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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 11  |  Issue : 1  |  Page : 116-119

Assessment of multidrug-resistant tuberculosis patient's skin drug reaction in Zanzibar: A certain causal relationship with Clofazimine


1 Zanzibar Integrated HIV, Hepatitis, Tuberculosis and Leprosy Program, Mnazi Mmoja, Zanzibar, Tanzania
2 Department of Curative Services, Ministry of Health, Dodoma, Tanzania

Date of Submission30-Aug-2021
Date of Decision18-Sep-2021
Date of Acceptance18-Nov-2021
Date of Web Publication12-Mar-2022

Correspondence Address:
Dennis Modestus Lyakurwa
Department of Curative Services-Ministry of Health, PO Box 743, Dodoma
Tanzania
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_176_21

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  Abstract 


Drug-resistant tuberculosis (DR-TB) is a serious public health of concern. We present the management of multidrug-resistant (MDR)-TB with skin reaction in Zanzibar in a patient who had prior exposure to anti-TB drugs. The reaction developed 4 months later, following MDR-TB treatment, stopped when the drug was withdrawn, and reappeared when reintroduced. Close monitoring is important in managing DR-TB cases, and an active DR-TB safety, monitoring, and management is required to detect, monitor, and manage adverse events timely.

Keywords: Adverse events, multidrug-resistant tuberculosis, Tanzania, treatment, Zanzibar


How to cite this article:
Mohamed SA, Mshana JO, Abubakar K, Juma AH, Mussa IA, Hamad MF, Juma JK, Khalid FJ, Lyakurwa DM. Assessment of multidrug-resistant tuberculosis patient's skin drug reaction in Zanzibar: A certain causal relationship with Clofazimine. Int J Mycobacteriol 2022;11:116-9

How to cite this URL:
Mohamed SA, Mshana JO, Abubakar K, Juma AH, Mussa IA, Hamad MF, Juma JK, Khalid FJ, Lyakurwa DM. Assessment of multidrug-resistant tuberculosis patient's skin drug reaction in Zanzibar: A certain causal relationship with Clofazimine. Int J Mycobacteriol [serial online] 2022 [cited 2022 May 21];11:116-9. Available from: https://www.ijmyco.org/text.asp?2022/11/1/116/339501




  Introduction Top


Multidrug-resistant tuberculosis (MDR-TB) has been an emerging global public health threat and area of serious concern on to global efforts of TB control initiative. South-East Asian and African regions have the highest TB burden globally. While India remains the topmost country with more TB cases, North India records higher MDR-TB prevalence rates.[1] Recent data on the number of MDR-TB cases enrolled into treatment in Tanzania in 2019 were 518 patients. The prevalence of MDR-TB is 1.0% among the new cases and 12.0% among the retreated cases.[2] In 2017–2020, Zanzibar notified about 300 total TB cases annually, of which 1%–3% are MDR-TB cases. The Cloves Farming Islands started initiation of treatment to DR-TB patients in 2017 at Mnazi Mmoja Referral Hospital, a center of excellence for MDR-TB management, and to date, 36 DR-TB patients have been initiated DR-TB treatment within the isles.[3] Prevalence of adverse events (AEs) associated with MDR-TB is very high in Tanzania, with a recent report citing about 80% in 2009–2011.[4]

Clofazimine is a fat-soluble riminophenazine antibiotic that has been used for the treatment of leprosy for more than 40 years.[5] Prolonged use of clofazimine leads to accumulation of crystal-like drug inclusions in tissue macrophages, resulting in skin and internal organ pigmentations that range from red-brown to black.[6],[7] Skin pigmentation is the most common side effect of the clofazimine occurring in more than 94% of the patients using this medicine.[8] Clofazimine-containing regimen was more associated with skin pigmentation and hepatotoxicity though it has shown a better efficacy for the treatment of MDR-TB, and its side effects are manageable under programmatic conditions.[6],[9],[10]


  Case Report Top


A 45-year-old woman, MDR-TB contact and HIV-negative, was initially diagnosed and started treatment for pulmonary TB in December 2020. A follow-up 2nd-month sputum revealed 2+ smear results with poor clinical progress, characterized with loss of appetite and fever with 38.7°C, but baseline chest X-ray was essentially normal. Sputum examination using GeneXpert showed that the patient had MTB RIF positive. The line probe assay (LPA) for this patient was sensitive for isoniazid, rifampicin, and fluoroquinolones.

Following diagnosis, our case received patient education and counseling and consented for 20 months of treatment with an individualized bedaquiline-based regimen. On February 16, 2021, the patient was enrolled into treatment consisting of bedaquiline 400 mg od, then for 2 weeks, then 200 mg od (3/week) for 22 weeks, linezolid 600 mg, cycloserine 500 mg, levofloxacin 1 g, clofazimine 100 mg od, and Vitamin B6 100 mg.

