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A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis.

Whitfield MG, Soeters HM, Warren RM, York T, Sampson SL, Streicher EM, van Helden PD, van Rie A - PLoS ONE (2015)

Bottom Line: Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary.Among 1,815 phenotypically resistant isolates, 608 unique SNPs occurred at 397 distinct positions throughout the pncA gene.The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics.

View Article: PubMed Central - PubMed

Affiliation: SA MRC Centre for TB Research, Stellenbosch University, South Africa; DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, South Africa; Division of Molecular Biology and Human Genetics, Stellenbosch University, South Africa; Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.

ABSTRACT

Background: Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradicate persister bacilli. The worldwide burden of PZA resistance remains poorly described.

Methods: Systematic PubMed, Science Direct and Scopus searches for articles reporting phenotypic (liquid culture drug susceptibility testing or pyrazinamidase activity assays) and/or genotypic (polymerase chain reaction or DNA sequencing) PZA resistance. Global and regional summary estimates were obtained from random-effects meta-analysis, stratified by presence or risk of multidrug resistant TB (MDR-TB). Regional summary estimates were combined with regional WHO TB incidence estimates to determine the annual burden of PZA resistance. Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary.

Results: Pooled PZA resistance prevalence estimate was 16.2% (95% CI 11.2-21.2) among all TB cases, 41.3% (29.0-53.7) among patients at high MDR-TB risk, and 60.5% (52.3-68.6) among MDR-TB cases. The estimated global burden is 1.4 million new PZA resistant TB cases annually, about 270,000 in MDR-TB patients. Among 1,815 phenotypically resistant isolates, 608 unique SNPs occurred at 397 distinct positions throughout the pncA gene.

Interpretation: PZA resistance is ubiquitous, with an estimated one in six incident TB cases and more than half of all MDR-TB cases resistant to PZA globally. The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics. These findings caution against relying on PZA in current and future TB drug regimens, especially in MDR-TB patients.

No MeSH data available.


Related in: MedlinePlus

Distribution of reported single nucleotide polymorphisms (SNPs) throughout the pncA gene.Dashed lines indicate the open reading frame for the pncA gene.
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pone.0133869.g004: Distribution of reported single nucleotide polymorphisms (SNPs) throughout the pncA gene.Dashed lines indicate the open reading frame for the pncA gene.

Mentions: The 66 [27,59–123] articles provided SNP data from 8,651 M. tuberculosis clinical isolates. According to WHO region, five [60,68,69,78,102] articles were from Africa, 14 [27,70–72,79,81–83,97,100,105,107,114,120] from the Americas, two [80,92] from the Eastern Mediterranean, 17 [61,62,84–86,93,96,103,104,106,108–110,115–117,119] from Europe, six [59,63,73,118,121,123] from South East Asia, and 22 [64–67,74–77,87–91,94,95,98,99,101,111–113,122] from the Western Pacific. A SNP in the pncA region was detected in the 1,815 of the 8,651 isolates, with 608 unique polymorphisms in 397 positions in the gene (S2 Table). SNPs were found throughout the entire pncA gene and flanking region with no particular clustering or hot spots (Fig 4). There are however, a few SNPs which were found to be more frequently than others such as -11 and 195, but even the 20 most frequent SNPs only represented one third of all isolates with phenotypic PZA resistance.


A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis.

Whitfield MG, Soeters HM, Warren RM, York T, Sampson SL, Streicher EM, van Helden PD, van Rie A - PLoS ONE (2015)

Distribution of reported single nucleotide polymorphisms (SNPs) throughout the pncA gene.Dashed lines indicate the open reading frame for the pncA gene.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4517823&req=5

pone.0133869.g004: Distribution of reported single nucleotide polymorphisms (SNPs) throughout the pncA gene.Dashed lines indicate the open reading frame for the pncA gene.
Mentions: The 66 [27,59–123] articles provided SNP data from 8,651 M. tuberculosis clinical isolates. According to WHO region, five [60,68,69,78,102] articles were from Africa, 14 [27,70–72,79,81–83,97,100,105,107,114,120] from the Americas, two [80,92] from the Eastern Mediterranean, 17 [61,62,84–86,93,96,103,104,106,108–110,115–117,119] from Europe, six [59,63,73,118,121,123] from South East Asia, and 22 [64–67,74–77,87–91,94,95,98,99,101,111–113,122] from the Western Pacific. A SNP in the pncA region was detected in the 1,815 of the 8,651 isolates, with 608 unique polymorphisms in 397 positions in the gene (S2 Table). SNPs were found throughout the entire pncA gene and flanking region with no particular clustering or hot spots (Fig 4). There are however, a few SNPs which were found to be more frequently than others such as -11 and 195, but even the 20 most frequent SNPs only represented one third of all isolates with phenotypic PZA resistance.

Bottom Line: Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary.Among 1,815 phenotypically resistant isolates, 608 unique SNPs occurred at 397 distinct positions throughout the pncA gene.The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics.

View Article: PubMed Central - PubMed

Affiliation: SA MRC Centre for TB Research, Stellenbosch University, South Africa; DST/NRF Centre of Excellence for Biomedical TB Research, Stellenbosch University, South Africa; Division of Molecular Biology and Human Genetics, Stellenbosch University, South Africa; Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa.

ABSTRACT

Background: Pyrazinamide (PZA) is crucial for tuberculosis (TB) treatment, given its unique ability to eradicate persister bacilli. The worldwide burden of PZA resistance remains poorly described.

Methods: Systematic PubMed, Science Direct and Scopus searches for articles reporting phenotypic (liquid culture drug susceptibility testing or pyrazinamidase activity assays) and/or genotypic (polymerase chain reaction or DNA sequencing) PZA resistance. Global and regional summary estimates were obtained from random-effects meta-analysis, stratified by presence or risk of multidrug resistant TB (MDR-TB). Regional summary estimates were combined with regional WHO TB incidence estimates to determine the annual burden of PZA resistance. Information on single nucleotide polymorphisms (SNPs) in the pncA gene was aggregated to obtain a global summary.

Results: Pooled PZA resistance prevalence estimate was 16.2% (95% CI 11.2-21.2) among all TB cases, 41.3% (29.0-53.7) among patients at high MDR-TB risk, and 60.5% (52.3-68.6) among MDR-TB cases. The estimated global burden is 1.4 million new PZA resistant TB cases annually, about 270,000 in MDR-TB patients. Among 1,815 phenotypically resistant isolates, 608 unique SNPs occurred at 397 distinct positions throughout the pncA gene.

Interpretation: PZA resistance is ubiquitous, with an estimated one in six incident TB cases and more than half of all MDR-TB cases resistant to PZA globally. The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics. These findings caution against relying on PZA in current and future TB drug regimens, especially in MDR-TB patients.

No MeSH data available.


Related in: MedlinePlus