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What Is Resistance? Impact of Phenotypic versus Molecular Drug Resistance Testing on Therapy for Multi-and Extensively Drug-Resistant Tuberculosis
Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany; Univ Lubeck, Germany.
Res Ctr Borstel, Germany.
Univ Cambridge, England.
Res Ctr Borstel, Germany; German Ctr Infect Res DZIF, Germany.
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2018 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 2, article id e01550-17Article in journal (Refereed) Published
Abstract [en]

Rapid and accurate drug susceptibility testing (DST) is essential for the treatment of multi-and extensively drug-resistant tuberculosis (M/XDR-TB). We compared the utility of genotypic DST assays with phenotypic DST (pDST) using Bactec 960 MGIT or Lowenstein-Jensen to construct M/XDR-TB treatment regimens for a cohort of 25 consecutive M/XDR-TB patients and 15 possible anti-TB drugs. Genotypic DST results from Cepheid GeneXpert MTB/RIF (Xpert) and line probe assays (LPAs; Hain GenoType MTBDRplus 2.0 and MTBDRsl 2.0) and whole-genome sequencing (WGS) were translated into individual algorithmderived treatment regimens for each patient. We further analyzed if discrepancies between the various methods were due to flaws in the genotypic or phenotypic test using MIC results. Compared with pDST, the average agreement in the number of drugs prescribed in genotypic regimens ranged from just 49% (95% confidence interval [ CI], 39 to 59%) for Xpert and 63% (95% CI, 56 to 70%) for LPAs to 93% (95% CI, 88 to 98%) for WGS. Only the WGS regimens did not contain any drugs to which pDST showed resistance. Importantly, MIC testing revealed that pDST likely underestimated the true rate of resistance for key drugs (rifampin, levofloxacin, moxifloxacin, and kanamycin) because critical concentrations (CCs) were too high. WGS can be used to rule in resistance even in M/XDR strains with complex resistance patterns, but pDST for some drugs is still needed to confirm susceptibility and construct the final regimens. Some CCs for pDST need to be reexamined to avoid systematic false-susceptible results in low-level resistant isolates.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY , 2018. Vol. 62, no 2, article id e01550-17
Keywords [en]
Mycobacterium tuberculosis; antibiotic resistance; molecular genetics
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:liu:diva-145246DOI: 10.1128/AAC.01550-17ISI: 000423443600009PubMedID: 29133554OAI: oai:DiVA.org:liu-145246DiVA, id: diva2:1188338
Note

Funding Agencies|German Ministry of Education and Research (BMBF) for German Center of Infection Research (DZIF); Health Innovation Challenge Fund [HICF-T5-342, WT098600]; UK Department of Health; Wellcome Trust; European Society of Mycobacteriology; Hain Lifescience; Pacific Biosciences Inc.; Illumina Inc.

Available from: 2018-03-07 Created: 2018-03-07 Last updated: 2018-04-13

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