Genetics and pulmonary medicine bullet  5: Genetics of drug resistant tuberculosis

Telenti, Amalio

doi:10.1136/thx.53.9.793

Cited by 45 publications

(18 citation statements)

References 62 publications

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“…39 In our study, genetic alterations (mutations, deletions, or insertions) in the promoter region oxyRahpC were identified in 13.2% of INH-resistant strains, as described similarly in previously published reports. 16,29,39,45 Conversely, taken together our data clearly demonstrate that most strains with oxyR-ahpC region mutations have alterations at other loci (katG or inhA), which may readily explain the INH resistance phenotype. 16,39 Our results showed, however, that 17% of the INH-resistant isolates had no detectable alterations at the studied loci.…”

Section: Discussionmentioning

confidence: 94%

Molecular Analysis of Isoniazid and Rifampin Resistance inMycobacterium tuberculosisIsolates Recovered from Barcelona

Coll

Aragón²,

Alcaide³

et al. 2005

Microbial Drug Resistance

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We studied the presence of mutations in the whole katG gene and specific regions of the oxyR-ahpC and mabAinhA regulatory region in 61 Mycobacterium tuberculosis isoniazid-resistant isolates. An 81-bp region of the rpoB gene was also sequenced in 17 rifampin-resistant strains. Alterations in the katG gene were detected in 55% of the isolates. Mutation in codon 315 was the most prevalent (32%). Strains showed a high level of resistance, and most maintained a substantial catalase-peroxidase activity. Three strains with an isoniazid MIC of Ն32 g/ml lacked catalase-peroxidase activity. Two of them had deletions in the catalytic domain of the KatG protein. One strain with deletion and three strains with mutations in the C-terminal domain showed low-level resistance and conserved the catalase-peroxidase activity. Mutations in the mabA-inhA regulatory region were identified in 32% of the isolates. All had low-level resistance, and the vast majority conserved catalase-peroxidase activity. Seventeen percent of the isoniazid-resistant isolates had no detectable alterations at the studied loci. Resistance to rifampin was associated with mutations in the 81-bp of the rpoB gene in all cases. IS6110 analysis indicated that recent transmission contributed substantially to the emergence of isoniazid-resistant tuberculosis in Barcelona through short transmission chains. A rapid genotypic assay, including the 315-katG codon and the ؊15 nucleotide of the mabA-inhA regulatory region, may cover 62% of isoniazid-resistant strains in Barcelona. In contrast, the targeting of the 81-bp region of rpoB would detect all our rifampin-resistant isolates. 107

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Section: Discussionmentioning

confidence: 94%

Molecular Analysis of Isoniazid and Rifampin Resistance inMycobacterium tuberculosisIsolates Recovered from Barcelona

Coll

Aragón²,

Alcaide³

et al. 2005

Microbial Drug Resistance

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“…Most of the low-level-resistance isolates in this work demonstrated mutations in the mabA-inhA regulatory region. These alterations result in the upregulation of gene expression and thus in increased amounts of these enzymes, which overwhelm the inhibitory action of INH (20). Since INH is in its active form, it may be acting on other possible targets (12) which render the bacilli not completely viable and incapable of supporting phage infection.…”

Section: Discussionmentioning

confidence: 99%

Use of a Mycobacteriophage-Based Assay for Rapid Assessment of Susceptibilities of Mycobacterium tuberculosis Isolates to Isoniazid and Influence of Resistance Level on Assay Performance

