American Journal of Therapeutics 0, 1–3 (2016)
Linezolid Induced Reversible Peripheral Neuropathy Venugopalan Y. Vishnu, MD, Manish Modi, MD, DM, Manoj K. Goyal, MD, DM,* and Vivek Lal, MD, DM
Linezolid has been increasingly used for several severe infections including multidrug-resistant tuberculosis. Peripheral neuropathy is a rare side effect of linezolid and is conventionally considered as irreversible. Here, we report a case of reversible neuropathy induced by linezolid. Keywords: linezolid, peripheral neuropathy, small fibre neuropathy
INTRODUCTION
CASE REPORT
Linezolid (an oxazolidinone antibiotic) acts primarily by binding to 50s ribosomal subunit thereby inhibiting bacterial protein synthesis.1 It was introduced first in 1996 and was approved by the Food and Drug Administration in 2000. It is currently being used primarily for the treatment of a variety of drug-resistant organisms such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and multidrug-resistant Mycobacterium tuberculosis, among others.2,3 The common adverse effects of this drug include gastrointestinal side effects, headache, tongue discoloration, oral candidiasis, etc. The well-known side effects include thrombocytopenia and optic neuropathy.4 With increasing usage, the list of adverse effects of this drug is growing and more and more adverse events are being reported. We describe here the case of a middle-aged woman with multidrugresistant tuberculosis, being treated with linezolid, who developed severe peripheral neuropathy within 3 weeks of its use.
A 35-year-old previously healthy woman was diagnosed with multidrug-resistant tuberculosis (MDRTB) elsewhere based on sputum culture and sensitivity results. She was started on ethionamide, isoniazid, para-aminosalicylic acid, and then linezolid (1.2 g/d) was added. Within 20 days of the initiation of linezolid, she started having painful paresthesias in both the legs. However, all the drugs were continued while she was given symptomatic treatment for paresthesias. She presented to us after 2 months of treatment. At the time of presentation, she had severe painful paresthesias interfering with sleep and all other activities of daily living. She had severe impairment of pain and temperature sensation, mild impairment of joint position, sense and vibration at distal toes, and weakness of extensor hallucis longus and intrinsic foot muscles. She was complaining of paresthesias on the tips of both fingers for the previous 1 week. Reflexes were absent in the legs and were preserved in the upper limbs. She was diagnosed as a case of small and large fiber neuropathy and was evaluated. Her nerve conduction studies revealed motor sensory axonal neuropathy affecting both the legs in the form of decreased sensory and motor action potential amplitudes. However, the upper limb nerve conduction studies were normal. She had evidenced autonomic involvement in both the lower limbs and upper limbs in the form of absent sympathetic skin response. In view of temporal relation with linezolid, a possibility of linezolid-induced neuropathy was considered and linezolid was stopped. As the patient was showing
Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. The authors have no conflicts of interest to declare. *Address for correspondence: Assistant Professor, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. E-mail: goyal_mk@ yahoo.com
1075–2765 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
2
clinical and radiological (CT chest) improvement in status of pulmonary TB, all the drugs other than linezolid were continued. She started showing improvements 2 weeks after stopping the drug. At 4-month follow-up, she was totally free of her symptoms and her clinical examination indicated her condition to be normal except for mild impairment in temperature in both feet and sluggish ankle jerks.
