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Jpn. J. Infect. Dis., 64, 509-512, 2011

Short Communication

Efficacy and Safety of Linezolid in the Treatment of Extensively Drug-Resistant Tuberculosis Shen-Jie Tang1,2†, Qing Zhang1,2†, Lin-Hai Zeng1,2, Hua Sun1,2, Jin Gu1,2, Xiao-Hui Hao1,2, Yi-Dian Liu1,2, Lan Yao1,2, and He-Ping Xiao1,2* 1Tuberculosis

Diagnosis and Treatment Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai; and 2Shanghai Key Laboratory of Tuberculosis, Shanghai, China (Received May 10, 2011. Accepted August 15, 2011)

SUMMARY: Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in vivo. This study aims to evaluate the efficacy and safety of linezolid in the treatment of extensively drug-resistant tuberculosis (XDR-TB). We used a linezolid-containing regimen in the treatment of 14 XDR-TB patients. Two years of individualized chemotherapy regimens were adopted on the basis of the patients' medication history and the results of drug susceptibility testing. The patients received 600 mg of linezolid twice a day for the first 1–2 months, followed by once a day thereafter. Eleven patients (78.6z) showed significant improvement in clinical symptoms. Chest computed tomography revealed that 10 patients (71.4z) showed cavity closure. Smear conversion and culture conversion were achieved in all 14 patients (100z) with an average of 64 and 63 days, respectively. The exact proportions of serious and minor adverse events determined by linezolid were 21.4z (3/14) and 64.3z (9/14), respectively. These data show that linezolid-containing chemotherapy for the treatment of XDR-TB may significantly improve clinical symptoms, promote lesion absorption and cavity closure, and accelerate sputum conversion. Further, adverse reactions can be tolerated and resolved with suitable intervention. In recent years, extensively drug-resistant tuberculosis (XDR-TB) (i.e., bacillary resistance to rifampicin, isoniazid, fluoroquinolone, at least one second-line injectable drug [e.g., amikacin, kanamycin, or capreomycin]) has been identified in more than 59 countries. Because of changes in international travel and migration patterns, the threat of XDR-TB is global (1–3). Treatment outcomes for XDR-TB are poor because of the lack of effective drugs (4). Linezolid (LZD) was the first oxazolidinone to be developed and introduced for clinical use, and it exhibited good activity against different species of mycobacteria, including resistant mycobacterial strains (5). The minimal inhibitory concentration to inhibit 90z growth (MIC90) of Mycobacterium tuberculosis was in the range of 1–2 mg/L for LZD. The MICs of LZD against nontuberculous mycobacteria are higher than the MICs of LZD against M. tuberculosis (6–8). Recent reports of case series have suggested that LZD may be effective in treating multidrug-resistant (MDR)-TB and XDR-TB. Long-term LZD application, however, has been associated with myelosuppression and neurotoxicity (9,10). To further evaluate the clinical efficacy and safety of LZD in the treatment of XDRTB, we took the lead in adopting LZD-containing chemotherapy to treat 14 XDR-TB patients in China and have reported a case series with no comparison group.

Fourteen patients who were diagnosed with XDR-TB using microbiological tests between April 2009 and January 2010 were enrolled. The inclusion criteria were as follows: (i) age, 18–66 years; (ii) M. tuberculosis in the sputum culture that was confirmed using the BACTEC MIGT 960 Mycobacterial Testing System (Becton Dickinson, Sparks, Md., USA) within 60 days before the regimen was initiated and diagnosed as XDR according to the World Health Organization (WHO) criteria (11); (iii) active TB suggested by chest radiography; and (iv) informed consent obtained from the patients. The exclusion criteria were as follows: (i) allergic to LZD; (ii) severe cardiovascular, liver, kidney, or blood system diseases or other serious illnesses; (iii) mental illness; and (iv) pregnancy or lactation. On the basis of these criteria, we enrolled 10 men and 4 women who were 31–66 years of age (average age, 45 ± 10 years). The study protocol was approved by the Ethics Committee of the Shanghai Pulmonary Hospital. In our study, 2 years of individualized treatment regimens were adopted according to each patient's drug-use history and the results of recent drug susceptibility testing, and the treatment was started as soon as informed consent was obtained. The laboratory is quality controlled within the WHO proficiency system. Drugs were selected according to the 5 groups of anti-TB drugs recommended by WHO in 2008 (11). All the patients received 600 mg of LZD (Zyvox}; Pfizer Inc., New York, N.Y., USA) twice a day at the beginning of the regimen for a maximum period of 2 months, followed by once a day thereafter. The complete XDR-TB treatment regimen listed in Table 1 was started at the same time as the initiation of the LZD regimen. Hypoxemia was defined as a partial pressure of

