Microdialysis study of imipenem distribution in muscle and lung extracellular fluids of infected rats

Background

Imipenem is frequently used in ICUs to treat nosocomial infections. As infections mainly occur in tissue extra-cellular fluid, unbound antibiotic concentrations in this compartment are responsible for the antimicrobial effect. Micro-dialysis allows the measurement of unbound antibiotic concentrations. The aim of this study was to investigate the imipenem distribution in the blood, muscle and lung by micro-dialysis in a rat model of A. baumannii pneumonia, by comparing unbound concentrations between tissues and blood.

Method

Three days before the pharmacokinetic experiment, seven rats were rendered neutropenic by cyclophosphamide intra-peritoneal administration (150 mg/kg body weight). The day before the experiment, under isoflurane anaesthesia, rats were equipped with a femoral vein catheter, an internal jugular vein and a muscle microdialysis probe. At the end of this surgery, animals were infected intratracheally with an A. baumannii suspension (10⁷CFU/ml). The day of the experiment, after tracheotomy and thoracotomy under isoflurane anaesthesia, the lung microdialysis probe was inserted. The study was conducted under inhaled anaesthesia and mechanical ventilation. Imipenem recoveries in the three media were determined in each rat by retrodialysis by drug before imipenem administration (30 mg/kg over 30 min intravenously), then microdialysis samples were collected during 150 min. At the end of experiment, after euthanasia, the lungs were removed and a quantitative bacteriological study was performed to confirm pneumonia.

Results

Decay of free concentrations in the blood, muscle and lung over time were monoexponential and the concentration profiles in these three media were virtually superimposed (Fig. 1). Accordingly, AUC tissue (muscle and lung) to AUC blood ratios were virtually equal to 1. Compared with values previously determined in non-infected rats, a higher interindividual variability was observed in these three media for all the pharmacokinetic parameters, probably due to the immunodeficiency and/or infection [1].

Figure 1

Unbound imipenem concentrations: (a) mean concentrations in blood, muscle and lung; mean ± SD concentrations in (b) lung, (c) blood and (d) muscle.

Conclusion

In this rat model of A. baumannii pneumonia, the imipenem distribution in the lung and muscle could be predicted from unbound blood concentrations since unbound blood, muscle and lung concentrations were superimposed.