Therapeutic drug monitoring–guided treatment of XDR TB with an RpoB I491F mutation - a case report

Sep 29, 2026

XDR TB requires individualized regimens, and WHO recommends at least 18 months, yet emerging strains with the RpoB I491F mutation may be missed by routine rapid diagnostics. A female patient from Ukraine presented with cough and fever in Germany after prior TB therapy; molecular testing detected Mtb but not rifampicin resistance. Phenotypic testing showed borderline rifampicin resistance and multidrug resistance, while targeted Deeplex Myc-TB sequencing confirmed RpoB I491F. Treatment in Cologne combined terizidone, amikacin, meropenem/clavulanate, and pretomanid, with subsequent clinical and radiological improvement described.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages4

Reading Time10 min

AccessFree to download

Background

WHO guidance and diagnostic challenge

Case Presentation

Prior TB treatment and initial testing

Laboratory Findings

Phenotypic resistance and genomic confirmation

Treatment and Course

Regimen selection and outcomes

JAC Antimicrob Resist [https://doi.org/10.1093/jacamr/dlaf251](https://doi.org/10.1093/jacamr/dlaf251) JACAntimicrobial Resistance Therapeutic drug monitoring–guided treatment of XDR TB with an RpoB I491F mutation—a case report Angela Klingmüller1†, Sylvia Zuber1†, Ada M. Hoffmann2, Niklas Köhler3,4,5,6, Isabelle Suárez1, Tim Preßel7, Stefan Niemann4,8,9, Viola Dreyer 4,8, Laurent A. Decosterd10, Eva Choong10, Beatrice Schütz11, Inna Friesen9† and Jan Rybniker1,12,13*† 1Department I of Internal Medicine, Division of Infectious Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; 2Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Medical Faculty and University Hospital of Cologne, Cologne, Germany; 3Clinical Infectious Diseases, Research Center Borstel, Leibniz Lung Center, Borstel, Germany; 4German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Borstel, Germany; 5Center for Clinical Studies, Research Center Borstel, Leibniz Lung Center, Borstel, Germany; 6Institute for Infection Research and Vaccine Development (IIRVD), Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 7Eurofins MVZ Medizinisches Labor Gelsenkirchen GmbH, Eurofins GeLaMed, Gelsenkirchen, Germany; 8Research Center Borstel, Leibniz Lung Center, Molecular and Experimental Mycobacteriology, Borstel, Germany; 9Research Center Borstel, Leibniz Lung Center, Supranational and National Reference Center for Mycobacteria, Borstel, Germany; 10Department of Laboratory Medicine and Pathology, Laboratory of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; 11Klinikum Dorsten, St Elisabeth-Krankenhaus, Dorsten, Germany; 12German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany; 13Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany *Corresponding author. E-mail: [jan.rybniker@uk-koeln.de](jan.rybniker@uk-koeln.de) †These authors contributed equally to this work. XDR TB is characterized by resistance to isoniazid and rifampicin, alongside resistance to at least one fluoroquinolone and one additional WHO group A drug, such as bedaquiline or linezolid.1 Individualized XDR TB treatment regimens with a minimum duration of 18 months are recommended by the WHO.1 A recent concern is the emergence of XDR M. tuberculosis (Mtb) strains with a particular RpoB mutation, I491F, that is not detected by routine molecular WHO-recommended rapid diagnostics. Mtb strains with the RpoB I491F mutation are highly dominant in Eswatini and have been reported in several other countries.2–5 According to the WHO catalogue, the I491F mutation is classified as conferring borderline resistance to rifampicin in phenotypic drug susceptibility testing.6 In October 2023, a female patient from Ukraine presented with symptoms of cough and fever to a German hospital. The patient had previously been treated for pulmonary TB in Ukraine in 2015 with a four-drug regimen for 2 months; however, due to nausea, rifampicin was discontinued, and treatment was continued with isoniazid, ethambutol and pyrazinamide for an additional 4 months. In 2023, sampling of sputum and bronchoalveolar lavage fluid revealed acid-fast bacilli. The Xpert® MTB/RIF Ultra (Cepheid) test yielded positive results for Mtb, but negative results for rifampicin resistance, prompting the initiation of standard four-drug treatment in a German secondary level hospital. However, phenotypic resistance testing of the culture revealed borderline rifampicin resistance with an MIC at the critical concentration (CC) of 0.5 mg/L, along with resistance to isoniazid, pyrazinamide and ethambutol. Subsequent genomic and phenotypic analyses identified resistance to fluoroquinolones, bedaquiline, linezolid and clofazimine. Targeted sequencing using the Deeplex® Myc-T

FAQs

Why was rifampicin resistance initially not detected in the case?

The Xpert MTB/RIF Ultra test was positive for Mtb but negative for rifampicin resistance. Phenotypic testing later revealed borderline rifampicin resistance at the critical concentration.

How was the RpoB I491F mutation identified?

Targeted sequencing using the Deeplex Myc-TB assay detected an I491F mutation in RpoB, after phenotypic and genomic analyses indicated resistance patterns.

What treatment regimen was started in December 2023 and how was it chosen?

The regimen included terizidone, amikacin, meropenem with clavulanic acid, and pretomanid. Pretomanid was favored over delamanid based on recently published evidence supporting pretomanid efficacy in relevant regimens.

Sep 29, 2026

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