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Antimicrobial Agents and Chemotherapy, June 2006, p. 2265-2267, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00190-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of Acinetobacter baumannii-Infected Rats

Claire Dahyot,1,2 Sandrine Marchand,1,3 Greisiele Lorena Pessini,1 Claudine Pariat,1 Bertrand Debaene,2 William Couet,1,3* and Olivier Mimoz1,2

EA 3809, Faculté de Médecine et de Pharmacie de Poitiers, Poitiers, France,1 Département d'Anesthésie et Réanimation Chirurgicale, CHU de Poitiers, Poitiers, France,2 Laboratoire de Toxicologie-Pharmacocinétique, CHU de Poitiers, Poitiers, France3

Received 13 February 2006/ Returned for modification 24 March 2006/ Accepted 7 April 2006


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ABSTRACT
 
The aim of this study was to investigate imipenem distribution in muscle and lung interstitial fluids of rats with Acinetobacter baumannii pulmonary infection. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.


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TEXT
 
Imipenem (IPM) is frequently used in intensive care units to treat nosocomial infections such as Acinetobacter baumannii pneumonia (1). Because infections mainly occur in tissue extracellular fluids (ECFs), corresponding free antibiotic concentrations are responsible for the antimicrobial effect, and these can be measured by microdialysis. However most microdialysis studies designed to measure free antibiotic concentrations in tissue ECFs have been performed with muscle (2, 3, 6, 14); a few have been performed with lung tissue but only for noninfected animals (4, 9), including one study by our group with IPM (10). The aim of the present study was to investigate the lung ECF distribution of IPM in a rat model of A. baumannii pneumonia.

IPM monohydrate-sodium cilastatin salt (Tienam; Merck Sharp & Dohme-Chibret Laboratories, Paris, France) was used to prepare imipenem solutions in saline or Ringer solution for intravenous administration or probe perfusion, respectively. Experiments were done in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication 85-23, revised 1985). Three days before the pharmacokinetic experiment, seven male Sprague-Dawley rats (Janvier Laboratories, Le Genest-St-Isle, France), weighing 331 ± 40 g, were rendered transiently neutropenic by intraperitoneal injection of 150 mg · kg of body weight–1 of cyclophosphamide (Endoxan; Baxter Oncology, Halle/Künsebeck, Germany). The day before the experiment, rats were anesthetized and equipped with a vein femoral catheter and blood and muscle microdialysis CMA/20 probes (polycarbonate; molecular mass cutoff, 20,000 Da; membrane length, 10 mm; CMA microdialysis; Phymep, Paris, France) as previously described (10). Animals were then infected intratracheally (12) with 0.3 ml of an A. baumannii suspension containing between 7 and 8 log10 CFU · ml–1 prepared the day before in Mueller-Hinton broth (Fluka, Biochemika Sigma Aldrich Chimie, St Quentin Fallavier, France). The strain (CIP 7034) was isolated from a human with pneumonia and kindly provided by P. Nordmann (Le Kremlin Bicêtre, France). On the day of the experiment, rats were anesthetized in a hermetic enclosure supplied with an air-oxygen-isoflurane mixture (1.5%) (Forene; Abbot, Rungis, France) at a flow rate of 500 ml · min–1 (Anesthesia Unity, Univentor 400; Phymep, Paris, France). Under anesthesia, rats were tracheotomized and mechanically ventilated and the lung microdialysis probe was implanted (10). Compared to our previous study with noninfected rats, oxygen was increased to 60% and isoflurane decreased to 1.2% until the end of the experiment (10). After insertion probes were perfused with Ringer solution at a flow rate of 2 µl · min–1 for 30 min. Individual in vivo recoveries were estimated by retrodialysis by drug and followed by a washout period (10). Then rats received an intravenous infusion of 30 mg · kg–1 of IPM at a flow rate of 10 ml · h–1 over a 30-min period. From the surgery to the start of IPM infusion, a saline infusion was maintained at a flow rate of 1.2 ml · h–1 to prevent dehydration. Dialysates from muscle, lung, and blood were collected over 150 min, at 10-min intervals during the first 60 min and 15-min intervals during the last 90 min, and handled as previously described (10). At the end of the experiment, euthanasia was performed and lungs were removed, weighed, and homogenized in 5 ml of saline. A serial 10-fold dilution of the homogenate was plated onto Mueller-Hinton agar (Fluka, Biochemika Sigma Aldrich Chimie, St Quentin Fallavier, France) for quantitative bacteriological cultures. Pharmacokinetic parameters were determined in each individual rat by a noncompartmental approach according to standard procedures and using WinNonLin 4.0.1 software (Pharsight Corporation, Mountain View, California).