DISCUSSION Linezolid is a new synthetic antibiotic of the oxazolidinones family; it interferes with the formation of ribosomal complexes with mRNA and tRNA. Recently, linezolid has become a treatment of choice in infections that are difficult to control due to its favorable pharmacokinetics and excellent antimicrobial activities against methicillin-resistant and vancomycin-resistant gram-positive pathogens.5 It is also being increasingly used for the treatment of multidrug-resistant tuberculosis, which is more frequent in developing countries such as India. In their meta-analysis, Sotgiu et al, found excellent efficacy of linezolid for the treatment of MDR-TB. They, however, cautioned that its administration should be limited to severe cases when an additional active anti-TB drug is needed because of its tolerability issues, which include gastrointestinal side effects, headache, myelosuppression, optic neuropathy, and peripheral neuropathy. A dosage of 600 mg/d (either as a single dose or divided into 2 doses) seems the best recommendation, as it minimizes the occurrence of adverse events without compromising efficacy and the patient should be monitored continuously for any side effects. The patient in the present study received a dose of 600 mg daily and despite recommended dosages, she developed features of peripheral neuropathy within 15 days of its use.3,6 Several authors have reported peripheral neuropathy associated with prolonged use of linezolid.7–12 In most of these case reports, the patients were treated for 6 months or more, that is, much beyond the usual recommended period of 28 days. Also, while most of the authors have stressed on irreversibility of findings after stopping treatment, there are few case reports of resolution of neuralgia after stopping treatment.9,10 Although neuropathy has been reported earlier with linezolid, our case is unique in several ways. First, our patient developed neuropathy after 3 weeks of starting linezolid rather than after prolonged use as reported in literature. This might be related to the use of concomitant neurotoxic agents such as ethionamide and para-aminosalicylic acid. As neuropathy subsided once linezolid was stopped while other agents were American Journal of Therapeutics (2016) 0(0)
Vishnu et al
being continued, there is no doubt on causal relationship with linezolid. This stresses on the need for having higher index of suspicion of this complication during coadministration with other neurotoxic agents. Second, our patient showed significant improvement after stopping treatment, which is again in contrast to previous reports. This may be related to the fact that this patient was not exposed to the drug for an exceedingly long period, but she did have severe neuropathy at presentation and thus it needs to be kept in mind that linezolid-induced neuropathy may be reversible. Third, while some reports have documented dominant small fiber neuropathy5 and others have documented sensory neuropathy-like presentation,9 our patient had features of small and large fiber (both sensory and motor) involvement, thus expanding clinical spectrum of linezolid-induced neuropathy. The mechanism of linezolid neurotoxicity nerve is not clear. However, it is proposed to inhibit mitochondrial protein synthesis and lead to mitochondrial dysfunction based on evidence of reduced mitochondrial respiratory chain enzyme activities in the affected tissues.5 Thus, whether there is role for coadministration of agents such as coenzyme Q or antioxidants in preventing the neuropathy is debatable. Our patient did not receive any of these therapies and improved spontaneously. However, this issue may need to be addressed in larger studies in future. Another major risk factor in other than duration of linezolid use is the dosage of the drug. In this regard, a recent study has evaluated the efficacy of intermittent linezolid versus daily treatment in MDR-TB and found much lower risk of side effects with equal efficacy.13 Whether, in future, this would be the standard treatment at least for the management of these patients needs to be determined.
CONCLUSION Linezolid use is associated with the risk of peripheral neuropathy, which may occur quite early as documented in this case. Early recognition and prompt stoppage of the drug may be the key to successful recovery of neuropathy in these patients.
REFERENCES 1. Swaney SM, Aoki H, Ganoza MC, et al. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother. 1998;42:3251–3255. 2. Patel R, Rouse MS, Piper KE, et al. In vitro activity of linezolid against vancomycin-resistant enterococci, methicillinresistant staphylococcus aureus and penicliin-resistant www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Reversible Peripheral Neuropathy
3.
4.
5.
6.
7.
streptococcus pneumoniae. Diagn Microbiol Infect Dis. 1999; 34:119–122. Sotgiu G, Centis R, D’Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012;40:1430–1442. Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug resistant gram positive infections: experience from compassionate use program. Clin Infect Dis. 2003;36:159–168. Chao CC, Sun HY, Chang YC, et al. Painful neuropathy with skin denervation after prolonged use of linezolid. J Neurol Neurosurg Psychiatry. 2008;79:97–99. Schecter GF, Scott C, True L, et al. Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2010;50:49–55. Corallo CE, Paull AE. Linezolid-induced neuropathy. Med J Aust. 2002;177:332.
www.americantherapeutics.com
3 8. Bressler AM, Zimmer SM, Gilmore JL, et al. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis. 2004;4:528–531. 9. Zivkovic SA, Lacomis D. Severe sensory neuropathy associated with long-term linezolid use. Neurology. 2004;64:926–927. 10. Ferry T, Ponceau B, Simon M, et al. Possibly linezolidinduced peripheral and central neurotoxicity: report of four cases. Infection. 2005;33:151–154. 11. Rho JP, Sia IG, Crum BA, et al. Linezolid induced peripheral neuropathy. Mayo Clin Proc. 2004;79:927– 930. 12. Legout L, Senneville E, Gomel JJ, et al. Linezolid induced neuropathy. Clin Infect Dis. 2004;38:767–768. 13. Chang KC, Yew WW, Cheung SW, et al. Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug-resistant tuberculosis? Antimicrob Agents Chemother. 2013;57:3445–3449.