During follow-up, she attained culture conversion by the 2nd month, body weight was fairly stable, no lymphadenopathy was observed, the serum transaminases and serum creatinine were normal, and she had no any gastrointestinal symptom. The full blood picture presented with normal level of leukocytes, neutrophils, eosinophils, and lymphocytes. At month 4 of treatment on June 17, 2021, the patient complained having oral thrush [Figure 1]. She had no flu-like symptoms, generalized rashes, blisters, or fever. With the communication of MDR-TB experts and the presentation through ECHO, the MDR-TB management team stopped clofazimine because it was thought that it might be the cause of reaction.
Figure 1: Start of the reaction on June 17, 2021

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On June 26, 2021, the oral thrushes worsened into oral ulceration [Figure 2], and the team decided to stop all second-line treatment anti-TB medicines and start injection hydrocortisone 100 mg stat followed by oral nystatin, Vitamin A capsules, cetirizine tablets, and topical application of histamine cream and keep the patient under close observation.
Figure 2: Ten days after starting reaction on June 26, 2021

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At follow-up on July 2, 2021, some improvement was observed [Figure 3], so we decided to reintroduce the dose of MDR-TB drugs one by one with very close observation so as to identify the drug that causes adverse reactions to the patient. The reintroduction of medicines started with levofloxacin on July 6, 2021, followed by others until August 2, 2021, when she had attained a daily full course of her MDR-TB regimen [Table 1]. On August 12, 2021, the patient started again to experience the eruption of the skin patches and rashes/ulcers on the lips together with oral thrush. Finally, the decision to substitute the clofazimine with delamanid was reached on August 20, 2018, and few days later, the AE was resolved [Figure 4].
Figure 3: Improvement after stopping all medication on July 2, 2021

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Table 1: Reintroduction of MDR-TB medicines

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Figure 4: The picture taken on August 20, 2021, showing reaction reappearance

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Written informed consent was obtained from the patient to publish this case report. A copy of the written consent is available for review from the Editor in Chief of this Journal.


  Discussion Top


In this report, we document the management of clofazimine drug reactions in Zanzibar. The patient developed oral/lip thrush/ulcer during MDR-TB treatment. The causality assessment using WHO-UM method of standardized case causality assessment[11] revealed a plausible time to event without other explanation and positive de-challenge and re-challenge to clofazimine. Finally, the event stopped completely after substituting clofazimine with delamanid.

Our case is a previous treated bacteriologically confirmed TB case. Several studies showed that previous TB treatment has strong association with MDR-TB disease.[1],[12] This suggests prompt diagnosis using drug susceptibility testing and appropriate and timely treatment. Further, other studies have shown that wide use of fluoroquinolones for treatment of other infections, community-acquired pneumonias, or first-line TB may potentiate for higher prevalence of fluoroquinolone resistance, which may result in higher relapse rates. This is different from our case as she had no previous history of using fluoroquinolones, and her LPA was sensitive to fluoroquinolones.

Clofazimine is associated with more efficacy than the standard longer, and it is tolerable than many other medications for DR-TB. Clofazimine has synergetic effects with moxifloxacin, levofloxacin, pretomanid, a novel quinolone (UB-8902), and bedaquiline.[6] Unlike the adverse drug reaction, the culture conversions for our patient were attained at month 1 which indicates a good performance of this regimen, similar to other studies.[8]

Ours is a special case of interest of clofazimine-related AEs in Zanzibar. The case report highlights some of the challenges of managing MDR-TB AEs that may result into poor outcome if not well managed. The identification of the cause of the AE and substitution of the offending drug were fundamental steps for ensuring the safety of our patient.

Our case emphasized a close follow-up and proper management of AEs by engaging the patient through education and counseling about the AEs that are likely to occur and pose a threat to the MDR-TB patient's outcome. The major concern with MDR-TB treatment is AEs, usually resulting in at least one AE for every MDR-TB patient. Moreover, we display the involvement of the MDR-TB management team and experts using ECHO in the management of difficult cases in Zanzibar [Figure 5]. This was similar to the study[13] that showed better outcomes of MDR-TB care using ECHO.
Figure 5: The picture taken on August 24, 2021, after substitution of clofazimine

