Leprosy Mailing List – November 26, 2019
Ref.: (LML) Key biological facts about drug-resistant bacteria
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
It seems helpful to remind ourselves of the key biological facts about drug resistant bacteria. Drug-resistance is a threat that can block our path to ending Hansen's Disease (HD), and could even increase HD. The study from Rosa et al (Brazil) demonstrated how real and near that threat is.
1. Drug resistant bacteria arise by spontaneous mutation, independent of drug treatment.
That said, mutagens tend to increase mutation. There is some evidence for stressors such as sub-lethal concentrations of drug being randomly mutagenic (not specific to the drug), by way of intracellular oxidative stress.
Spontaneous mutation occurs from drug-susceptibility to drug-resistance and vice versa.
2. The equilibrium frequency of drug-resistant mutants is given by the ratio of the respective rates of mutation to and from drug-resistance when the replication rate of each sub-population is equal.
For example, drug-resistant mutants in an untreated bacterial population will maintain a frequency of 1 in 1000 if the rates of mutation to and from resistance are 1 in 10^-12 and 1 in 10^-9 respectively.
When replication rates are unequal, it is necessary to apply an appropriate fraction to obtain the equilibrium frequency.
3. 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 drug-resistant mutants. That is an inescapable fact.
The more bactericidal the drug, the more effectively and rapidly it increases the frequency of drug-resistant mutants.
4. Monotherapy selects mutants resistant to a single drug and therefore hastens eventual multiple-drug resistance.
Therefore, MDT is preferable to monotherapy and multi-drug chemoprophylaxis against HD is much safer than single-drug chemoprophylaxis. This is especially true because LL patients with subtle signs can easily be mistaken for disease-free contacts.
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. It is better to end HD.
Joel Almeida
Further reading
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
Benjak A, Avanzi C, Singh P et al. Phylogenomics and antimicrobial resistance of the leprosy bacillus Mycobacterium leprae. Nature Communications volume 9, Article number: 352 (2018)
Lederberg J, Lederberg EM. Replica plating and indirect selection of bacterial mutants J Bacteriol. 1952 Mar; 63(3): 399–406
Elseth, G. D. and Baumgardner, K. D. Population Biology. New York: van Nostrand, 1981.
Martinez JL, Baquero F. Mutation Frequencies and Antibiotic Resistance.
Antimicrobial Agents and Chemotherapy Jul 2000, 44 (7) 1771-1777; DOI: 10.1128/AAC.44.7.1771-1777.2000
Almeida, JG. A Quantitative Basis for Sustainable Anti-Mycobacterium leprae Chemotherapy in Leprosy Control Programs. Int J Lepr (1992) 60(2):255-268.
Kohanski MA, DePristo MA, Collins JJ (2010) Sublethal antibiotic treatment leads to multidrug resistance via radical-induced mutagenesis. Mol Cell 37: 311–320
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
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.
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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