Julián González-Martín

Hospital Clínic de Barcelona

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Griselda Tudó

Universitat de Barcelona

Alexandre López-Gavín

Hospital Clínic de Barcelona

Pere Coll

Belarusian State Medical University

Elena Portell-Buj

Universitat de Barcelona

Emma Rey-Jurado

Clínica Alemana

Alfredo Adán

Hospital Clínic de Barcelona

Fernando Alcaide

Universitat de Barcelona

Blanca Molins

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Montserrat Español

Hospital de Sant Pau

Mateu Espasa

Hospital Clínic de Barcelona

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Universitat de Barcelona

Hospital Clínic de Barcelona

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Instituto de Salud Carlos III

Centro de Investigación Biomédica en Red

Universitat Autònoma de Barcelona

Fundació Clínic per a la Recerca Biomèdica

Barcelona Institute for Global Health

Departament de Salut

Hospital General Universitario Gregorio Marañón

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How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Kamela C. S. Ng Philip Supply Frank Cobelens Cyril Gaudin Julián González-Martín

ABSTRACT Rifampicin heteroresistance – where rifampicin-resistant and -susceptible tuberculosis (TB) bacilli co-exist – may result in failed standard TB treatment and potential spread of rifampicin-resistant strains. Detection of rifampicin heteroresistance in routine rapid diagnostic tests (RDTs) allows for patients to receive prompt and effective multidrug-resistant-TB treatment, and may improve rifampicin-resistant TB control. The limit of detection (LOD) of rifampicin heteroresistance for phenotypic drug susceptibility testing by the proportion method is 1%, yet is insufficiently documented for RDTs. We therefore aimed to determine, for the four RDTs (XpertMTB/RIF, XpertMTB/RIF Ultra, GenoTypeMTBDR plus v2.0, and GenoscholarNTM+MDRTBII), the LOD per probe and mutation, validated by colony-forming-unit-counting and targeted deep sequencing (Deeplex-MycTB). We selected one rifampicin-susceptible and four rifampicin-resistant strains, with mutation D435V, H445D, H445Y, and S450L respectively, mixed them in various proportions in triplicate, tested them with each RDT, and determined the LODs per mutation type. Deeplex-MycTB revealed concordant proportions of the minority resistant variants in the mixtures. The Deeplex-MycTB-validated-LODs ranged from 20-80% for XpertMTB/RIF, 20-70% for Xpert Ultra, 5-10% for GenoTypeMTBDR plus v2.0, and 1-10% for GenoscholarNTM+MTBII for the different mutations. Deeplex-MycTB, GenoTypeMTBDR plus v2.0, and GenoscholarNTM+MDRTBII, provide explicit information on rifampicin heteroresistance for the most frequently detected mutations. Classic Xpert and Ultra report rifampicin heteroresistance as rifampicin resistance, while Ultra may denote rifampicin heteroresistance through ‘mixed patterns’ of wild-type and mutant melt probe melt peak temperatures. Overall, our findings inform end-users that the threshold for reporting resistance in case of rifampicin heteroresistance is the highest for Classic Xpert and Ultra, to resolve phenotypic and genotypic discordant rifampicin-resistant TB results.

10.1101/632851

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Citations (1)

A novel strategy based on genomics and specific PCR reveals how a multidrug-resistant Mycobacterium tuberculosis strain became prevalent in Equatorial Guinea 15 years after its emergence

Clinical Microbiology and Infection (2016)

Laura Pérez‐Lago Santiago Izco M. Herranz Griselda Tudó María Carcelén

GeneXpert MTB/RIF

Strain (injury)

Molecular Epidemiology

10.1016/j.cmi.2016.10.006

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Citations (11)

In Vitro Biofilm Formation in Mycobacterium avium-intracellulare Complex

Archivos de Bronconeumología (2021)

Elena Portell-Buj Alexandre López-Gavín Julián González-Martín Griselda Tudó

Mycobacterium avium complex

Mycobacterium avium-intracellulare infection

10.1016/j.arbr.2020.07.019

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Citations (1)

Comparison of four-colour IS6110-fAFLP with the classic IS6110-RFLP on the ability to detect recent transmission in the city of Barcelona, Spain

Tuberculosis (2009)

Sònia Borrell Nicola Thorne Montserrat Español Chloe Mortimer Àngels Orcau

Molecular Epidemiology

10.1016/j.tube.2009.03.003

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Citations (3)

In vitro activity of 12 antimicrobial peptides against Mycobacterium tuberculosis and Mycobacterium avium clinical isolates

Journal of Medical Microbiology (2018)

Elena Portell-Buj Andrea Vergara Izaskun Alejo-Cancho Alexandre López-Gavín Maria Rosa Monté

Tuberculosis (TB) remains a major threat to human health worldwide. The increasing incidence of non-tuberculous mycobacterial infections and particularly those produced by Mycobacterium avium has emphasized the need to develop new drugs. Additionally, high levels of natural drug resistance in non-tuberculous mycobacteria (NTM) and the emergence of multidrug-resistant (MDR) TB is of great concern. Antimicrobial peptides (AMPs) are antibiotics with broad-spectrum antimicrobial activity. The objective was to assess the activity of AMPs against Mycobacterium tuberculosis and M. avium clinical isolates. MICs were determined using microtitre plates and the resazurin assay. Mastoparan and melittin showed the greatest activity against M. tuberculosis, while indolicidin had the lowest MIC against M. avium. In conclusion, AMPs could be alternatives for the treatment of mycobacterial infections. Further investigation of AMPs' activity in combination and associated with conventional antibiotics and their loading into drug-delivery systems could lead to their use in clinical practice.

