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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 10  |  Issue : 2  |  Page : 129-135

Early safety and efficacy of linezolid-based combination therapy among patients with drug-resistant tuberculosis in North-western Nigeria


1 Multidrug-Resistant Tuberculosis Unit, Infectious Disease Hospital, Kano, Kano State, Nigeria
2 Department of Medicine, College of Health Sciences, Bayero University, Kano, Kano State, Nigeria
3 Department of Medicine, Muhammad Abdullahi Wase Teaching Hospital, Kano, Kano State, Nigeria

Date of Submission13-Mar-2021
Date of Acceptance17-Apr-2021
Date of Web Publication14-Jun-2021

Correspondence Address:
Farouq Muhammad Dayyab
Infectious Diseases Hospital, Zone 1 Municipal, No. 1 Weather Head, Kano, Kano State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_57_21

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  Abstract 


Background: The emergence of drug-resistant tuberculosis (DRTB) has continued to pose a threat to public health in sub-Saharan Africa and globally. Despite the high burden of tuberculosis (TB) in Nigeria, there are paucity of data on the safety and efficacy of newer agents and repurposed drugs used in the treatment of DRTB. Methods: This prospective cohort study was conducted at a regional DRTB treatment center in Kano, Northwestern Nigeria. Descriptive statistics, Mann–Whitney U-test, and Chi-square or Fisher's exact test were used to analyze the data as appropriate. Results: The median age of the patients was 32 years (interquartile range 26–42 years). Of the 39 patients, 34 (87.18%) were males. The majority of the patients came from the rural areas 25 (64.10%). By 10 months of initiation of combination therapy, 25 (64.10%) of the patients were alive, culture negative and on treatment while 14 (35.90%) of the patients have died. Out of the 39 patients in the cohort, 26 (66.67%) patients had at least one serious adverse event. The most common serious adverse events were hematological disorders (13 [35.14%] of 37 events) and neurological disorders (11 [29.73%] of 37 events). Peripheral neuropathy (P < 0.0001), anemia (P = 0.029), and skin reaction (P = 0.021) occurred more frequently among linezolid interrupters. Conclusions: In conclusion linezolid-based combination therapy, with linezolid at a dose of 600mg daily is associated with satisfactory culture conversion rate by 10 months of therapy. However, linezolid may be associated with peripheral neuropathy that may warrant interruption of the drug.

Keywords: Drug efficacy, drug safety, drug resistance, drug treatment, individualized regimen, linezolid, Nigeria


How to cite this article:
Dayyab FM, Iliyasu G, Ahmad BG, Habib AG. Early safety and efficacy of linezolid-based combination therapy among patients with drug-resistant tuberculosis in North-western Nigeria. Int J Mycobacteriol 2021;10:129-35

How to cite this URL:
Dayyab FM, Iliyasu G, Ahmad BG, Habib AG. Early safety and efficacy of linezolid-based combination therapy among patients with drug-resistant tuberculosis in North-western Nigeria. Int J Mycobacteriol [serial online] 2021 [cited 2021 Sep 17];10:129-35. Available from: https://www.ijmyco.org/text.asp?2021/10/2/129/318382




  Introduction Top


The emergence of drug-resistant tuberculosis (DRTB) has continued to pose a threat to public health in sub-Saharan Africa[1] and globally.[2],[3] According to the World Health Organization (WHO), Mycobacterium tuberculosis (TB) has infected 32% of the world population.[4] In 2015, 10.4 million incident cases of TB were estimated to occur globally and 60% of the burden was in India, Indonesia, China, Nigeria, Pakistan, and South Africa.[5] Strains of Mycobacterium TB with in vitro resistance to at least isoniazid and rifampicin are referred to as multi-DRTB (MDRTB).[6] Rifampicin-resistant TB refers to drug-resistance at least to rifampicin. While preextensively DRTB refers to MDRTB plus either resistance to fluoroquinolone or second-line injectable drug, extensively drug resistance TB refers to MDRTB plus resistance to both fluoroquinolone and second-line injectable.[7] A low success rate is associated with the treatment of fluoroquinolone-resistant and extensively-DRTB.[8],[9],[10] Recently, new and repurposed drugs have been shown to be effective in the treatment of MDRTB.[11],[12]

