Safety of Longer Linezolid Regimen in Children with Drug Resistance Tuberculosis and Extensive Tuberculosis in Southwest China

Journal Pre-proof Safety of Longer Linezolid Regimen in Children with Drug Resistance Tuberculosis and Extensive Tuberculosis in Southwest China ZhenZhen Zhang, ZhenLi Cheng, QuanBo Liu, TingTing Shang, Li Jiang, Zhou Fu, Kun Zhu, Xiao Wang, Juan Chen, HongMei Xu

PII:

S2213-7165(19)30252-8

DOI:

https://doi.org/10.1016/j.jgar.2019.09.019

Reference:

JGAR 1056

To appear in:

Journal of Global Antimicrobial Resistance

Received Date:

13 June 2019

Revised Date:

12 September 2019

Accepted Date:

27 September 2019

Please cite this article as: Zhang Z, Cheng Z, Liu Q, Shang T, Li J, Zhou F, Zhu K, Wang X, Chen J, HongMei X, Safety of Longer Linezolid Regimen in Children with Drug Resistance Tuberculosis and Extensive Tuberculosis in Southwest China, Journal of Global Antimicrobial Resistance (2019), doi: https://doi.org/10.1016/j.jgar.2019.09.019

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Safety of Longer Linezolid Regimen in Children with Drug Resistance Tuberculosis and Extensive Tuberculosis in Southwest China ZhenZhen Zhang1,2 *, ZhenLi Cheng 3*, QuanBo Liu1,TingTing Shang 1, Li Jiang1,Zhou Fu4, Kun Zhu5, Xiao Wang1, Juan Chen1,6, HongMei Xu1,2# 1: Department of Infectious Disease, Children’s Hospital of ChongQing Medical University, ChongQing, China

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2: Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, ChongQing, China;

3：Department of cardiology, Children’s Hospital of ChongQing Medical University, ChongQing,

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China

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4: Department of Respiratory Disease, Children’s Hospital of ChongQing Medical University, ChongQing, China

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5: Department of radiology, Children’s Hospital of ChongQing Medical University, ChongQing,

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China

6: The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese

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Ministry of Education, ChongQing, China; *: both authors contributed equally to this paper

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#: Correspondence: Pro. HongMei Xu, Address: No.136 ZhongShan Er Road,YuZhong District, ChongQing, China. E-mail: [email protected]

Highlights 

There was high adverse events rate of Linezolid longer regimen in children with drugresistance tuberculosis and extensive tuberculosis.



Most frequent side effect of Linezolid was hematological toxicity including leukopenia Anemia, neuropathy could happened at the late stage of linezolid treatment course.



Low dose of Linezolid to weight band (10-15mg/Kg/d) was suggested for children in long regimen.



Linezolid exhibited good curative response in children with sever tuberculosis such as

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congenital tuberculosis

Abstract Objective: Linezolid (LZD) has been listed as the group A medications for the treatment of multi-

drug resistance tuberculosis (MDR-TB) and extensive drug resistance tuberculosis (XDR-TB) in longer regimen (18-20 month) by WHO recently. However, little is known about the safety of LZD in longer TB treatment regimen in children. Methods: Here, we reported 31children who received LZD treatment for drug resistance

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tuberculosis (DR-TB) and extensive tuberculosis from September,2016 to March 2019. The average course of LZD treatment was 8.56 months (range from 1m to 24m).

Results: 3/31patients (41.94%) had suspected or confirmed adverse events (AEs) related to

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LZD including digestive symptom, hematologic toxicity, neuropathy and lactic acidosis.

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Hematologic toxicity were the most frequent AEs presented as leukopenia (9/13) and anemia (5/13). No hepatotoxic and nephrotoxic were observed in all 31 patients. Two patients suffered

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from life-threaten lactic acidosis when LZD dose increased to 1.2g daily, and they finally

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recovered through LZD retrieving.

