Correlation between Pyrazinamide Activity and
            <i>pncA</i>
            Mutations in
            <i>Mycobacterium tuberculosis</i>
            Isolates in Taiwan

Huang, Tung Po; Lee, Susan Shin-Jung; Tu, Hui Zin; Huang, Wei‐Chieh; Chen, Yao Shen; Huang, Chung Kai; Wann, Shue Ren; Lin, Hsi Hsun; Liu, Yung Ching

doi:10.1128/aac.47.11.3672-3673.2003

Cited by 43 publications

(36 citation statements)

References 17 publications

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“…However, these were mainly selected pyrazinamide-resistant cases with a high MIC. Subsequent studies have shown a lower prevalence of pncA mutations in pyrazinamide-resistant cases (2,9). We also found a lower prevalence of nonsynonymous pncA mutations (67% of isolates).…”

Section: Discussionsupporting

confidence: 71%

“…Mutations are highly diverse and are widely dispersed throughout the pncA gene, limiting the chances of successful development of simple screening methods, such as line probe assays. Furthermore, not all pyrazinamide-resistant M. tuberculosis isolates have mutations in this gene (9). For instance, mutations in the rpsA gene, encoding ribosomal protein S1, have been described recently as a novel mechanism for pyrazinamide resistance (21).…”

mentioning

confidence: 99%

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Validation of pncA Gene Sequencing in Combination with the Mycobacterial Growth Indicator Tube Method To Test Susceptibility of Mycobacterium tuberculosis to Pyrazinamide

et al. 2012

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Pyrazinamide is important in the treatment of tuberculosis. Unfortunately, the diagnosis of pyrazinamide resistance is hampered by technical difficulties. We hypothesized that mutation analysis combined with the mycobacterial growth indicator tube (MGIT) phenotypic method would be a good predictor of pyrazinamide resistance. We prospectively analyzed 1,650 M. tuberculosis isolates referred to our tuberculosis reference laboratory in 2008 and 2009. In our laboratory, the MGIT 960 system was used for pyrazinamide resistance screening. If a pyrazinamide-resistant strain was detected, we performed a pncA gene mutation analysis. A second MGIT 960 susceptibility assay was performed afterwards to evaluate the accuracy of the pncA mutation analysis to detect true-or false-positive MGIT results. We observed pyrazinamide resistance in 69 samples using the first MGIT 960 analysis. In a second MGIT 960 analysis, 47 of the 69 samples proved susceptible (68% false positivity). Sensitivity of nonsynonymous pncA mutations for detecting resistant isolates was 73% (95% confidence interval [CI], 61% to 73%), and specificity was 100% (95% CI, 95% to 100%). A diagnostic algorithm incorporating phenotypic and molecular methods would have a 100% positive predictive value for detecting pyrazinamide-resistant isolates, indicating that such an algorithm, based on both methods, is a good predictor for pyrazinamide resistance in routine diagnostics.

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

Validation of pncA Gene Sequencing in Combination with the Mycobacterial Growth Indicator Tube Method To Test Susceptibility of Mycobacterium tuberculosis to Pyrazinamide

et al. 2012

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“…This is correlated with the observation that resistance to PZA has been described for M. tuberculosis isolates with normal PZase activity encoded by the wild-type pncA gene, thus constituting an inherent limitation of the test (14,27,38). In the present study also, 6 out of 35 PZA-resistant isolates were classified as sensitive by the PZase test.…”

Section: Discussionsupporting

confidence: 59%

Comparative Evaluation of Löwenstein-Jensen Proportion Method, BacT/ALERT 3D System, and Enzymatic Pyrazinamidase Assay for Pyrazinamide Susceptibility Testing of Mycobacterium tuberculosis

