Mitochondrial Toxicity Associated with Linezolid
Abstracts & Commentary
By Dean L. Winslow, MD, FACP, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor of Medicine, Stanford University School of Medicine. Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron, and is on the speaker's bureau for Pfizer/Agouron.
This article originally appeared in the May 2006 issue of IDA. It was reviewed by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center. Dr. Price is Assistant Professor of Medicine, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau of Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck. Dr. Price reports no financial relationship relevant to this field of study.
Synopsis: Six patients developed lactic acidosis during prolonged linezolid therapy, possibly as the result of mitochondrial protein synthesis.
Sources: Palenzuela L, et al. Does Linezolid Cause Lactic Acidosis by Inhibiting Mitochondrial Protein Synthesis? Clin Infect Dis. 2005;40: e113-e116; Soriano A, et al. Mitochondrial Toxicity Associated with Linezolid. N Engl J Med. 2005;353:2305-2306.
Linezolid is an oxazolidinone antibiotic which has proven to be very useful in the treatment of Gram positive bacterial infections, including methicillin-resistant S. aureus (MRSA). Its lipophilic properties and good penetration into pulmonary tissue allow it excellent activity in vivo in pneumonia due to MRSA, and its superiority to vancomycin has been demonstrated in clinical trials. While generally well-tolerated when given short term with prolonged therapy, myelosuppression (especially thrombocytopenia) is commonly seen. Less commonly, peripheral neuropathy and metabolic acidosis have been seen in linezolid treated patients.
Palenzuela and colleagues describe 3 patients who developed lactic acidosis while receiving prolonged linezolid therapy. Peripheral blood samples from these patients were examined by sequencing PCR fragments amplified from 12S and 16S rRNA, and direct sequencing of the PCR products was performed to identify known polymorphisms. To determine the frequency of polymorphisms in 100 control patients, restriction fragment length polymorphism (RFLP) analysis was performed using restriction enzymes to specifically identify the substitutions in question. One patient was found to have a homoplasmic A2706G in 16S rRNA, one patient had a homoplasmic G3010A in 16S rRNA, and the third patient had no rRNA polymorphisms identified.
Soriano and colleagues also describe 3 patients who experienced linezolid-induced mitochondrial toxicity manifested by weakness and lactic academia. In all patients, mitochondrial respiratory chain complex II (succinate dehydrogenase, synthesized by cytoplasmic ribosomes) demonstrated normal activity in PBMC samples, but complex IV (cytochrome c oxidase, synthesized by mitochondrial ribosomes) activity was reduced.
Linezolid inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit and prevents the formation of the initiation complex which requires interactions with tRNA, mRNA, and the 30S ribosomal subunit.1,2 Due to the similarities between the conserved domains of rRNAs in bacterial and human mitochondrial ribosomes, it is likely that linezolid causes mitochondrial toxicity by inhibiting protein synthesis. The 16s rRNA polymorphisms described by Palenzuela et al in 2 patients may confer genetic susceptibility to linezolid toxicity in a manner similar to the A1555G substitution in mitochondrial 12S rRNA, which confers susceptibility to aminoglycoside-induced hearing loss.3 While chloramphenicol is seldom used now, older physicians were quite familiar with manifestations of mitochondrial toxicity associated with the use of this agent, which included anemia (which occurred commonly in patients treated for more than a few days) and the rarely seen grey baby syndrome of cardiovascular collapse in premature neonates associated with reduced metabolism of the drug. Chloramphenicol exhibits reversible binding to the 50S subunit of the bacterial ribosome at a locus which prevents the attachment of the amino acid-containing end of the aminoacyl-transfer RNA to its binding region.4 Another class of antimicrobial agents commonly recognized as causing mitochondrial toxicities includes the nucleoside analogue HIV reverse transcriptase inhibitors, particularly the dideoxynucleoside agents. Nucleoside analogue toxicity is most commonly manifested by peripheral neuropathy, lipoatrophy, and less commonly by myopathy, encephalopathy, and hepatic steatosis with lactic acidosis.
Preclinical toxicity studies of linezolid performed by Pharmacia/Upjohn in rats and dogs, in retrospect, suggests mitochondrial toxicity, although specific studies to show this was the mechanism of toxicities observed were not performed. Myelosuppression was observed in both rats and dogs, which was time- and dose-dependent.5 In addition, decreased food consumption, diarrhea, and mucosal histopathological changes (atrophy of intestinal mucosa and necrosis of crypt epithelial cells) were observed in rats. While not seen in the Pharmacia/Upjohn preclinical studies, the oxazolidinones were originally discovered by scientists at the DuPont Company, which advanced one compound, DuP 721, to Phase I clinical trials in the mid-1980s. Interestingly, the oxazolidinones were abandoned by DuPont in the late 1980s due to progressive fatal anorexia, which was seen in rats and dogs. My recollection is that nonspecific histopathologic changes similar to those reported by Pharmacia/Upjohn were seen in the DuPont preclinical pharm/tox studies. No mechanism of this was conclusively shown at that time but, in retrospect, it seems likely that this represented mitochondrial toxicity.
Due to its mechanism of action, it should not be surprising that linezolid is capable of causing mitochondrial toxicity. While linezolid is clearly an important drug for the treatment of antibiotic-resistant gram positive bacterial infections, clinicians should be aware of the potential for mitochondrial toxicity, particularly with prolonged therapy, and monitoring for myelosuppression and lactic acidosis should be routine.
1. Livermore DM. Linezolid In Vitro: Mechanism and Antibacterial Spectrum. J Antimicrob Chemother. 2003;51:ii9-ii16.
2. Eustice DC, et al. Mechanism of Action of DuP 721: Inhibition of an Early Event During Initiation of Protein Synthesis. Antimicrob Agents Chemother. 1988;32:1218-1222.
3. Hutchin T, Cortopassi G. Proposed Molecular and Cellular Mechanism for Aminoglycoside Ototoxicity. Antimicrob Agents Chemother. 1994;38:2517-2520.
4. Yamaguchi A, et al. Delta pH-Dependent Accumulation of Tetracycline in Escherichia coli. Antimicrob Agents Chemother. 1991;35:53-56.
5. Pharmacia/Upjohn, Linezolid Summary Basis for Approval. FDA/CDER Website www.fda.gov/cder/