid findings are not helpful in distinguishing between drug-induced aseptic meningitis and bacterial meningitis. Blood tests and brain CT or MRI scans were not diagnostic. Determining the temporal relationship between amoxicillin use and aseptic meningitis is critical for diagnosis. Compared with bacterial meningitis patients, the CSF glucose level of AIAM patients is usually lower, while that of DIAM patients is normal [36]. Another difference between bacterial meningitis and DIAM is the high level of C-reactive protein (CRP). The symptoms of DIAM usually recover within 10–14 days, which is different from viral meningitis [18]. However, the symptoms of AIAM disappeared within 7 days.

The causative drug needs to be discontinued in cases of DIAM [30]. Symptoms associated with meningitis can be given symptomatic treatment, such as pain relievers for headache and antiemetic drugs for nausea and vomiting. Patients with immunoglobulin (IVIG)-related DIAM received hydration, analgesics, and systemic corticosteroids [37‐39]. Antitumor necrosis factor drugs were also considered in some serious cases [40]. However, there was no significant difference in the clinical course, regardless of whether the patient received treatment.

AIAM is reversible and usually does not require any further treatment after drug withdrawal. When AIAM is suspected, the drug should be discontinued if possible. A third-generation cephalosporin may be given empirically to avoid any risk of infection until CSF results are available [31]. AIAM patients may relapse after challenge. We do not recommend that patients rechallenge amoxicillin or amoxicillin clavulanic acid in cases of previous aseptic meningitis. Rechallenging amoxicillin or amoxicillin clavulanate potassium can lead to a recurrence of aseptic meningitis.

There is a possible association between amoxicillin-containing products and the risk of aseptic meningitis. Identifying AIAM is a challenge, and patients with meningitis should be asked about their medication history in detail to avoid unnecessary testing and treatment.