Mitochondrial Toxicity Associated with Linezolid
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《新英格兰医药杂志》
To the Editor: Linezolid belongs to a family of antimicrobial agents (oxazolidinones) that inhibit bacterial protein synthesis by preventing the fusion of 30S and 50S ribosomal subunits.1 Hyperlactatemia, metabolic acidosis, and peripheral neuropathy are adverse effects of linezolid,2,3 which could be related to the drug's capacity for interference with mitochondrial function.4 We studied mitochondria from three patients in whom asthenia and hyperlactatemia developed during a prolonged course of oral linezolid (600 mg every 12 hours).
Patient 1, a 25-year-old man with Enterococcus faecium infection of a knee prosthesis, received oral linezolid. After three months, mild asthenia and hyperlactatemia developed (lactate levels of 40, 59, and 41 mg per deciliter, as measured on three occasions; normal, <20 mg per deciliter). Patient 2, a 75-year-old man with Waldenstr?m's macroglobulinemia and a cerebral abscess due to Nocardia otitidiscaviarum, was treated with oral linezolid, levofloxacin, and minocycline. He had severe asthenia and hyperlactatemia (lactate levels, 26 and 28 mg per deciliter, as measured on two occasions) after two months of treatment. Patient 3, a 55-year-old man, received oral linezolid because of infection of a knee prosthesis with methicillin-resistant coagulase-negative staphylococci. Mild asthenia and hyperlactatemia developed (lactate levels, 29 and 44 mg per deciliter, as measured on two occasions) after 1.5 months of treatment. After withdrawal of linezolid, lactate levels returned to normal in all patients.
Blood samples were collected during treatment to obtain peripheral-blood mononuclear cells (PBMCs). Mitochondrial studies in PBMCs consisted of the spectrophotometric determination of enzyme activity for mitochondrial respiratory-chain complex II (succinate dehydrogenase, synthesized by cytoplasmic ribosomes) and complex IV (cytochrome c oxidase, partially synthesized by mitochondrial ribosomes) and the polarographic measurement of spontaneous intracellular oxidation.5 In all patients, complex II activity was within the normal range, whereas complex IV activity was below normal in all three patients (Figure 1). In addition, the complex IV inhibition in Patient 2 was associated with an abnormal capacity of the mononuclear cells to use oxygen.
Figure 1. Mitochondrial Function in Peripheral-Blood Mononuclear Cells from Three Patients.
The left ordinate shows units of complex II and IV activity, and the right ordinate units of spontaneous cell oxidation. The horizontal lines and shaded areas denote the mean values and ranges measured in 18 healthy controls (mean age, 62±19 years) with normal levels of venous lactate.
Since all complex II proteins are synthesized by cytoplasmic ribosomes, whereas some complex IV proteins are synthesized by mitochondrial ribosomes, our results suggest that linezolid interferes with mitochondrial protein synthesis, probably owing to similarities between bacterial and mitochondrial ribosomes.
Alex Soriano, M.D.
Oscar Miró, Ph.D.
Josep Mensa, M.D.
Hospital Clinic
08036 Barcelona, Spain
asoriano@clinic.ub.es
References
Livermore DM. Linezolid in vitro: mechanism and antibacterial spectrum. J Antimicrob Chemother 2003;51:Suppl 2:ii9-ii16.
Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med 2003;348:86-87.
Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004;4:528-531.
Palenzuela L, Hahn NM, Nelson RP Jr, et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clin Infect Dis 2005;40:e113-e116.
Lopez S, Miro O, Martinez E, et al. Mitochondrial effects of antiretroviral therapies in asymptomatic patients. Antivir Ther 2004;9:47-55.
Patient 1, a 25-year-old man with Enterococcus faecium infection of a knee prosthesis, received oral linezolid. After three months, mild asthenia and hyperlactatemia developed (lactate levels of 40, 59, and 41 mg per deciliter, as measured on three occasions; normal, <20 mg per deciliter). Patient 2, a 75-year-old man with Waldenstr?m's macroglobulinemia and a cerebral abscess due to Nocardia otitidiscaviarum, was treated with oral linezolid, levofloxacin, and minocycline. He had severe asthenia and hyperlactatemia (lactate levels, 26 and 28 mg per deciliter, as measured on two occasions) after two months of treatment. Patient 3, a 55-year-old man, received oral linezolid because of infection of a knee prosthesis with methicillin-resistant coagulase-negative staphylococci. Mild asthenia and hyperlactatemia developed (lactate levels, 29 and 44 mg per deciliter, as measured on two occasions) after 1.5 months of treatment. After withdrawal of linezolid, lactate levels returned to normal in all patients.
Blood samples were collected during treatment to obtain peripheral-blood mononuclear cells (PBMCs). Mitochondrial studies in PBMCs consisted of the spectrophotometric determination of enzyme activity for mitochondrial respiratory-chain complex II (succinate dehydrogenase, synthesized by cytoplasmic ribosomes) and complex IV (cytochrome c oxidase, partially synthesized by mitochondrial ribosomes) and the polarographic measurement of spontaneous intracellular oxidation.5 In all patients, complex II activity was within the normal range, whereas complex IV activity was below normal in all three patients (Figure 1). In addition, the complex IV inhibition in Patient 2 was associated with an abnormal capacity of the mononuclear cells to use oxygen.
Figure 1. Mitochondrial Function in Peripheral-Blood Mononuclear Cells from Three Patients.
The left ordinate shows units of complex II and IV activity, and the right ordinate units of spontaneous cell oxidation. The horizontal lines and shaded areas denote the mean values and ranges measured in 18 healthy controls (mean age, 62±19 years) with normal levels of venous lactate.
Since all complex II proteins are synthesized by cytoplasmic ribosomes, whereas some complex IV proteins are synthesized by mitochondrial ribosomes, our results suggest that linezolid interferes with mitochondrial protein synthesis, probably owing to similarities between bacterial and mitochondrial ribosomes.
Alex Soriano, M.D.
Oscar Miró, Ph.D.
Josep Mensa, M.D.
Hospital Clinic
08036 Barcelona, Spain
asoriano@clinic.ub.es
References
Livermore DM. Linezolid in vitro: mechanism and antibacterial spectrum. J Antimicrob Chemother 2003;51:Suppl 2:ii9-ii16.
Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med 2003;348:86-87.
Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004;4:528-531.
Palenzuela L, Hahn NM, Nelson RP Jr, et al. Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clin Infect Dis 2005;40:e113-e116.
Lopez S, Miro O, Martinez E, et al. Mitochondrial effects of antiretroviral therapies in asymptomatic patients. Antivir Ther 2004;9:47-55.