Singh¹,

Wesley²,

Jadaun³

et al. 2007

J Clin Microbiol

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Pyrazinamide (PZA) is an important first-line antituberculosis drug because of its sterilizing activity against semidormant tubercle bacilli. In spite of its very high in vivo activity, its in vitro activity is not apparent unless an acidic environment is available, which makes PZA susceptibility testing difficult by conventional methods. The present study was, therefore, planned to assess the performance of the colorimetric BacT/ALERT 3D system and compare the results with those from conventional tests, i.e., the Löwenstein-Jensen (LJ) proportion method (pH 4.85) and Wayne's pyrazinamidase (PZase) assay, using 107 clinical isolates. The concordance among all of these tests was 89.71% after the first round of testing and reached 92.52% after resolution of the discordant results by retesting. Prolonged incubation of the PZase tube for up to 10 days was found to increase the specificity of the PZase test. The concordances between LJ proportion and BacT/ALERT 3D, LJ proportion and the PZase assay, and BacT/ALERT 3D and the PZase assay were found to be 99.06%, 93.46%, and 92.52%, respectively. Using the LJ results as the gold standard, the sensitivities of BacT/ALERT 3D and the PZase assay were 100 and 82.85%, respectively, while the specificity was 98.61% for both of the tests. The difference between the sensitivities of BacT/ALERT 3D and the PZase assay was significant (P ‫؍‬ 0.025). The mean turnaround times for the detection of resistant and susceptible results by BacT/ALERT 3D were 8.04 and 11.32 days, respectively. While the major limitations associated with the PZase assay and the LJ proportion method are lower sensitivity in previously treated patients and a longer time requirement, respectively, the BacT/ ALERT 3D system was found to be rapid, highly sensitive, and specific.

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“…However, these methods also have their shortcomings: the PZase test lacks sensitivity (resistant strains may be PZase positive) (5), and pncA mutations are highly diverse and widely scattered throughout the gene and regulatory region, thus limiting the chances to develop a simple and rapid commercial assay. Moreover, not all PZA-resistant M. tuberculosis isolates have mutations in the pncA gene (17), and another gene (rpsA), coding for ribosomal protein S1, has recently been involved in a newly described mechanism of low-level PZA resistance (18). The aim of the present study was to develop a method able to rule out major errors recently reported with the M960 system when testing the susceptibility of M. tuberculosis to PZA.…”

mentioning

confidence: 98%

Prevention of False Resistance Results Obtained in Testing the Susceptibility of Mycobacterium tuberculosis to Pyrazinamide with the Bactec MGIT 960 System Using a Reduced Inoculum

Piersimoni¹,

Mustazzolu

Giannoni

et al. 2013

J Clin Microbiol

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bThe susceptibility of 211 clinical isolates of Mycobacterium tuberculosis complex (201 M. tuberculosis and 10 Mycobacterium bovis isolates) to pyrazinamide (PZA) was assessed by the nonradiometric Bactec MGIT 960 system (M960). Detection of PZA resistance was followed by a repeat testing using a reduced inoculum (RI) of 0.25 ml instead of 0.5 ml. According to the first M960 analysis, resistance was observed in 55 samples. In the RI assay, 32 samples turned out to be susceptible and 23 proved to be resistant (58.2% false positivity). The Bactec 460 assay confirmed as resistant those strains detected by the RI assay, while discrepant results were found susceptible. Mutation analysis performed on 13 M. tuberculosis isolates detected pncA mutations in 11 samples. On the basis of our data, we suggest using the RI assay to confirm all PZA resistance results obtained with the standard M960 assay. Further studies are required to confirm our findings.

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Correlation between Pyrazinamide Activity and pncA Mutations in Mycobacterium tuberculosis Isolates in Taiwan

Cited by 43 publications

References 17 publications

Validation of pncA Gene Sequencing in Combination with the Mycobacterial Growth Indicator Tube Method To Test Susceptibility of Mycobacterium tuberculosis to Pyrazinamide

Validation of pncA Gene Sequencing in Combination with the Mycobacterial Growth Indicator Tube Method To Test Susceptibility of Mycobacterium tuberculosis to Pyrazinamide

Comparative Evaluation of Löwenstein-Jensen Proportion Method, BacT/ALERT 3D System, and Enzymatic Pyrazinamidase Assay for Pyrazinamide Susceptibility Testing of Mycobacterium tuberculosis

Prevention of False Resistance Results Obtained in Testing the Susceptibility of Mycobacterium tuberculosis to Pyrazinamide with the Bactec MGIT 960 System Using a Reduced Inoculum

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