Table 1.

Case reports of amoxicillin/clavulanic acid and aseptic meningitis in males in VigiBase

Case	Age/sex	Medications	Reactions	Indication	Dose	Time to onset	Notes/outcome
1	25 y/M	Amox/Clav (S)	Aseptic meningitis Headache	Furuncle	1 gm, 3 per d, oral	13 d	CT/MRI/EEG within normal limits. LP (Lyme, herpes) negative. Ruled out limbic encephalitis.
2	77 y/M	Amox/Clav (S) Acetylsalicyclic acid (C) Simvastatin (C) Pantoprazole (C)	Aseptic meningitis	Bursitis	2220 mg, 3 per 1 d, oral	3 d	MRI/EEG/angiogram LP (HIV, Borrelia, syphilis, herpes, enterovirus, tick borne virus, varicella virus, parvovirus, flavivirus) negative Positive dechallenge.
3	63 y/M	Amox/Clav (S) Amlodipine; valsartan (C) Hydrochlorothiazide (C)	Aseptic meningitis Cephalgia	Bronchitis	1 dosage form, 2 per d, oral		LP consistent with aseptic meningitis. Multiple serologies for infectious and autoimmune diseases negative. Positive dechallenge. Positive rechallenge (one prior episode)
4	79 y/M	Amox/Clav (S)	Aseptic meningitis	Stomatitis			Present and past extensive evaluations for infectious and autoimmune diseases negative. Positive rechallenge (two prior episodes). Published case report. Militao et al.6
5	1 m/M	Amox/Clav (S)	Aseptic meningitis Feeding disorder neonatal Epilepsy Erythrocytes decreased Fever Haemtocrit decreased Haemoglobin decreased Leukocyte count decreased	Infection prophylaxis	2.5 ml, 2 per d	2 d	Had been treated for E.coli sepsis for 3 wk prior. Discharged on amox/clav as outpatient. Returned to hospital after third oral dose with meningitis.
6	58 y/M	Amox/Clav (S)	Aseptic meningitis	Skin infection		1 d	LP negative. Positive dechallenge. History of two previous rechallenges. Published case report: Preito‐Gonzalez et al.7
7	31 y/M	Amox/Clav (S)	Meningitis aseptic Headache Cervical pain Consciousness abnormal	Otitis media acute	1000 mg, 3 per d	11 d
8	66 y/M	Amoxicillin (S) Amox/Clav (S)	Meningitis aseptic	Dental pain		4 d	CT negative. LP with lymphocytic pleocytosis. History of two previous episodes. Reported by allergist. Allergy skin tests with beta lactam antibiotics negative. Published case report. Alarcon et al.8
9	63 y/M	Amox/Clav (S)	Meningitis aseptic
10	35 y/M	Amox/Clav (S) Ibuprofen (S)	Meningitis aseptic	Acute tonsillitis	‐, 3 per 24 h 600 mg, 3 per 24 h	5 d	Positive dechallenge LP with lymphocytic predominance
11	72 y/M	Amox/Clav (S) Terazosin (C) Moxifloxacin (S) Ceftriaxone (S) Aciclovir (S) Ampicillin (S)	Lymphocytic meningitis Anorexia Constipation Headache Consciousness decreased Vomiting projectile Shivering Temperature elevation Neck stiffness	Pyrexia with respiratory symptoms	875 mg, 3 per 1 d	8 d	Medical history of polyarthritis rheumatica, oesophagitis, colorectal polyp, and prostatism. All other antimicrobials added after patient hospitalised, although listed as “suspected.” Positive dechallenge and rechallenge
12	82 y/M	Amox/Clav (S) Terbutaline (S) Heparin (S) Macrogol 4000 (S) Ipratropium (S) Ceftriaxone (S) Spiramycin (S) Influenza vaccine (C)	Lymphocytic meningitis	Bronchopneumonia	Oral	8 d	Medical history of hypertension, cardiac insufficiency, diabetes, history of bladder cancer, and nephrectomy. Other medications in narrative: Simvastatin, molsidomine, diltiazem, irbesartan, clopidogrel, sitaglipine, fluticasone, and salmerterol. Hospitalised and treated for pneumonia with ceftriaxone and spiramycin for 4–5 days. Discharged on Augmentin. Returned to hospital with fever and confusion. LP and EEG performed. Positive dechallenge.
13	65 y/M	Amox/Clav (S) Amoxicillin (S) Pneumococcal vaccine (S) Influenza vaccine (S) Candesartan (C) Moxonidine (C) Pantoprazole (C) Oxybutynin (C) Methionine (C)	Meningitis aseptic Injection site inflammation	Injection site inflammation	‐,‐ oral 2 gm, 6 per d IV	4–5 days	Medical history: Paraplegia, type 2 diabetes. Injection site reaction after vaccination, treated with amox/clav. LP with lymphocytes and elevated protein. Cultures and pcrs negative.
14	86 y/M	Amox/Clav (S) Amoxicillin (S) Celiprolol (C)	Meningitis aseptic	Complication of internal prosthetic device, implant, and graft	2 gm, − per d PO 12 gm, 1 per d IV		Recovered
15	/M	Amoxicillin (S)	Meningitis aseptic	Cellulitis	Oral	2 d	Positive dechallenge
