Leprosy Mailing List – April 8, 2021
Ref.: (LML) Clofazimine has important anti-microbial efficacy
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
In LML (4 April 2021) Dr. Vijayaraghavan suggested that "The very aim of adding clofazimine in MDT is to reduce the inflammatory reaction associated with Hansen's disease." Thanks to him for this interesting assertion. However, the anti-microbial efficacy of clofazimine is far from negligible. It is measurable in the mouse foot pad.
Figure 1. Decline in viable HD bacilli (log n of daily rate) according to single-drug treatment of infected mice (1) (see annex).
Daily clofazimine demonstrably has greater anti-microbial efficacy than monthly rifampicin. Only daily rifampicin has greater anti-microbial efficacy than daily clofazimine. In MDT, the main anti-microbial efficacy, apart from the initial dose of rifampicin, comes from the daily clofazimine. Reducing the area under the curve of drug concentration over time generally reduces the anti-microbial efficacy of each drug. Therefore duration, frequency and dosage of treatment all influence the anti-microbial efficacy of a drug. Adherence to treatment by patients affects all three, as do policies and practices of professionals. Adverse effects of drugs tend to influence adherence, and hence affect the apparent efficacy of a drug under field conditions.
Daily ofloxacin (among other effective fluoroquinolones) can match the anti-microbial effect of daily clofazimine. Therefore fluoroquinolones are one option for replacing clofazimine. Enlightened private practitioners and centres of excellence in India, Brazil and other endemic countries already use clofazimine-free combinations of potent anti-microbial drugs (eg., rifapentine + moxifloxacin + minocycline or rifampicin + moxifloxacin + minocycline, among other regimens, sometimes fortified with other effective drugs such as macrolides).
Dr. Vijayaraghavan also expressed doubts about whether HD is an infectious disease. It is true that for the vast majority of people, with good specific immunity to HD bacilli, or where sources of concentrated bacilli are very rare (e.g., most parts of Europe now), HD behaves largely as a non-infectious disease. Further, active door-to-door case-finding campaigns reveal many previously undiscovered cases, but these mostly have non-infectious types of HD shedding few or no bacilli. However, doing away with anti-microbial treatment would be dangerous, for the reasons given below.
The natural history of HD in individuals was well observed before the advent of the sulfones. Nodular lepromatous HD was seen relatively frequently.
The illustration. Untreated nodular lepromatous HD (photo by the late Dr. Colin McDougall) (see annex).
Thanks to effective anti-microbial drugs, full-blown nodular LL HD, with relentless bilateral disfiguration and repeated ENL episodes, all leading to premature mortality, is seldom seen nowadays. It seems more humane to kill HD bacilli rather than allow patients to experience the full weight of unrestrained bacillary proliferation.
Also, among high BI (bacillary index) patients the incidence rate of painful, swollen nerves of ENL was much greater following only 12 monthly doses of MDT compared to 24 monthly doses of MDT. (2) The one-year MDT group showed a 600% increase in the risk of ENL with neuritis compared to the two-year MDT group, during months 13 to 24 after the start of MDT. It seems humane to prevent the suffering of ENL episodes as far as possible, including by protecting anergic LL patients (polar LL) against reinfection. When clofazimine (300 mg/day), prednisolone and even thalidomide, methotrexate and cochine fail to control ENL, simply adding other effective anti-microbials has been known to result in dramatic improvement.(3) In patients without any empirical evidence of drug-resistance to clofazimine, the anti-microbial effect of clofazimine appears to play a central role in the control of ENL.
In endemic areas currently, LL patients who complete MDT are denied anti-microbial protection against reinfection, too frequently and for too long a delay. Such enforced anti-microbial neglect is needlessly cruel to patients. It also maintains transmission despite all other efforts. A lot of the unnecessary suffering and pain can be avoided simply by prolonging anti-microbial protection till smear negativity.
Further, mass multi-drug administration together with integrated skin camps and MDT till smear negativity demonstrably reduced the incidence rate of HD by 92% among those who received a single dose of ROM (rifampicin + ofloxacin + minocycline) compared to those who did not, (4) and the incidence rate of HD in this population declined by over 84% during two annual rounds of mass multi-drug administration.(5) This decline is swifter than the 10%/year or less reported from Norway in the pre-sulfone era, (6) or the 16% to 20%/year demonstrated using MDT till smear negativity (7, 8). Steadily shutting down sources of concentrated bacilli in hyper-endemic areas, with this highly effective approach including mass multi-drug administration, could remove the need for protection of anergic LL patients against (re)infection.
Conclusion
Clofazimine has important anti-microbial efficacy, which is likely to be as (or more) important than its anti-inflammatory effects in controlling ENL. Successful projects indicate how to use anti-microbial drug combinations to achieve rapid, major, epidemiological impact. The more carefully and thoroughly we assemble clues from the front lines into a coherent picture, the more surely and rapidly will we succeed.
Joel Almeida
References
1. Almeida, JG. A Quantitative Basis for Sustainable Anti-Mycobacterium leprae Chemotherapy in Leprosy Control Programs. Int J Lepr (1992) 60(2):255-268
2. Balagon MVF, Gelber RH, Abalos RM, Cellona RV. Reactions following completion of 1 and 2 year multidrug therapy (MDT) Am J Trop Med Hyg 2010 Sep;83(3):637-44. doi: 10.4269/ajtmh.2010.09-0586 reviewed in LML 7 Jan 2021
3. Arora P, Sardana K, Agarwal A, Lavania M. Resistance as a cause for chronic steroid dependent ENL - a novel paradigm with potential implications in management. Lepr Rev (2019) 90, 201– 205
4. Workshop on the prevention of leprosy, Pohnpei, Federated States of Micronesia. 25-27 MAY 1999 sponsored by the Sasakawa Memorial Health Foundation Tokyo, Japan and the Western Pacific Regional Office of the World Health Organization. Int J Lepr, 67(4) (SUPPLEMENT)
5. Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev. 2000;71(Suppl):S21–3.
6. Irgens LM. Leprosy in Norway. An epidemiological study based on a national patient registry. Lepr Rev, Volume 51, Supplement 1, March 1980
7. Norman G, Bhushanam JDRS, Samuel P. Trends in leprosy over 50 years in Gudiyatham Taluk, Vellore, Tamil Nadu. Ind J Lepr 2006. 78(2): 167-185. reviewed in LML 29 Oct 2020
8. Li HY, Weng XM, Li T et al. Long-Term Effect of Leprosy Control in Two Prefectures of China, 1955-1993. Int J Lepr Other Mycobact Dis. 1995 Jun;63(2):213-221. reviewed in LML 16 Nov 2019
LML - S Deepak, B Naafs, S Noto and P Schreuder
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Contact: Dr Pieter Schreuder << editorlml@gmail.com
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