The mean bacterial count in lung homogenates was 5.9 ± 0.7 log10 CFU · g–1 (range, 5.3 to 7.2). In vivo IPM recovery by loss varied between 32.1% ± 3.7% and 58.1% ± 2.3% in blood, between 22.6% ± 2.7% and 51.3% ± 3.2% in muscle, and between 14.8% ± 1.0% and 23.3% ± 0.3% in lung (mean ± standard deviation). Decreases of free IPM concentrations in blood, muscle, and lung tissue with time were monoexponential, and the concentration profiles in these three tissue types were almost identical in all rats, including at early times postdosing (Fig. 1). Pharmacokinetic parameters are presented in Table 1. Areas under the curves (AUCs) were not statistically different between blood, muscle, and lung. Accordingly tissue-to-blood AUC ratios were close to unity (Table 1).


Figure 1
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  		FIG. 1. Individual unbound concentrations of IPM in rats with A. baumannii pneumonia treated by a 30-min intravenous infusion of 30 mg · kg–1 of IPM. Solid ovals, blood; open ovals, muscle; solid triangles, lung.


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  		TABLE 1. Pharmacokinetic parameters (means ± standard deviations) obtained from free IPM concentrations determined by microdialysis in blood, muscle, and lung, using a rat model of A. baumannii pneumonia after a 30-min intravenous infusion of 30 mg · kg–1 of IPM

These results are consistent with data previously published by our group (7, 10). Mean values of IPM blood pharmacokinetic parameters (clearance and volume of distribution) were close to those previously reported (10) but with more interindividual variability. More interestingly in this experimental model of A. baumannii pneumonia, free tissue-to-blood AUC ratios were virtually equal to 1 as already reported for noninfected rats (10).

Most microdialysis studies in animals compared free tissue concentrations to total plasma levels (6, 8). It was often concluded that total plasma levels were higher than free tissue concentrations (5, 6, 8, 14), and corrections for protein binding in order to compare free concentrations in blood and tissues were not often done (6, 8). In fact because drug distribution in soft tissues such as muscle or lung is presumably governed by passive diffusion, unbound concentrations in blood and tissue ECFs should be identical at equilibrium (15). So in order to better address this more relevant issue, we have developed an approach using microdialysis both in tissues and in blood, allowing multiple direct determinations of concomitant unbound drug concentrations in blood and tissue ECFs (7, 10, 11). We have demonstrated that in agreement with basic pharmacokinetic concepts (15) and at least with IPM, free concentrations in blood and tissues were identical in various tissues or fluids such as lung (10), muscle (10), or peritoneal fluid (7) or in various experimental conditions including hypovolemia (11). The present study confirms that even in the presence of infection, unbound IPM AUCs are not statistically different in blood, lung, and muscle, still consistent with theory. Similarly a lack of effect of infection on IPM distribution in peritoneal fluid was recently observed using an experimental model of peritonitis (7). Yet the present observation is not consistent with the findings of a previous study conducted with infected critically ill patients (16). However, muscle-to-blood AUC ratios much less than unity were found not only in patients (estimated as approximately 10% on average) but also in healthy volunteers (about 50% on average). Because IPM is almost totally unbound (13), plasma protein binding cannot explain these results. The authors hypothesized that a reduced tissue perfusion could contribute to this effect (16). However, a reduced blood flow could have an effect on the rate but not the extent of IPM distribution in ECF of soft tissues such as muscle or lung (10). Alternatively, experimental bias due in particular to the absence of probe recovery estimate in every individual subject may have possibly contributed to this apparently limited tissue distribution (16).

In conclusion and in agreement with previous experiments as well as with theory, the present study has not been able to demonstrate an effect of infection on IPM distribution in the ECF of soft tissues such as lung.


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ACKNOWLEDGMENTS
 
We thank Pharsight Corporation for the free supply of WinNonLin through the PAL program and P. Nordmann for the strain of A. baumannii.


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FOOTNOTES
 
* Corresponding author. Mailing address: EA 3809, Pôle Biologie Santé (PBS), Médecine-Sud, Niveau 1, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France. Phone: 33-5-49-45-43-79. Fax: 33-5-49-45-43-78. E-mail: william.couet{at}univ-poitiers.fr. Back


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Antimicrobial Agents and Chemotherapy, June 2006, p. 2265-2267, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00190-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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