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DRUG RECORD

 

LINEZOLID

OVERVIEW
Linezolid

 

Introduction

Linezolid is a relatively new and distinctive antibiotic, a single member of an oxazolidinone class, that is used for serious or problematic infections caused by resistant enterococcal or staphylococcal organisms.  Prolonged therapy with linezolid has been linked to rare instances of lactic acidosis and liver injury probably as a result of hepatic mitochondrial toxicity.

 

Background

Linezolid (lin ayz' oh lid) is a synthetic antibiotic that belongs to the oxazolidinone class.  It has broad bacteriocidal activity against gram positive organisms such as enterococci and staphylococci and most streptococci.  It also has moderate activity against Mycobacterium tuberculosis.  Linezolid acts by blocking bacterial protein synthesis, probably as a result of blocking the formation of the functional ribosomal 70S subunit.  Linezolid was approved for use in the United States in 2000 and is currently indicated for treatment of vancomycin-resistant enterococcal infections, for nosocomial pneumonia due to staphylococci (either methicillin-sensitive or -resistant) and skin and tissue infections caused by Staphylococcus aureus or pyogenes.  Because of its activity against multidrug resistant enterococci and staphylococci, the use of linezolid is usually reserved for severe infections where methicillin or penicillin resistance is found.  Linezolid is available in tablets of 400 and 600 mg under the name Zyvox.  It is also available as an oral suspension and a solution for intravenous administration.  Linezolid is typically given as a 7 to 14 day course of 400 or 600 mg twice daily.  Longer courses are sometimes used for persistent infections.  Common minor side effects include nausea, diarrhea, abdominal upset, headache and skin rash.  Rare, but severe side effects include serotonin syndrome, thrombocytopenia, optic and peripheral neuropathy, pancreatitis and lactic acidosis.

 

Hepatotoxicity

Therapy with linezolid has been associated with mild and transient elevations in serum aminotransferase and alkaline phosphatase levels in 1% to 10% of patients, although similar rates of elevations occur in patients with infections treated with comparable agents, and enzyme elevations were not found in normal volunteers given linezolid for short periods.  On the other hand, ALT elevations during therapy have been higher with higher doses of linezolid, but in all instances the elevations occurred without symptoms and resolved with discontinuation of the drug.

 

Although the agent has been available for a limited time and its use has been restricted, several instances of clinically apparent liver disease with jaundice have been reported with linezolid therapy.  A case of a hypersensitivity response with rash, eosinophilia and renal insufficiency (DRESS syndrome) with mild serum enzyme elevations has been reported.  More frequently, linezolid has been linked to cases of lactic acidosis, generally arising after 1 to 8 weeks of therapy and sometimes associated with evidence of liver injury and jaundice.  Lactic acidosis is usually due to injury and dysfunction of hepatic mitochondria, with resulting microvesicular steatosis and disturbed hepatic function (not necessarily accompanied by jaundice or even ALT or alkaline phosphatase elevations).  Other serious side effects associated with mitochondrial damage due to linezolid therapy include peripheral and optic neuropathy, pancreatitis, serotonin syndrome and renal injury.  The mitochondrial injury is believed to be due to the inhibition of mitochondrial ribosomal function that matches the known effect of linezolid on bacterial ribosomal function.  Lactic acidosis occurs after 1 to 8 weeks of treatment and can be severe, although it resolves rapidly with discontinuation.  In contrast, the optic and peripheral neuropathy due to linezolid resolves more slowly and can be permanent.  Lactic acidosis can be fatal and hepatic dysfunction and jaundice have been mentioned in severe cases of lactic acidosis attributed to linezolid.

 

Mechanism of Injury

The etiology of serum enzyme elevations during linezolid therapy is not known and may relate more to the underlying condition rather than injury from linezolid.  Lactic acidosis and peripheral neuropathy from linezolid are probably due to inhibition of mitochondrial ribosomal function and protein synthesis.  Indeed, several mitochondrial DNA polymorphisms [2706A>G and 3010G>A] have been identified in patients who developed lactic acidosis while on linezolid that may have represented a genetic predisposition to this adverse event.