Conclusion: There was high rate of AEs of Linezolid treatment in children who received long

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time regimen, and the AEs might relate to treat course and dose. Hematologic toxicity was the most frequent AE in children. It is necessary to monitor the blood test and lactic concentration

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regularly during Linezolid treatment. Key words: linezolid, drug-resistance tuberculosis, safety, adverse events

1. Introduction Tuberculosis (TB) is the leading cause of death from single infectious agent. According to the WHO Global Tuberculosis Report 2018, around 10 million people developed TB in 2017 consisting of 5.8 million men, 3.2million women and 1 million children

[1]

. Timely diagnosis

and treatment of TB in children remains great challenge worldwide. Children usually have atypical clinical symptoms and paucibacillary in sputum or aspirated fluid when infected with

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MTB [2]. Despite new technology such as Xpert MTB/RIF or LPA improved TB diagnosis and drug-resistance TB screening in pediatric to some extent, the situation hasn’t changed

dramatically. Except for diagnosis, treatment is another tough problem for children. Children

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seems vulnerable to anti-tuberculosis drugs, one report indicated that children had higher risk [3].

Furthermore,

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of drug induced liver injury than adults (6.9% in children vs 2.4% in adults)

there are less choices for children who are intolerant to first-line anti-tuberculosis medicine,

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new medicine aimed to DR-TB are constrained in children. For example, bedaquiline is

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recommended to adolescents (>12-year-old) with body weight more than 33 kg, while delamanid is indicated for children older than 6-year-old and with body weight more than 20

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kg [4-6]. Finally, Optimal dosage for anti-tuberculosis medicine is undetermined in children, especially in infant under 6-month-old. Treatment for children tuberculosis are mostly

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empirical. Studies focused on diagnosis and treatment of pediatric TB through new technology and medicine for children are still highly priority in future. Linezolid (LZD) is an oxazolidinone antibiotic which is effective for multi-drug resistance

tuberculosis (MDR-TB)

[7-8].

In the updated WHO consolidated guidelines on drug-resistant

tuberculosis treatment, linezolid combined with bedaquiline, fluoroquinolones (levofloxacin and

moxifloxacin) are listed as the group A medications for MDR-TB or extensive drug resistance tuberculosis (XDR-TB) in longer regimen (18-20 month)

[9]

, which indicated the vital role of

LZD in DR-TB treatment. The main side effect of LZD are hematological toxicity, optic neuropathy and hyperlacticaemia. Lee et al revealed that about 80% of XDR patients had adverse reactions that were possibly or probably related to LZD for long time usage in adults.[10] In another RCT study applying LZD for XDR-TB in China, Zhang et al reported 81.8% patients

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had events that were possibly or probably related to linezolid, most adverse events resolved after reducing the dosage of linezolid or temporarily discontinuing linezolid[11].

Seldom studies focused on the safety of LZD in pediatric population. Herein, we described

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the safety of LZD in children for longer treatment in DR-TB and extensive tuberculosis

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patient’s intolerance of first-line anti-tuberculosis medicine. Through this study, we attempt to

2. Patients and Methods

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better understand the safety and appropriate usage of LZD in children.

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We retrospectively reviewed records of children diagnosed as tuberculosis who received LZD treatment in the Children’s hospital of ChongQing Medical university during

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September,2016 to March 2019. The diagnosis of TB was set up according to the Guidance for national tuberculosis programs on the management of tuberculosis in children, 2nd edition[12].

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Briefly, patients with history of TB contact or similar symptom of tuberculosis were further evaluated by tuberculin skin test (TST), IGRA, radiology or histological, bacterial confirmation (Acid -Fast Bacilli, TB-PCR, Xpert MTB/RIF and culture). Patients without etiological evidence were treated empirically and diagnosed clinically (supplementary data 1). The DRTB diagnosis was made when Xpert MTB/RIF test indicated positive simultaneously. Patients

with poor responding to first-line therapy after 3-6 months regular first-line anti-TB treatment were suspected as DR-TB and switch to DR-TB regimen after the consent of parents. The DRTB refers to any confirmed or clinical suspected resistance to first-line or second-line antituberculosis drug. Extensive tuberculosis was defined as extrapulmonary tuberculosis other than lymphadenopathy, military tuberculosis, dissemination tuberculosis or presence of cavities or bilateral disease on chest radiography [9].

