Leprosy Mailing List – May 7, 2021
Ref.: (LML) Rifampicin-resistant mutant bacilli are accumulating rapidly
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
A recent report from an Indian centre reveals that rifampicin-resistant mutant HD (leprosy) bacilli are accumulating rapidly. In 2017, rifampicin-resistant bacilli were detected in only 2% of patients with signs of recurrence, in that area. By 2020, this figure had risen to 12.3%.(1) Further, 5% of previously untreated patients in that area were demonstrated to have rifampicin-resistant mutants.(2) Interestingly, patients with rifampicin-resistant recurrence and new patients with rifampicin-resistant mutant bacilli were observed to live in close geographical proximity. This is consistent with transmission of rifampicin-resistant bacilli.
Previously, a Brazilian total-population survey of a hyperendemic area showed that over 40% of patients with signs of recurrent disease had mutant bacilli simultaneously resistant to rifampicin and dapsone.(3) Therefore precautions against drug-resistance seem wise:
a) Use multiple drug combinations always, instead of single drugs (e.g., avoid SDR PEP)
b) ensure that MDT in LL patients is prolonged sufficiently for all drug-resistant mutant bacilli to be killed.
The astronomical number of bacilli in untreated LL patients, as high as 10 billion bacilli per gram of tissue,(4) greatly exceeds that in nearly all other mycobacterial diseases. Further, LL patients tend to show only subtle signs of disease. Most peripheral health workers tend to mistake such "covert" LL cases for HD-free persons. Yet nasal smears or skin smears show densely packed acid-fast bacilli with astronomical numbers of bacilli. Giving such "covert" LL cases a single drug inevitably favours drug-resistant mutant bacilli. This hastens hard-to-treat drug resistant HD.
Further, clofazimine-resistance currently is likely to be under-reported. That is because we have discontinued tests that can detect bacilli with drug-resistant phenotypes. However, clinicians in endemic countries encounter patients who do not respond to MDT, and patients have been known to remain unresponsive to even 300mg of clofazimine given daily.(5) They still responded well to other anti-microbial drugs, suggesting that clofazimine-resistant bacilli were responsible for the clinical non-response. Testing for phenotypically drug-resistant HD bacilli seems useful, because bacilli with recognised drug-resistant genotypes form only a subset of bacilli with drug-resistant phenotypes. We still have a lot to learn about whole-genome and epigenetic control of phenotypic drug resistance in HD bacilli.
Drug resistance is like falling off a cliff - easy to do, difficult to reverse. We aim for the mountaintop of zero HD transmission. However, we are walking beside the cliff edge of drug resistance. It is easy to push endemic countries over that cliff edge by using single drugs (e.g., SDR PEP).
Solutions
Given that single drug use is a problem, what is the solution? Multiple drug use, consistently. Multiple drugs not only kill HD bacilli more surely and rapidly, but also they delay the selection of drug-resistant mutant bacilli. This is true in even LL patients. Multiple drugs to replace single drugs is a settled principle of anti-microbial use, in order to delay the selection of drug-resistant mutants.
MDT uses a combination of drugs. The Schieffelin Centre, Karigiri, located in a low income area of India, demonstrated a 16%/year decline and achieved near-zero incidence rate, of new LL patients, using MDT until smear negativity.(6) Only when Karigiri switched to fixed duration MDT (24 months or 12 months), for even LL patients, did the annual incidence rate of new LL cases start showing an increase.
Likewise, the world's most effective intervention for hyperendemic hot spots used multiple drugs, not single drugs. The Sasakawa Health Foundation/WHO intervention in hyperendemic zones of FS Micronesia achieved 84% decline of new cases in only 2 years by using a combination of drugs for mass administration to adults. Rifampicin + ofloxacin + minocycline proved highly effective there. (7, 8) Therefore, it is not necessary or desirable to use or promote single drug use (SDR PEP) in endemic countries. Multiple drugs can be used instead, invariably.
It seems important also to repurpose a wider range of anti-microbials against HD bacilli. This means measuring the effect of a wider range of drugs against HD bacilli in animals or other models, with some urgency. Isoniazid demonstrably has bacteriostatic effect against HD bacilli, (9) contrary to some mistaken recent claims, (10) and it formed a part of the successful multi-drug combination that virtually eradicated HD from Malta. (11) There are more effective drugs. Thioamides, fluoroquinolones, macrolides, tetracyclines, aminoglycosides are among the drug classes that have shown activity against HD bacilli. The comparison of minimal inhibitory concentration in the laboratory with maximum tolerated concentrations in patients, plus due attention to drug toxicity and adverse effects, will allow us to use promising drugs intelligently.
Conclusions
Rifampicin resistance is accumulating rapidly, in endemic countries such as India and Brazil. Multi-drugs work, and they delay drug-resistance. This is true for treatment as well as prophylaxis. We could use multi-drugs consistently instead of single drugs, whether for treatment or prophylaxis. Drug resistance is like falling off a cliff - easy to do, difficult to reverse. We could unite to beat drug resistance, so that HD remains easily treatable. Otherwise MDT, the backbone of our HD control efforts, could lose its effectiveness.
Joel Almeida
References
1. Singh I, Lavania M, Ahuja M et al. A FOUR-YEAR RETROSPECTIVE STUDY SHOWS INCREASING RATES OF ANTIMICROBIAL DRUG RESISTANCE IN ENDEMIC REGION IN INDIA FOR M. LEPRAE. Abstracts of the 31st biennial conference of the Indian Association of Leprologists, Hyderabad, India. April 2021. pp. 96-97
2. Ahuja M, Lavania M, Sharma R et al. MOLECULAR SCREENING OF NEWLY DIAGNOSED LEPROSY CASES FOR DRUG RESISTANCE IN M.LEPRAE. Abstracts of the 31st biennial conference of the Indian Association of Leprologists, Hyderabad, India. April 2021. p. 97
3. Rosa PS, D'Espindula HRS, Melo ACL et al. Emergence and transmission of drug/multidrug-resistant Mycobacterium leprae in a former leprosy colony in the Brazilian Amazon. Clinical Infectious Diseases. 1 July 2019, ciz570, https://doi.org/10.1093/cid/ciz570
4. Hastings RC, Gillis TP, Krahenbuhl JL, Franzblau SG. Leprosy Clin Microbiol Rev 1988 Jul;1(3):330-48. doi: 10.1128/cmr.1.3.330.
5. 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
6. 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 October 2020
7. 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)
8. Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev. 2000;71(Suppl):S21–3
9. Shepard CC. A Survey of the Drugs with Activity Against M.leprae in Mice. Int J Lepr 1971. 39(2): 340-8.
10. Richardus JH, Mieras L, Saunderson P et al. Leprosy post-exposure prophylaxis risks not adequately assessed – Author's reply. CORRESPONDENCE| Lancet Global Health VOLUME 9, ISSUE 4, E402-E403, APRIL 01, 2021.
11. Freerksen E, Rosenfeld M, Depasquale G.The Malta Project--a country freed itself of leprosy. A 27-year progress study (1972-1999) of the first successful eradication of leprosy. Chemotherapy Sep-Oct 2001;47(5):309-31. doi: 10.1159/000048539
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