 

Outcome and Management

The serum aminotransferase and alkaline phosphatase elevations that occur during linezolid therapy are self-limited and resolve once therapy is stopped.  There are no reports of cross sensitization and hepatic injury from linezolid in persons with hepatic injury from other antibiotics or sulfonamides.  The lactic acidosis due to linezolid has been linked to injury to hepatic mitochondria and with microvesicular steatosis, but is usually rapidly reversed with withdrawal of therapy.  Treatment with carnitidine, antioxidants, thiamine and prednisone has been used, but has not been shown to be effective.  Use of intravenous 20% glucose infusions, which are effective in treating the lactic acidosis of acute fatty liver of pregnancy, Reye syndrome and fialuridine therapy, has not been studied.

 

Drug Class:  Antiinfective Agents, Miscellaneous, Oxazolidinones

 

Other Drugs in the Subclass, Oxazolidinones:  Tedizolid

 

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PRODUCT INFORMATION
Linezolid

 

REPRESENTATIVE TRADE NAMES
Linezolid – Zyvox®


DRUG CLASS
Antiinfective Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Linezolid 165800-03-3 C16-H20-F-N3-O4 Linezolid  chemical structure

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REFERENCES
Linezolid

 

References updated: 24 February 2014

  1. Zimmerman HJ. Hepatic injury from the treatment of infectious and parasitic diseases.  In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999. pp 589-637.  (Expert review of hepatotoxicity published in 1999, before the availability of linezolid which is not mentioned).

  2. Moseley RH. Antibacterial and Antifungal Agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd Edition. Amsterdam:  Elsevier, 2013. p. 463-81.  (Review of hepatotoxicity of antibiotics; linezolid is not discussed).

  3. MacDougall C, Chambers HF. Oxazolidinones (Linezolid).  Protein synthesis inhibitors; miscellaneous antibacterial agents. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1537-8.  (Textbook of pharmacology and therapeutics).

  4. Stevens DL, Smith LG, Bruss JB, McConnell-Martin MA, Duvall SE, Todd WM, et al. Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000; 44: 3408-13. PubMed Citation  (836 patients treated for average of 13 days at 133 centers, 2/3 cured, no serious adverse events attributed to linezolid and no "significant" changes in chemistry tests).

  5. Antony SJ, Diaz-Vasquez E, Stratton C. Clinical experience with linezolid in the treatment of resistant gram-positive infections. J Natl Med Assoc 2001; 93: 386-91. PubMed Citation  (Among 19 patients with serious resistant Gram positive infections treated with linezolid on a compassionate use basis, 79% had clinical cure; two patients had mild elevations in liver tests, but no details given).

  6. Kaplan SL, Patterson L, Edwards KM, Azimi PH, Bradley JS, Blumer JL, et al.; Linezolid Pediatric Pneumonia Study Group. Pharmacia and Upjohn. Linezolid for the treatment of community-acquired pneumonia in hospitalized children. Linezolid Pediatric Pneumonia Study Group. Pediatr Infect Dis J 2001; 20: 488-94. PubMed Citation  (Phase II trial of iv followed by oral linezolid in 78 children treated for 6 to 41 days; ALT elevations occurred in 6.4% [75-253 U/L], but all resolved in follow up).

  7. Rubinstein E, Cammarata S, Oliphant T, Wunderink R; Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32: 402-12. PubMed Citation  (396 patients treated with either linezolid or vancomycin at 90 sites had similar rates of clinical response and side effects; liver tests were abnormal in 1.0% of linezolid vs 1.6% of vancomycin treated patients).

  8. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med 2003; 348: 86-7. PubMed Citation  (52 year old woman developed intractable nausea and vomiting 11 weeks after starting linezolid and was found to have lactic acidosis [9.9 μmol/L] which was reversed after stopping drug; no mention of hepatic abnormalities).

  9. Bernard L, Stern R, Lew D, Hoffmeyer P. Serotonin syndrome after concomitant treatment with linezolid and citalopram. Clin Infect Dis 2003; 36: 1197. PubMed Citation  (81 year old man developed severe lactic acidosis, thrombocytopenia and serotonin syndrome 3 weeks after starting linezolid while also taking citalopram [ALT 66 U/L, CPK 766 U/L, lactate 17.5 μmol/L, pH 6.9], leading to cardiac arrest and hepatic failure, but no information on liver function or histology were given).

