Linezolid‐associated small‐fiber neuropathy

Dear Editor, Linezolid is the first of a new class of oxazolidinone antibiotics, which was approved in Germany in 2002. Linezolid has high activity against methicillinand vancomycin-resistant gram-positive pathogens, is 100% bioavailable, and can be given orally (Moellering, 2003). Its profile of adverse events is considered to be acceptable and mainly concerns diarrhea, headache, nausea and vomiting, and taste disorder (Halle et al., 2002). Optic and peripheral neuropathies have been reported with long-term use of linezolid (Bressler et al., 2004; Zivkovic and Lacomis, 2005). The cases of linezolid-associated peripheral neuropathy were sensory-motor axonal, mainly large fiber, and variably recovered after discontinuation of linezolid. Recently, Chao et al. (2008) reported a painful small-fiber neuropathy after prolonged use of linezolid. They demonstrated in skin biopsy denervation and signs of reinnervation. We wish to emphasize this clinical observation by reporting a further case. A 54-year-old, otherwise healthy,woman had undergone left knee replacement, which was complicated by severe wound infection and beginning sepsis with methicillin-resistant Staphylococcus aureus. A total of five surgical wound revisions were necessary. Linezolid was given for 16 weeks in a dosage of 600 mg twice daily. The knee wound healed with this antibiotic regimen. After the 15th week of linezolid therapy, the patient reported numbness and continuing burning pain in both feet. She had allodynia. Sleep was greatly disturbed due to pain. At this time, linezolid was discontinued. However, symptoms persisted and prompted neurological consultation. Examination showed sensory loss in a stocking distribution. Differentiation of cold and warm stimuli was severely impaired using the tip therm probe on both feet. Vibration at toes and ankles was significantly diminished. The remainder of the neurological examination was normal except an absent left knee reflex. Nerve conduction studies in the lower limbs were normal. The following tests were normal or negative: oral glucose tolerance test; D-xylose test; vitamins B1, B6, B12, and E; folic acid; methylmalonic acid; liver and renal function; serum electrophoresis and quantitative measurement of immunoglobulins, carbohydrate deficient transferrin, hemoglobin, leucocytes, thrombocytes, thyroid stimulating hormone, and thyroxin; Bence Jones proteins in urine; analysis of cerebrospinal fluid; tests for borreliosis, lues, varicella zoster, HIV, and hepatitis C; and tests for the immunologic parameters antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, and antibodies in Sjögren disease (Neundörfer, 1993). Treatment with gabapentin resulted in moderate pain relief. At 3-month follow-up, clinical signs were unchanged. Based on the clinical findings, we diagnosed smallfiber neuropathy in our patient. There was no evidence of dysfunction of the large-diameter motor and sensory nerves based on clinical and electrodiagnostic findings. In our patient, we strongly assume an association between the neuropathy and the intake of linezolid for two reasons. First, signs and symptoms of small-fiber neuropathy began after the 15th week of linezolid use, i.e., there was a close temporal relation between linezolid administration and onset of symptoms. This is in keeping with other published cases of neuropathy that occurred after prolonged use of linezolid (Corallo and Paull, 2002; Bressler et al., 2004). Second, we did not find an alternative explanation for the occurrence of polyneuropathy. In their patient, Chao et al. (2008) demonstrated histological signs of reinnervation with concomitant clinical improvement after discontinuation of linezolid. However, in our patient, we could not detect a substantial clinical improvement after discontinuation of linezolid, as reported in the majority of other cases. The cause of nerve injury by linezolid is unclear (Zivkovic and Lacomis, 2005). It is speculated that linezolid may cause mitochondrial dysfunction and thus damage optic and peripheral nerves (Lee et al., 2003).