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

Solomon H Mariam,Joakim Aronsson,Sven Hoffner,Dan I Andersson,Jim Werngren,Sebastien Gagneux

doi:10.1371/journal.pone.0021147

Solomon H Mariam, Joakim Aronsson + Show 4 more

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https://doi.org/10.1371/journal.pone.0021147

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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.

Highlights

In 2009, tuberculosis disease (TB) due to Mycobacterium tuberculosis infections caused an estimated 1.3 million deaths globally [1]
To address the extent of heterogeneity and dynamics in antibiotic resistant variants during a monoclonal infection in a host, we examined serial M. tuberculosis Beijing isolates obtained from one patient during a 9-year period of infection and disease where the successive accumulation of resistance mutations made the infection untreatable and caused death of the patient
The third through seventh isolates were resistant to isoniazid, rifampicin and streptomycin and this triple resistance developed within about six months (Table 1)

Summary

Introduction

In 2009, tuberculosis disease (TB) due to Mycobacterium tuberculosis infections caused an estimated 1.3 million deaths globally [1]. The risk of resistance development will be determined by a number of different factors, including the antibiotic selective pressure (set by the number, dosing and quality of the used drugs), any pre-existing resistances in the infecting clone, the immune status of the treated individuals and their compliance with the drug regime [2,3,4]. The primary drugs used in treatment of M. tuberculosis infections are isoniazid and rifampicin and resistance to these drugs may be caused by mutations in a number of genes, including inhA, katG, and ndh, (isoniazid) and rpoB (rifampicin) [8,9,10,11]. Other primary drugs used include ethambutol, pyrazinamide and streptomycin where mutations in the embB (ethambutol), pncA (pyrazinamide) and rpsL/rrs (streptomycin) genes confer resistance [12,13,14]. Examples of second-line drugs include aminoglycosides, polypeptides, fluoroquinolones, thioamides, cycloserine and p-aminosalicylic acid [15]

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