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 Table of Contents  
CASE REPORT
Year : 2016  |  Volume : 4  |  Issue : 1  |  Page : 21-23

Linezolid induced pancytopenia in a patient of extensively drug-resistant pulmonary tuberculosis: An unusual outcome


Department of Pulmonary Medicine, KGMU, Lucknow, Uttar Pradesh, India

Date of Web Publication23-Dec-2015

Correspondence Address:
Rajiv Garg
Department of Pulmonary Medicine, KGMU, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2320-8775.159874

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  Abstract 

Linezolid (Lnz) is the first oxazolidinones to be developed and introduced in clinical use. Its use is growing by day and day in the treatment of resistant pulmonary tuberculosis (TB). Lnz has been associated with adverse hematological effects, primarily thrombocytopenia. But pancytopenia is a very rare complication. Myelosuppression is a rare and a serious side effect of Lnz. Here, we present a case of extensively drug-resistant pulmonary TB, which was started on Lnz. Patient returned 1-month back with clinical presentation suggestive of pancytopenia which was confirmed on bone marrow aspiration and was attributed to the use of Lnz. Patient improved on stopping the Lnz and adding steroid for a short course. This case report emphasizes the importance of both the use of Lnz for well-defined indications and appropriate hematological monitoring during the course of treatment.

Keywords: Linezolid, myelosuppression, tuberculosis


How to cite this article:
Garg R, Mishra AK, Kushwaha RS, Singh A. Linezolid induced pancytopenia in a patient of extensively drug-resistant pulmonary tuberculosis: An unusual outcome. J Assoc Chest Physicians 2016;4:21-3

How to cite this URL:
Garg R, Mishra AK, Kushwaha RS, Singh A. Linezolid induced pancytopenia in a patient of extensively drug-resistant pulmonary tuberculosis: An unusual outcome. J Assoc Chest Physicians [serial online] 2016 [cited 2019 Dec 16];4:21-3. Available from: http://www.jacpjournal.org/text.asp?2016/4/1/21/159874


  Introduction Top


Due to little clinical experience with the use of linezolid (Lnz) in the management of mycobacterial infections little is known about its adverse effect. Lnz has been associated with adverse hematological effects, primarily thrombocytopenia. But pancytopenia is a very rare complication. Myelosuppression is a rare and a serious side effect of Lnz. This case report emphasizes the importance of the use of Lnz for well-defined indications and appropriate hematological monitoring during the course of treatment.


  Case Report Top


A 20-year-old female, previously treated case of tuberculosis (TB) was prescribed capreomycin, moxifloxacin, amoxicillin clavulanic acid, and Lnz 600 mg for extensively drug-resistant (XDR) pulmonary TB. Initial pretreatment baseline and 7th day blood parameters were within normal limits. 1 month later, patient was admitted in our department with complaints of hemoptysis, severe epistaxis, bleeding from oral ulcers, melena, abdominal pain and increased bleeding from wound sites, ecchymotic patches over lower limb from last 3 days. The patient's hematology results were consistent with pancytopenia, and Lnz was the suspected as the offending cause. With the initiation of intravenous hydration and blood transfusion and the discontinuation of Lnz, the patient's condition and blood counts improved by the following week. Steroid was given for refractory drug-induced myelosuppression. [Table 1] summarizes the patient's hematological parameters at baseline, at the time of admission, 1-week post-Lnz discontinuation and after giving steroids. The bone marrow aspirate [Figure 1] revealed cellular marrow with evidence of dysmorphic changes in all lineages (drug induced).
Table 1: Hematological parameters corresponding to day from the start of Lnz therapy

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Figure 1: Bone marrow aspirate revealed cellular marrow with evidence of dysmorphic changes in all lineages (drug induced)

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  Discussion Top


The minimum inhibitory concentration of Lnz to inhibit the growth of 90% of organisms for Mycobacteriumtuberculosis is in the range of 1–2 mgL-1.[1] Because of limited experience with the use of Lnz as an antitubercular drug, its adverse effects are not fully known. Lnz has been associated with adverse hematological effects, primarily thrombocytopenia.[2] But myelosuppression is a rarely reported complication.[2] Multidrug-resistant (MDR) and (XDR) TB is a growing clinical and public health concern.[3] To treat these forms of TB is very difficult and clinical outcome is usually not satisfactory.[4],[5],[6] Acquired drug resistance is a very serious and difficult problem nowadays in the treatment of TB. Since the first report of XDR-TB strains in 2007[7] in India, the problem is continuously increasing. Use of Lnz is increasing as newer (Group V) drug for the treatment of MDR and XDR pulmonary TB. Although previous studies have suggested that Lnz (1200 mg/day) may be effective for treating MDR-TB and XDR-TB [8],[9],[10],[11],[12] potential toxicity (e.g. myelosuppression and neurotoxicity) could limit its prolonged use. The use of Lnz is especially relevant in a country like India, which bears the burden of a third of the world's MDR-TB patients. Lnz is indicated for the treatment of Gram-positive bacterial infections, including bacterial pneumonia, skin and soft tissue infections, and vancomycin-resistant enterococcal infections, MDR, and XDR pulmonary TB. The most common adverse effects include diarrhea, nausea, and headache; less common side effects include hypertension, lactic acidosis, and elevated liver enzymes. The most severe adverse effects, seen with prolonged use of Lnz are irreversible peripheral neuropathy, optic neuropathy, and reversible myelosuppression.[13]

