Rifampicin tolerance and growth fitness among isoniazid-resistant clinical Mycobacterium tuberculosis isolates from a longitudinal study.

Vijay S., Bao NLH., Vinh DN., Nhat LTH., Thu DDA., Quang NL., Trieu LPT., Nhung HN., Ha VTN., Thai PVK., Ha DTM., Lan NH., Caws M., Thwaites GE., Javid B., Thuong NT.

Antibiotic tolerance in Mycobacterium tuberculosis reduces bacterial killing, worsens treatment outcomes, and contributes to resistance. We studied rifampicin tolerance in isolates with or without isoniazid resistance (IR). Using a minimum duration of killing assay, we measured rifampicin survival in isoniazid-susceptible (IS, n=119) and resistant (IR, n=84) isolates, correlating tolerance with bacterial growth, rifampicin minimum inhibitory concentrations (MICs), and isoniazid-resistant mutations. Longitudinal IR isolates were analyzed for changes in rifampicin tolerance and genetic variant emergence. The median time for rifampicin to reduce the bacterial population by 90% (MDK90) increased from 1.23 days (IS) and 1.31 days (IR) to 2.55 days (IS) and 1.98 days (IR) over 15-60 days of incubation, indicating fast and slow-growing tolerant sub-populations. A 6 log10-fold survival fraction classified tolerance as low, medium, or high, showing that IR is linked to increased tolerance and faster growth (OR = 2.68 for low vs. medium, OR = 4.42 for low vs. high, p-trend = 0.0003). High tolerance in IR isolates was associated with rifampicin treatment in patients and genetic microvariants. These findings suggest that IR tuberculosis should be assessed for high rifampicin tolerance to optimize treatment and prevent the development of multi-drug-resistant tuberculosis.

DOI

10.7554/elife.93243

Type

Journal article

Journal

eLife

Publication Date

09/2024

Volume

13

Addresses

Oxford University Clinical Research Unit, Ho Chi Minh, Viet Nam.

Keywords

Humans, Mycobacterium tuberculosis, Tuberculosis, Tuberculosis, Multidrug-Resistant, Isoniazid, Rifampin, Antitubercular Agents, Microbial Sensitivity Tests, Longitudinal Studies, Drug Resistance, Bacterial

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