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A severe linezolid‐induced rhabdomyolysis and lactic acidosis in Leigh syndrome

To the Editor, Recently, De Vries et al. reported the results of a Delphi-based workshop to develop consensus guidelines for physicians prescribing drugs for patients with mitochondrial diseases. The pharmacological management of these subjects is a challenge for two main reasons: the need to avoid specific drugs for a well-characterized mitochondrial toxicity, such as valproate in POLG mutation carriers, and the unpredictability of adverse drug reactions, also due to the genetic complexity of mitochondrial disorders. We report a 24-year-old female patient with m.13513G > A and adult onset Leigh syndrome who was admitted to the intensive care unit (ICU) of our hospital for supportive treatment of medical complications after surgery of thyroid cancer. She reached developmental milestones appropriately and no psychomotor retardation or regression was documented. She subsequently developed a progressive syndrome characterized by bilateral ptosis, external ophthalmoplegia, severe deafness, cerebellar ataxia, and exercise intolerance. On admission in ICU, the serum lactate was 1.8 mmol/L (upper limit of normal 2.2 mmol/L) and the creatine kinase (CK) level was slightly elevated (254 IU/L; upper limit of normal 170 IU/L). Linezolid (600 mg twice daily) was started to treat a methicillin-resistant S. aureus (MRSA) pneumonia. After two doses of this drug, she presented very severe muscle pain, tachycardia, nausea, vomiting, and tachypnea, quickly followed by severe muscle weakness resulting in flaccid quadriplegia. The serum lactate at this time was 9 mmol/L and the remaining laboratory tests documented a marked increase in CK (146 000 IU/L) associated with an increase in creatinine values (respectively, 8 mg/dL; n.v. 0.5-1), a glomerular filtration rate of 9.8 mL/min and the need for dialysis. Linezolid was discontinued and the next day the lactate was 4.6 mmol/L and returned to baseline levels in 5 days. Muscle involvement improved significantly after about 10 days with CK values returning to pre-linezolid levels in 7 days. At the same time, renal function also improved and dialysis treatment was stopped. Linezolid, an oxazolidinone antibiotic, inhibits the synthesis of bacterial proteins by preventing the fusion of 30S and 50S ribosomal subunits and is widely used in ICUs for the efficacy against multidrug-resistant Gram-positive infections. Reported linezolid-induced adverse drug reactions a include lactic acidosis, optic and peripheral neuropathy, and rhabdomyolysis. A possible cause of these clinical aspects is the capacity of this drug to interfere with mitochondrial function. The hypothesis of mitochondrial involvement is reinforced by some reports in literature including the case of linezolid-induced lactic acidosis in a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes patient. For this reason, although De Vries and colleagues have expressed a strong consensus for the use of linezolid in mitochondrial diseases with the only precaution of monitoring lactate levels, whenever possible we recommend avoiding this antibiotic in patients with primitive mitochondrial dysfunction. In fact, lactate monitoring hardly provides information in order to predict the development of acute severe lactic acidosis and/or rhabdomyolysis. In conclusion, our experience suggests that, for their unpredictability, it is not possible to prevent serious adverse events induced by linezolid such as those described in these fragile patients.