After oral administration, linezolid is rapidly absorbed and readily distributed to body tissues penetrating well into bronchoalveolar tissues.[13],[14] Its mechanism of action involves protein synthesis inhibition at the early stage of translation.[15] Previous studies have shown that linezolid, an oxazolidinone, has in vitro bacteriostatic activity against strains of mycobacterium TB.[16],[17] This activity has been shown to occur even against MDRTB and Extensively drug resistant tuberculosis (XDRTB) strains.[18] Although linezolid-based combination therapy has substantial toxicity such as myelosuppression and peripheral neuropathy, there are reports indicating that linezolid-based combination therapy is associated with improved culture conversion rate and survival.[19] Studies have shown that despite rapid sterilization of Mycobacterium TB, the toxicity of linezolid may require the discontinuation of the drug.[19] Prolongation of the QT interval is another known effect of the new DRTB medications; however, a recent review by Ferlazzo et al. in Armenia, India, and South Africa highlighted the relative safety of these new and repurposed agents.[20]

Despite the high burden of TB in Nigeria,[21] there are a paucity of data on the safety and efficacy of newer agents and repurposed drugs used in the treatment of DRTB. Here, we highlight the early safety and efficacy of linezolid-based combination therapy for the treatment of DRTB at a TB reference center in North Western, Nigeria.


  Methods Top


Study design and participants

This prospective cohort study was conducted at a regional DRTB treatment center in Kano, Northwestern Nigeria. We included all consecutive patients with DRTB who started on linezolid-based combination therapy between January 1, 2018 and December 31, 2019 and data were censored on July 31, 2020. The treatment site is supported by the National TB and Leprosy Control Program (NTBLCP) and the Global Fund new funding model grant for DRTB. Linezolid-based combination therapy was used as part of individualized treatment for DRTB. Patients were eligible to receive linezolid-based combination if they had drug resistance to either fluoroquinolone or second-line injectable drug in addition to rifampicin-resistance.[22] All patients were admitted for 4 months and started on the treatment based on the NTBLCP guidelines.[22] Thereafter, the patients are discharged to continue treatment in the community setting for a total treatment duration of 20 months.

Ethical approval for the study was obtained from the Health Research Ethics Committee of Kano State Ministry of Health (MOH/Off/797/T. I/690). All patients were counselled on the potential benefits and adverse effects of the drugs, and written informed consent was obtained from each patient.

Study procedures

Hospital admission, laboratory investigations, and treatment for patients with DRTB were offered free of charge to patients. Using the national guideline, all the patients were commenced on a 6-months intensive phase of bedaquiline, linezolid, clofazimine, para-aminosalicylic acid, pyrazinamide, high dose isoniazid, and either moxifloxacin or second-line injectable based on susceptibility pattern. Linezolid was administered at doses recommended by the NTBLCP guidelines (600mg daily). All other medications were administered based on the NTBLCP guidelines.[22]

Baseline laboratory investigations were conducted in all patients at the time of admission and repeated monthly if indicated. These investigations include liver and renal function tests, serum electrolytes, thyroid function tests, chest radiograph, hemoglobin measurement, electrocardiography, and other indicated tests. All the patients had a baseline electrocardiogram (ECG) done before the commencement of the second line medications. Corrected QT (QTc) was determined using the Framingham formula (QTc = QT + 0.154 [1 – RR]), according to the National treatment protocol.[22]

Monitoring and management for drug safety were done actively based on the guidelines on active TB drug safety monitoring and management of the NTBLCP in line with WHO recommendations.[22] All serious adverse events were reported to the NTBLCP within 24 h. Adverse events were graded as Grade 1, 2, 3, and 4 if they are mild, moderate, severe and life-threatening, respectively.

