PK-PD modeling of β-lactam antibiotics: In vitro or in vivo models?

Abstract

A modified E max -pharmacokinetic-pharmacodynamic (PK-PD) model was previously proposed in literature for describing the antimicrobial activity of b-lactam antibiotics based on in vitro experiments. However, bacteria behave differently in vitro and in vivo. Thus, the aims of this study were to model the killing effect of piperacillin (PIP) against Escherichia coli on immunocompromised infected rats using this model and to compare the parameters obtained in vitro and in vivo for the same bacteria/drug combination. The PK-PD parameters determined in vitro and in vivo were as follows: generation rate constant of 1.30 ± 0.10 and 0.76 ± 0.20 h À1 , maximum killing effect of 3.11 ± 0.27 and 1.38 ± 0.20 h À1 and concentration to produce 50% of the maximum effect of 5.44 ± 0.03 and 1.31 ± 0.27 lg ml À1 , respectively. The comparison between the in vitro and in vivo parameters was not straightforward and had to take into consideration the intrinsic differences of the models involved. So far, the main application of the PK-PD model evaluated is for the comparison of different antimicrobial agent's potency and efficacy, under equivalent conditions.

Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

“…Given that in many cases plasma concentrations may not reflect tissue concentrations (9,18,22) and infection may (22) or may not (13) alter the antimicrobial tissue disposition, knowledge of the antimicrobial pharmacologically active free interstitial concentrations is crucial to better design dosing regimens (23). Our results showed discrepancies between the free plasma and free interstitial lung concentrations in the rat model of biofilm infection, which mimics the pulmonary infection observed in CF patients.…”

Pharmacokinetic-Pharmacodynamic Modeling of Antibacterial Drugs

“…Even though serum concentration is often used as a surrogate for the concentration at the actual site of infection, there are some in vivo experimental models in which the drug concentration can be fairly easy to measure at the target site, e.g., cerebrospinal fluid for the meningitis model (Lutsar et al, 1997) or the epithelial lining fluid for the pneumonia model (Rodvold et al, 2009). The microdialysis technique offers the possibility of obtaining the unbound (free) interstitial concentration at the site of infection (Liu et al, 2002;de Araujo et al, 2011). It is noteworthy that the drug concentration in tissue homogenates is generally not a good representation of the drug concentration at the target site since the drug is normally not homogenously distributed in the different compartment of tissues (interstitial fluids, intracellular fluids, different cell types, etc.…”

“…Thigh infection model. The mouse thigh infection model was first introduced by Eagle et al (1953) and has been further developed and widely used by others (Kunst and Mattie, 1978;Gerber et al, 1982;Hoogeterp et al, 1988;Vogelman et al, 1988;Craig et al, 1991;Jumbe et al, 2003;DeRyke et al, 2007;Andes et al, 2009;Dudhani et al, 2010;de Araujo et al, 2011). The thigh infection is produced by injecting bacteria (10 5 -10 8 CFU in a volume of 0.1 ml of broth) into the thigh of anesthetized mice.…”

“…This model structure has also been shown to be applicable for characterizing the growth and killing kinetics following antibacterial drug treatment in vivo (Zhi et al, 1988;de Araujo et al, 2011). In 1988, Zhi and colleagues used the murine peritonitis model to follow the bacterial count data over time (every 10 minutes during 3 hours) after different drug exposures (Zhi et al, 1988).…”

Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

“…The free local drug concentrations in specific tissues of the body can differ from those found in the systemic circulation and possibly be more representative of the drug distribution at the active site (14). Our research group has been using microdialysis to investigate antibacterials and antifungals tissue penetration in healthy and infected rodents, including norfloxacin (15) and piperacillin (16) in skeletal muscle, gatifloxacin in muscle and lung (17), and voriconazole (18) and fluconazole (19) in renal cortex.…”