American Journal of Therapeutics (2016) 0(0)
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Linezolid Induced Reversible Peripheral Neuropathy Venugopalan Y. Vishnu, MD, Manish Modi, MD, DM, Manoj K. Goyal, MD, DM,* and Vivek Lal, MD, DM
Linezolid has been increasingly used for several severe infections including multidrug-resistant tuberculosis. Peripheral neuropathy is a rare side effect of linezolid and is conventionally considered as irreversible. Here, we report a case of reversible neuropathy induced by linezolid. Keywords: linezolid, peripheral neuropathy, small fibre neuropathy
INTRODUCTION
CASE REPORT
Linezolid (an oxazolidinone antibiotic) acts primarily by binding to 50s ribosomal subunit thereby inhibiting bacterial protein synthesis.1 It was introduced first in 1996 and was approved by the Food and Drug Administration in 2000. It is currently being used primarily for the treatment of a variety of drug-resistant organisms such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium and multidrug-resistant Mycobacterium tuberculosis, among others.2,3 The common adverse effects of this drug include gastrointestinal side effects, headache, tongue discoloration, oral candidiasis, etc. The well-known side effects include thrombocytopenia and optic neuropathy.4 With increasing usage, the list of adverse effects of this drug is growing and more and more adverse events are being reported. We describe here the case of a middle-aged woman with multidrugresistant tuberculosis, being treated with linezolid, who developed severe peripheral neuropathy within 3 weeks of its use.
A 35-year-old previously healthy woman was diagnosed with multidrug-resistant tuberculosis (MDRTB) elsewhere based on sputum culture and sensitivity results. She was started on ethionamide, isoniazid, para-aminosalicylic acid, and then linezolid (1.2 g/d) was added. Within 20 days of the initiation of linezolid, she started having painful paresthesias in both the legs. However, all the drugs were continued while she was given symptomatic treatment for paresthesias. She presented to us after 2 months of treatment. At the time of presentation, she had severe painful paresthesias interfering with sleep and all other activities of daily living. She had severe impairment of pain and temperature sensation, mild impairment of joint position, sense and vibration at distal toes, and weakness of extensor hallucis longus and intrinsic foot muscles. She was complaining of paresthesias on the tips of both fingers for the previous 1 week. Reflexes were absent in the legs and were preserved in the upper limbs. She was diagnosed as a case of small and large fiber neuropathy and was evaluated. Her nerve conduction studies revealed motor sensory axonal neuropathy affecting both the legs in the form of decreased sensory and motor action potential amplitudes. However, the upper limb nerve conduction studies were normal. She had evidenced autonomic involvement in both the lower limbs and upper limbs in the form of absent sympathetic skin response. In view of temporal relation with linezolid, a possibility of linezolid-induced neuropathy was considered and linezolid was stopped. As the patient was showing
Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India. The authors have no conflicts of interest to declare. *Address for correspondence: Assistant Professor, Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India. E-mail: goyal_mk@ yahoo.com
1075–2765 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
2
clinical and radiological (CT chest) improvement in status of pulmonary TB, all the drugs other than linezolid were continued. She started showing improvements 2 weeks after stopping the drug. At 4-month follow-up, she was totally free of her symptoms and her clinical examination indicated her condition to be normal except for mild impairment in temperature in both feet and sluggish ankle jerks.
