Fluoroquinolones and rifampin combination in the backdrop of heteroresistant tuberculosis

The impact of heteroresistance on tuberculosis (TB) treatment outcomes is unclear, as is the role of different rifampin and isoniazid exposures on developing resistance mutations. Hollow fiber system model of TB (HFS-TB) units were inoculated with drug-susceptible ( ) and treated with isoniazid and...

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Vydané v:Antimicrobial agents and chemotherapy Ročník 69; číslo 2; s. e0108424
Hlavní autori: Vogensen, Vanessa B, Singh, Sanjay, Allende, Christopher J, Engelthaler, David M, Boorgula, Gunavanthi D, Thomas, Tania A, Sturkenboom, Marieke G G, Akkerman, Onno W, Gumbo, Tawanda, Srivastava, Shashikant
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States 13.02.2025
Predmet:
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Drug Resistance, Multiple, Bacterial - genetics
Drug Therapy, Combination
Fluoroquinolones - pharmacology
Fluoroquinolones - therapeutic use
Humans
Isoniazid - pharmacology
Isoniazid - therapeutic use
Levofloxacin - pharmacology
Microbial Sensitivity Tests
Moxifloxacin
Mutation
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - genetics
Rifampin - pharmacology
Rifampin - therapeutic use
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - microbiology
drug-resistance
fluoroquinolones
Mycobacterium tuberculosis
hollow fiber model
pharmacokinetics/pharmacodynamics
ISSN:1098-6596, 1098-6596
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Shrnutí:The impact of heteroresistance on tuberculosis (TB) treatment outcomes is unclear, as is the role of different rifampin and isoniazid exposures on developing resistance mutations. Hollow fiber system model of TB (HFS-TB) units were inoculated with drug-susceptible ( ) and treated with isoniazid and rifampin exposure identified in a clinical trial as leading to treatment failure and acquired drug resistance. Systems were sampled for drug concentration measurements, estimation of total and drug-resistant , and small molecule overlapping reads (SMOR) analysis for the detection of heteroresistance. In the second HFS-TB study, systems were inoculated with an isoniazid-resistant clinical strain and treated with various combinations of isoniazid, rifampin, moxifloxacin, and levofloxacin for 28 days. Linear regression and exponential decline models were used for data analysis. Suboptimal isoniazid and rifampin exposures failed to kill drug-susceptible in the HFS-TB. Standard susceptibility methods failed to detect drug resistance, but SMOR detected isoniazid and rifampin heteroresistance, as well as fluoroquinolone, to which bacilli were not exposed. mutations arising from low rifampin exposures were Q513K and H526N, whereas those from regimen adequate rifampin but low isoniazid concentrations were S531L. Moxifloxacin-rifampin combination sterilized the HFS-TB units inoculated with the isoniazid-resistant in 14 days compared with 21 days of treatment with levofloxacin-rifampin, with no further emergence of drug resistance. Early detection of isoniazid and rifampin heteroresistance could provide an opportunity to individualize the therapy and protect fluoroquinolones when added to the MDR-TB treatment regimen.
Bibliografia:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1098-6596
1098-6596
DOI:10.1128/aac.01084-24