Abstract
We describe a case of aseptic meningitis following the administration of moxifloxacin in a 45-year-old man with human immunodeficiency virus (HIV). At presentation he was receiving tuberculosis treatment on a modified regimen following severe hepatotoxicity; this included moxifloxacin, started 8 days previously. Initial cerebrospinal fluid (CSF) analysis was grossly abnormal. Anti-viral and -bacterial treatments were started. All microbiological tests proved negative and his moxifloxacin was withheld resulting in a complete normalisation of CSF. Drug-induced aseptic meningitis is a diagnosis of exclusion and presents a serious diagnostic dilemma. The decision to withhold medication cannot be taken lightly.
Keywords
Introduction/background
We present the case of a 45-year-old gentleman from southern Africa, presenting with a two-day history of general malaise, retro-orbital headache, nausea and profound myalgia. He had a background history of human immunodeficiency virus (HIV), neurosyphilis, genital herpes simplex virus (HSV) and schistosomiasis and treated latent tuberculosis (TB).
Case report
At the time of presentation, he was receiving treatment for active pulmonary TB. Due to severe hepatotoxicity, he was two months into a modified regimen including isoniazid, rifampicin and pyridoxine. As a fourth agent, moxifloxacin had been added eight days earlier as a substitute for the more hepatotoxic pyrazinamide. This regimen had been adopted according to the British HIV Association guidelines for the re-introduction of TB medications following drug-induced hepatotoxicity. 1
The CSF white cell differential showed 100% mononuclear cells. Protein was 118 mg/dL and glucose was 4.3 mmol/L. The Gram stain revealed no organisms. He was treated empirically for bacterial meningitis and viral encephalitis with intravenous cefotaxime, vancomycin, acyclovir and steroids, as per hospital protocol. Further microbiological workup of his CSF included negative cryptococcal antigen and India ink stain. His meningococcal, pneumococcal, HSV, varicella zoster virus (VZV), enterovirus, cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) polymerase chain reaction (PCR) tests were negative. CSF for acid-fast bacilli was negative and all TB cultures were negative at six weeks. His peripheral blood cultures, faecal cultures and mid-stream urine were negative for microbiological growth.
In order to minimise his TB treatment interruption, the decision was made to re-introduce moxifloxacin following normalisation of the CSF, two days later. Approximately 90-minutes post-ingestion, he began complaining of a severe retro-orbital headache, sweats, pruritus and nausea. On examination he was unwell; diaphoretic, photophobic and tachycardic with a widespread blanching macular rash. These symptoms were identical to his original presenting symptoms. Advice was sought from the Immunology service as to whether these symptoms could be drug induced, and the possibility of moxifloxacin-induced aseptic meningitis was raised. Immunology review suggested a type III hypersensitivity immune complex reaction secondary to moxifloxacin administration.
Discussion
Certain drugs have historically been associated with drug-induced aseptic meningitis (DIAM). These include non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, intravenous immunoglobulins and monoclonal antibodies. 2 This type of reaction is typically a type I or type III hypersensitivity reaction. The interval between the onset of symptoms varies, from minutes to months post-ingestion of the offending agent.2,3 The literature suggests that NSAIDs are frequently the culprit in DIAM. 3 In relation to other drug classes, beta-lactams and trimethoprim-containing antibiotics have been frequently reported as a cause. 4
One case report describes an 84-year-old woman diagnosed with seven episodes of meningitis over a seven-year period. On her final admission, she presented with fever and headache. History revealed a recent course of amoxicillin prescribed by her GP for treatment of a lower respiratory tract infection. CSF analysis revealed raised protein, low glucose and 20 polymononuclear cells. She was diagnosed with partially treated bacterial meningitis. Review of her medical notes revealed that prior to each admission for suspected meningitis she had received short course of amoxicillin for 3–5 days for suspected respiratory infections.
Serial presentation and CSF analysis showed similar results with resolution of symptoms and normalisation of CSF. She was advised to avoid penicillin and one-year post follow-up she had not represented. 5
Forty cases of trimethoprim-related aseptic meningitis have been described in the literature. Aseptic meningitis is associated with underlying immune-mediated disorders, including HIV.2,4,6 A separate review of 39 cases of DIAM revealed that CSF analysis in these cases frequently contained mononuclear cells; however, lymphocytes and eosinophils have also been described. The CSF typically contains normal to low glucose and high levels of protein. The article also describes a range of symptoms, such as headache, arthromyalgia, fever, nausea, vomiting and hypotension, all of which correlated with our patient’s presentation. No reaction to moxifloxacin has been previously described; however, DIAM has been attributed to ciprofloxacin therapy. This may indicate a drug class effect, with fluoroquinolones, a possible trigger for DIAM.
The mechanism of action of DIAM is not fully understood. It is thought that different groups of drugs work through different mechanisms.1,2 Antibiotics may cause immune complex reaction.2,3,7 In co-trimoxazole-induced aseptic meningitis, immune complexes have been found in plasma but not in CSF. Some authors suggest that immune complex deposition on the choroid plexus causes necrotising vasculitis of small vessels, resulting in meningitis.2,3
DIAM is a diagnosis of exclusion and presents a serious diagnostic dilemma as our case highlights. Meningitis is a life-threatening emergency and does not allow for delay in initiation of antibiotic therapy. It is crucial to commence empiric antibiotics whilst awaiting CSF results. A diagnosis of DIAM can be made if resolution of the symptoms occurs once the drug is stopped. DIAM may be considered when the following features are present: (1) improvement in symptoms and CSF with drug cessation, (2) resolution of symptoms in those with auto-immune conditions without the use of steroids, (3) definite relationship between symptom occurrence and the initiation and re-initiation of the drug and (4) a lack of meningeal irritation on MRI. 4
Conclusion
This case highlights a previously undescribed moxifloxacin-induced aseptic meningitis. Interesting points include the patient’s complex medical history, severe immunosuppression and the severity of symptoms on presentation. DIAM can only be confirmed by removal and subsequent re-exposure of the patient to the offending drug. This requires accepting a great deal of clinical uncertainty on the part of the physician. As a result, DIAM presents complex diagnostic and management challenges. Drug re-exposure should therefore only be attempted when other avenues of investigation have been exhausted.
Footnotes
Conflict of interest
The authors declare no conflict of interest.
Funding
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.