All patients had baseline sputum GeneXpert assay, smear for acid-fast bacilli, culture (on solid and liquid media) and drug susceptibility testing for the first and second-line drugs at a regional laboratory in Aminu Kano Teaching Hospital.

Study outcomes

We assessed efficacy based on sputum culture conversion at 10 months of treatment defined as two consecutive culture negative results obtained at least 2 weeks apart in a patient with positive sputum culture at baseline. Regardless of baseline sputum culture status, all patients with negative culture status at 10 months were also said to have effective treatment outcome.

Treatment safety was assessed based on the occurrence of serious adverse events defined as patient demise from any cause or disability or any other life-threatening event occurring in the first 10 months of therapy. Particular attention was given to interruption of linezolid therapy defined as permanent discontinuation of the drug based on the occurrence of moderate or severe peripheral neuropathy. Severity of peripheral neuropathy was graded on clinical grounds.

Statistical analysis

Data were collected prospectively at the site into specially designed forms. Data were then extracted from the forms and entered into a Microsoft Excel (Version 2013; Microsoft Corporation, Redmond, WA, USA) spreadsheet and cleaned. Data were analyzed using, JMP Pro software (JMP Version 12.0.1, SAS Institute Inc., Cary, NC, USA). Using descriptive statistics, the results were presented as frequencies and percentages. Median and interquartile range (IQR) was used to summarize the quantitative variables. The Mann–Whitney U-test and Chi-square or Fisher's exact test were used to compare quantitative and qualitative variables, respectively.


  Results Top


Demographic and clinical characteristics

During the study period (January 1, 2018 to December 31, 2019), 39 patients were initiated on linezolid-based combination therapy for DRTB. The median age of the patients was 32 years (IQR 26–42 years). Of the 39 patients, 34 (87.18%) were males [Table 1]. Twenty-four of the patients were self-employed at the time of admission, 3 (7.69%) were civil servants, while 12 (30.77%) were not employed. The majority of the patients came from the rural areas 25 (64.10%). At presentation, 14 (35.90%) of the patients were categorized as relapse, 16 (41.03%) treatment after failure, and 9 (23.08%) new cases. Of the 30 patients that were treated for TB before, 18 (46.15%) were treated once, 11 (28.21%) were treated twice while 1 (2.56%) was treated thrice.
Table 1: Demographic and clinical characteristics of patients on linezolid-based combination therapy

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One of the patients had both pulmonary and extrapulmonary TB, whereas the rest had pulmonary TB only. Majority of the patients had no comorbidity, while there was one case each of diabetes, hypertension, and psychosis. Three of the 39 patients were HIV positive, 3 (7.69%) were positive for the hepatitis C virus, 7 (17.95%) were positive for hepatitis B virus, and 1 (2.56%) other patient had both HIV and hepatitis B virus infection. The patients studied had rifampicin-resistance in addition to either fluoroquinolone (7/39) or second-line injectable (23/39) anti-TB drug resistance. Nine of the patients had preextensively DRTB with resistance to both rifampicin, isoniazid and either fluoroquinolone (3/39) or second-line injectable agent (6/39).

The baseline sputum acid-fast bacilli were positive in 19 (48.72%) and negative in 20 (51.28%) patients.

Among the 26 patients that had their baseline solid LJ cultures documented, 15 were positive and 11 were negative for Mycobacterium TB.

For the 6-month intensive phase of treatment, all the patients 39 (100%) were on individualized therapy comprising of bedaquiline, linezolid, clofazimine, para-aminosalicylic acid, pyrazinamide, and high dose isoniazid, whereas 10 (25.64%) and 29 (74.36%) received additional injectable second line and moxifloxacin, respectively.