  10. French G. Safety and tolerability of linezolid. J Antimicrob Chemother 2003; 51 (Suppl 2): ii45-53. PubMed Citation  (Review of adverse events reported in clinical trials of linezolid reported similar rates of adverse events to comparative drugs; diarrhea, nausea and headache in 1-5%: abnormal "liver tests" in 1.0% vs 0.3% of controls. In one study ALT elevations occurred in 2.5% with low- and 9.8% with high-dose linezolid, all elevations were mild and reversible, and similar in rate to comparative agents; overall ALT >2 times ULN occurred in 7.4% vs 7.2%; list of serious adverse events includes "hepatitis").

  11. Moellering RC. Linezolid: the first oxazolidinone antimicrobial. Ann Intern Med 2003; 138: 135-42. PubMed Citation  (Clinical review of linezolid use; no mention of hepatic injury).

  12. Rubinstein E, Isturiz R, Standiford HC, Smith LG, Oliphant TH, Cammarata S, et al. Worldwide assessment of linezolid's clinical safety and tolerability: comparator-controlled phase III studies. Antimicrob Agents Chemother 2003; 47: 1824-31. PubMed Citation  (Safety assessment in 2046 patients who received linezolid vs 2001 on comparator drugs found similar rates of diarrhea [4.3 vs 3.2%], nausea [3.4 vs 2.3%], headache [2.2 vs 1.3%], liver test abnormalities [1.0 vs 0.3%], serious adverse events [11.4 vs 10.6%], and deaths [4.8 vs 4.9%]; two patients on oxacillin-dicloxacillin developed "hepatitis", but no cases described for linezolid cohort).

  13. Stalker DJ, Jungbluth GL, Hopkins NK, Batts DH. Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemother 2003; 51: 1239-46. PubMed Citation  (Healthy volunteers given linezolid for up to 18 days had no "clinically important" changes from baseline in laboratory values).

  14. Chen YS, Lee SC, Kim WJ. Efficacy and tolerability of linezolid in treating severe skin and soft tissue infections caused by Gram-positive pathogens. J Formos Med Assoc 2004; 103: 349-54. PubMed Citation

  15. Kopterides P, Papadomichelakis E, Armaganidis A. Linezolid use associated with lactic acidosis. Scand J Infect Dis 2005; 37: 153-4. PubMed Citation  (Elderly man with severe methicillin-resistant staphylococcus aureus infection developed rising lactate (2.0→12.5 μmol/L) over 7 days of linezolid therapy, resolved with discontinuation, no evidence of liver injury).

  16. Soriano A, Miró O, Mensa J. Mitochondrial toxicity associated with linezolid. N Engl J Med 2005; 353: 2305-6. PubMed Citation  (Three patients with asthenia and lactic acidosis after 1.5-3 months of linezolid therapy were studied for mitochondrial function in peripheral blood mononuclear cells; complex IV enzymatic activity was decreased).

  17. Bishop E, Melvani S, Howden BP, Charles PG, Grayson ML. Good clinical outcomes but high rates of adverse reactions during linezolid therapy for serious infections: a proposed protocol for monitoring therapy in complex patients. Antimicrob Agents Chemother 2006; 50: 1599-602. PubMed Citation  (Retrospective analysis of 44 patients treated with linezolid for more than 7 days (8-185 days) found cure in 73%, but adverse reactions in 64%, including 25% requiring ICU care: platelet decreases, anemia, gastrointestinal upset, and 10% with serious adverse events of neuropathy, serotonin syndrome and/or lactic acidosis; recommended prospective monitoring).

  18. De Vriese AS, Coster RV, Smet J, Seneca S, Lovering A, Van Haute LL, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis 2006; 42: 1111-7. PubMed Citation  (Patient treated with linezolid and rifampicin for 4 months developed loss of vision and lactic acidosis [24.5 μmol/L], renal failure and flaccid paralysis; muscle, liver, kidney and white cells were studied; liver showed micro- and macro-vesicular steatosis, decreased activity and protein of respiratory chain complexes I and IV in mitochondria, but normal mtDNA and morphology by electron microscopy).

