Dynamics of Antibiotic Resistant Mycobacterium tuberculosis during Long-Term Infection and Antibiotic Treatment

Abstract

For an infecting bacterium the human body provides several potential ecological niches with both internally (e.g. host immunity) and externally (e.g. antibiotic use) imposed growth restrictions that are expected to drive adaptive evolution in the bacterium, including the development of antibiotic resistance. To determine the extent and pattern of heterogeneity generated in a bacterial population during long-term antibiotic treatment, we examined in a monoclonal Mycobacterium tuberculosis infection antibiotic resistant mutants isolated from one patient during a 9-years period. There was a progressive accumulation of resistance mutations in the infecting clone. Furthermore, apparent clonal sweeps as well as co-existence of different resistant mutants were observed during this time, demonstrating that during treatment there is a high degree of dynamics in the bacterial population. These findings have important implications for diagnostics and treatment of drug resistant tuberculosis infections.

Pre-Existing Isoniazid Resistance, but Not the Genotype of Mycobacterium Tuberculosis Drives Rifampicin Resistance Codon Preference in Vitro

“…This homogeneity for INH and RIF resistance conferring mutations in sequential isolates from a single patient was corroborated by others [45]. These reports imply that the selection pressure exerted by antibiotic usage can significantly reduce the spectrum of viable mutants and evolutionary pathways are probably restricted as a result [21], [46].…”

Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007–2009

“…Finally, patients with a previous history of TB may be more likely to have minority subpopulations of mycobacteria with additional resistance to other first-line agents (i.e., heteroresistance or polyclonal infection). 19,20 This would be difficult to detect in a single clinical sample, but could contribute to a poorer treatment response and eventually be picked up as apparent ‘acquisition’ of MDR-TB. All of these possibilities merit further evaluation.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…Several studies in individual patients who have developed progressive drug resistance over time have documented the initial acquisition of isoniazid resistance as a result of one or more mutations, followed by acquisition of resistance to rifampicin or ethambutol (or both), pyrazinamide, and finally, the second-line and third-line drugs. [15][16][17] The order in which resistance is acquired might reflect the number of different mutations that lead to resistance to a specific drug, 14 the relative fitness costs associated with specific mutations (ie, mutations might lead to less successful survival and reproduction of the organism), 18 or phenotypic changes following an initial drug-resistance mutation that might facilitate the acquisition of further mutations. 19 When resistance to one or more drugs is acquired in this way, it is referred to as secondary resistance.…”