*Corresponding author: Mailing address: Department of Tuberculosis, Shanghai Pulmonary Hospital, No. 507, Zhengmin Road, Shanghai 200433, China. Tel: +86-2165115006, Fax: +86-21-65111298, E-mail: xiaoheping_ sars@163.com †These two authors contributed equally to this study. 509


Table 1. General characteristic of the 14 XDR-TB patients Duration of Lung Patient No. of Gender Age previous field no. treatment (y) involved cavity 1 2 3

M F M

45 31 39

20 13 10

5 3 6

1 4 1

4 5 6 7

M M M M

34 40 47 66

14 16 2 3

5 5 5 5

4 5 2 5

8 9 10 11 12 13 14

F F F M M M M

59 44 37 46 46 38 52

2 4 12 10 12 5 1

6 5 6 5 6 5 5

1 2 4 3 4 3 2

1):

Extrapulmonary TB left endobronchial TB tracheal TB right side tuberculous pyopneumothorax no no no right tuberculous pleurisy no no left endobronchial TB no no no no

Drug resistance profile before treatment1)

Chemotherapy regimen1)

SHREAmCmOfx H, Z, Gfx, Pas, Pto, Clr, Amx/Clv, LZD SHREAmOfx H, Z, Cm, Mfx, Pas, Pto, Clr, LZD SHRECmOfx H, Z, Mfx, Pas, Pto, Clr, Amx/Clv, LZD SHREAmCmOfx SHREAmCmOfx SHREAmCmOfx SHREAmOfx

H, H, H, H,

Z, Mfx, Pas, Amx/Clv, LZD Z, Gfx, Pas, Pto, Clr, Amx/Clv, LZD Z, Mfx, Pas, Pto, Clr, LZD Z, Mfx, Pas, Clr, Amx/Clv, LZD

SHREAmCmOfx SHRAmCmOfx SHRAmOfx SHREAmCmOfx SHREAmCmOfx SHREAmCmOfx SHREAmCmOfx

H, H, H, H, H, H, H,

Z, E, Z, Z, Z, Z, Z,

Lfx, Pas, Pto, Amx/Clv, LZD Z, Mfx, Pas, Clr, LZD E, Cm, Mfx, Pas, LZD Lfx, Pas, Pto, Amx/Clv, LZD Lfx, Pas, Pto, Amx/Clv, LZD Mfx, Pas, Pto, Amx/Clv, LZD Lfx, Pas, Pto, Amx/Clv, LZD

S, streptomycin; H, isoniazid; R, rifampin; E, ethambutol; Am, amikacin; Cm, capreomycin; Ofx, ofloxacin; Pas, p-aminosalicylic acid; Lfx, levofloxacin; Pto, prothionamide; Z, pyrazinamide; Amx/Clv, amoxicillin/clavulanate; Mfx, moxifloxacin; Clr, clarithromycin, Gfx, gatifloxacin; LZD, linezolid.