Treatment efficacy

Of the 15 patients with positive cultures, 13 (50.00%), 1 (3.85%), and 1 (3.85%) patients achieved culture conversion at 1, 2, and 3 months of initiation of treatment, respectively. By 10 months of initiation of combination therapy, 25 (64.10%) of the patients were alive, culture negative and on treatment while 14 (35.90%) of the patients have died. At the time of writing this report (July 31, 2020), 2/25 of the patients that are alive, have been declared cured, 3/25 were categorized as treatment completed while 20/25 have remained culture negative and are on treatment.

Treatment safety

Out of the 39 patients in the cohort, 26 (66.67%) patients had at least one serious adverse event. As shown in [Table 2] (fatal cases at censoring) and [Table 3] (nonfatal cases at censoring), a total of 37 serious adverse events were reported with a median of 1.0 (IQR 1.0–2.0) serious adverse event per patient. The most common serious adverse events were hematological disorders (13 [35.14%] of 37 events), neurological disorders (11 [29.73%] of 37 events), cardiorespiratory disorders (8 [21.62%] of 37 events), and gastrointestinal disorders (3 [8.11%] of 37 events). Among the 26 patients with serious adverse events, 14 patients died. Eight of the patients that died had extensive lung fibrosis culminating into fatal cardiorespiratory failure, one diabetic patient had exacerbation of hepatitis B-related chronic liver disease nearly 4 months into therapy with fatal outcome, one hypertensive patient developed fatal cerebrovascular disease 2 months after the commencement of therapy. Furthermore, one patient had anemia, bilateral optic neuritis, and fatal massive hematemesis of undetermined cause, one patient was assessed to have hypothyroidism posthumously and another patient developed fatal complications related to blood transfusion. Another patient with a history of schizophrenia that had HIV and was not on antiretroviral therapy at the time of admission, died of sepsis nearly 1 month after the commencement of therapy. Eight serious adverse events led to permanent withdrawal of linezolid with unresolved consequences. Overall, 9 serious adverse events were classified as Grade 4 in severity, 16 were classified as Grade 3 or less while 12 were not graded. Twenty-one serious adverse events were potentially related to linezolid. Of the 37 serious adverse events, 13 resolved. The mean baseline QTc of the patients was 372 ms, and only one had a follow up QTc recording above 500 ms (i.e., QTc of 518 ms) at 1 week after the commencement of therapy. The patient had clinical and electrocardiographic features of corpulmonale and is among the eight patients mentioned above that died from cardiorespiratory failure. He died 10 days after the commencement of therapy.
Table 2: Serious adverse events reported by patients on linezolid-based combination therapy (fatal cases at censoring)

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Table 3: Serious adverse events reported by patients on linezolid-based combination therapy (nonfatal cases at censoring)

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As shown in [Table 4], peripheral neuropathy (P < 0.0001), anemia (P = 0.029), and skin reaction (P = 0.021) occurred more frequently among linezolid interrupters. Overall, severe anemia (Hb <8 g/dl) and peripheral neuropathy occurred among 12 (30.77%) and 16 (41.03%) patients at a median of 9.9 weeks (IQR 8–12.7 weeks) and 8.4 weeks (6–13.9 weeks) after linezolid treatment initiation, respectively.
Table 4: Adverse effects stratified by linezolid interruption (permanent withdrawal of the drug)

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Patients who developed neurotoxicity were managed by increasing vitamin B6 dosage, use of oral or topical analgesic, pregabalin, and/or amitriptyline. Linezolid was suspended indefinitely in patients who developed neuropathy graded as Grade 2 or more. Blood transfusion, nutritional support, iron and folic acid supplementation as indicated, were used to manage patients with anemia.


  Discussion Top


Prior reports of DRTB in Nigeria have been cross-sectional reviews,[23],[24] microbiological studies,[25],[26] retrospective reviews,[27],[28] and a few prospective studies.[29],[30] To our knowledge, this might be the first prospective study in Nigeria that describes the efficacy and safety of linezolid-based therapy among patients with DRTB treated under programmatic conditions. We found that a substantial number of the patients were young males from rural areas. Most achieved sputum culture conversion by 2 months of treatment. Hematological and neurological disorders were the most common serious adverse events reported.

