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Antimicrobial Agents and Chemotherapy, June 2005, p. 2356-2361, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2356-2361.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of Noninfected Rats

Sandrine Marchand,1,2,{dagger} Claire Dahyot,3,{dagger} Isabelle Lamarche,1 Olivier Mimoz,1,3 and William Couet1,2*

EA 3809, Faculté de Médecine et de Pharmacie, BP 199, 34 rue du Jardin des Plantes, 86005 Poitiers Cedex, France,1 Laboratoire de Pharmacocinétique, PBS, CHU La Milétrie, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France,2 Département d'Anesthésie et Réanimation Chirurgicale, CHU La Milétrie, 86021 Poitiers, France3

Received 2 September 2004/ Returned for modification 30 October 2004/ Accepted 14 February 2005


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The aim of this study was to investigate the imipenem distribution in muscle and lung interstitial fluids by microdialysis in rats and to compare the free concentrations in tissue with the free concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle, and lung. Imipenem recoveries in these three media were determined in each rat by retrodialysis by drug period before drug administration. Imipenem was infused intravenously at a dose of 120 mg · kg–1 over 30 min, and microdialysis samples were collected for 150 min. The whole study was conducted with nonhydrated rats (n = 4) and hydrated rats (n = 6) while the animals were under isoflurane anesthesia. The decay of free concentrations in blood, muscle, and lung with time were monoexponential; and the concentration profiles in these three media were virtually superimposed in both groups. Accordingly, the ratios of the area under the curve (AUC) for tissue (muscle or lung) to the AUC for blood were always virtually equal to 1. Compared to values previously determined with awake rats, clearance was reduced by 2 and 1.5 in nonhydrated and hydrated rats, respectively, but the volume of distribution was unchanged. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
As for many other drugs, pharmacokinetic studies of antibiotics most often rely on plasma data. However, since most infections occur in tissue extracellular fluid, it has been realized that free antibiotic concentrations in the interstitial fluid at the target site are responsible for the antibacterial effect. Although from a theoretical point of view unbound drug concentrations in blood and interstitial fluid of peripheral tissues without physiological barriers such as muscle or lung should be identical at equilibrium (26), the relevance of using plasma antibiotic concentrations rather than tissue antibiotic concentrations has frequently been challenged (21). For many years skin blister studies have been very popular for the monitoring of free antibiotic concentrations in extracellular fluids, but more recently, microdialysis has appeared to be the technique of choice (10). Amino ß-lactam antibiotics have gained considerable attention in recent years, and because unbound concentrations in muscle are relatively accessible and should constitute reasonable predictors of the unbound concentrations in more therapeutically relevant tissues such as lung tissue, many microdialysis studies have been conducted in muscles in both rats (7, 11, 19, 22, 25) and humans (5, 17, 28, 29). However, only two animal studies (11, 22) have been conducted to compare free antibiotic concentrations in muscle and lung.

Imipenem (IPM) is an antibiotic used to treat severe infections of all body systems (3, 18, 32), particularly lower pulmonary infections (1). It is frequently used in intensive care units for the treatment of nosocomial infections (6). A recent microdialysis study in muscle and subcutaneous tissue has shown that the IPM tissue distribution in seriously ill patients is reduced compared with that in healthy volunteers (28), confirming previous observations with piperacillin (5). Several hypotheses including reduced tissue perfusion could be proposed to explain the impaired distribution of IPM in tissue. However, because of the numerous differences between healthy subjects and patients, including age, kidney and cardiovascular function, as well as drug treatment, no clear explanation could be proposed for this reduced tissue distribution (28).

Because experiments with animals allow a better control of such confounding parameters, our objective was to investigate the tissue IPM distribution, initially in healthy rats, with a special focus on the comparison between muscle and lung free interstitial fluid concentrations as well as free blood levels.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals. IPM monohydrate-sodium cilastatin salt (Tienam; Merck Sharp & Dohme-Chibret Laboratories, Paris, France) was used to prepare imipenem solutions in 0.9% NaCl or Ringer solution for intravenous administration and probe perfusion, respectively. All chemicals used were of analytical grade, and all solvents were of high-performance liquid chromatography (HPLC) grade.

