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

Objectives The clinical features of aseptic meningitis associated with amoxicillin are unknown. The main objective of this study was to investigate the clinical characteristics of amoxicillin-induced aseptic meningitis (AIAM) and provide a reference for clinical diagnosis and treatment. Methods AIAM-related studies were collected by searching the relevant databases from inception to October 31, 2022. Results AIAM usually occurred 3 h to 7 days after amoxicillin administration in 13 males and 9 females. Twenty-one patients (95.5%) had recurrent AIAM with a total of 62 episodes. Fever (19 cases, 86.4%) and headache (18 cases, 81.8%) were the most common symptoms. Typical cerebrospinal fluid (CSF) findings were leukocytosis (100%) with lymphocytic predominance (14 cases, 63.6%), elevated protein (20 cases, 90.1%), normal glucose (21 cases, 95.5%) and negative culture (21 cases, 100%). Brain magnetic resonance imaging showed mild meningeal enhancement in one patient. The symptoms resolved mainly within 1–4 days after drug discontinuation in all patients. Conclusion Clinical attention should be given to the adverse effects of AIAM. The medication history of patients with suspected meningitis should be investigated to avoid unnecessary examination and antibiotic treatment.


Introduction
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][2][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.

Inclusion and exclusion criteria
Case reports and clinical study series were included.Reviews, basic studies, replication studies, and studies of other antibiotic-induced AM were excluded.

AIAM definition
AIAM was defined as the time relationship with amoxicillin-containing products, CSF leukocytosis (> 5 cells/µl), negative culture, and symptom recovery after drug withdrawal.For patients with several episodes, we selected the most recent episode for data extraction.

Data Extraction
Two independent authors collected patients' nationality, sex, age, drug usage and dosage, meningitis symptoms, neuroimaging results, cerebrospinal fluid results, treatment regimens and clinical outcomes and then summarized the data.For patients with several episodes, we selected the most recent episode for data extraction.
Two patients (9.1%) had a history of multiple food allergies.Of the 16 patients (27.3%) for whom the administration method was described, 15 (68.2%) were administered orally, and 1 patient (4.5%) was administered by intravenous injection.Both amoxicillin and amoxicillin clavulanate doses were within the recommended range in the 10 patients (45.5%) with records.
Among the 22 patients, 18 patients underwent magnetic resonance imaging (MRI) examination; 17 patients showed no abnormality, and 1 patient showed mild meningeal enhancement on MRI.Computed tomography (CT) was performed in 17 patients with no abnormalities.CSF cultures found no evidence of bacteria or viruses in 22 patients.

Treatment and prognosis
Amoxicillin and amoxicillin clavulanate were eventually discontinued in all patients.Ten patients (45.5%) received empirical antibiotic treatment.Meningitis symptoms recovered in 20 patients (90.9%) within 12h-14d after drug withdrawal, and the clinical outcome was not described for 2 patients (9.1%).

Discussion
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, Fig. 1 Flowchart of the study selection process for reported cases of amoxicillin-induced aseptic meningitis 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-cellmediated 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  [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][38][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.

Limitations
There are some limitations to our study.First, the sample size was small, our study was limited to case series and single case reports, and statistical analysis was hampered, making it difficult to confirm or disprove certain clinical features associated with AIAM.Second, the level of detail provided was different in each case.Therefore, it is subject to a certain degree of data interpretation.Despite its limitations, we believe that this study still has some reference value.

Conclusion
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.

Table 1
Basic information of the 22 patients includedAC Amoxicillin clavulanic acid, A amoxicillin, COPD Chronic obstructive pulmonary disorder, CKD chronic kidney disease, na not available

Table 2
Clinical manifestations, cerebrospinal fluid examination results, treatment and prognosis of the 22 included patients AET Antibiotic experiential treatment, CSF cerebrospinal fluid, D Discounted, CT Computed tomography, MRI Magnetic resonance imaging, na not available, RBC Red blood cells