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 Table of Contents  
Year : 2016  |  Volume : 5  |  Issue : 5  |  Page : 64-65

Pathogenesis of multi drug-resistant and extensively drug-resistant tuberculosis as a determinant of future treatment success

Biomedical Informatics Research Center, Laboratory for Pathogenesis of Clinical Drug Resistance and Persistence, Alvarado Medical Center, San Diego State University, San Diego, CA, USA

Date of Web Publication17-Feb-2017

Correspondence Address:
Faramarz Valafar
6367 Alvarado Court, Suite 206, San Diego, CA 92120
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.ijmyco.2016.11.017

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Keywords: Drug resistance, Extensively drug-resistant, Multidrug-resistant, Pathogenesis, Treatment, Tuberculosis

How to cite this article:
Valafar F. Pathogenesis of multi drug-resistant and extensively drug-resistant tuberculosis as a determinant of future treatment success. Int J Mycobacteriol 2016;5, Suppl S1:64-5

How to cite this URL:
Valafar F. Pathogenesis of multi drug-resistant and extensively drug-resistant tuberculosis as a determinant of future treatment success. Int J Mycobacteriol [serial online] 2016 [cited 2020 Sep 26];5, Suppl S1:64-5. Available from: http://www.ijmyco.org/text.asp?2016/5/5/64/200489

  Introduction Top

Multidrug-resistant (MDR)/extensively drug-resistant (XDR) tuberculosis (TB) is a significant threat to global TB control [1]. In most cases, treatment of MDR/XDR TB is not standardized, and clinicians have adopted a variety of treatment strategies. These strategies include switching to a regimen of new drugs, increasing the dosage of the same drugs, rarely used drugs (which have widespread resistance), etc. Drug resistance is a manmade phenomenon that is driven by treatment strategy (i.e., regimen). These divergent approaches may differentially drive the evolution of bacteria. Some instances of this evolution have already occurred [2]. The community's focus has been on drug resistance; therefore, the consequence of this divergence is usually by different mechanisms of resistance [2],[3]. However, the full scope of the consequential microevolution frequently goes unnoticed because it also affects important factors such as fitness and virulence. In this study, we aimed to develop a comprehensive understanding of the consequences of differential TB treatment to build more accurate prognostics for future treatments.

  Methods Top

We studied 385 (mostly XDR) clinical Mycobacterium tuberculosis isolates from five countries: India, the Philippines, Moldova, South Africa, and Sweden. Whole genome sequencing was performed on Pacific Biosciences (1380 Willow Road, Menlo Pak, CA 94025, USA) RS I and II platforms. Drug susceptibility testing for eight first- and second-line drugs was performed on mycobacteria growth indicator tubes (MGIT) (MGIT960; Bactec, Becton, Dickinson and Company, 1 Becton Drive, Franklin Lakes, New Jersey 07417-1880, USA) for all isolates. Each isolate's mechanisms of resistance to each drug was identified and mapped to the geographic origin of the isolate. Genome-wide phylogenomics was used for ancestral reconstruction. Clonality was studied to identify outbreaks and used as a proxy for measuring virulence. Growth curves in MGIT were also studied for the estimation of fitness.

  Results Top

Some mechanisms of resistance seem to be region-specific. Several clonal expansions were identified among the MDR and XDR isolates from India and South Africa. Growth curve analysis identified two distinct processes. The first process has a lower growth rate and subsides after a few days, but it predominantly drives the growth in the initial days. The second process has a distinctly higher growth rate and begins a few days later (or has an immeasurable growth rate in the first few days) and drives all or most of the growth after the first few days of incubation. We observed isolates that seemed to start their second phase very late or not at all.

  Discussion Top

Specificity of a mechanism of resistance to a region is a great concern and a phenomenon that is not well understood. However, it is a clear indication of the multiplicity of an evolutionary path to a phenotypic resistance state. The evolutionary past is a determinant of the evolutionary trajectory; therefore, the concern is that bacteria will continue to evolve differentially in different regions of the world and hence will require different treatment strategies. In such a scenario, a standard global treatment of TB will have to be abandoned. The missing (or delayed) secondary growth process is also of grave concern because it allows the bacterium to escape growth-based phenotypic detection. This is the World Health Organization's recommendation, and most prevalent method, for determining resistance; therefore, this escape undoubtedly is a path to achieving an MDR/XDR state and undermines global TB control. Such resistant isolates would be labeled as “susceptible” and standard treatment would continue, and thereby provide time for the development of additional resistance. The clonal expansion of MDR/XDR bacteria clearly dispels the notion that highly resistant isolates are less fit or virulent. This factor may be true for some bacteria; however, we also found much contradicting evidence. This finding indicates differential microevolution and results in differential fitness and virulence.

  Conflicts of interest Top

The authors have no conflicts of interest to declare.

  Acknowledgments Top

This work was funded by a grant from the National Institute of Allergy and Infection Diseases (NIAID; grant no. R01AI105185).

  References Top

World Health Organization (WHO), Global Tuberculosis Report 2015, WHO, Geneva, Switzerland, 2015.  Back to cited text no. 1
N. Casali, V. Nikolayevskyy, Y. Balabanova, et al, Microevolution of extensively drug-resistant tuberculosis in Russia, Genome Res. 22 (2012) 735–745.  Back to cited text no. 2
J.N. Torres, L.V. Paul, T.C. Rodwell, et al, Novel katG mutations causing isoniazid resistance in clinical M. tuberculosis isolates, Emerg. Microbes Infect. 4 (2015). e42–e42.  Back to cited text no. 3

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