Leprosy Mailing List – December 15, 2023
Ref.: (LML) Do drugs cause drug resistance?
From: Joel Almeida, Mumbai, India
Dear Pieter and colleagues,
Drug resistance can reduce the efficacy of our treatments. If left unchecked, it can in effect even return HD patients on low incomes to the pre-antimicrobial era. It seems helpful to remind ourselves of the key biological facts about drug resistance.
1. Drug resistant bacteria arise by spontaneous mutation, independent of drug treatment. (1)
That said, mutagens increase mutation. There is some evidence for sub-lethal concentrations of drug being randomly mutagenic (not specific to the drug), by way of intracellular oxidative stress. (2)
2. Spontaneous mutation occurs from drug-susceptibility to drug-resistance and vice versa.
3. The equilibrium frequency of drug-resistant mutants is given by the ratio of the respective rates of mutation to and from drug-resistance. (3)
For example, drug-resistant mutants in an untreated bacterial population will maintain a frequency of 1 in 1,000,000 if the rates of mutation to and from resistance are 1 in 10^-6 and 1 in 10^-12 respectively.
4. Monotherapy kills drug-susceptible bacteria (S) and spares drug-resistant bacteria (R).
In formal terms, by definition (where t = time)
R(t+1)/R(t) > S(t+1)/S(t)
Therefore, R(t+1)/S(t+1) > R(t)/S(t)
Monotherapy selects pre-existing drug-resistant mutants. That is an inescapable fact.
The more bactericidal the drug, the more effectively does it eliminate drug-susceptible bacteria while sparing drug-resistant mutants. Accordingly, the more rapid is the increase in frequency of drug-resistant mutants among the remaining viable bacteria. That is why the use of single drugs for prophylaxis is dangerous in proportion to the bactericidal potency of the drug used. For example, use of telacebec or rifapentine if used as single drugs for prophylaxis would be likely to select pre-existing drug-resistant mutant bacilli much more efficiently and rapidly than a less bactericidal drug.
5. The principle of anti-microbial imbalance
Even in drug combinations, if there is a wide difference in anti-microbial potency between one drug and the others, then a similar selection of bacteria resistant to the most potent drug will occur. For example, in experiments reported in my PhD thesis (Univ of London 1991) M. smegmatis exposed to a combination of streptomycin + rifampicin showed selection of streptomycin-resistant bacilli. Streptomycin has greater bactericidal potency against M. smegmatis than rifampicin. But the bactericidal effect of rifampicin+dapsone against M. smegmatis approaches that of streptomycin. Streptomycin + dapsone again selects streptomycin-resistant mutants. But Streptomycin + rifampicin + dapsone does not rapidly select streptomycin-resistant mutants. That is because the combination rifampicin+dapsone kills the bacteria as rapidly as does streptomycin alone.
In HD it is important to match the bactericidal potency of the most potent drug in a combination with the potency of the remaining drugs in the combination. With increasingly potent drugs, even a single dose can make a big impact on the frequency of mutant bacilli resistant to the most potent drug in a combination.
6. Monotherapy pre-selects mutants resistant to a single drug and therefore hastens eventual multiple-drug resistance.
Therefore multi-drug chemoprophylaxis against HD is much safer than single-drug chemoprophylaxis. This is especially true because undiagnosed highly bacillated LL patients can show only subtle signs. They easily can be misclassified as disease-free. This happens especially in the absence of smear microscopy or qPCR or other approaches to rule out "de novo" LL HD. Rifampicin on its own, when given to such an unrecognised patient, selects rifampicin-resistant mutants. The solution is to be much more rigorous in ruling out LL HD. Just a quick look for patches by relatively inexperienced and minimally trained peripheral health workers is unlikely to suffice. How to ensure that no "de novo" LL HD patient is missed forms an important topic deserving its own separate discussion.
7. Monitoring the frequency of drug-resistant bacteria over time requires prospective studies using more sensitive and precise methods than commonly used. qPCR or RT-PCR with serial dilutions of reference bacillary populations and standard curves could help detect changes in the frequency of drug-resistant bacteria among newly diagnosed LL patients over time. A lot of the selection of drug-resistant mutants happens below the surface, like rocks accumulating under water. Nobody finds out until ships start sinking.
Meanwhile, are we against replacing single-drug chemoprophylaxis with multiple-drug chemoprophylaxis, whether before or after MDT? It has been nearly 3 decades since mass multi-drug admin in hot spots (ROM, rifampicin + ofloxacin + minocycline) produced up to 40%/year decline in the incidence rate of HD. (5,6) Are we really keen to drag the people of endemic countries backwards? Are we keen to regress to single drug use, even for contacts with covert undiagnosed LL HD?
Drug-resistance is the threat that could block our path to ending HD, as suggested by experience with other diseases. (7-9) It would be good for us to swim with the tide of scientific knowledge rather than against it. Otherwise our practices unintentionally might increase HD instead of ending it.
Brazil has struck an important blow against rifampicin-resistant HD bacilli by not allowing SDR-PEP (LPEP). Endemic countries can be truly grateful to Brazil. Fiction keeps us mired in stagnation. Are we opposed to facts?
Joel Almeida
References
1. Lederberg J, Lederberg EM. REPLICA PLATING AND INDIRECT SELECTION OF BACTERIAL MUTANTS J Bacteriol. 1952 Mar; 63(3): 399–406.
2. Kohanski MA, DePristo MA, Collins JJ (2010) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37: 311–320
3. Elseth, G. D. and Baumgardner, K. D. Population Biology. New York: van Nostrand, 1981.
4. Almeida, JG. A Quantitative Basis for Sustainable Anti-Mycobacterium leprae Chemotherapy in Leprosy Control Programs. Int J Lepr (1992) 60(2):255-268.
5. 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)
6. Diletto C, Blanc L, Levy L. Leprosy chemoprophylaxis in Micronesia. Lepr Rev. 2000;71(Suppl):S21–3.
7. Colijn C, Cohen T, Ganesh A, Murray M (2011) Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during Therapy. PLoS ONE 6(3): e18327. https://doi.org/10.1371/journal.pone.0018327
8. Zuber JA, Takala-Harrison S Multidrug-resistant malaria and the impact of mass drug administration Infect Drug Resist. (2018) Mar 1;11:299-306. doi: 10.2147/IDR.S123887. eCollection 2018.
9. Rijnders B, Rokx C, Antiretroviral Monotherapy for HIV: Game Over or Future Perspectives?, Clinical Infectious Diseases, Volume 69, Issue 9, 1 November 2019, Pages 1506–1508, https://doi.org/10.1093/cid/ciy1136
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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