Leprosy Mailing List – November 6, 2023
Ref.: (LML) Lymecycline in leprosy– hope or hype
From: Sunil Dogra, Bangalore, India
Dear Dr Pieter AM Schreuder & Colleagues,
Subject: Lymecycline in leprosy– hope or hype
We were greatly intrigued by a recently published original article titled "Comparison between Lymecycline with Multidrug Therapy and Standard Multidrug Regimen (WHO-MDT) in the Treatment of Multibacillary Leprosy Patients: A Retrospective Cohort Study." 1 This study must have ignited curiosity of leprologists about the potential of lymecycline as an adjunct treatment for multibacillary leprosy. However, we find it necessary to address a notable concern stemming from the authors' reliance on a non-peer-reviewed unpublished pilot study to establish this premise.2 Building upon this study and existing literature, we aim to provide a critical assessment and elucidate the role of lymecycline in the therapeutic landscape for leprosy.
It must be noted that there are no in vitro studies on the activity of lymecycline against Mycobacterium leprae, and so also is the lack of clinical and experimental studies on the effectiveness of lymecycline against leprosy. The single clinical study conducted by Diaz et al. should be approached with caution due to several significant limitations that need to be taken into account before any firm conclusions can be drawn from their findings. 1 Potential confounders like leprosy reactions and baseline nerve function impairment (NFI) were not matched among cases and controls in this study. The reported significant reduction in NFI in about 90% of the patients makes lymecycline seem more like a wonder drug, which can protect against the most serious accompaniment of leprosy: nerve damage. However, most of the studies with MDT have reported even worsening of the NFI in a considerable number of patients.3 Similarly, the claimed reduction of more than 50% in the incidence of reactions, especially type-2, is unusual– reactions represent another important morbidity in multibacillary leprosy. Secondly, the unusually high 'recurrence rate' of lesions observed in the cohort (30.77%), particularly in the standard MDT group (50%), raises concerns about potential resistance/ treatment unresponsiveness to MDT components. This observation makes drawing any meaningful conclusions challenging, especially without baseline matched screening for drug resistance and NFI.
Minocycline, another member of the same pharmacological group, is a well-established pharmaceutical choice for leprosy management, substantiated by extensive clinical studies and readily accessible efficacy data in the existing literature.4 In contrast, there is currently insufficient evidence to assert the superiority of lymecycline over this well-documented drug. It is worth highlighting that previous research, particularly in the context of acne treatment, has indicated a comparable adverse profile for both minocycline and lymecycline.5 Furthermore, both minocycline and lymecycline share the convenience of once-daily dosing.
Diaz et al reported significant decline in the bacteriological index (BI) by a staggering 3 points within one year in the lymecycline-MDT group, compared to the meager 0.7 point reduction in the standard MDT groups.1 This is an extraordinary outcome in stark contradiction to the existing body of knowledge on leprosy treatment. Even 3 months of treatment with lymecycline is claimed to have produced significant fall in BI. Numerous well-established longitudinal studies on leprosy patients have repeatedly demonstrated that bacteriological clearance is a slow process, with each log decline in BI typically taking 1-2 years.6 Such gradual clearance rates have been observed even in the context of the most potent bactericidal regimens containing clarithromycin and ofloxacin. 7, 8 Yet, the authors boldly claim that lymecycline, a tetracycline-based bacteriostatic antibiotic, can achieve a level of bacteriological clearance unheard of in the treatment of leprosy. The reported histopathological changes were even more dramatic: the epidermis became acanthotic and the Grenz zone disappeared.1 The granulomas shrank and became uniformly organized and a significant decrease of AFB and foamy histocytes occurred only after 3 months of treatment. In light of the observed slow clearance of granulomas and persistence of foamy histocytes even after many years of treatment, this observation is to be taken with extra caution.9
The high efficacy of lymecycline in improving the NFI, reducing the recurrence of lesions and reactions, and overall patient improvement in the control group has been attributed to its neuroprotective, anti-apoptotic, and immunomodulatory properties based on studies primarily conducted on animals and a limited number of uncontrolled human studies.10 However, these findings in experimental studies have only been observed with doxycycline and minocycline given in the doses of 40-80mg/kg of body weight. These doses in humans are obviously impractical and too toxic. The lack of well-designed comparative studies on humans prevents drawing meaningful conclusions. Therefore, the current evidence does not support the claimed benefits of lymecycline in humans.