  19. Jaksic B, Martinelli G, Perez-Oteyza J, Hartman CS, Leonard LB, Tack KJ. Efficacy and safety of linezolid compared with vancomycin in a randomized, double-blind study of febrile neutropenic patients with cancer. Clin Infect Dis 2006; 42: 597-607. PubMed Citation  (Controlled trial of linezolid vs vancomycin for an average of 11 days in 453 patients with cancer and febrile neutropenia found similar safety and efficacy; "the distribution of biochemical test results, including mean values, changes from baseline values and abnormal values, was similar between groups").

  20. McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother 2006; 50: 2042-9. PubMed Citation  (Like chloramphenicol and tetracycline, the oxazolidinones bind to bacterial as well as mitochondrial ribosomes and inhibit protein synthesis, the binding site being conserved between mitochondrial and gram-positive bacteria).

  21. Pea F, Scudeller L, Lugano M, Baccarani U, Pavan F, Tavio M, et al. Hyperlactacidemia potentially due to linezolid overexposure in a liver transplant recipient. Clin Infect Dis 2006; 42: 434-5. PubMed Citation  (59 year old liver transplant recipient developed increased lactate levels after 11 days of linezolid therapy, returning to normal with discontinuation; no mention of other liver tests).

  22. Narita M, Tsuji BT, Yu VL. Linezolid-associated peripheral and optic neuropathy, lactic acidosis, and serotonin syndrome. Pharmacotherapy 2007; 27: 1189-97. PubMed Citation  (Review and summary of published literature on severe side effects of linezolid).

  23. Vardakas KZ, Ntziora F, Falagas ME. Linezolid: effectiveness and safety for approved and off-label indications. Expert Opin Pharmacother 2007; 8: 2381-400. PubMed Citation  (Review of pharmacokinetics, efficacy and safety of linezolid with no mention of hepatic abnormalities).

  24. Wiener M, Guo Y, Patel G, Fries BC. Lactic acidosis after treatment with linezolid. Infection. 2007; 35: 278-81. PubMed Citation  (80 year old woman presented with shortness of breath and lactic acidosis after 19 days of linezolid [pH 7.0, lactate 19 μmol/L], with rapid recovery upon switching to daptomycin).

  25. Metzxas EI, Falagas ME.  Update on the safety of linezolid. Expt Opin Drug Saf 2009; 8: 485-91. PubMed Citation  (Summary of pooled results of clinical trials of linezolid in 2046 patients; severe side effects occurred in 0.4% including cytopenia, neurological side effects and lactic acidosis; ALT elevations also occurred, and "some patients had to discontinue treatment because of these abnormalities").

  26. Savard S, Desmeules S, Riopel J, Agharazii M. Linezolid-Associated Acute Interstitial Nephritis and Drug Rash With Eosinophilia and Systemic Symptoms (DRESS) Syndrome. Am J Kidney Dis 2009; 54: e17-20. PubMed Citation  (84 year old woman developed pruritus, rash, facial edema and eosinophilia on the 7th day of linezolid therapy with interstitial nephritis and mild hepatitis [AST ~90 U/L, GGT ~105 U/L], with rapid response to prednisone after stopping linezolid).

  27. De Bus L, Depuydt P, Libbrecht L, Vandekerckhove L, Nollet J, Benoit D, Vogelaers D, Van Vlierberghe H. Severe drug-induced liver injury associated with prolonged use of linezolid. J Med Toxicol 2010; 6: 322-6. PubMed Citation  (55 year old woman developed jaundice and lactic acidosis after 50 days of linezolid and meropenem therapy [bilirubin 12.1 mg/dL, ALT 113 U/L, Alk P 2486 U/L, pH 7.27, lactate 121 mg/dL], with signs of liver failure, but resolving spontaneously over next 3 months).

  28. Garazzino S, Tovo PA. Clinical experience with linezolid in infants and children. J Antimicrob Chemother 2011; 66 Suppl 4: iv23-iv41. PubMed Citation  (Linezolid has been approved for use in children in whom side effects appear to be less common; transient elevations in serum aminotransferase levels may occur during therapy).

  29. Gould FK. Linezolid: safety and efficacy in special populations. J Antimicrob  Chemother 2011; 66 Suppl 4: iv3-iv6. PubMed Citation  (Review that states "Linezolid can induce hepatic transaminases and has been associated with cholestasis, but these abnormalities are infrequent, minor and rarely lead to therapy being truncated").