et al. 2006

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We standardized and assessed the performance of an in-house microtiter assay for determining the susceptibilities of Mycobacterium tuberculosis clinical isolates to isoniazid based on mycobacteriophage amplification technology. Seventy isolates (43 resistant and 27 sensitive according to the BACTEC 460 radiometric method and MIC determination) were studied. The isoniazid resistance molecular mechanism was previously determined by sequencing the entire katG gene and the mabA-inhA regulatory region. The sensitivity of the mycobacteriophage-based assay in detecting isoniazid resistance was 86.1%, the specificity achieved was 92.6%, and the overall accuracy was 88.6%. In order to assess the possible influence of resistance levels on the mycobacteriophage-based-assay sensitivity, the results were analyzed according to the isoniazid MICs. All the isolates exhibiting high-level resistance (MIC > 2 g/ml) were scored as resistant by the mycobacteriophagebased assay (100% concordance), and 95% showed mutations or deletions in the catalytic domain of the katG gene. In contrast, 26.1% of the low-level-resistance strains (MICs, 0.25 to 1 g/ml) were misclassified, and 66.7% had alterations in the mabA-inhA regulatory region. The mycobacteriophage-based assay could be used as a rapid method to detect the isoniazid susceptibility pattern, although data from those areas with high rates of low-level-resistance strains should be interpreted with caution. The features of the assay make it suitable for widespread application due to its low technical demand and cost.Despite intensive research done to improve tuberculosis (TB) diagnosis and drug susceptibility testing techniques, TB still remains one of the most threatening curable infectious diseases. Providing rapid diagnosis and antibiotic resistance detection systems is essential to prevent transmission, although these tools should be affordable in terms of cost and technical demand for those countries with limited resources and a high incidence of TB. In the vast majority of developing countries, conventional mycobacteriological techniques for culture isolation and antibiotic susceptibility testing are slow. More-rapid and newer methods such as the BACTEC 460 method (8) and the mycobacterium growth indicator tube method (22) are expensive and require sophisticated technology. There is an urgent need for accurate, simple, rapid, and inexpensive drug susceptibility testing methods adequate for widespread implementation.Several studies have reported promising results using mycobacteriophages for the rapid, simple, and inexpensive determination of drug susceptibilities (5, 6, 7, 23), especially for isoniazid (INH) and rifampin (RIF) resistance detection. These mycobacteriophage-based assays (MBAs) depend upon the ability of resistant mycobacteria to support phage replication after being exposed to drugs, while sensitive bacilli are not able to support phage infection. Extracellular phages are inactivated with a virucidal agent, whereas intracellular phages are protected and replicate...

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“…Since immunocompromised patients are more likely to develop disease and to do so more rapidly than immunocompetent patients [6], extensive transmission of drugresistant strains may occur. HIV-positive patients might also be more likely to frequent settings in which they could be exposed to drug-resistant strains of tuberculosis, such as hospitals [7], and may be more susceptible to drug-resistant tuberculosis strains that are possibly less virulent [8]. Furthermore, HIV infection may impair the absorption of some antituberculosis drugs, contributing to the development of resistance [9].…”

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confidence: 99%

The association between HIV and antituberculosis drug resistance

French¹,

Glynn²,

Kruijshaar³

et al. 2008

Eur Respir J

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In the UK, HIV is considered to be a risk factor for antituberculosis drug resistance. Evidence of the association is, however, inconclusive and there are few population-level data. The present study investigated the association in England and Wales during the period 1999-2005.National tuberculosis surveillance data for adults were matched to HIV/AIDS reports. Unmatched cases were assumed to be HIV-negative. Separate analyses were conducted on new tuberculosis cases and those with a previous diagnosis. Logistic regression was used for univariable and multivariable analyses.There were 1,657 previously diagnosed cases (80 HIV-positive) and 18,130 new cases (1,156 HIV-positive). Isoniazid resistance was found in 8.1% of previously diagnosed cases and 6.6% of new cases, and multidrug resistance in 2.8% and 0.7%, respectively. There was no evidence of an association between HIV and antituberculosis drug resistance among previously diagnosed cases. Among new cases, there was no overall association between HIV and isoniazid or multidrug resistance after adjusting for confounding factors. White HIV-positive patients were more likely to have multidrug resistance, but numbers were small. In contrast to some previous studies, this large, up-to-date study provides little evidence that HIV co-infected tuberculosis patients in England and Wales are at increased risk of firstline antituberculosis drug resistance.

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Genetics and pulmonary medicine bullet 5: Genetics of drug resistant tuberculosis

Cited by 45 publications

References 62 publications

Molecular Analysis of Isoniazid and Rifampin Resistance inMycobacterium tuberculosisIsolates Recovered from Barcelona

Molecular Analysis of Isoniazid and Rifampin Resistance inMycobacterium tuberculosisIsolates Recovered from Barcelona

Use of a Mycobacteriophage-Based Assay for Rapid Assessment of Susceptibilities of Mycobacterium tuberculosis Isolates to Isoniazid and Influence of Resistance Level on Assay Performance

The association between HIV and antituberculosis drug resistance

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