Animals. Ten male Sprague-Dawley rats from Janvier Laboratories (Le Genest-St-Isle, France) weighing 288 ± 20 g (mean ± standard deviation [SD]) were used and divided into two groups, a nonhydrated group (n = 4) and a hydrated group (n = 6). All animals were acclimatized in wire cages in a 12-h light-dark cycle for a minimum of 5 days before the beginning of the experiment to allow them to adjust to the new environment. During this period, they had free access to food (A03, Safe; Villemoisson-sur-Orge, France) and water. Ethical approval was obtained from the local animal ethics committee.

Surgery. (i) Vein probe implantation. On the day of the experiment, the rats were anesthetized by isoflurane (Forene; Abbot, Rungis, France) inhalation. They were placed in a hermetic enclosure which was supplied with an air-isoflurane (3.9%) mixture at a flow rate of 500 ml · min–1 (Anaesthesia Unity, Univentor 400; Phymep, Paris, France). When the animals were sleeping, a mask was placed on the muzzle, and the concentration of isoflurane was decreased to 1.9% during the insertion of the probe into the vein and muscle.

The rats were then placed in the dorsal position with the tail toward the experimenter. An incision was made in the skin to expose the right pectoral muscle. An introducer (corresponding to a needle inserted into a tube) was inserted through the pectoral muscle into the right jugular vein. By removing the needle, the blood rose in the tube and a microdialysis CMA/20 probe (polycarbonate; cutoff, 20,000 Da; membrane length, 10 mm; CMA Microdialysis; Phymep) was inserted through the tubing. During surgery, the vein probe was connected to a CMA 102 microdialysis pump (CMA Microdialysis; Phymep) and perfused with 0.1% low-molecular-weight heparin solution at a flow rate of 3.5 µl · min–1. After insertion, the vein microdialysis probe was flushed at 10 µl · min–1 for approximately 15 min to remove bubbles; the flow rate was then decreased to 3.5 µl · min–1 until the end of the surgery. The probe was then secured by suturing it to the pectoral muscle, and the tubing was removed.

(ii) Muscle probe implantation. The right hind leg muscle (biceps femoris) was used for the insertion of the CMA/20 microdialysis probe (polycarbonate; cutoff, 20,000 Da; membrane length, 10 mm; CMA Microdialysis; Phymep). The muscle was exposed, and the probe was inserted with the help of an introducer, which was removed after insertion. The probe was finally secured by suturing it to the muscle. During insertion, the muscle probe was connected to a CMA 102 microdialysis pump (CMA Microdialysis; Phymep) and perfused with Ringer solution (perfusion fluid T1 for peripheral tissues; CMA Microdialysis; Phymep) at a flow rate of 3.5 µl · min–1. As for the vein microdialysis probe, the muscle probe was flushed at 10 µl · min–1 for approximately 15 min to remove the bubbles. The flow rate was then decreased to 3.5 µl · min–1 until the end of surgery.

(iii) Implantation of vein femoral catheter. A polyethylene catheter constituted with the connection of a small-diameter catheter (inner diameter, 0.26 mm; outer diameter, 0.61 mm; Phymep) with a larger one (inner diameter, 0.58 mm; outer diameter, 0.96 mm; Harvard, Les Ulis, France) was implanted in the left femoral vein of the anesthetized rat. The femoral catheter, together with the inlets and the outlets of the probes, was passed subcutaneously so that they exited at the nape. For the hydrated group, saline was administered at a flow rate of 1.2 ml · h–1 directly after the implantation of the femoral catheter and until the beginning of IPM infusion.

(iv) Tracheotomy. The animals were immobilized in a supine position with cervical hyperextension, and the rate of isoflurane flow was increased to 3.5% in order to make the anesthesia deeper. A median incision was made from the suprasternal hollow over 2 cm in the direction of the muzzle. To expose the trachea, the adipose tissue and the muscles were spread. Two silk threads were placed under the trachea, which was incised between the second and the third tracheal rings. The tracheal tube was then inserted and fixed with the previously placed threads. The rats were artificially ventilated with an air-isoflurane mixture (3.5%) at a flow rate of 460 ml · min–1 throughout the experiment by using a rodent respirator (model 683 apparatus; Harvard), with a frequency of 65 to 68 min–1 and a volume of 2.25 to 2.5 ml. After the tracheotomy and before the thoracotomy, the amount of isoflurane was decreased to 2.2%.

