Abstract
Purpose
Lactic acidosis is a rare complication of linezolid (LZD) therapy, and its incidence and risk factors remain unknown. This study aimed to compare the incidence of LZD-associated lactic acidosis (LALA) and vancomycin (VAN)-associated lactic acidosis (VALA) and investigate the risk factors for LALA.
Methods
We performed a retrospective cohort study using propensity score-matched analyses comparing the incidence of lactic acidosis between LZD and VAN therapy. We included adult patients administered LZD or VAN between April 2014 and March 2016 and extracted patient baseline data. In a case–control study, we identified the risk factors of lactic acidosis in patients treated with LZD.
Results
We identified 94 and 313 patients who were administered LZD and VAN, respectively. The incidence of lactic acidosis after LZD and VAN therapy was 10.6 and 0.3%, respectively. After propensity score-matched analyses, the incidence of lactic acidosis with LZD therapy was significantly higher than that with VAN therapy [10.0% (8/80) vs. 0% (0/80), respectively; risk difference, 0.1; 95% confidence interval (CI), 0.03–0.17; p = 0.004]. In a case–control study, 10 patients with LALA were matched to 20 non-lactic acidosis patients by age and sex. Patients with LALA were more likely to have renal insufficiency than non-lactic acidosis patients that were in the univariate analysis (odds ratio, 7.4; 95% CI, 1.0–84.4; p = 0.02).
Conclusions
This study indicates that LALA occurs more frequently than VALA does and is associated with renal insufficiency. Therefore, close monitoring of kidney function and serum lactate is recommended during LZD therapy.
Similar content being viewed by others
References
Sazdanovic P, Jankovic SM, Kostic M, Dimitrijevic A, Stefanovic S (2016) Pharmacokinetics of linezolid in critically ill patients. Expert Opin Drug Metab Toxicol 12(6):595–600. https://doi.org/10.1517/17425255.2016.1170807
Narita M, Tsuji BT, Yu VL (2007) Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 27(8):1189–1197. https://doi.org/10.1592/phco.27.8.1189
Apodaca AA, Rakita RM (2003) Linezolid-induced lactic acidosis. N Engl J Med 348(1):86–87. https://doi.org/10.1056/NEJM200301023480123
Im JH, Baek JH, Kwon HY, Lee J-S (2015) Incidence and risk factors of linezolid-induced lactic acidosis. Int J Infect Dis 31:47–52. https://doi.org/10.1016/j.ijid.2014.12.009
Beekmann SE, Gilbert DN, Polgreen PM (2008) Toxicity of extended courses of linezolid: results of an Infectious Diseases Society of America Emerging Infections Network survey. Diagn Microbiol Infect Dis 62(4):407–410. https://doi.org/10.1016/j.diagmicrobio.2008.08.009
Huang W, Castelino RL, Peterson GM (2016) Lactic acidosis and the relationship with metformin usage: case reports. Medicine 95(46):e4998. https://doi.org/10.1097/MD.0000000000004998
Palenzuela L, Hahn NM, Nelson RP et al (2005) Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clin Infect Dis 40(12):e113–e116. https://doi.org/10.1086/430441
Soriano A, Miró O, Mensa J (2005) Mitochondrial toxicity associated with linezolid. N Engl J Med 353(21):2305–2306. https://doi.org/10.1056/NEJM200511243532123
Sujata LM, Russell GB, Hire D, Cardona C, Bleyer AJ (2009) Lactic acidosis from linezolid in a hospitalized patient with kidney failure. Infect Dis Clin Prac 17(6):404–406. https://doi.org/10.1097/IPC.0b013e31819b8bf4
Wiener M, Guo Y, Patel G, Fries BC (2007) Lactic acidosis after treatment with linezolid. Infection 35(4):278–281. https://doi.org/10.1007/s15010-007-6302-x
Lee YR, Powell N, Bonatti H, Sawyer RG, Barroso L, Pruett TL, Sifri CD, Volles D (2008) Early development of lactic acidosis with short term linezolid treatment in a renal recipient. J Chemother 20(6):766–767. https://doi.org/10.1179/joc.2008.20.6.766
Contou D, Fichet J, Grimaldi D, Cariou A (2011) Early life-threatening lactic acidosis following a single infusion of linezolid. Int J Antimicrob Agents 38(1):84–85. https://doi.org/10.1016/j.ijantimicag.2011.01.025
Velez JCQ, Janech MG (2010) A case of lactic acidosis induced by linezolid. Nat Rev Nephrol 6(4):236–242. https://doi.org/10.1038/nrneph.2010.20