Time- and dose-dependent reversible myelosuppression was observed in preclinical studies with Lnz.[14] The mechanism of Lnz-induced hematological adverse events remains uncertain at present. Controversy exists as to whether Lnz myelotoxicity resembles that of chloramphenicol.[15],[16] Reversible chloramphenicol bone marrow suppression is dose-dependent and is thought to occur by the inhibition of mitochondrial protein synthesis.[17] The reversibility of Lnz's hematological effects [2],[14],[15],[18],[19],[20] suggests that a similar mechanism may be involved.[16],[17],[19] Laboratory evidence [16] has suggested that Lnz-induced thrombocytopenia may be an immune-mediated phenomenon of platelet destruction. Preliminary evidence indicated a high toxicity profile for its long-term use at the dose of 600 mg b.i.d., as up to 25–45% of cases reported severe anemia and/or thrombocytopenia and peripheral and optic neuropathy.[7],[21],[22],[23] A daily 300 mg dose of Lnz may be useful for increasing the chances of culture conversion in the treatment of patients with intractable MDR/XDR-TB and might have fewer side effects, especially neurotoxicity, compared with a daily 600 mg dose of Lnz therapy.[24] Reversible myelosuppression is manageable and common with antibiotics [25],[26],[27] [Table 2]. A summary [14] of the hematological effects observed during clinical trials reported thrombocytopenia in 2.4% of Lnz patients versus 1.5% for controls while pancytopenia was not observed. Hence, we thought of reporting this unusual outcome. Current recommendations suggest monitoring of complete blood counts in predisposed patients. Given Lnz's efficacy for treating resistant mycobacteria, the benefits of Lnz treatment may outweigh the potential risk of reversible myelosuppression. Complete blood counts should be monitored weekly, particularly for those patients who receive Lnz for longer than 14 days, those with preexisting myelosuppression, those with a chronic infection who have received previous or concomitant antibiotic therapy, and those receiving concomitant drugs that produce bone marrow suppression. Our patient possessed the first of these specified risk factors and, unfortunately, failed to return to the clinic for scheduled blood work. The severity of this adverse event documented in this case report emphasizes the importance of hematological monitoring during Lnz therapy.
Table 2: Drugs causing pancytopenia

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  Conclusion Top


Keeping in mind the severity of adverse events that long-term Lnz treatment can have it should be used only for well-documented and well-defined indications. Continuous monitoring of blood parameters of patients undergoing long-term Lnz therapy on regular intervals should be ensured. Regular frequent visits should be advised for patients on long-term Lnz therapy. Before starting Lnz treatment complete routine baseline hematological evaluation must be done.

 
  References Top

1.
Alcalá L, Ruiz-Serrano MJ, Pérez-Fernández Turégano C, García De Viedma D, Díaz-Infantes M, Marín-Arriaza M, et al. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis that are susceptible or resistant to first-line antituberculous drugs. Antimicrob Agents Chemother 2003;47:416-7.  Back to cited text no. 1
    
2.
Kuter DJ, Tillotson GS. Hematologic effects of antimicrobials: Focus on the oxazolidinone linezolid. Pharmacotherapy 2001;21:1010-3.  Back to cited text no. 2
    
3.
Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: Systematic review and meta-analysis. Lancet Infect Dis 2009;9:153-61.  Back to cited text no. 3
    
4.
Kim HR, Hwang SS, Kim HJ, Lee SM, Yoo CG, Kim YW, et al. Impact of extensive drug resistance on treatment outcomes in non-HIV-infected patients with multidrug-resistant tuberculosis. Clin Infect Dis 2007;45:1290-5.  Back to cited text no. 4
    
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Kwon YS, Kim YH, Suh GY, Chung MP, Kim H, Kwon OJ, et al. Treatment outcomes for HIV-uninfected patients with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Infect Dis 2008;47:496-502.  Back to cited text no. 5
    