Similar to our findings, the majority of DRTB patients are young adult males in Sudan, India, Armenia, and South Africa.[20],[31]

Majority of patients in our cohort are from the rural areas and have been treated for TB before. Reports from Sudan republic indicated that poor previous treatment outcome is common among MDRTB patients from the rural areas.[31],[32] This finding was said to be due to the low-income status of rural residence with difficulty in paying for transport to centres where care is accessed leading to the high level of default and treatment failure. The new second line anti tuberculous drugs have a tendency to cause QTc prolongation, especially delamanid and bedaquiline. Among our cohort of 39 patients; one had a follow up QTc above 500 ms. Although the patient was on QTc prolonging medications including bedaquiline, moxifloxacin, and clofazimine, the patient had cor pulmonale which has been reported to cause QTc prolongation in the literature.[33],[34] We therefore cannot attribute the QTc prolongation observed in this patient to the medications given the presence of comorbidities and the findings of Ferlazzo et al. who buttressed the safety of these new medications.[20]

The preliminary results from our study support the efficacy of linezolid-based combination therapy for DRTB. By 10 months of therapy, all patients that are alive in our cohort were culture negative irrespective of baseline culture status. Its worthy of note that all the patients in our cohort received clofazimine as part of their DRTB therapy. Improved culture conversion rates have been reported among DRTB patients on linezolid and clofazimine.[35],[36]

In accordance with religious and cultural factors, none of the patients in our study had autopsy because, patients are buried immediately after death. Therefore, the assessment of cause of death among our patients was mainly on clinical grounds.

Similar to our study, high rates of adverse events related to linezolid were reported among MDRTB patients in several previous studies.[37],[38],[39] Anemia, pancytopenia, and polyneuropathy were experienced by 18.8% of MDRTB patients treated with linezolid in Portugal.[40] In New York City, hematological, gastrointestinal, and neurological adverse events were experienced by 81%, 81%, and 44% of MDRTB patients treated with linezolid.[19] The interruption of linezolid in 20.5% of our patients is similar to the reports from South Africa where 19% of the patients discontinued the drug due to system-specific toxicity.[41] Neuropathy after commencing linezolid occurred earlier in our patients (median of 8.4 weeks) compared to South African (median of 18 weeks) and New York City (median of 16 weeks) cohorts.[19],[41] This finding may be because of the differences in study design and differences in patient follow-up periods between the studies. Furthermore, manifestation of anemia occurred between 8 and 12.7 weeks, 8–12 weeks, and 7 weeks of commencing linezolid therapy in our cohort, South African and New York City cohort, respectively.[19],[41] Previous studies suggested that reduction of the dose of linezolid at specific times adverse drug reactions occur, might help to mitigate the adverse effects of the drug.[19],[41],[42] Whereas hematopoietic system toxicity of linezolid is dose-dependent, neurotoxicity of the drug has been described to be duration-dependent.[42]

Our study is limited by small sample size. Some useful data for follow-up such as ECG recordings were missing due to programmatic factors. Nonetheless, we have provided a glimpse of the epidemiology, safety, and efficacy of linezolid-based combination therapy for DRTB in Nigeria.


  Conclusion Top


Linezolid-based combination therapy, with linezolid at a dose of 600 mg daily is associated with satisfactory culture conversion by 10 months of therapy. However, linezolid may be associated with peripheral neuropathy that may warrant interruption of the drug. Our study corroborates previous studies on the use of linezolid to treat DRTB in TB endemic countries, under programmatic conditions. There is a need to liberalize the provision of TB diagnosis and treatment centres as well as health education to the rural areas within Nigeria, in order to curb the emergence and spread of drug resistance TB.

Ethical clearance

Ethical approval for the study was obtained from the Health Research Ethics Committee of Kano State Ministry of Health (MOH/Off/797/T. I/690). All patients were counselled on the potential benefits and adverse effects of the drugs, and written informed consent was obtained from each patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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