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Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin

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ABSTRACT

Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical Mycobacterium tuberculosis strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Löwenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wild-type strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.

No MeSH data available.


Wild-type and non-wild-type MIC distributions for the four fluoroquinolones under investigation relative to their gyrA and gyrB genotypes (see Table S1 in the supplemental material). The tentative ECOFF represents the upper limit of the wild-type distribution. All clinical strains, with the exception of H37Rv, harbored the gyrA S95T mutation that is known not to confer fluoroquinolone resistance and was consequently excluded from the analysis (13).
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Figure 1: Wild-type and non-wild-type MIC distributions for the four fluoroquinolones under investigation relative to their gyrA and gyrB genotypes (see Table S1 in the supplemental material). The tentative ECOFF represents the upper limit of the wild-type distribution. All clinical strains, with the exception of H37Rv, harbored the gyrA S95T mutation that is known not to confer fluoroquinolone resistance and was consequently excluded from the analysis (13).

Mentions: A total of 92.9% (117/126) of the strains in this study belonged to the East Asian lineage (see Table S1 in the supplemental material) (11). We found that the MIC distributions for all four fluoroquinolones were bimodal (Fig. 1A to D), where the more susceptible of the two distributions represented the phenotypically wild-type distributions, whereas the remaining strains were, by definition, phenotypically non-wild type. Based on visual inspection, we therefore set tentative epidemiological cutoff values (ECOFFs) for MIC determination using the MABA method at 2, 1, 0.5, and 0.25 μg/ml for OFX, AFX, LFX, and MFX, respectively (12). Not all phenotypically wild-type strains were identical genotypically (i.e., all 126 Chinese strains harbored the known gyrA S95T mutation that does not correlate with resistance [7, 13]), but after the exclusion of this polymorphism, we found a nearly perfect correlation between the tentative ECOFFs and nonsynonymous mutations in the two subunits of DNA gyrase, encoded by gyrA and gyrB.


Wild-Type and Non-Wild-Type Mycobacterium tuberculosis MIC Distributions for the Novel Fluoroquinolone Antofloxacin Compared with Those for Ofloxacin, Levofloxacin, and Moxifloxacin
Wild-type and non-wild-type MIC distributions for the four fluoroquinolones under investigation relative to their gyrA and gyrB genotypes (see Table S1 in the supplemental material). The tentative ECOFF represents the upper limit of the wild-type distribution. All clinical strains, with the exception of H37Rv, harbored the gyrA S95T mutation that is known not to confer fluoroquinolone resistance and was consequently excluded from the analysis (13).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4997829&req=5

Figure 1: Wild-type and non-wild-type MIC distributions for the four fluoroquinolones under investigation relative to their gyrA and gyrB genotypes (see Table S1 in the supplemental material). The tentative ECOFF represents the upper limit of the wild-type distribution. All clinical strains, with the exception of H37Rv, harbored the gyrA S95T mutation that is known not to confer fluoroquinolone resistance and was consequently excluded from the analysis (13).
Mentions: A total of 92.9% (117/126) of the strains in this study belonged to the East Asian lineage (see Table S1 in the supplemental material) (11). We found that the MIC distributions for all four fluoroquinolones were bimodal (Fig. 1A to D), where the more susceptible of the two distributions represented the phenotypically wild-type distributions, whereas the remaining strains were, by definition, phenotypically non-wild type. Based on visual inspection, we therefore set tentative epidemiological cutoff values (ECOFFs) for MIC determination using the MABA method at 2, 1, 0.5, and 0.25 μg/ml for OFX, AFX, LFX, and MFX, respectively (12). Not all phenotypically wild-type strains were identical genotypically (i.e., all 126 Chinese strains harbored the known gyrA S95T mutation that does not correlate with resistance [7, 13]), but after the exclusion of this polymorphism, we found a nearly perfect correlation between the tentative ECOFFs and nonsynonymous mutations in the two subunits of DNA gyrase, encoded by gyrA and gyrB.

View Article: PubMed Central - PubMed

ABSTRACT

Antofloxacin (AFX) is a novel fluoroquinolone that has been approved in China for the treatment of infections caused by a variety of bacterial species. We investigated whether it could be repurposed for the treatment of tuberculosis by studying its in vitro activity. We determined the wild-type and non-wild-type MIC ranges for AFX as well as ofloxacin (OFX), levofloxacin (LFX), and moxifloxacin (MFX), using the microplate alamarBlue assay, of 126 clinical Mycobacterium tuberculosis strains from Beijing, China, of which 48 were OFX resistant on the basis of drug susceptibility testing on Löwenstein-Jensen medium. The MIC distributions were correlated with mutations in the quinolone resistance-determining regions of gyrA (Rv0006) and gyrB (Rv0005). Pharmacokinetic/pharmacodynamic (PK/PD) data for AFX were retrieved from the literature. AFX showed lower MIC levels than OFX but higher MIC levels than LFX and MFX on the basis of the tentative epidemiological cutoff values (ECOFFs) determined in this study. All strains with non-wild-type MICs for AFX harbored known resistance mutations that also resulted in non-wild-type MICs for LFX and MFX. Moreover, our data suggested that the current critical concentration of OFX for Löwenstein-Jensen medium that was recently revised by the World Health Organization might be too high, resulting in the misclassification of phenotypically non-wild-type strains with known resistance mutations as wild type. On the basis of our exploratory PK/PD calculations, the current dose of AFX is unlikely to be optimal for the treatment of tuberculosis, but higher doses could be effective.

No MeSH data available.