  30. Carson J, Cerda J, Chae JH, Hirano M, Maggiore P. Severe lactic acidosis associated with linezolid use in a patient with the mitochondrial DNA A2706G polymorphism. Pharmacotherapy 2007; 27: 771-4. PubMed Citation  (35 year old woman developed severe lactic acidosis 35 days after starting linezolid; had mitochondrial DNA polymorphism that may have predisposed her to injury).

  31. Scotton P, Fuser R, Torresan S, Carniato A, Giobbia M, Rossi C, Inojosa WO, Vaglia A. Early linezolid-associated lactic acidosis in a patient treated for tuberculous spondylodiscitis. Infection 2008; 36: 387-8. PubMed Citation  (81 year old woman developed acidosis 12 days after starting intravenous linezolid [pH 7.24, lactate 18.6 mmol/L], isoniazid, rifampin and ethambutol for atypical tuberculosis, recovering within a week of stopping and later tolerating isoniazid, pyrazinamide and rifampin).

  32. Lee YR, Powell N, Bonatti H, Sawyer RG, Barroso L, Pruett TL, Sifri CD, Volles D. Early development of lactic acidosis with short term linezolid treatment in a renal recipient. J Chemother 2008; 20: 766-7. PubMed Citation  (56 year old woman with urosepsis and renal transplant developed metabolic acidosis which worsened with linezolid therapy, but resolved once it was stopped).

  33. Boutoille D, Grossi O, Depatureaux A, Tattevin P. Fatal lactic acidosis after prolonged linezolid exposure for treatment of multidrug-resistant tuberculosis. Eur J Intern Med 2009; 20: e134-5. PubMed Citation  (48 year old man developed lactic acidosis 3 months after starting oral linezolid for resistant tuberculosis [pH 7.32, lactate 11.6 mmol/L], while linezolid was stopped, he was found dead 3 weeks later).

  34. Fernández de Orueta L, Díaz V, Ramírez M, Alvarez R. [Linezolid-induced lactic acidosis]. Enferm Infecc Microbiol Clin 2009; 27: 550-1. PubMed Citation  (72 year old woman developed lactic acidosis beginning 34 days after starting linezolid with severe distress by day 39 [pH 6.93, lactate 6.1 mmol/L], resolving rapidly upon stopping).

  35. Velez JC, Janech MG. A case of lactic acidosis induced by linezolid. Nat Rev Nephrol 2010; 6: 236-42. PubMed Citation  (36 year old man wtih end stage renal disease on dialysis developed lactic acidosis 6 weeks after starting oral linezolid for vancomycin resistant Enterococcus fecalis [pH 7.31, lactate 12.5 mmol/L, ALT 89 U/L], resolving within a week of stopping; ribsomoal DNA polymorphism 2706A>G found, similar to two cases in the literature).

  36. De Bus L, Depuydt P, Libbrecht L, Vandekerckhove L, Nollet J, Benoit D, Vogelaers D, et al. Severe drug-induced liver injury associated with prolonged use of linezolid. J Med Toxicol 2010; 6: 322-6. PubMed Citation  (55 year old woman developed jaundice and itching 6-7 weeks after starting linezolid and merepenem [bilirubin 12.1 mg/dL, ALT 113 U/L, Alk P 2,486 U/L, pH 7.27, lactate 121 mg/dL], with biopsy showing microvesicular steatosis and slowly resolving after stopping antibiotics, the patient later dying of septic shock).

  37. Cope TE, McFarland R, Schaefer A. Rapid-onset, linezolid-induced lactic acidosis in MELAS. Mitochondrion 2011; 11: 992-3. PubMed Citation  (21 year old man with mitochrondrial encephalomyopathy, lactic acidosis and stoke-like episode syndrome [MELAS] developed tachypnea and rising lactate levels within a day of starting linezolid, returning to baseline rapidly upon stopping).

  38. Su E, Crowley K, Carcillo JA, Michaels MG. Linezolid and lactic acidosis: a role for lactate monitoring with long-term linezolid use in children. Pediatr Infect Dis J 2011; 30: 804-6. PubMed Citation  (Three children [0.5, 0.5 and 16 years old], two boys and one girl, with hepatic and or intestinal insufficiency developed lactic acidosis during extended therapy [53, 31 and 7 days] with oral linezolid, resolving rapidly upon stopping in two, but with progressive acidosis and death in 1 child).

