Trimethoprim-Sulfamethoxazole-lnduced Aseptic Meningitis
Meningitis is an inflammation of the meninges and is usually caused by a viral or bacterial infection. Differentiation of the etiology of meningitis into aseptic and bacterial is very important because of the differences in the severity of illness, treatment modalities and prognostic implications. Encephalitis is an inflammation of the brain in response to an infection that can be caused by a variety of agents, usually accompanied by brain swelling. Aseptic meningitis is an illness characterized by serous inflammation of the linings of the brain (i.e., meninges), usually with an accompanying mononuclear pleocytosis. Aseptic meningitis syndrome is not caused by pyogenic bacteria but can be caused by multiple conditions, including infectious viral and nonviral causes and many noninfectious etiologies.
It is a combination of trimethoprim/sulfamethoxazole (TMP/SMX) in the ratio of 1:5 (IV or PO) that slowly kills bacteria by inhibiting folic-acid metabolism, a necessary chemical for both bacteria and humans, and each is an effective antibiotic when used alone. TMP/SMX has excellent tissue penetration, including bone, prostate and CNS. It is prescribed for the treatment of urinary tract infections (UTIs), severe middle-ear infections in children, long-lasting or frequently recurring bronchitis in adults, inflammation of the intestine due to a severe bacterial infection, and travelers’ diarrhea. TMP/SMX is also prescribed for the prophylaxis and treatment of Pneumoystis carinii pneumonia in people with weakened immune systems, including HIV (used for treating HIV infection in combination with other medicines) patients.
Drug-induced aseptic meningitis (DIAM) is commonly seen with nonsteroidal anti-inflammatory drugs (NSAIDS), antibiotics (with TMP/SMX being the most frequently implicated), intravenous immunoglobulins and OKT3 antibodies, among many others (Table 1). DIAM can mimic an infectious process as well as meningitides that are secondary to systemic disorders for which these drugs are used. An important mediator that has been implicated in the process has been substantial production of interleukin (IL)-6, with no production of IL-1, IL-2 and tumor necrosis factor (TNF)-oc seen in the purified peripheral blood mononuclear cells. IL-1 and TNF-oc are the major cytokines that mediate inflammation produced by activated macrophages. They induce endothelial adhesion molecules and IL-6 for activation in natural immunity. Non-drug-related etiologies in the differential of aseptic meningitis include viral (HIV infection, herpes, enteroviruses, mumps), bacterial, fungal, parasitic, malignancy and autoimmune diseases.
TMP/SMX is in a group of drugs called sulfonamides, which prevent the growth of bacteria in the body. Rare but sometimes fatal reactions have occurred with use of sulfonamides. These reactions, among many others, include aseptic meningitis.
While many side effects of TMP/SMX have been described, there is little emphasis in the literature in relation to it causing meningitis. DIAM seen with TMP/SMX occurs predominantly in patients with some degree of immune compromise resulting from AIDS, organ transplantation, collagen vascular disease and cancer.