Table 2. Treatment profile of linezolid (LZD) and efficacy Patient no.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Duration of 600 mg LZD twice a day (days) Duration of LZD administration (months) Time to symptom improvement (days) Time to cavity shrink (months) Time to cavity closure (months)1) Time to smear conversion (days) Time to culture conversion (days)

42 6 8 1 4 42 8

7 6 7 2 — 8 8

30 11 7 2 5 63 8

35 6 7 1 6 35 63

14 8.5 2 1 — 87 91

42 7 14 1 2 70 77

14 6 2 1 5 210 210

29 2 2 2 4 70 77

56 6 7 2 3 70 84

21 6 5 5 6 180 150

21 6 7 2 3 14 28

14 6 14 2 3 21 28

42 2 7 2 — 14 28

21 6 14 3 — 21 28

1):

—, not closed.

oxygen (PaO2) value in the range of 60–80 mmHg using arterial blood gas analysis. Respiratory failure was defined as PaO2 lower than 60 mmHg using arterial blood gas analysis. Neutropenia was defined as a leukocyte count lower than 4.0 × 109/L. Moderate anemia was defined as hemoglobin level in the range of 6–9 g/dL. Severe anemia was defined as hemoglobin level lower than 6 g/dL. All the 14 patients with XDR-TB exhibited pulmonary TB (Table 1); the longest disease duration was 20 years and the shortest was 2 years, with an average of 8.8 ± 6.0 years. All the patients were HIV-negative. Three patients had diabetes mellitus; 4, tracheal and bronchial TB; and 2, tuberculous pleurisy, 1 of whom had an additional complication of right tuberculous pyopneumothorax. Three patients had hypoxemia and 4 had respiratory failure; these patients were supplied with O2 tubes. Two patients had chronic obstructive pulmonary disease and 2 had hypoproteinemia. All the 14 patients complained of cough and sputum expectoration. Five patients complained of chest tightness and shortness of breath, 3 had hemoptysis, and 4 had fever with body temperature higher than 38.59C; 3 of these 4 patients had temperatures higher than 39.59C. In the 14 XDR-TB cases, the longest duration of LZD treatment was 11 months and the shortest duration was

2 months, with an average of about 6.5 months (Table 2). The body temperature of 3 of the 4 patients with fever returned to normal on the 2nd day after treatment, and the body temperature of the remaining patient returned to normal on the 5th day. Cough and sputum expectoration of all the 14 patients were significantly improved. Chest tightness, short of breath, diabetes mellitus, and hemoptysis were also improved; all 4 patients with respiratory failure recovered after 1 week, while 2 of the 3 patients with hypoxemia recovered and the remaining patient improved. The 2 patients with hypoproteinemia improved after chemotherapy and supportive therapy. Altogether, 11 patients (78.6z) showed significant improvement in clinical symptoms. The weight of 13 patients was maintained or increased. Six months after LZD-containing treatment, chest computed tomography revealed that 10 patients (71.4z) showed cavity closure. Smear conversion was achieved in all 14 patients (100z). The onset of smear conversion occurred after 8 to 210 days of therapy, with an average of 64 days. Culture conversion was achieved in all 14 patients (100z). The time from the start of LZD-containing treatment to culture conversion ranged from 8 to 210 days, with an average of 63 days. However, neither smear nor culture conversion times were related to the duration of 1,200 mg LZD treatment (r = -0.151 and 510