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For each patients the following data was selected for analysis: age; gender; nutritional

status; diagnosis; dosage and duration of linezolid therapy; adverse events. The grades of adverse events were refer to Common Terminology Criteria for Adverse Events (CTCAE)

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v5.0[13] (supplementary table2)，adverse events without classification on CTCAE5.0 were

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defined as mild, moderate and severe. Statistical analysis was performed using PASW Statistics

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22.0 (SPSS Inc. Chicago, IL, USA). Statistical significance was accepted at P≤0.05. 3.Results

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3.1 Patients data and characteristics

Of the 31 patients that received LZD therapy, 20 children were diagnosed as drug-resistance

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tuberculosis (DR-TB). The left patients received LZD treatment due to intolerance of first-line anti-tuberculosis medicine. LZD was given intravenously and then converted to oral

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administration with the same dose as intravenous administration. The average age was 7.27 years, ranged from 28 days to 17 years. 19/31 (61.29%) patients were male, 12/31 patients (38.71%) were female. All patients were HIV negative. As to the types of tuberculosis, 7 patients had TB in pulmonary, pleura and bronchus. 22 patients were extensive tuberculosis, 2 patients diagnosed as congenital tuberculosis treated with LZD either. The average duration of

LZD was 8.58 months, patients with DR-TB had much longer LZD duration than Non-DR-TB (10.72 vs 5.32, P<0.05). The demographic and clinical characteristics was summarized in Table 1 (Table 1). The regimen of DR-TB was composed of Linezolid, Fluoroquinolones (levofloxacin/moxifloxacin), amikacin, ethambutol and any one of following medicines: pyrazinamide, ethionamide, prothionamide, high dose isoniazid (0.4g/d). 3.2 Safety of LZD in longer time treatment

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13 of 31(41.94%) patients had suspected AEs according to the CTCAE v5.0. The most

common AEs was hematologic toxicity including leukopenia and anemia, followed by digestive

symptom (such as nausea and vomiting), hyperlacticaemia, neuropathy and hypoglycemia

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(Fig1a). Despite hematologic toxicity was the most frequent AEs related to LZD, most patients

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only had mild to moderate adverse events referred to Grade1-2 AEs and insisted LZD treatment without retrieval. By contrast, patients suffer from neuropathy and hyperlacticaemia were

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usually serious and resulted in permanently discontinue of LZD treatment (Table 2). The

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majority of AEs occurred in first 6 months after LZD being applied. However, a 9-year-old patient developed blurred vision 18-month post LZD treatment in our observation, the patient

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gradually recovered since LZD ceased. These results indicated serious side effect of LZD could occur at the late stage of treatment (Fig1b).

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As to the dosage, most patients received the dosage of LZD among10-15mg/Kg/d, with

maximum 0.6g daily. Tow patients increased LZD dose from 0.6g daily to 0.6g, 12-hourly and both developed serious adverse events (SAE). One patient complained with nausea and vomiting 1 month after LZD adjustment, blood test demonstrated obviously elevation of lactic acid range from 2.03 to 4.58mmol/L (ref. 0-2.1mmol/L). The other patient developed life-

threaten lactic acidosis (peck blood lactic acid: 13.9 mmol/L) combined with conscious disorder, dyspnea, serious anemia (Hb:52g/L), and hypoglycemia (1.59mmol/L) 1 month after LZD dose increased. Both two patients didn’t monitor the blood and lactic acid at local hospital since LZD dose increased. Fortunately, they finally recovered after withdraw of LZD and received symptomatic treatment. 4. Discussion

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Linezolid exerts antibiotic effect via inhibiting initiation of bacterial protein synthesis binding to the 23S RNA peptidyl transferase center (PTC) of the 50S subunit of the prokaryotic ribosome [14-15].

As human mitochondrial ribosomal RNA has homologous structures to bacterial ribosomal

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targets, the main drug toxic caused by LZD is mitochondrial toxicity which manifests [16-18].

Zhang et al systematically

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myelosuppression, neuropathy, and hyperlactatemia clinically

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reviewed the safety of LZD in MDR-TB treatment, 55% experienced adverse events and over a third (35%, 95% CI: 22-47) suffered major toxicities. The most common adverse events were

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peripheral neuropathy (31%) and anemia (25%) [19]. In our study, the AEs rate of LZD was 41.94%

which was comparatively lower than Zhang’s report, and the most common AEs of LZD in our [11]

. In

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observation was leukopenia (9/13) which was different from Zhang’s study as well

Zhang’s study, they discovered anemia was the leading side effect of LZD in MDR-TB patients.

