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

Abstract

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.

The Application of Hollow Fiber Cartridge in Biomedicine

“…A compartment model is added to the system to simulate the in vitro experiment of different half-life drugs [ 15 ]. Based on the apparent volume of distribution (V), when the drug distribution in the body reaches dynamic equilibrium and the volume of the model, the dosage can be calculated [ 16 ]. HFIM is used to study Mycobacterium tuberculosis , for which the EMA issued a qualification opinion.…”

“…It can also be combined with the mechanism model to predict the effect of different administration schemes [ 56 ]. In the study of the bactericidal effect of levofloxacin and ceftazidime on P. aeruginosa , it was also found that the inhibitory effect of the combination regimen on drug resistance in patients with normal renal function and renal insufficiency was different, and nodes of drug resistance could also be observed in the in vitro model [ 16 ].…”

Pharmacodynamics of Linezolid Plus Fosfomycin Against Vancomycin–Resistant Enterococcus faecium in a Hollow Fiber Infection Model

“…More recently, the hollow-fiber infection model (HFIM), which has been widely used to explore how to rationally use antibiotics and reduce bacterial resistance, can provide valuable information about the interactions between antibiotics, bacteria, and host ( Nielsen and Friberg, 2013 ; Burgos and Rodvold, 2019 ; Zhao et al, 2020 ; Agyeman et al, 2021 ). In the HFIM, Tsuji et al (2012) found that the front-loaded dose of linezolid against VREfm could provided the maximal bacterial reductions of about 3 log 10 CFU/ml, but the front-loaded regimens did not inhibit the expansion of resistant subpopulations against VREfm with resistant alleles.…”

Experimental Validation of a Mathematical Framework to Simulate Antibiotics with Distinct Half-Lives Concurrently in an In Vitro Model

“…With a more sophisticated experimental setup, the dynamic model can be further modified to mimic two antibiotic exposures simultaneously, where the elimination half-lives of the individual antibiotics are distinctively different [4]. This framework has been the "gold standard" of the field for more than three decades, and has been used by multiple investigator groups to evaluate combination therapy [5][6][7][8][9][10][11][12][13][14][15][16][17].…”