Garrabou G, Soriano A, López S et al (2007) Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia. Antimicrob Agents Chemother 51(3):962–967. https://doi.org/10.1128/AAC.01190-06
Del Pozo JL, Fernandez-Ros N, Saez E, Herrero JI, Yuste JR, Banales JM (2014) Linezolid-induced lactic acidosis in two liver transplant patients with the mitochondrial DNA A2706G polymorphism. Antimicrob Agents Chemother 58(7):4227–4229. https://doi.org/10.1128/AAC.02856-14
Carson J, Cerda J, Chae J-H, Hirano M, Maggiore P (2007) Severe lactic acidosis associated with linezolid use in a patient with the mitochondrial DNA A2706G polymorphism. Pharmacotherapy 27(5):771–774. https://doi.org/10.1592/phco.27.5.771
Tanaka M, Takeyasu T, Fuku N (2004) Mitochondrial genome single nucleotide polymorphisms and their phenotypes in the Japanese. Ann N Y Acad Sci 1011(1):7–20. https://doi.org/10.1196/annals.1293.002
Tanaka M, Cabrera VM, González AM, Larruga JM, Takeyasu T, Fuku N, Guo LJ, Hirose R, Fujita Y, Kurata M, Shinoda K, Umetsu K, Yamada Y, Oshida Y, Sato Y, Hattori N, Mizuno Y, Arai Y, Hirose N, Ohta S, Ogawa O, Tanaka Y, Kawamori R, Shamoto-Nagai M, Maruyama W, Shimokata H, Suzuki R, Shimodaira H (2004) Mitochondrial genome variation in eastern Asia and the peopling of Japan. Genome Res 14(10a):1832–1850. https://doi.org/10.1101/gr.2286304
Song T, Lee M, Jeon H-S et al (2015) Linezolid trough concentrations correlate with mitochondrial toxicity-related adverse events in the treatment of chronic extensively drug-resistant tuberculosis. EBioMedicine 2(11):1627–1633. https://doi.org/10.1016/j.ebiom.2015.09.051
Palanichamy MG, Sun C, Agrawal S et al (2003) Phylogeny of mitochondrial DNA macrohaplogroup N in India, based on complete sequencing: implications for the peopling of South Asia. Am J Hum Genet 75:966–978
Achilli A, Rengo C, Magri C, Battaglia V, Olivieri A, Scozzari R, Cruciani F, Zeviani M, Briem E, Carelli V, Moral P, Dugoujon JM, Roostalu U, Kivisild T, Bandelt HJ, Richards M, Villems R, Santachiara-Benerecetti AS, Semino O, Torroni A (2004) The molecular dissection of mtDNA haplogroup H confirms that the Franco-Cantabrian glacial refuge was a major source for the European gene pool. Am J Hum Genet 75(5):910–918. https://doi.org/10.1086/425590
Matsumoto K, Takeshita A, Ikawa K, Shigemi A, Yaji K, Shimodozono Y, Morikawa N, Takeda Y, Yamada K (2010) Higher linezolid exposure and higher frequency of thrombocytopenia in patients with renal dysfunction. Int J Antimicrobial Agents 36(2):179–181. https://doi.org/10.1016/j.ijantimicag.2010.02.019
Nukui Y, Hatakeyama S, Okamoto K, Yamamoto T, Hisaka A, Suzuki H, Yata N, Yotsuyanagi H, Moriya K (2013) High plasma linezolid concentration and impaired renal function affect development of linezolid-induced thrombocytopenia. J Antimicrob Chemother 68(9):2128–2133. https://doi.org/10.1093/jac/dkt133
Acknowledgments
We would like to thank Editage (www.editage.com) for the English language editing and Publication Support.
Author information
Authors and Affiliations
Contributions
NM, YK, and SB contributed to conception and design of the study. All authors contributed to acquisition of data and data analysis. NM mainly contributed to drafting this article. All authors contributed to the critical revision and gave final approval of the manuscript.
Corresponding author
Ethics declarations
This study was approved by the NTMC ethics committee (IRB protocol number: R16-102) and was carried out in accordance with the Declaration of Helsinki principles. The need for patient consent was waived owing to the retrospective nature of the study. Information about the study was made public through postings on facility notice boards and webpages. Patients and their representative agents had the right to refuse study participation.
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Mori, N., Kamimura, Y., Kimura, Y. et al. Comparative analysis of lactic acidosis induced by linezolid and vancomycin therapy using cohort and case–control studies of incidence and associated risk factors. Eur J Clin Pharmacol 74, 405–411 (2018). https://doi.org/10.1007/s00228-017-2377-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00228-017-2377-1