Characterization of multiple and extensively drug resistant Mycobacterium tuberculosis isolates with different ofloxacin-resistance levels

Chernyaeva, Ekaterina; Федорова, Е А; Zhemkova, Galina; Korneev, Yuriy; Kozlov, Andrei P.

doi:10.1016/j.tube.2013.02.005

Cited by 18 publications

(9 citation statements)

References 13 publications

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“…In our population, in which the prevalence of FQ resistance was 12%, the sensitivity, specificity, and positive and negative predictive values were the 92.9%, 99.2%, 94.2%, and 99.1%, respectively. The sensitivity and specificity were similar to those previously published (11,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: Discussionsupporting

confidence: 88%

“…The second major result of our study is that FQ r isolates harbored more substitutions in GyrA or GyrB than is generally reported in the literature (93% versus an average of 81% in the 13 studies providing both gyrA and gyrB sequence data; P ϭ 0.02) ( Tables 2 and 4) (11,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Among these substitutions found in the FQ r isolates, we observed a higher proportion in GyrB than was previously published (11.5% versus an average of 3%) (11).…”

Section: Discussionmentioning

confidence: 51%

“…The previously published studies in this field of investigation have some limitations: (i) most studies evaluated the performance of molecular diagnosis for FQ r isolates only (11,(16)(17)(18), (ii) most studies were performed on retrospectively chosen isolates with a high prevalence of FQ resistance (most were Ͼ50%) (11), and (iii) only half of the studies included sequencing of gyrA/gyrB (11,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). To our knowledge, the present study is the largest study published that was performed prospectively, apart from that by Hu et al (28), which was performed prospectively and included fewer isolates selected from a population in which the prevalence of FQ resistance was similar to that studied here (14 versus 12%).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Diagnosis of Fluoroquinolone Resistance in Mycobacterium tuberculosis

Bernard

Véziris

Brossier

et al. 2015

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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Molecular Diagnosis of Fluoroquinolone Resistance in Mycobacterium tuberculosis

Bernard

Véziris

Brossier

et al. 2015

Antimicrob Agents Chemother

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“…Mutations in genes encoding DNA gyrase subunits gyrA and gyrB are the most common mechanism conveying FQ resistance in TB (6,7). The most frequent resistance-associated mutations occur in a conserved region of the gyrA gene (codons 74 to 113) and, less frequently, the gyrB gene (codons 461 to 499), known as the quinolone resistance-determining region (QRDR) (2,7,8).…”

mentioning

confidence: 99%

Mutations in gyrA and gyrB among Fluoroquinolone- and Multidrug-Resistant Mycobacterium tuberculosis Isolates

Chien

Chiu

Chien

et al. 2016

Antimicrob Agents Chemother

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In order to correlate the mutations inside the entire gyrA and gyrB genes with the level of resistance to ofloxacin (OFX) and moxifloxacin (MFX) in isolates of multidrug-resistant Mycobacterium tuberculosis (MDR-TB), a total of 111 isolates were categorized into OFX-susceptible (MIC, <2 g/ml) and low-level (MIC, 4 to 8 g/ml) and high-level (MIC, >16 g/ml) OFX-resistant isolates and MFX-susceptible (MIC, <0.5 g/ml) and low-level (MIC, 1 to 2 g/ml) and high-level (MIC, >4 g/ml) MFXresistant isolates. Resistance-associated mutations inside the gyrA gene were found in 30.2% of OFX-susceptible and 72.5% and 72.2% of low-level and high-level OFX-resistant isolates and in 28.6% of MFX-susceptible and 58.1% and 83.9% of low-level and high-level MFX-resistant isolates. Compared with OFX-susceptible isolates, low-level and high-level OFX-resistant isolates had a significantly higher prevalence of mutations at gyrA codons 88 to 94 (17.0%, 65.0%, and 72.2%, respectively; P < 0.001) and a higher prevalence of the gyrB G512R mutation (0.0%, 2.5%, and 16.7%, respectively; P ‫؍‬ 0.006). Similarly, compared with MFXsusceptible isolates, low-level and high-level MFX-resistant isolates had a significantly higher prevalence of mutations at gyrA codons 88 to 94 (14.3%, 51.6%, and 80.6%, respectively; P < 0.001) as well as a higher prevalence of the gyrB G512R mutation (0.0%, 0.0%, and 12.9%, respectively; P ‫؍‬ 0.011). D94G and D94N mutations in gyrA and the G512R mutation in gyrB were correlated with high-level MFX resistance, while the D94A mutation was associated with low-level MFX resistance. The prevalence of mutations at gyrA codons 88 to 94 and the gyrB G512R mutation were higher among fluoroquinolone (FQ)-susceptible East Asian (Beijing) and Indo-Oceanic strains than they were among Euro-American strains, implying that molecular techniques to detect FQ resistance may be less specific in areas with a high prevalence of East Asian (Beijing) and Indo-Oceanic strains. F luoroquinolones (FQs) are used as second-line drugs for the treatment of tuberculosis (TB). These broad-spectrum antibacterial agents with bactericidal activity against Mycobacterium tuberculosis exert their bactericidal effects by inhibiting mycobacterial DNA gyrase activity, which prevents bacterial DNA from unwinding and replicating (1-3).Moxifloxacin (MFX), a "fourth-generation" FQ, has been shown to have better activity against M. tuberculosis than ofloxacin (OFX) and is recommended by the World Health Organization (WHO) for the treatment of multidrug-resistant TB (MDR-TB; defined as resistant to at least two of the most effective antituberculosis drugs, isoniazid and rifampin) (2, 3). Unfortunately, the widespread use of FQs to treat bacterial infections has led to the emergence of FQ-resistant MDR-TB and extensively drug-resistant TB (XDR-TB; defined as MDR-TB resistant to any FQ and a second-line injectable drug) (4, 5), thereby complicating patient care.Mutations in genes encoding DNA gyrase subunits gyrA and gyrB are the most common mechanism conveying ...