DISCUSSION Linezolid is a new synthetic antibiotic of the oxazolidinones family; it interferes with the formation of ribosomal complexes with mRNA and tRNA. Recently, linezolid has become a treatment of choice in infections that are difficult to control due to its favorable pharmacokinetics and excellent antimicrobial activities against methicillin-resistant and vancomycin-resistant gram-positive pathogens.5 It is also being increasingly used for the treatment of multidrug-resistant tuberculosis, which is more frequent in developing countries such as India. In their meta-analysis, Sotgiu et al, found excellent efficacy of linezolid for the treatment of MDR-TB. They, however, cautioned that its administration should be limited to severe cases when an additional active anti-TB drug is needed because of its tolerability issues, which include gastrointestinal side effects, headache, myelosuppression, optic neuropathy, and peripheral neuropathy. A dosage of 600 mg/d (either as a single dose or divided into 2 doses) seems the best recommendation, as it minimizes the occurrence of adverse events without compromising efficacy and the patient should be monitored continuously for any side effects. The patient in the present study received a dose of 600 mg daily and despite recommended dosages, she developed features of peripheral neuropathy within 15 days of its use.3,6 Several authors have reported peripheral neuropathy associated with prolonged use of linezolid.7–12 In most of these case reports, the patients were treated for 6 months or more, that is, much beyond the usual recommended period of 28 days. Also, while most of the authors have stressed on irreversibility of findings after stopping treatment, there are few case reports of resolution of neuralgia after stopping treatment.9,10 Although neuropathy has been reported earlier with linezolid, our case is unique in several ways. First, our patient developed neuropathy after 3 weeks of starting linezolid rather than after prolonged use as reported in literature. This might be related to the use of concomitant neurotoxic agents such as ethionamide and para-aminosalicylic acid. As neuropathy subsided once linezolid was stopped while other agents were American Journal of Therapeutics (2016) 0(0)
Vishnu et al
being continued, there is no doubt on causal relationship with linezolid. This stresses on the need for having higher index of suspicion of this complication during coadministration with other neurotoxic agents. Second, our patient showed significant improvement after stopping treatment, which is again in contrast to previous reports. This may be related to the fact that this patient was not exposed to the drug for an exceedingly long period, but she did have severe neuropathy at presentation and thus it needs to be kept in mind that linezolid-induced neuropathy may be reversible. Third, while some reports have documented dominant small fiber neuropathy5 and others have documented sensory neuropathy-like presentation,9 our patient had features of small and large fiber (both sensory and motor) involvement, thus expanding clinical spectrum of linezolid-induced neuropathy. The mechanism of linezolid neurotoxicity nerve is not clear. However, it is proposed to inhibit mitochondrial protein synthesis and lead to mitochondrial dysfunction based on evidence of reduced mitochondrial respiratory chain enzyme activities in the affected tissues.5 Thus, whether there is role for coadministration of agents such as coenzyme Q or antioxidants in preventing the neuropathy is debatable. Our patient did not receive any of these therapies and improved spontaneously. However, this issue may need to be addressed in larger studies in future. Another major risk factor in other than duration of linezolid use is the dosage of the drug. In this regard, a recent study has evaluated the efficacy of intermittent linezolid versus daily treatment in MDR-TB and found much lower risk of side effects with equal efficacy.13 Whether, in future, this would be the standard treatment at least for the management of these patients needs to be determined.
CONCLUSION Linezolid use is associated with the risk of peripheral neuropathy, which may occur quite early as documented in this case. Early recognition and prompt stoppage of the drug may be the key to successful recovery of neuropathy in these patients.
REFERENCES 1. Swaney SM, Aoki H, Ganoza MC, et al. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother. 1998;42:3251–3255. 2. Patel R, Rouse MS, Piper KE, et al. In vitro activity of linezolid against vancomycin-resistant enterococci, methicillinresistant staphylococcus aureus and penicliin-resistant www.americantherapeutics.com
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Reversible Peripheral Neuropathy
3.
4.
5.
6.
7.
streptococcus pneumoniae. Diagn Microbiol Infect Dis. 1999; 34:119–122. Sotgiu G, Centis R, D’Ambrosio L, et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J. 2012;40:1430–1442. Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug resistant gram positive infections: experience from compassionate use program. Clin Infect Dis. 2003;36:159–168. Chao CC, Sun HY, Chang YC, et al. Painful neuropathy with skin denervation after prolonged use of linezolid. J Neurol Neurosurg Psychiatry. 2008;79:97–99. Schecter GF, Scott C, True L, et al. Linezolid in the treatment of multidrug-resistant tuberculosis. Clin Infect Dis. 2010;50:49–55. Corallo CE, Paull AE. Linezolid-induced neuropathy. Med J Aust. 2002;177:332.
www.americantherapeutics.com
3 8. Bressler AM, Zimmer SM, Gilmore JL, et al. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis. 2004;4:528–531. 9. Zivkovic SA, Lacomis D. Severe sensory neuropathy associated with long-term linezolid use. Neurology. 2004;64:926–927. 10. Ferry T, Ponceau B, Simon M, et al. Possibly linezolidinduced peripheral and central neurotoxicity: report of four cases. Infection. 2005;33:151–154. 11. Rho JP, Sia IG, Crum BA, et al. Linezolid induced peripheral neuropathy. Mayo Clin Proc. 2004;79:927– 930. 12. Legout L, Senneville E, Gomel JJ, et al. Linezolid induced neuropathy. Clin Infect Dis. 2004;38:767–768. 13. Chang KC, Yew WW, Cheung SW, et al. Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug-resistant tuberculosis? Antimicrob Agents Chemother. 2013;57:3445–3449.
American Journal of Therapeutics (2016) 0(0)
Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