  39. Contou D, Fichet J, Grimaldi D, Cariou A. Early life-threatening lactic acidosis following a single infusion of linezolid. Int J Antimicrob Agents 2011; 38: 84-5 PubMed Citation  (81 year old man with chronic hepatitis C on ventilatory support for pneumonia with Enterococcus fecalis superinfection developed lactic acidosis within hours of starting intravenous linezolid [pH 7.03, lactate 16 mmol/L], and resolving within hours of stopping).

  40. Leach KL, Brickner SJ, Noe MC, Miller PF. Linezolid, the first oxazolidinone antibacterial agent. Ann N Y Acad Sci 2011 Mar; 1222: 49-54. PubMed Citation  (Overview from the sponsor of the discovery, development, mechanism of action, pharmacology, and spectrum of activity of linezolid, the first of a new class of antibiotics).

  41. Garazzino S, Krzysztofiak A, Esposito S, Castagnola E, Plebani A, Galli L, Cellini M, et al. Use of linezolid in infants and children: a retrospective multicentre study of the Italian Society for Paediatric Infectious Diseases. J Antimicrob Chemother 2011; 66: 2393-7. PubMed Citation  (Retrospective analysis of 75 hospitalized children who received linezolid for an average of 26 days found that only 2 developed abnormal liver tests [>5 times ULN], but no details provided).

  42. Simon A, Müllenborn E, Prelog M, Schenk W, Holzapfel J, Ebinger F, Klabunde-Cherwon A, et al. Use of linezolid in neonatal and pediatric inpatient facilities--results of a retrospective multicenter survey. Eur J Clin Microbiol Infect Dis 2012; 31: 1435-42. PubMed Citation  (Retrospective analysis of 108 children treated with linezolid [126 courses] in 9 hospitals in Germany and Austria found transiently elevated liver enzymes occurred during 5 courses, but no mention of clinically apparent liver injury).

  43. Rose PC, Hallbauer UM, Seddon JA, Hesseling AC, Schaaf HS. Linezolid-containing regimens for the treatment of drug-resistant tuberculosis in South African children. Int J Tuberc Lung Dis 2012; 16: 1588-93. PubMed Citation  (Among 7 children with multidrug resistant tuberculosis treated with oral linezolid, 3 [all of whom were HIV infected and on antiretroviral therapy] had serious adverse events including 1 with pancreatitis [8 months], 1 with pancreatitis and lactic acidosis [7 months], and 1 with peripheral neuropathy and pancytopenia], 1 with lactic acidosis and 1 with bone marrow hypoplasia, resolving on stopping or lowering the dose of linezolid).

  44. Miyawaki A, Ueda T, Nakao A, Adachi M, Ohya M, Yamada I, Takesue Y, et al. Linezolid-induced lactic acidosis followed by severe hypophosphatemia after discontinuation of linezolid. Surg Infect (Larchmt) 2013; 14: 229-30. PubMed Citation  (75 year old man developed lactic acidosis 72 days after starting oral linezolid [pH 7.09, lactate >25 mmol/L], developing severe hypophosphatemia, but ultimately recoverying completely; no mention of liver injury).

  45. Kraleti S, Soultanova I. Pancytopenia and lactic acidosis associated with linezolid use in a patient with empyema. J Ark Med Soc 2013; 110: 62-3. PubMed Citation  (32 year old man developed pancytopenia, acidosis and enzyme elevations after a 14 day course of linezolid [bilirubin 1.5 mg/dL, ALT 29 U/L, Alk P 192 U/L, lactate 3.7 mmol/L], resolving within 10 days of stopping).

  46. Holmaas G, Lærum JH, Schjøtt J, Leiva RA. A man in his seventies with a long-term infection and severe acid-base imbalance. Tidsskr Nor Laegeforen 2014; 134: 315-319. PubMed Citation  (70 year old man developed lactic acidosis while on long term linezolid [bilirubin not given, ALT 1080 U/L, Alk P normal, INR >7.5, pH 7.03, lactate 27 mmol/L], with prompt improvement on stopping drug).

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Linezolid
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