16	74 y/M	Amoxicillin (S) Ibuprofen (S) Codeine (S) Caffeine; Papaver somniferum; paracetamol (S)	Aseptic meningitis	Prophylactic	Oral	7 d	Recovered with withdrawal of all meds. “Negative rechallenge with paracetamol makes it possible to exclude it from suspect treatments”
17	62 y/M	Amoxicillin (S)	Aseptic meningitis	Antibiotic prophylaxis	Oral	6 h	Positive dechallenge. Positive rechallenge (one prior episode). Extensive evaluation. No evidence of type 1 or type 2 hypersensitivity. Published case report: Kastenbauer et al.5
18	75 y/M	Amoxicillin (S)	Tonic–clonic epilepsy Lymphocytic meningitis	Tooth infection	Oral	2 d	Positive dechallenge. Positive rechallenge (two prior episodes).
19	65 y/M	Amoxicillin (S) Amox/Clav (S) Tiaprofenic acid (S) Hydroxyzine (C)	Meningitis aseptic	Tooth pain Tooth abscess	Oral	5 d	Extensive evaluations of CSF, including entervirus, herpes, EBV, CMV, Lyme, and syphilis. Positive dechallenge.
20	52 y/M	Amoxicillin (S)	Aseptic meningitis	Bronchitis	Oral	11 d	Admitted with confusion, afebrile. EEG and LP performed. Initially treated with IV amoxicillin and acyclovir. Positive dechallenge.
21	78 y/M	Amoxicillin (S)	Confusional state Malaise Consciousness loss Aseptic meningitis	Pneumopathy	3 g, 1 per 1 d. Oral	1 d	LP performed. PCRs negative. High cells and protein. Positive dechallenge.
22	20 y/M	Amoxicillin (S) Codeine; paracetamol (C)	Aseptic meningitis	Dental disorder prophylaxis	2 g, 1 per Oral	2 d	Elevated IgE to ampicillin. Positive dechallenge. Positive rechallenge (three prior episodes with penicillin agents)
23	46 y/M	Amoxicillin (S)	Aseptic meningitis	Suspicion of Lyme disease	Oral	1 day	Positive dechallenge.
24	72 y/M	Amoxicillin (S)	Meningitis aseptic Upper respiratory tract infection	Oropharyngeal pain	500 mg tid Oral		Positive dechallenge.
25	42 y/M	Amoxicillin (S) Paraaminobenzoic acid (C) Ibuprofen (C)	Meningitis aseptic	Acute upper respiratory infection, unspecified	1.5 g per 1 d	3 d	Positive dechallenge.
26	17 y/M	Amoxicillin (S) Ibuprofen (S)	Meningitis aseptic		Oral	8 d	No narrative
27	55 y/M	Amoxicillin (S)	Meningitis aseptic	Prophylaxis	500 mg Oral		Positive dechallenge. No narrative
28	55 y/M	Amoxicillin (S)	Meningitis aseptic Phonophobia Tachycardia				Positive dechallenge. No narrative
29	55 y/M	Amoxicillin (S)	Meningitis aseptic Headache Chills Pyrexia	Antibiotic prophylaxis	500 mg single dose		Positive dechallenge. No narrative
30	44 y/M	Amoxicillin (S) Amox/Clav (S)	Meningitis aseptic Gingival pain Influenza Lymphadenopathy No therapeutic response Rash maculo‐papular Sinusity	Tooth abscess Sinusitis	Oral		Amoxicillin duration 7 d, Amox/Clav duration 12 d. Positive dechallenge recorded for amox/clav No narrative
31	55 y/M	Amoxicillin (S)	Meningitis aseptic	Dental disorder prophylaxis	500 mg, 1 per 1 d Oral		Positive dechallenge No narrative
32	86 y/M	Amox/Clav (S) Hydrochlorothiazide;Irbesartan (S) Clopidogrel (C) Metoprolol (C) Amiodarone (C) Tolterodine (C) Metformin (C) Simvastatin (C) Levothyroxine (C) Insulin lispro (C)	Meningitis aseptic Confusion Vomiting Sodium depletion	Bronchitis/pneumonia	Oral	4 d	Positive dechallenge Positive rechallenge
33	20 y/M	Amoxicillin (S) Paracetamol (C)	Meningitis aseptic	Acute pharyngitis	2 g, − per d Oral	6 d	Positive dechallenge No narrative
34	80 y/M	Amox/Clav (S) Amoxicillin (S) Clarithromycin (C)	Meningitis aseptic Tooth ache Urinary tract infection Lyme disease				No narrative
35	72 y/M	Amoxicillin (S)	Meningitis aseptic Unevaluable event Photophobia				No narrative
36	60 y/M	Amoxicillin (S) Ibuprofen (S) Simvastatin (C) Amlodipine (C) Hydrochlorothiazide (C) Folic acid (C)	Meningitis aseptic			Oral	No narrative

Abbreviations: CMV, Cytomegalovirus; CT, computed tomography; CSF, cerebrospinal fluid; EBV, Epstein–Barr virus; EEG, electroencephalography, HIV, human immunodeficiency virus; IV, intravenous; LP, lumbar puncture; MRI, magnetic resonance imaging; PO, per os. The table includes a line listing of all reports included in the analysed case series. (S) and (C) in the Medications column designate if a drug was reported as Suspected or Concomitant in relation to the ADR. All Reactions and Indications are encoded in MedDRA terminology.