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Recently, another group in South Africa explored the safety of LZD in 17 MDR-TB children, they reported anemia was more common than leukopenia in hematological toxicity. In our observation, many patients had mild anemia at the base-line. This might cause underestimate of LZD-related anemia in our study. In the other aspect, the difference in LZD dose might ascribed to the discrepancy in tow studies. In Zhang’s research, the patients received LZD at a

start dose of 1.2g per day for a period of 4-6 weeks then followed by a dose of 0.3-0.6g per day. While in our study, most patients treated with LZD with the dose of 10mg/kg/d, no exceed to 0.6g daily. Accumulating studies suggested the toxicity of LZD were dose-dependent. McKee et al reported the LZD concentration that inhibited 50% of mitochondrial protein synthesis (IC50) in the tissue of experimental animals was 3.37-5.26 mg/L. This concentration overlaps with the one which

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obtained from adults after a standard 600 mg 12-hourly regimen (1-6 mg/L) [20]. The Sentinel Project

on Pediatric Drug-Resistant Tuberculosis recommended the dosage of LZD as 10 mg/kg once daily for children at least 12 years old and of 10 mg/kg twice daily for children less than 12 years (not to

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exceed a maximum dose of 600mg daily) [6]. Anthony et al. discovered the LZD plasma AUCs were

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higher than previously published values in MDR-TB children cohort following a 10 mg/kg dose

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daily [21]. In our observation, patients following the dose of 10-15mg/Kg/d exhibited good tolerance or mild AEs. Two patients developed lactic acidosis as the LZD dose increased from 0.6g daily to

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1.2g daily during treatment. The dosage of these two patients exceeded the recommend dosage, which cause the development of SAEs and cessation of LZD treatment.

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Except for the dosage, LZD adverse effect also related to the course of treatment. For example, the neurological complications appear to be developing after 2 months on therapy, while

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hematological toxicity occurs within the first 2 months of therapy [22]. Anthony et al reported that the median (IQR) time to any linezolid-related adverse event for children was 3.2 months (1.8 to 13.9 month). We also found more than 80% LZD related AEs appeared in the first 6 month, and the

hyperlacticaemia developed in 2 months after the dosage adjust. However, LZD related neuropathy occurred late in our observation which appeared 18-month post treatment. Thus,

regular side effect monitor is necessary for children with LZD long regimen. Till now, LZD was recommended only for patients with MDR or XDR tuberculosis. No priority was confirmed in drug sensitive pulmonary tuberculosis in adults

[23]

. By contrast, a

study demonstrated that severe TB could benefit from LZD regimen in children. Zhao et al retrospectively reviewed the efficacy and safety of LZD in Tuberculous Meningitis (TBM) children and found that LZD improved early outcome of childhood TBM with low associated

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adverse effects rate. They suggested that LZD might be a good candidate for severe tuberculosis. In this study, 11 drug sensitive children accepted LZD treatment due to intolerance to first-line anti-tuberculosis medicine. Most children showed good tolerance to LZD. This indicated the

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potential role of LZD as a substitution if patients are intolerant to first line anti-tuberculosis

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medicine.

Several obvious limitations exist in our study. First, there were not enough cases enrolled

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in this study, which might cause bias for analysis. As the low culture positive rate and

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unavailability of drug-susceptibility testing, it is impossible for us to understand the

detail of DR-TB. This will restrict further analyze for the efficacy of LZD in different

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types of DR-TB in children. In addition, this is a mono-center, retrospective study, the evidence grade for this study is not high comparing with multi-center, RCT study. Finally, as

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most patients were still in the treatment course, the AEs of LZD we described reflect the possible AEs related to LZD under different dose and time course. As some AEs such as peripheral neuropathy might appear at any time of treatment duration, therefore, further adherence should carry in future. In conclusion, despite high rate of AEs are observed in LZD long time treatment, most

of them are mild and reservable in children. The most common AE of LZD in long-time regime was hematological toxicity, and it seems that SAEs might occur if LZD dose exceed than 0.6g daily in children. We recommended 10mg/Kg/d, daily for LZD in longer regimen and regularly monitor blood test and lactic acid level during treatment.

Declarations

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Author contributions: Zhang ZZ ,Fu Z and Xu HM conception or design of the work; Cheng ZL, Shang TT and Jiang L data collection; Liu QB and Wang X: data analysis and interpretation; Zhu K: radiology results analysis; Chen J: critical revision of the article; Zhang ZZ, Cheng ZL, Shang TT, Liu QB, Jiang L, Zhu K, Wang X, Fu Z, Chen J and Xu HM: Final approval of the version to be published.