Table 3. Adverse event of linezolid in the treatment of XDR-TB

r = -0.138, respectively; P = 0.605 and P = 0.637, respectively) (Table 2). The results of the blood test, urine test, blood coagulation index, and liver and kidney function tests and the electrocardiogram (ECG) of each patient were monitored every week. None of the 14 patients had liver or renal damage. The ECG showed no prominent abnormalities. One patient had diabetic nephropathy with positive result for urine protein; this returned to normal after symptomatic treatment. Three patients intermittently tested positive for urine protein, but their renal function (serum creatinine and urea nitrogen) was normal. Four patients (28.6z) had gastrointestinal adverse reactions such as nausea after about 2–4 weeks of treatment with 600 mg of LZD twice a day, but these resolved spontaneously after the dose of LZD was reduced to 600 mg once a day. Six patients (42.9z) developed hematological adverse reactions, including 1 case of neutropenia, 4 cases of asymptomatic moderate anemia, and 1 case of severe anemia, in the 2nd week of treatment with 600 mg LZD twice a day. The bone marrow function of the patient with severe anemia normalized 2 weeks after blood transfusion and the discontinuation of LZD. Anemia did not recur when treatment was resumed with 600 mg LZD once a day. Mild to moderate peripheral neuropathy affecting the lower limbs was observed in 3 patients (21.4z) between the 2nd and 3rd months. The clinical manifestations were numbness, pain, and tingling in the toes. One patient complained of difficulty in walking. These symptoms resolved after concomitant treatment with vitamin B6 and methylcobalamin. Two patients developed optic neuropathy in the 6th month, which completely resolved in both patients 1 month after the discontinuation of LZD. The exact proportions of serious and minor adverse events determined by LZD were 21.4z (3/14) and 64.3z (9/14), respectively (Table 3). XDR-TB is the most serious form of drug-resistant TB. Its clinical treatment outcome is extremely poor with high and rapid mortality attributable to the lack of effective treatments. China is one of the world's 27 countries with the highest burden of MDR-TB/XDRTB (12,13). We took the lead in using a LZD-containing regimen in China to treat 14 patients with XDR-TB. Our results show that at least in the short term, using a LZD-containing regimen to treat XDR-TB can significantly improve clinical symptoms, promote lesion absorption and cavity closure, and accelerate sputum negative conversion. There is no unanimous opinion on the dose and duration of LZD treatment (14–16). Although no statistically significant difference was observed in the efficacy of LZD at the doses of 600 mg and 1,200 mg per in our small-sample study, it is still not clear whether a longer duration of LZD treatment at the dose of 1,200 mg per day might be more effective for treating XDR-TB patients. The suitable dose of LZD for treating XDRTB patients needs to be further demonstrated in clinical practice. According to the literature and our experience, we recommend that patients initially receive 1,200 mg of LZD twice a day and that the dosage be reduced to 600 mg once a day or once every 2 days after 4–8 weeks. The total course of treatment can be up to 6–12 months. The incidence of adverse reactions attributable to

Patient no.

Adverse event1)

1 2 3 4 5 6 7 8 9 10 11 12 13 14

peripheral and optic neuropathy (SAE) neutropenia nausea nausea, peripheral and optic neuropathy (SAE) nausea anemia severe anemia (SAE) none peripheral neuropathy none anemia anemia anemia nausea

1):

SAE, serious adverse event.

long-term application of LZD is high (9,10,17). Our results show that adverse events attributable to LZD treatment included gastrointestinal and hematological reactions as well as optic and peripheral neuropathy. These adverse events were resolved upon discontinuation of or reduction in the dosage of LZD. Among the 14 patients treated with LZD-containing regimens for an average of 6 months, 3 patients discontinued or temporarily discontinued the treatment because of an adverse reaction; others discontinued the treatment because of financial reasons. We believe that despite the high incidence of adverse reactions, some of them serious, the overall drug program would not be affected as long as close observation and timely and correct intervention are performed. Hematological adverse reactions occurred in the 2nd month after treatment initiation. Therefore, it is necessary to monitor blood and other indices weekly at the beginning. The onset of peripheral neuritis was observed after 2–3 months of therapy; the onset was earlier than that observed in some reports (10,14). Visual loss occurred later, usually around the 6th month of treatment. Both clinicians and patients should be alert. Our results indicate that treating XDR-TB with a LZD-containing regimen may have high efficacy and may improve the quality of life. Meanwhile, patients and clinicians should be fully aware of and monitor adverse reactions, and appropriate interventions should be administered. In conclusion, we suggest that LZD be recommended for the treatment of XDR-TB. Acknowledgments We acknowledge the outstanding contributions from the technicians and nursing staff at Shanghai Pulmonary Hospital. We also express our thanks to Fang Yuanyuan and Lv Yan for their time and effort in data collection and patients follow-up. This study was supported by the Key Project of Chinese National Programs (grant no. 2009ZX10003–017).

Conflict of interest None to declare. REFERENCES 1. Tang, S.J. and Xiao, H.P. (2009): Advances in the study of extensively drug resistant tuberculosis. Chin. J. Tuber. Respir. Dis., 32, 380–383 (text in Chinese with English summary).

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