Background: The objectives of this study were to investigate the dynamics of different resistant mechanisms in P.aeruginosa populations that have evolved under fluoroquinolone pressure, and any interactions between these mechanisms in the evolutionary trajectories. Methods:In this study, bacteria of the strain ATCC27853 were selected under different concentrations of levofloxacin and ciprofloxacin for six parallel lineages. The four target genes in the quinolone-resistance determining region were amplified and then Sanger sequencing was used to find the mutations. The expression of four efflux pump proteins were evaluated by real-time PCR, using the relative quantitation method, and the ATCC27853 was selected as a control.Results: we found that the P.aeruginosa was killed by ciprofloxacin earlier than levofloxacin. We found five different mutations in three subunits of QRDRs in our study; gyrA was the main mutated gene for conferring resistance to fluoroquinolone. A greater number of mutations appeared at 4mg/L for levofloxacin and at 2mg/L for ciprofloxacin. The main efflux pump that was expressed was MexCD-OprJ, and the first over expressed was evident at 0.5mg/L for levofloxacin and 0.25mg/L for ciprofloxacin. Conclusions:The mutation of gyrA 83 and overexpression of MexCD-OprJ were the main mechanisms that conferred resistance of P.aeruginosa to levofloxacin and ciprofloxacin. Ciprofloxacin had a stronger ability to kill the bacteria, while may render bacteria more susceptible to resistance. Background:Pseudomonas aeruginosa (P.aeruginosa) is a Gram-negative opportunistic human pathogen that can cause patients suffering from cystic fibrosis (CF) to become immune-compromised, occasionally leading to death [1]. Fluoroquinolones (FQ), which have favorable pharmacokinetic/pharmacodynamic properties are one of the major classes of antibiotics used in the treatment of infections caused by P.aeruginosa. P.aeruginosa has a large variety of available resistance mechanisms, and these may act in combination, rendering even the most potent agents useless [2].The most prevalent mechanisms contributing to FQ resistance in P.aeruginosa involve mutations in the quinolone-resistance determining regions (QRDRs), for example, gyrA and gyrB in DNA gyrase and
Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as both monotherapy and combination therapy, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16-20 mL/min) renal function.Common clinical administration regimens to provide reference values were also evaluated. Methods:The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853). This simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. The total and resistant populations were quantified. Drug concentrations were determined by High-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8h, whilst combination regimens resulted in 2-to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6h, and was seen at 0h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0h, there was a certain downward trend after 8h, while resistant population in the normal renal function group increased after 16h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted. Background:P. aeruginosa is a common conditional pathogen of hospital acquired pneumonia, especially in patients in intensive care units (ICUs) who require respiratory support [1]. Abnormal renal function is common in ICUs patients. Doses of antibacterial therapy need to be adjusted for ICUs patients. This is because the kidney is the main organ for drug elimination, so without dose adjustment, the accumulation of drugs and their metabolites in plasma would increase the possibility of toxicity [2]. At present, the resistance to P. aeruginosa is increasing [3]. About 15% of P. aeruginosa strains are
Fluoroquinolone resistance in Pseudomonas aeruginosa typically arises through site-specific mutations and overexpression of efflux pumps. In this study, we investigated the dynamics of different resistance mechanisms in P. aeruginosa populations that have evolved under fluoroquinolone pressure, as well as the interactions between these mechanisms in evolutionary trajectories. Bacteria of strain ATCC27853 were selected under different concentrations of ciprofloxacin and levofloxacin for six parallel lineages, followed by amplification of four target genes in the quinolone-resistance determining region (QRDR) and Sanger sequencing to identify the mutations. The expression of four efflux pump proteins was evaluated by real-time polymerase chain reaction using the relative quantitation method, with the ATCC27853 strain used as a control. We found that ciprofloxacin killed P. aeruginosa sooner than did levofloxacin. Further, we identified five different mutations in three subunits of QRDRs, with gyrA as the main mutated gene associated with conferring fluoroquinolone resistance. Additionally, we found a larger number of mutations appearing at 2 mg/L and 4 mg/L of ciprofloxacin and levofloxacin, respectively. Moreover, we identified the main efflux pump being expressed as MexCD-OprJ, with initial overexpression observed at 0.25 mg/L and 0.5 mg/L of ciprofloxacin and levofloxacin, respectively. These results demonstrated gyrA83 mutation and MexCD-OprJ overexpression as the primary mechanism conferring ciprofloxacin and levofloxacin resistance in P. aeruginosa. In addition, we also show that ciprofloxacin exhibited a stronger ability to kill the bacteria while potentially rendering it more susceptible to resistance.
Background: The purpose of this study was to investigate the bactericidal effects of levofloxacin and ceftazidime as both monotherapy and combination therapy, and to determine their effects on resistance suppression in patients with normal and abnormal (Ccr:16–20 mL/min) renal function. Common clinical administration regimens to provide reference values were also evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853). This simulated common clinical administration regimens for patients with different renal function. Ten regimens were stratified into 2 categories based on renal function, and each category contained 3 monotherapy regimens and 2 combination therapy regimens. The total and resistant populations were quantified. Drug concentrations were determined by High-performance liquid chromatography (HPLC). Results: Monotherapy regimens resulted in about 0.5-log-CFU/mL bacterial kill in the total population at 6 or 8h, whilst combination regimens resulted in 2- to 3-log-CFU/mL within 2 days. For levofloxacin monotherapy regimens in patients with normal renal function, resistance emergence was seen after 6h, and was seen at 0h in the ceftazidime monotherapy regimen, as well as in all regimens of patients with abnormal renal function. Although resistant subpopulation in combination regimens with abnormal renal function began to increase at 0h, there was a certain downward trend after 8h, while resistant population in the normal renal function group increased after 16h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.
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