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Similar finding of clofazimine drug reaction was observed in a female Peru patient who developed skin pigmentation after receiving 200 mg of clofazimine for 6 months. The reaction improved after decrease of a clofazimine dose to 100 mg.[14] The delayed type 4 hypersensitivity reaction was minimal and well tolerated by this patient just after reducing the dose. This was different from a clofazimine drug reaction developed by an MDR-TB patient in India, which was more severe and required a drug complete termination. Indian team performed a skin patch test and found that clofazimine had extremely positive reaction (+3) to clofazimine, strongly positive reaction (+2) to kanamycin, and weakly positive reaction (+1) to cycloserine. No reaction was observed to moxifloxacin, amoxiclav, PAS, and co-trimoxazole. Therefore, they permanently terminated the clofazimine and re-challenged with cycloserine and kanamycin.[15] In our case, we did not have facilities for skin patch tests though we thought this useful for detecting type 1 and 4 hypersensitivity skin reactions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kumar A, Singh AK, Upadhyay V, Pandey J. Epidemiology of Multi - Drug - Resistant Tuberculosis in. Biomed Biotechnol Res J 2018;2:112–21.  Back to cited text no. 1
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WHO. Global Tuberculosis Report 2020. Geneva: WHO; 2020.  Back to cited text no. 2
    
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Mohamed SA. Technical Report on Quarterly Cohort Analysis in Zanzibar. Unguja: Zanzibar Intergrated HIV Hepatitis Tuberculosis and Leprosy Program; 2021.  Back to cited text no. 3
    
4.
Mpagama SG, Heysell SK, Ndusilo ND, Kumburu HH, Lekule IA, Kisonga RM, et al. Diagnosis and interim treatment outcomes from the first cohort of multidrug-resistant tuberculosis patients in Tanzania. PLoS One 2013;8:e62034.  Back to cited text no. 4
    
5.
Murashov MD, LaLone V, Rzeczycki PM, Keswani RK, Yoon GS, Sud S, et al. The physicochemical basis of clofazimine-induced skin pigmentation. J Invest Dermatol 2018;138:697-703.  Back to cited text no. 5
    
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Nugraha RV, Yunivita V, Santoso P, Aarnoutse RE, Ruslami R. Clofazimine as a treatment for multidrug-resistant tuberculosis: A review. Sci Pharm 2021;89:1-18.  Back to cited text no. 6
    
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Bakhtiari S, Sehatpour M, Mortazavi H, Bakhshi M. Orofacial manifestations of adverse drug reactions: A review study. Clujul Med 2018;91:27-36.  Back to cited text no. 7
    
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Tang S, Yao L, Hao X, Liu Y, Zeng L, Liu G, et al. Clofazimine for the treatment of multidrug-resistant tuberculosis: Prospective, multicenter, randomized controlled study in China. Clin Infect Dis 2015;60:1361-7.  Back to cited text no. 8
    
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Duan H, Chen X, Li Z, Pang Y, Jing W, Liu P, et al. Clofazimine improves clinical outcomes in multidrug-resistant tuberculosis: A randomized controlled trial. Clin Microbiol Infect 2019;25:190.  Back to cited text no. 9
    
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Hwang TJ, Dotsenko S, Jafarov A, Weyer K, Falzon D, Lunte K, et al. Safety and availability of clofazimine in the treatment of multidrug and extensively drug-resistant tuberculosis: Analysis of published guidance and meta-analysis of cohort studies. BMJ Open 2014;4:e004143.  Back to cited text no. 10
    
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WHO-UM. The use of the WHO-UMC system for standardized case causality assessment. Uppsala Monit Cent 2014;48:194-203.  Back to cited text no. 11
    
12.
Ahmad AM, Akhtar S, Hasan R, Khan JA, Hussain SF, Rizvi N. Risk factors for multidrug-resistant tuberculosis in urban Pakistan: A multicenter case-control study. Int J Mycobacteriol 2012;1:137-42.  Back to cited text no. 12
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Peter DD, Mziray SR, Lekule IA, Kitundu V, Mohamed S, Kisonga RM, et al. Project extension for community healthcare outcomes improves care and treatment for multidrug-resistant tuberculosis patients in Tanzania. Int J Mycobacteriol 2021;10:182-7.  Back to cited text no. 13
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14.
Pecho-Silva S, Navarro-Solsol AC. First case report in Latin America: Oral treatment of multidrug-resistant tuberculosis with delamanid and bedaquiline in combination with linezolid, moxifloxacin and clofazimine following a DRESS syndrome in a peruvian patient. Pulmonology 2021;27:77-9.  Back to cited text no. 14
    
15.
Khan S, Andries A, Pherwani A, Saranchuk P, Isaakidis P. Patch-testing for the management of hypersensitivity reactions to second-line anti-tuberculosis drugs: A case report. BMC Res Notes 2014;7:537.  Back to cited text no. 15
    


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