|Year : 2022 | Volume
| Issue : 1 | Page : 116-119
Assessment of multidrug-resistant tuberculosis patient's skin drug reaction in Zanzibar: A certain causal relationship with Clofazimine
Saida Abuubakar Mohamed1, Julius O Mshana1, Khamis Abubakar1, Ali Hamid Juma1, Issa A Mussa1, Mohd Foum Hamad1, Juma Khamis Juma1, Farhat Jowhar Khalid1, Dennis Modestus Lyakurwa2
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 Submission||30-Aug-2021|
|Date of Decision||18-Sep-2021|
|Date of Acceptance||18-Nov-2021|
|Date of Web Publication||12-Mar-2022|
Dennis Modestus Lyakurwa
Department of Curative Services-Ministry of Health, PO Box 743, Dodoma
Source of Support: None, Conflict of Interest: None
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 The reaction developed 4 months later, following MDR-TB treatment, stopped when the drug was withdrawn, and reappeared when reintroduced.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 25];11:116-9. Available from: https://www.ijmyco.org/text.asp?2022/11/1/116/339501
| Introduction|| |
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. 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. 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. Prevalence of adverse events (AEs) associated with MDR-TB is very high in Tanzania, with a recent report citing about 80% in 2009–2011.
Clofazimine is a fat-soluble riminophenazine antibiotic that has been used for the treatment of leprosy for more than 40 years. 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., Skin pigmentation is the most common side effect of the clofazimine occurring in more than 94% of the patients using this medicine. 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.,,
| Case Report|| |
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.
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.
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 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|| |
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 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., 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. 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.
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 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. 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. 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
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]