Correspondence
Linezolid-Induced Lactic Acidosis
N Engl J Med 2003; 348:86-87January 2, 2003
- Article
To the Editor:
Linezolid is an oxazolidinone antibiotic used to treat a variety of gram-positive infections, including those due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, as well as nocardia species.1,2 Lactic acidosis is an adverse effect that has been associated with other drugs, including metformin and the nucleoside reverse-transcriptase inhibitors,3 but not with linezolid. We report a case in which severe lactic acidosis developed as an adverse effect of linezolid treatment.
A 52-year-old woman presented with fever, chills, and a two-week history of intermittent cough. Computed tomography (CT) of her chest revealed an infiltrate in the right middle lobe, as well as mediastinal adenopathy. Nocardia otitidis-caviarum was isolated from bronchoalveolar-lavage fluid as well as from a mediastinal biopsy specimen. Additional CT scanning revealed disseminated disease with involvement of the brain, kidneys, and adrenals.
The patient was initially treated with trimethoprim–sulfamethoxazole but had serious side effects that necessitated discontinuation. She was subsequently switched to linezolid and clarithromycin. Her treatment was complicated by myelosuppression, nausea, and vomiting, and gatifloxacin was substituted for the clarithromycin in the hope of relieving the nausea. During the subsequent five weeks, she had persistent vomiting and ongoing myelosuppression. Endoscopy revealed duodenal ulcers, and pantoprazole was started. The patient was hospitalized for intractable nausea and vomiting after 11 weeks of treatment with linezolid and 5 weeks of treatment with gatifloxacin. The findings on repeated endoscopy were normal. The patient was euvolemic and received intravenous fluids during hospitalization.
Because she had low bicarbonate levels, the patient's lactate level was checked and found to be more than 9.9 mmol per liter. Both antibiotics were stopped, resulting in a normalization of lactate levels at 1.4 mmol per liter after 10 days. Both antibiotics were then restarted, but the lactate level measured seven days later was 4.8 mmol per liter. Her nausea returned. The gatifloxacin was discontinued, and the lactate level had increased to 6.5 mmol per liter one week later. Discontinuation of linezolid resulted in normalization of the lactate level after two weeks. There were no other changes in medications during that time. The patient was then treated with moxifloxacin. Her lactate levels remained normal, and the disseminated nocardiosis resolved.
Lactic acidosis is a toxic effect of linezolid whose mechanism is unknown. Other drugs, including metformin and nucleoside reverse-transcriptase inhibitors, have been associated with lactic acidosis. In the case of nucleoside reverse-transcriptase inhibitors, lactic acidosis is thought to involve mitochondrial toxicity,4,5 and linezolid may have a similar effect. As we report here, a potentially serious side effect occurred in a patient receiving linezolid. The serum lactate level in patients taking linezolid should be measured if they have nausea or a low serum bicarbonate level.
5 ReferencesAaron A. Apodaca, M.D.
Robert M. Rakita, M.D.
Virginia Mason Medical Center, Seattle, WA 98111
resaaa@vmmc.org 1
Diekema DJ ,Jones RN . Oxazolidinone antibiotics. Lancet 2001;358:1975-1982
CrossRef | Web of Science | Medline2
Brown-Elliot BA ,Ward SC ,Crist CJ ,Mann LB ,Wilson RW ,Wallace RJ Jr . In vitro activities of linezolid against multiple Nocardia species. Antimicrob Agents Chemother 2001;45:1295-1297
CrossRef | Web of Science | Medline3
Gerard Y ,Maulin L ,Yazdanpanah Y , et al. Symptomatic hyperlactataemia: an emerging complication of antiretroviral therapy. AIDS 2000;14:2723-2730
CrossRef | Web of Science | Medline4
Brinkman K ,ter Hofstede HJM ,Burger DM ,Smeitink JA ,Koopmans PP . Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998;12:1735-1744
CrossRef | Web of Science | Medline5
Cote HCF ,Brumme ZL ,Craib KJP , et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811-820
Full Text | Web of Science | Medline
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1
Karen Joy Shaw, Michael R. Barbachyn. (2011) The oxazolidinones: past, present, and future. Annals of the New York Academy of Sciences 1241:1, 48-70
CrossRef2
Thomas E. Cope, Robert McFarland, Andrew Schaefer. (2011) Rapid-onset, linezolid-induced lactic acidosis in MELAS. Mitochondrion 11:6, 992-993
