Phenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment

Ho, Jennifer; Jelfs, Peter; Sintchencko, Vitali

doi:10.1093/jac/dkt284

Cited by 47 publications

(54 citation statements)

References 21 publications

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“…This is consistent with two other studies reporting 4 of 94 (4.3%) and 4 of 202 (2.0%) strains with at least one rpoB mutation within the RRDR (7) (8). Two of the four strains had the mutation L533P.…”

supporting

confidence: 92%

“…Poor treatment outcome for four of four patients with phenotypically INH-resistant but RMP-susceptible isolates has been described by Williamson et al (7). With similar isolates, Ho et al found one TB relapse case among four patients (8). Recently, among selected first-failure and relapse patients, equally poor first-line retreatment outcomes were reported for strains with common or disputed mutations (21).…”

mentioning

confidence: 84%

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Occurrence of rpoB Mutations in Isoniazid-Resistant but Rifampin-Susceptible Mycobacterium tuberculosis Isolates from Germany

Andres

Hillemann

Rüsch-Gerdes

et al. 2014

Antimicrob Agents Chemother

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Four out of 143 phenotypically isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis strains that were isolated from patients in Germany in 2011 had mutations in the rifampin resistance-determining region of rpoB. After performing drug susceptibility testing (DST) with two methods, the proportion method on Löwenstein-Jensen medium and using the Bactec 960 Mycobacteria Growth Indicator Tube system, we conclude that the two methods are equally reliable for phenotypic DST and MIC determination.T he development of multidrug-resistant tuberculosis (MDR-TB), defined as resistance against at least isoniazid (INH) and rifampin (RMP), is assumed to occur as resistance to drugs serially acquired due to inadequate treatment. This includes the use of single drugs or single, usually effective drugs in the treatment of patients that are infected with resistant strains. INH-resistant but RMP-susceptible Mycobacterium tuberculosis strains may represent a source for the development of MDR strains in the case of nonadapted treatment.The molecular basis of RMP resistance is localized mainly in a specific region of the rpoB gene, the RMP resistance-determining region (RRDR), which enables rapid detection by molecular analysis (1). Extensive use of molecular assays consistently found, although rarely, isolates harboring rpoB mutations but which did not test resistant by phenotypical drug susceptibility testing (DST) methods (2, 3).In this study, we investigated the presence of rpoB mutations in all 143 INH-resistant and RMP-susceptible M. tuberculosis isolates from patients living in Germany that were submitted to the German National Reference Laboratory for Mycobacteria in 2011. In addition, RMP susceptibility was evaluated with two different DST methods. Primary detection and DST had been performed earlier by using the Bactec 960 Mycobacterial Growth Indicator Tube (MGIT) system (Becton, Dickinson, USA). The processing of the specimens, the DNA preparation, and the sequencing of katG and the ribosome binding site (RBS) of inhA for INH resistance and of the RRDR were carried out as described previously (4-6).Of the 143 M. tuberculosis strains, 139 strains showed no mutation, while four strains (2.8%) had at least one rpoB mutation within the RRDR. This is consistent with two other studies reporting 4 of 94 (4.3%) and 4 of 202 (2.0%) strains with at least one rpoB mutation within the RRDR (7) (8). Two of the four strains had the mutation L533P. The other two strains had the mutation D516Y in combination with a second mutation within the RRDR (N518D or E510H) ( Table 1). None of the sequencing profiles showed underlying wild-type peaks indicating heteroresistance. All mutations found have been described previously (9). The mutation N518D has been described in combination with L533P in a strain with high-level RMP resistance (10). Therefore, this mutation does not seem to have a reverse effect on a resistant phenotype in general. The second double mutation within rpoB, resulting in E510H D516Y, has been described in ...

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supporting

confidence: 92%

mentioning

confidence: 84%

Occurrence of rpoB Mutations in Isoniazid-Resistant but Rifampin-Susceptible Mycobacterium tuberculosis Isolates from Germany

Andres

Hillemann

Rüsch-Gerdes

et al. 2014

Antimicrob Agents Chemother

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“…The clinical relevance of these mutations still needs to be determined, however. Recent retrospective analyses of treatment outcomes in patients with isolates containing low-MIC mutations, such as the 516GAC¡TAC and 526CAC¡AAC mutations, appear to suggest that these mutations might still be associated with poor treatment outcomes in standard RIF-based first-line treatment regimens (32,34,35), but these studies had many unmeasured confounding factors that might have affected the results. In the long term, it will be critical to address the discordant phenotypic standards by which isolates with low-level MIC resistance are evaluated and to conduct studies on the clinical relevance of these mutations.…”

Section: Discussionmentioning

confidence: 99%

Predicting Extensively Drug-Resistant Mycobacterium tuberculosis Phenotypes with Genetic Mutations

et al. 2014

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“…Confirmation of these lower critical concentrations have come from clinical studies [209][210][211][212][213] and several investigations [214][215][216][217][218][219][220][221] of drug resistance-associated mutations in isolates with MICs below the standard breakpoint. Clinical studies using assumption-free methods such as machine learning have confirmed that these values (table 3) are in fact the MICs above which tuberculosis patients fail combination therapy.…”

Section: Rv1910cmentioning

confidence: 91%

“…Additionally, studies have been done in which treatment failed in patients who were infected with M tuberculosis who had drug target site mutations, but MICs were lower than current breakpoints, and were more consistent with the newly proposed breakpoints. [214][215][216][217][218][219][220][221] Therefore, the proposed concentrations have higher sensitivity for clinical decision making, and should be used to estimate the global burden of MDR tuberculosis.…”

Section: Rv1910cmentioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

533

474

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Phenotypically occult multidrug-resistant Mycobacterium tuberculosis: dilemmas in diagnosis and treatment

Abstract: While MTB RIF G(R) P(S) strains remain relatively uncommon, they can be associated with low-level rifampicin resistance and poorer treatment outcomes with rifampicin-based regimens. This recently recognized form of multidrug-resistant TB should be adequately detected and managed.

Cited by 47 publications

References 21 publications

Occurrence of rpoB Mutations in Isoniazid-Resistant but Rifampin-Susceptible Mycobacterium tuberculosis Isolates from Germany

Occurrence of rpoB Mutations in Isoniazid-Resistant but Rifampin-Susceptible Mycobacterium tuberculosis Isolates from Germany

Predicting Extensively Drug-Resistant Mycobacterium tuberculosis Phenotypes with Genetic Mutations

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

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