Dataset Information

Fluoroquinolone Use and Seasonal Patterns of Ciprofloxacin Resistance in Community-Acquired Urinary Escherichia coli Infection in a Large Urban Center.

ABSTRACT: Urinary tract infections caused by the bacterium Escherichia coli are among the most frequently encountered infections and are a common reason for antimicrobial prescriptions. Resistance to fluoroquinolone antimicrobial agents, particularly ciprofloxacin, has increased in recent decades. It is intuitive that variation in fluoroquinolone resistance is driven by changes in antimicrobial use, but careful study of this association requires the use of time-series methods. Between April 2010 and December 2014, we studied seasonal variation in resistance to ciprofloxacin, trimethoprim-sulfamethoxazole, and ampicillin in community-acquired urinary E. coli isolates in Montreal, Quebec, Canada. Using dynamic linear models, we investigated whether seasonal variation in resistance could be explained by seasonal variation in community antimicrobial use. We found a positive association between total fluoroquinolone use lagged by 1 and 2 months and the proportion of isolates resistant to ciprofloxacin. Our results suggest that resistance to ciprofloxacin is responsive to short-term variation in antimicrobial use. Thus, antimicrobial stewardship campaigns to reduce fluoroquinolone use, particularly in the winter when use is highest, are likely to be a valuable tool in the struggle against antimicrobial resistance.

SUBMITTER: Soucy JR

PROVIDER: S-EPMC7217283 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Fluoroquinolone Use and Seasonal Patterns of Ciprofloxacin Resistance in Community-Acquired Urinary Escherichia coli Infection in a Large Urban Center.

Soucy Jean-Paul R JR Schmidt Alexandra M AM Quach Caroline C Buckeridge David L DL

American journal of epidemiology 20200301 3

Urinary tract infections caused by the bacterium Escherichia coli are among the most frequently encountered infections and are a common reason for antimicrobial prescriptions. Resistance to fluoroquinolone antimicrobial agents, particularly ciprofloxacin, has increased in recent decades. It is intuitive that variation in fluoroquinolone resistance is driven by changes in antimicrobial use, but careful study of this association requires the use of time-series methods. Between April 2010 and Decem ...[more]

PMID: 31665215

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Project description:Fluoroquinolones (FQs) belong to the class of quinolone drugs that are used to treat Urinary tract infections (UTIs) through inhibition of E. coli DNA gyrase. Resistance to FQs poses a serious problem in the treatment against resistant strains of E. coli which are associated with Ser83 to Leu and Asp87 to Asn mutations at the quinolone resistance determining region (QRDR) of the GyrA subunit of DNA gyrase. Mutant DNA GyrA (mtDNA GyrA) is deemed to be a significant target for the development of novel FQ drugs. Due to resistance to FQ drugs, discovery or development of novel FQs is crucial to inhibit the mtDNA GyrA. Hence, the present study attempts to design and develop novel FQs that are efficient against resistant E. coli strains. A three-dimensional structure of the mtDNA GyrA protein was developed by homology modeling, following which 204 novel FQ analogs were designed using target based SAR. The designed ligands were then screened using molecular docking studies, through which the pattern of interaction between the ligands and the target protein was studied. As expected, the results of the docking study revealed that the molecules FQ-147, FQ-151 and FQ-37 formed hydrogen bonding and Van der Waals interactions with Leu83 and Asn87 (mutated residues), respectively. Further, the wild-type (WT), mtDNA GyrA and docking complex were studied by molecular dynamics (MD) simulations. Subsequently, all the screened compounds were subjected to a structure and ligand based pharmacophore study followed by ADMET and toxicity (TOPKAT) prediction. Finally, eighteen hit FQ analogs which showed good results for the following properties, viz., best binding score, estimated activity (MIC value) and calculated drug-like properties, and least toxicity, were shortlisted and identified as potential leads to treat UTI caused by FQ resistant E. coli. Apart from development of novel drug candidates for inhibition of mtDNA GyrA, the present study also contributes towards a superior comprehension of the interaction pattern of ligands in the target protein. To a more extensive degree, the present work will be useful for the rational design of novel and potent drugs for UTIs.

Project description:BACKGROUND: Wide use of ciprofloxacin and levofloxacin has often led to increased resistance. The resistance rate to these two agents varies in different clinical isolates of Enterobacteriaceae. Mutations of GyrA within the quinolone resistance-determining regions have been found to be the main mechanism for quinolone resistance in Enterobacteriaceae. It has been shown that only some of the mutations in the gyrA gene identified from clinical sources were involved in fluoroquinolone resistance. Whether different patterns of gyrA mutation are related to antimicrobial resistance against ciprofloxacin and levofloxacin is unclear. METHODS: The minimum inhibitory concentration (MIC) of ciprofloxacin and levofloxacin were determined by the agar dilution method followed by PCR amplification and sequencing of the quinolone resistance determining region of gyrA to identify all the mutation types. The correlation between fluoroquinolone resistance and the individual mutation type was analyzed. RESULTS: Resistance differences between ciprofloxacin and levofloxacin were found in 327 isolates of K. pneumoniae and E. coli in Harbin, China and in the isolates reported in PubMed publications. GyrA mutations were found in both susceptible and resistant isolates. For the isolates with QRDR mutations, the resistance rates to ciprofloxacin and levofloxacin were also statistically different. Among the 14 patterns of alterations, two single mutations (Ser83Tyr and Ser83Ile), and three double mutations (Ser83Leu+Asp87Asn, Ser83Leu+Asp87Tyr and Ser83Phe+Asp87Asn) were associated with both ciprofloxacin and levofloxacin resistance. Two single mutations (Ser83Phe and Ser83Leu) were related with ciprofloxacin resistance but not to levofloxacin. Resistance difference between ciprofloxacin and levofloxacin in isolates harboring mutation Ser83Leu+Asp87Asn were of statistical significance among all Enterobacteriaceae (P<0.001). CONCLUSIONS: Resistance rate to ciprofloxacin and levofloxacin were statistically different among clinical isolates of Enterobacteriaceae harboring GyrA mutations. Ser83Leu+Asp87Asn may account for the antimicrobial resistance difference between ciprofloxacin and levofloxacin.

Dataset Information

Fluoroquinolone Use and Seasonal Patterns of Ciprofloxacin Resistance in Community-Acquired Urinary Escherichia coli Infection in a Large Urban Center.

Publications

Fluoroquinolone Use and Seasonal Patterns of Ciprofloxacin Resistance in Community-Acquired Urinary Escherichia coli Infection in a Large Urban Center.

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