6.
Kim DH, Kim HJ, Park SK, Kong SJ, Kim YS, Kim TH, et al. Treatment outcomes and long-term survival in patients with extensively drug-resistant tuberculosis. Am J Respir Crit Care Med 2008;178:1075-82.  Back to cited text no. 6
    
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Jain S, Rodrigues C, Mehta A, Udwadia ZF. High prevalence of XDR-TB from a tertiary care hospital in India. Proceedings of the American Thoracic Society International Conference: Abstract A510. PATS 2007;4:A510.  Back to cited text no. 7
    
8.
Fortún J, Martín-Dávila P, Navas E, Pérez-Elías MJ, Cobo J, Tato M, et al. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother 2005;56:180-5.  Back to cited text no. 8
    
9.
von der Lippe B, Sandven P, Brubakk O. Efficacy and safety of linezolid in multidrug resistant tuberculosis (MDR-TB) – a report of ten cases. J Infect 2006;52:92-6.  Back to cited text no. 9
    
10.
Yew WW, Chau CH, Wen KH. Linezolid in the treatment of 'difficult' multidrug-resistant tuberculosis. Int J Tuberc Lung Dis 2008;12:345-6.  Back to cited text no. 10
    
11.
Condos R, Hadgiangelis N, Leibert E, Jacquette G, Harkin T, Rom WN. Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis. Chest 2008;134:187-92.  Back to cited text no. 11
    
12.
Eker B, Ortmann J, Migliori GB, Sotgiu G, Muetterlein R, Centis R, et al. Multidrug-and extensively drug-resistant tuberculosis, Germany. Emerg Infect Dis 2008;14:1700-6.  Back to cited text no. 12
    
13.
Pfizer, Inc. Zyvox Prescribing Information; 2007. Available from: http://www.zyvox.com/prescribingInfo.asp. [Last accessed on 2007 May 23].  Back to cited text no. 13
    
14.
Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, et al. Hematologic effects of linezolid: Summary of clinical experience. Antimicrob Agents Chemother 2002;46:2723-6.  Back to cited text no. 14
    
15.
Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible myelosuppression. JAMA 2001;285:1291.  Back to cited text no. 15
    
16.
Bernstein WB, Trotta RF, Rector JT, Tjaden JA, Barile AJ. Mechanisms for linezolid-induced anemia and thrombocytopenia. Ann Pharmacother 2003;37:517-20.  Back to cited text no. 16
    
17.
Yunis AA. Chloramphenicol toxicity: 25 years of research. Am J Med 1989;87:44N-8.  Back to cited text no. 17
    
18.
Nimeiri HS, Nemiary DS. Challenges with linezolid therapy and reversible pancytopenia. Ann Hematol 2003;82:533.  Back to cited text no. 18
    
19.
Halpern M. Linezolid-induced pancytopenia. Clin Infect Dis 2002;35:347-8.  Back to cited text no. 19
    
20.
Tahir N. Serotonin syndrome as a consequence of drug-resistant infections: An interaction between linezolid and citalopram. J Am Med Dir Assoc 2004;5:111-3.  Back to cited text no. 20
    
21.
World Health Organization. Anti-tuberculosis Drug Resistance in the World: The WHO/IUATLD Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Geneva: The World Health Organization; 2008. Available from: http://www.who.int/bulletin/volumes/90/2/11-092585.pdf. [Last accessed on 2014 Nov].  Back to cited text no. 21
    
22.
Sotgiu G, Lange C, Richardson MD, Matteelli A, Centis R, Eker B, et al. Comment on: Daily 300 mg dose of linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis. J Antimicrob Chemother 2009;64:879-83.  Back to cited text no. 22
    
23.
Rucker JC, Hamilton SR, Bardenstein D, Isada CM, Lee MS. Linezolid-associated toxic optic neuropathy. Neurology 2006;66:595-8.  Back to cited text no. 23
    
24.
Koh WJ, Kwon OJ, Gwak H, Chung JW, Cho SN, Kim WS, et al. Daily 300 mg dose of linezolid for the treatment of intractable multidrug-resistant and extensively drug-resistant tuberculosis. J Antimicrob Chemother 2009;64:388-91.  Back to cited text no. 24
    
25.
Beris P, Miescher PA. Hematological complications of antiinfectious agents. Semin Hematol 1988;25:123-39.  Back to cited text no. 25
    
26.
Girdwood RH. Drug-induced anaemias. Drugs 1976;11:394-404.  Back to cited text no. 26
    
27.
Kueh YK. Haematological adverse drug reactions in hospital practice. Ann Acad Med Singapore 1991;20:106-13.  Back to cited text no. 27
    


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    Tables

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