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Funding: This work was fund by The High-level Medical Reserved Personnel Training Project

of Chongqing; The medical research project of ChongQing Health Commission (Grant

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No:2018ZDXM041)

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Ethical Approval: Approved by Institutional Review Board of Children’s Hospital of

Chongqing Medical University

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Competing Interests : None declared.

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12. World Health Organization. Guidance for national tuberculosis programmes on the man

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agement of tuberculosis in children-2nd ed. Available from: www.who.int/tb/publications/ childtb_guidelines/en/

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13. Department of Health and Human Services, National Institutes of Health, National Can cer Institute: Common Terminology Criteria for Adverse Events v5.0 https://evs.nci.nih.

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gov/ftp1/CTCAE/CTCAE_5.0/

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action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Mol Cell. 2007; 26:393-402. doi: 10.1016/j.molcel.2007.04.005

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18. Wasserman S, Meintjes G, Maartens G. Linezolid in the treatment of drug-resistant tuberculosis: the challenge of its narrow therapeutic index, Expert Review of Anti-infective Therapy, 2016;14(10): 901-915. doi: 10.1080/14787210.2016.1225498.

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19. Zhang X, Falagas ME, Vardakas KZ, Wang R, Qin R, Wang J, et al. Systematic review and

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treatment of multidrug-resistant and extensively drug-resistant tuberculosis. J Thorac Dis. 2015; 7:603-615. doi: 10.3978/j.issn.2072-1439.2015.03.10.

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20. McKee EE, Ferguson M, Bentley AT, Marks TA. Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother.2006;50: 2042-2049.doi:

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10.1128/AAC.01411-05.

21. Garcia-Prats AJ, Schaaf HS, Draper HR, Garcia-Cremades M, Winckler J, Wiesner L, et al.

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Pharmacokinetics, optimal dosing, and safety of linezolid in children with multidrug-resistant tuberculosis: Combined data from two prospective observational studies. PLoS Med. 2019; 30;16(4): e1002789. doi: 10.1371/journal.pmed.1002789.

22. 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-

135. doi: 10.1016/j.ejim.2008.12.002.

23. Lee JK, Lee JY, Kim DK, Yoon HI, Jeong I, Heo EY, et al. Substitution of ethambutol with linezolid during the intensive phase of treatment of pulmonary tuberculosis: a prospective, multicentre, randomised, open-label, phase 2 trial, Lancet Infect Dis. 2019 Jan;19(1):46-55. doi:

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10.1016/S1473-3099(18)30480-8.

Figure Legend

Figure 1: linezolid-related adverse events in children with longer regimen. a): The whole incidence rate of different AEs related to LZD treatment. b): Kaplan-Meier survival curves for

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time to first adverse event of LZD in children.

Tables

Table1: demographic and clinical characteristics of patients with LZD regimen Characteristic

All patients

DR-TB

Non DR-TB

N=31(%)

N=20

N=11

p-value

0.0678

Age (years) 6(19.36)

2(10)

4(36.36)

1-6y

8(25.8)

4(20)

4(36.36)

7-12y

7(22.58)

6(30)

1(9.1)

13-18y

11(35.48)

8(40)

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<1y

3(27.27)

0.518

Male

19

13

6

Female

12

6

6

25

15

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10

6

4

2

7

5

2

22

15

7

Meningitis

15

10

5

Abdomen *

10

6

4

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Gender

Bone and spine

4

3

1

Cardiac

2

2

0

Lymphaden

4

4

0

2

0

2

8.56

10.72

5.32

Malnourished

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Yes

Site of TB Pulmonary only

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No

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Pulmonary and extrapulmonary

Congenital

Average duration of LZD

0.623

*abdomen tuberculosis including: liver, spleen, kidney, intestinal and peritoneum tuberculosis

0.044

Table 2: AEs that possible or probably related to LZD and the grade N 9 5 1 1 1

Grade1 4 2 0 0 0

Grade5 0 0 -

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Characteristic leukopenia anemia hypoglycemia blurred vision dizziness and tinnitus

AE Grade Grade2 Grade3 Grade4 3 2 0 2 0 1 0 0 1 0 1 0 1 0 0