CrossRef3
Erik Su, Kelli Crowley, Joseph A. Carcillo, Marian G. Michaels. (2011) Linezolid and Lactic Acidosis. The Pediatric Infectious Disease Journal 30:9, 804-806
CrossRef4
Jorge Cerdá, Ashita J Tolwani, David G Warnock. (2011) Critical care nephrology: management of acid–base disorders with CRRT. Kidney International
CrossRef5
Damien Contou, Jérôme Fichet, David Grimaldi, Alain Cariou. (2011) Early life-threatening lactic acidosis following a single infusion of linezolid. International Journal of Antimicrobial Agents 38:1, 84-85
CrossRef6
F. K. Gould. (2011) Linezolid: safety and efficacy in special populations. Journal of Antimicrobial Chemotherapy 66:Supplement 4, iv3-iv6
CrossRef7
Julia Drebes, Markus Perbandt, Carsten Wrenger, Christian Betzel. (2011) Purification, crystallization and preliminary X-ray diffraction analysis of ThiM from Staphylococcus aureus. Acta Crystallographica Section F Structural Biology and Crystallization Communications 67:4, 479-481
CrossRef8
S.B. Kombian, O.A. Phillips. (2011) In vitro electrophysiological investigations of the acute effects of linezolid and novel oxazolidinones on central nervous system neurons. Neuroscience 180, 53-63
CrossRef9
Frank R DeLeo, Michael Otto, Barry N Kreiswirth, Henry F Chambers. (2010) Community-associated meticillin-resistant Staphylococcus aureus. The Lancet 375:9725, 1557-1568
CrossRef10
Juan Carlos Q. Velez, Michael G. Janech. (2010) A case of lactic acidosis induced by linezolid. Nature Reviews Nephrology 6:4, 236-242
CrossRef11
Jean-Sebastien Rachoin, Lawrence S. Weisberg, Christopher B. McFadden. (2010) Treatment of lactic acidosis: Appropriate confusion. Journal of Hospital Medicine 5:4, E1-E7
CrossRef12
Christopher Vernon, Jennifer L. LeTourneau. (2010) Lactic Acidosis: Recognition, Kinetics, and Associated Prognosis. Critical Care Clinics 26:2, 255-283
CrossRef13
H. M. Nguyen, C. J. Graber. (2010) Limitations of antibiotic options for invasive infections caused by methicillin-resistant Staphylococcus aureus: is combination therapy the answer?. Journal of Antimicrobial Chemotherapy 65:1, 24-36
CrossRef14
Lucía Fernández de Orueta, Verónica Díaz, Marta Ramírez, Raquel Álvarez. (2009) Acidosis láctica inducida por linezolid. Enfermedades Infecciosas y Microbiología Clínica 27:9, 550-551
CrossRef15
Leon M. Sujata, Gregory B. Russell, Donald Hire, Cesar Cardona, Dwayne A. Pierce, Anthony J. Bleyer. (2009) Lactic Acidosis from Linezolid in a Hospitalized Patient With Kidney Failure. Infectious Diseases in Clinical Practice 17:6, 404-406
CrossRef16
Donald C. Vinh, Ethan Rubinstein. (2009) Linezolid: a review of safety and tolerability. Journal of Infection 59, S59-S74
CrossRef17
Howard S. Gold, Satish K. Pillai. (2009) Antistaphylococcal Agents. Infectious Disease Clinics of North America 23:1, 99-131
CrossRef18
Sashi Nadanaciva, John H. Willis, Melissa L. Barker, Dima Gharaibeh, Roderick A. Capaldi, Michael F. Marusich, Yvonne Will. (2009) Lateral-flow immunoassay for detecting drug-induced inhibition of mitochondrial DNA replication and mtDNA-encoded protein synthesis. Journal of Immunological Methods 343:1, 1-12
CrossRef19
David J Herrmann, William J Peppard, Nathan A Ledeboer, Melissa L Theesfeld, John A Weigelt, Bryan J Buechel. (2008) Linezolid for the treatment of drug-resistant infections. Expert Review of Anti-infective Therapy 6:6, 825-848
CrossRef20
P. Scotton, R. Fuser, S. Torresan, A. Carniato, M. Giobbia, C. Rossi, W. O. Inojosa, A. Vaglia. (2008) Early Linezolid-associated Lactic Acidosis in a Patient Treated for Tuberculous Spondylodiscitis. Infection 36:4, 387-388
CrossRef21
Tina Q Tan, Ram Yogev. (2008) Clinical pharmacology of linezolid: an oxazolidinone antimicrobial agent. Expert Review of Clinical Pharmacology 1:4, 479-489
CrossRef22
Donald P. Levine. (2008) Vancomycin: Understanding Its Past and Preserving Its Future. Southern Medical Journal 101:3, 284-291
CrossRef23
José Ramón Azanza, Emilio García-Quetglas, Belén Sádaba. (2008) Efectos adversos e interacciones de los nuevos antibióticos activos frente a cocos grampositivos. Enfermedades Infecciosas y Microbiología Clínica 26, 69-76
CrossRef24
Cindy A Loffler, Conan MacDougall. (2007) Update on prevalence and treatment of methicillin-resistant Staphylococcus aureus infections. Expert Review of Anti-infective Therapy 5:6, 961-981
CrossRef25
Peter K. Linden. 2007. Enterococci: Resistance Update and Treatment Options. , 89-110.