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“…The etiology of fluoroquinolone resistance is incompletely explained in published studies. Mutations in DNA gyrase that modify the fluoroquinolone target in M. tuberculosis were identified in 56% of the phenotypically resistant isolates in a systematic review (1), although the rates were much higher in some individual studies (2)(3)(4). In that review, isolates in 32 of 41 studies were assessed for DNA gyrase mutations via Sanger sequencing (1).…”

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confidence: 99%

High Proportion of Heteroresistance in gyrA and gyrB in Fluoroquinolone-Resistant Mycobacterium tuberculosis Clinical Isolates

Eilertson

Maruri

Blackman

et al. 2014

Antimicrob Agents Chemother

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Heteroresistance is the coexistence of populations with differing nucleotides at a drug resistance locus within a sample of organisms. Although Sanger sequencing is the gold standard for sequencing, it may be less sensitive than deep sequencing for detecting fluoroquinolone heteroresistance in Mycobacterium tuberculosis. Twenty-seven fluoroquinolone monoresistant and 11 fluoroquinolone-susceptible M. tuberculosis isolates were analyzed by Sanger and Illumina deep sequencing. Individual sequencing reads were analyzed to detect heteroresistance in the gyrA and gyrB genes. Heteroresistance to fluoroquinolones was identified in 10/26 (38%) phenotypically fluoroquinolone-resistant samples and 0/11 (P ‫؍‬ 0.02) fluoroquinolone-susceptible controls. One resistant sample was excluded because of contamination with the laboratory strain M. tuberculosis H37Rv. Sanger sequencing revealed resistance-conferring mutations in 15 isolates, while deep sequencing revealed mutations in 20 isolates. Isolates with fluoroquinolone resistance-conferring mutations by Sanger sequencing all had at least those same mutations identified by deep sequencing. By deep sequencing, 10 isolates had a single fixed (defined as >95% frequency) mutation, while 10 were heteroresistant, 5 of which had a single unfixed (defined as <95% frequency) mutation and 5 had multiple unfixed mutations. Illumina deep sequencing identified a higher proportion of fluoroquinolone-resistant M. tuberculosis isolates with heteroresistance than did Sanger sequencing. The heteroresistant isolates frequently demonstrated multiple mutations, but resistant isolates with fixed mutations each had only a single mutation.

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Characterization of multiple and extensively drug resistant Mycobacterium tuberculosis isolates with different ofloxacin-resistance levels

Cited by 18 publications

References 13 publications

Molecular Diagnosis of Fluoroquinolone Resistance in Mycobacterium tuberculosis

Molecular Diagnosis of Fluoroquinolone Resistance in Mycobacterium tuberculosis

Mutations in gyrA and gyrB among Fluoroquinolone- and Multidrug-Resistant Mycobacterium tuberculosis Isolates

High Proportion of Heteroresistance in gyrA and gyrB in Fluoroquinolone-Resistant Mycobacterium tuberculosis Clinical Isolates

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