Lymecycline has been with us for the last more than 6 decades. It has never been recommended for any serious infection- more so for the infections with Mycobacterium tuberculosis or Mycobacterium leprae. There is only one case report of an infection with Mycobacterium marinum where the cure was claimed with only 45 days of treatment with lymecycline.11 No more than this is available in the literature.
The current evidence base regrading use of lymecycline in leprosy, consisting of a retrospective study and one unpublished pilot study is insufficient to support inclusion of lymecycline as an adjunct to standard MDT in leprosy treatment.1, 2 In the absence of large well-designed prospective studies with controlled populations establishing the efficacy and safety of lymecycline, its unregulated use may contribute to the emergence of drug resistance in lepra bacilli.
Tarun Narang, MD FRCP; Hitaishi Mehta, MD; Shikha Shah, MD; Sunil Dogra, MD, FAMS, FRCP; Bhushan Kumar, MD, FRCP
Chandigarh, India
References
1. Diaz JCD, Abad-Venida ML, Espinoza-Thaebtharm A, Cathryn Salonga ME, Abad-Casintahan MF. Comparison between lymecycline with multidrug therapy and standard multidrug regimen (WHO-MDT) in the treatment of multibacillary leprosy patients: a retrospective cohort study. Int J Dermatol. 2023 Jul 5. doi: 10.1111/ijd.16767. Epub ahead of print
2. Salonga E, Casintahan MF. Lymecycline as treatment for leprosy: a pilot study. 2014.
3. Sales AM, Campos DP, Hacker MA, da Costa Nery JA, Düppre NC, Rangel E, Sarno EN, Penna MLF. Progression of leprosy disability after discharge: is multidrug therapy enough? Trop Med Int Health. 2013 Sep;18(9):1145-1153.
4. Narang T, Arshdeep, Dogra S. Minocycline in leprosy patients with recent onset clinical nerve function impairment. Dermatol Ther. 2017 Jan;30(1). doi: 10.1111/dth.12404. Epub 2016 Aug 23. PMID: 27550711.
5. Bossuyt L, Bosschaert J, Richert B, Cromphaut P, Mitchell T, Al Abadie M, et al. Lymecycline in the treatment of acne: an efficacious, safe and cost-effective alternative to minocycline. Eur J Dermatol. 2003;13(2):130-5.
6. Kumar A, Girdhar A, Girdhar BK. Pattern of bacillary clearance in multibacillary leprosy patients with multidrug therapy. Acta Leprol. 2003;12(3):123-8.
7. Villahermosa LG, Fajardo TT, Jr., Abalos RM, Cellona RV, Balagon MV, Dela Cruz EC, et al. Parallel assessment of 24 monthly doses of rifampin, ofloxacin, and minocycline versus two years of World Health Organization multi-drug therapy for multi-bacillary leprosy. Am J Trop Med Hyg. 2004;70(2):197-200.
8. Gunawan H, Sasmojo M, Putri HE, Avriyanti E, Hindritiani R, Suwarsa O. Clinical pilot study: clarithromycin efficacy in multibacillary leprosy therapy. Int J Mycobacteriol. 2018;7(2):152-5.
9. Desikan P, Desikan KV. Persistence of lepromatous granuloma in clinically cured cases of leprosy. Int J Lepr and other Mycobact Dis. 1995;63:417-31.
10. Orsucci D, Mancuso M, Filosto M, Siciliano G. Tetracyclines and neuromuscular disorders. Curr Neuropharmacol. 2012;10 (2):134–8
11. Neugebauer MG, Neugebauer SA, Almeida Junior HL, Mota LM. Treatment of Mycobacterium marinum with lymecycline: new therapeutic alternative? An Bras Dermatol. 2015;90(1):117-9
LML - S Deepak, B Naafs, S Noto and P Schreuder
LML blog link: http://leprosymailinglist.blogspot.it/
Contact: Dr Pieter Schreuder << editorlml@gmail.com
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