CrossRef26
M. Wiener, Y. Guo, G. Patel, B. C. Fries. (2007) Lactic Acidosis after Treatment with Linezolid. Infection 35:4, 278-281
CrossRef27
Masashi Narita, Brian T Tsuji, Victor L Yu. (2007) Linezolid-Associated Peripheral and Optic Neuropathy, Lactic Acidosis, and Serotonin Syndrome. Pharmacotherapy 27:8, 1189-1197
CrossRef28
John Carson, Jorge Cerda, Jong-Hee Chae, Michio Hirano, Peter Maggiore. (2007) Severe Lactic Acidosis Associated with Linezolid Use in a Patient with the Mitochondrial DNA A2706G Polymorphism. Pharmacotherapy 27:5, 771-774
CrossRef29
Richard H Drew. (2007) Emerging Options for Treatment of Invasive, Multidrug-Resistant Staphylococcus aureus Infections. Pharmacotherapy 27:2, 227-249
CrossRef30
Xia C Thai, Lou Ann Bruno-Murtha. (2006) Bell's Palsy Associated with Linezolid Therapy: Case Report and Review of Neuropathic Adverse Events. Pharmacotherapy 26:8, 1183-1189
CrossRef31
A. S. De Vriese, R. Van Coster, J. Smet, S. Seneca, A. Lovering, L. L. Van Haute, L. J. Vanopdenbosch, J.-J. Martin, C. Ceuterick-de Groote, S. Vandecasteele, J. R. Boelaert. (2006) Linezolid-Induced Inhibition of Mitochondrial Protein Synthesis. Clinical Infectious Diseases 42:8, 1111-1117
CrossRef32
David L Blazes, Catherine F Decker. (2006) Symptomatic hyperlactataemia precipitated by the addition of tetracycline to combination antiretroviral therapy. The Lancet Infectious Diseases 6:4, 249-252
CrossRef33
F. Pea, L. Scudeller, M. Lugano, U. Baccarani, F. Pavan, M. Tavio, M. Furlanut, G. D. Rocca, F. Bresadola, P. Viale. (2006) Hyperlactacidemia Potentially Due to Linezolid Overexposure in a Liver Transplant Recipient. Clinical Infectious Diseases 42:3, 434-435
CrossRef34
Soriano, Alex, Miró, Oscar, Mensa, Josep, . (2005) Mitochondrial Toxicity Associated with Linezolid. New England Journal of Medicine 353:21, 2305-2306
Full Text35
Mark H Wilcox. (2005) Update on linezolid: the first oxazolidinone antibiotic. Expert Opinion on Pharmacotherapy 6:13, 2315-2326
CrossRef36
Gary E. Stein. (2005) Safety of Newer Parenteral Antibiotics. Clinical Infectious Diseases 41:s5, S293-S302
CrossRef37
M. Hirano, L. Palenzuela, N. M. Hahn, R. P. Nelson, J. N. Arno, C. Schobert, R. Bethel, L. A. Ostrowski, M. R. Sharma, P. P. Datta, R. K. Agrawal, J. E. Schwartz. (2005) Does Linezolid Cause Lactic Acidosis by Inhibiting Mitochondrial Protein Synthesis?. Clinical Infectious Diseases 40:12, e113-e116
CrossRef38
Matteo Bassetti, Elda Righi, Antonio Di Biagio, Raffaella Rosso, Andrea Beltrame, Dante Bassetti. (2005) Role of linezolid in the treatment of orthopedic infections. Expert Review of Anti-infective Therapy 3:3, 343-352
CrossRef39
Carmen Hernández Prats, Francisca Llinares Tello, Eduardo Climent Grana, Cleofé Fernández Aracil. (2005) Neuropatía periférica y óptica asociada a linezolid en un paciente con infección por Mycobacterium bovis multirresistente. Medicina Clínica 124:20, 797-798
CrossRef40
PJ Harwood, PV Giannoudis. (2004) The safety and efficacy of linezolid in orthopaedic practice for the treatment of infection due to antibiotic-resistant organisms. Expert Opinion on Drug Safety 3:5, 405-414
CrossRef41
Adam M Bressler, Shanta M Zimmer, Jane L Gilmore, Jyoti Somani. (2004) Peripheral neuropathy associated with prolonged use of linezolid. The Lancet Infectious Diseases 4:8, 528-531
CrossRef42
Murugan Raghavan, Peter K Linden. (2004) Newer Treatment Options for Skin and Soft Tissue Infections. Drugs 64:15, 1621-1642
CrossRef43
(2003) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 12:5, 431-446
CrossRef44
&NA;. (2003) Linezolid. Reactions Weekly &NA;:934, 10
CrossRef
