Changes in MIC Alter Responses of Pseudomonas aeruginosa to Tobramycin Exposure

2020

BMC Pharmacol Toxicol

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 further evaluated. Methods: The 7-d hollow-fiber infection model was used to inject the Pseudomonas aeruginosa standard strain (ATCC27853), which 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. 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 8 h, 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 6 h, and was seen at 0 h 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 0 h, there was a definite downward trend after 8 h, while resistant population in the normal renal function group increased after 16 h. Conclusions: Combination therapy had greater bactericidal efficacy and resistance inhibition compared with monotherapy. Studying combination regimens in randomized clinical trials is warranted.

Section: Discussionmentioning

confidence: 79%

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

2020

BMC Pharmacol Toxicol

“…When AUC 0-24h /MIC≥100 and/or C max /MIC>8, the bactericidal effect was good for fluoroquinolones, and when T>MIC is more than 50%, it showed a good bactericidal effect for βlactams. However, as observed in some studies [21][22][23], treatment failure and rapid resistance emergence happened even when T>MIC reached or approached 100% for meropenem, or AUC 0-24h /MIC was 168 for tobramycin which was 4 times of the suggested breakpoint. So it is necessary to find effective ways to inhibit drug resistance.…”

Section: Discussionmentioning

confidence: 79%

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

He²,

2020

Preprint

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

“…When AUC 0-24h /MIC≥100 and/or C max /MIC>8, the bactericidal effect was good for fluoroquinolones, and when T>MIC is more than 50%, it showed a good bactericidal effect for βlactams. However, as observed in some studies [21][22][23], treatment failure and rapid resistance emergence happened even when T>MIC reached or approached 100% for meropenem, or AUC 0-24h /MIC was 168 for tobramycin which was 4 times of the suggested breakpoint. So it is necessary in order to find effective ways to inhibit drug resistance.…”

Section: Discussionmentioning

confidence: 79%

Levofloxacin-ceftazidime administration regimens combat Pseudomonas aeruginosa in the hollow-fiber infection model simulating abnormal renal function in critically ill patients

He²,

2020

Preprint

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.