Mycobacterium avium complex

10.1099/jmm.0.000912

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Citations (28)

In vitro activity against Mycobacterium tuberculosis of levofloxacin, moxifloxacin and UB-8902 in combination with clofazimine and pretomanid

International Journal of Antimicrobial Agents (2015)

Alexandre López-Gavín Griselda Tudó Andrea Vergara Juan Carlos Hurtado Julián González-Martín

Clofazimine

Bedaquiline

10.1016/j.ijantimicag.2015.08.004

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Citations (16)

Patterns of resistance of Mycobacterium tuberculosis in Spanish patients infected with human immunodeficiency virus type 1 (HIV-1)

Clinical Microbiology and Infection (1995)

Ana Guelar Julián González-Martín José M. Gatell Carlos Garcia-Tejero José Mallolas

Pyrazinamide

10.1111/j.1469-0691.1995.tb00453.x

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Citations (3)

Comparison of two-drug combinations, amikacin/tigecycline/imipenem and amikacin/tigecycline/clarithromycin against Mycobacteroides abscessus subsp. abscessus using the in vitro time-kill assay

The Journal of Antibiotics (2021)

Elena Portell-Buj Queralt Bonet-Rossinyol Alexandre López-Gavín Angely Román Mariana Fernández-Pittol

Nontuberculous mycobacteria include 198 mycobacterial species. Among these, Mycobacteroides abscessus is a rapidly growing mycobacteria that causes lung and skin infections. M. abscessus lung infections are difficult to treat due to the high levels of resistance to several classes of antibiotics. The current treatment is based on combining at least two or three antibiotics. However, treatment outcomes remain very poor. The objective was to compare the in vitro activity of amikacin, tigecycline, imipenem, and clarithromycin, alone and in two different three-drug combinations (amikacin/tigecycline/imipenem and amikacin/tigecycline/clarithromycin) against seven M. abscessus subsp. abscessus clinical isolates using the time-kill assay. The two combinations showed greater activity than the antibiotics tested individually. Even though both combinations showed similar activity as well as no antagonistic activity, the combination including imipenem could not be an alternative treatment against M. abscessus subsp. abscessus lung infections caused by clarithromycin susceptible isolates. However, this combination could be considered against clarithromycin resistant isolates. Future studies are necessary to confirm this hypothesis.

Tigecycline

Amikacin

Mycobacterium abscessus

Nontuberculous Mycobacteria

10.1038/s41429-020-00392-0

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Citations (4)

Differences in Drug-Susceptibility Patterns between Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium chimaera Clinical Isolates: Prospective 8.5-Year Analysis by Three Laboratories

Antibiotics (2022)

Mariana Fernández-Pittol Sara Batista-Arnau Angely Román Lorena San Nicolás Laura Oliver

Background: It has been suggested that Mycobacterium avium, Mycobacterium intracellulare, and M. chimaera have differential drug susceptibility patterns. We prospectively analyzed and compared the drug susceptibility patterns among these species over an 8.5-year period. Methods: A microdilution method (Slomyco®) was performed for drug susceptibility testing of 402 M. avium, 273 M. intracellulare, and 139 M. chimaera clinical isolates. Results: M. avium showed significantly higher resistance to moxifloxacin, ciprofloxacin, rifampicin, ethambutol, streptomycin, linezolid, cotrimoxazole, and clarithromycin. M. avium also showed higher minimum inhibitory concentrations (MIC) than M. intracellulare and M. chimaera against all drugs except ethionamide, to which M. intracellulare and M. chimaera showed greater resistance. Conclusions: Our series demonstrated differential drug resistance patterns among the most frequent M. avium complex species. M. avium was more resistant than M. intracellulare and M. chimaera versus eight antibiotics and showed greater MIC values to most of the antibiotics studied. These data suggest that knowledge of the local distribution and susceptibility profiles of these pathogens is essential for adequate clinical management.

Broth microdilution

Ethionamide

Antimycobacterial

Nontuberculous Mycobacteria

Mycobacterium avium-intracellulare infection

10.3390/antibiotics12010064

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Citations (9)

Direct detection in clinical samples of multiple gene mutations causing resistance of Mycobacterium tuberculosis to isoniazid and rifampicin using fluorogenic probes

Journal of Antimicrobial Chemotherapy (2005)

Mateu Espasa Julián González-Martín Fernando Alcaide Lina Marcela Aragón J. Lonca

Background: This study evaluates a method based on real-time PCR for direct detection in clinical samples of the common mutations responsible for isoniazid and rifampicin resistance of Mycobacterium tuberculosis.

10.1093/jac/dki132

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Citations (63)