(v) Lung probe implantation. The rats were placed on the left lateral decubitus. For the thoracotomy, an incision was made 3 cm below the right foreleg, and the right mean pulmonary lobe was individualized. An introducer, corresponding to a spinal needle (Yale Spinal; 20 gauge; 0.9 by 90 mm; Becton Dickinson S.A., Madrid, Spain), was inserted horizontally through the right median pulmonary lobe. A custom-made linear microdialysis probe (LMP 5.35.35; polyether sulfone; cutoff, 6,000 Da; membrane length, 5 mm; outer diameter, 0.6 mm; Microbiotech, Stockholm, Sweden) was inserted through this spinal needle, which was then removed. After the insertion, the pulmonary probe was connected to a CMA 102 microdialysis pump (CMA Microdialysis; Phymep) and perfused with Ringer solution at a flow rate of 2 µl · min–1. The pulmonary lobe was replaced in the rib cage, which was then superficially closed.

Design of infusion experiments. After insertion, the blood, muscle, and lung probes were perfused with blank Ringer solution at a flow rate of 1 µl · min–1 for 30 min for a stabilization period.

Recovery calculations. After stabilization, the experiment started with a retrodialysis by drug period, during which the probes were perfused at 2 µl · min–1 with Ringer containing IPM (10 µg · ml–1) for 45 min and then at 1 µl · min–1 for 15 min to equilibrate the system. After this equilibration period, microdialysate samples were collected automatically with a CMA/140 microfraction collector (CMA Microdialysis; Phymep) for 40 min by fractions corresponding to 10-min intervals. To determine the in vivo recovery by loss, IPM concentrations in the perfusate (Cin) and in dialysates (Cout) were determined by HPLC. This in vivo relative recovery by loss was expressed as a percentage (RLin vivo) and was calculated for each interval of time as (1)

(1)
The in vivo recovery used to correct the dialysate concentrations was the mean value obtained from the four individual determinations. A washout period of 1 h (45 min at 2 µl · min–1 and 15 min at 1 µl · min–1) with blank Ringer solution perfusion was allowed before the start of intravenous IPM administration to remove the IPM from the probes. The flow rate was maintained at 1 µl · min–1 for the rest of the study (pharmacokinetic investigation).

Imipenem administration. An intravenous infusion of IPM (Tienam) at a dose of 120 mg · kg–1 and at an infusion rate of 10 ml · h–1 was performed over 30 min.

Microdialysis experiment. In each group, at 14 min after the beginning of the intravenous IPM administration (which was time needed to flush the dead volume), the dialysates in 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.

Directly after collection, the microdialysis dialysates were diluted (1:3 [vol/vol] for dialysates collected at 10-min intervals and 1:2 [vol/vol] for the rest of the intervals) with a stabilizer (0.5 M HEPES buffer, pH 6.8; ethylene glycol; HPLC-grade water [1:0.5:0.5; vol/vol/vol]).

Stability of imipenem probe recoveries with time. Three dedicated rats were used to test the stability with time of the in vivo relative recovery by loss of IPM. Probes were perfused at 2 µl · min–1 with Ringer solution containing IPM (10 µg · ml–1) for 45 min and at 1 µl · min–1 for 15 min to equilibrate the system. After this equilibration period, microdialysate samples were collected automatically over 150 min by fractions corresponding to 15-min intervals (flow rate, 1 µl · min–1). The in vivo relative recovery by loss was calculated as described above (equation 1) for each interval of time.

Microdialysis sample analysis. Analysis of IPM in the dialysates was performed by an adaptation of a previously described HPLC assay (12, 13). Standard curves were prepared with IPM in water at concentrations ranging from 0.78 to 100 µg · ml–1. The diluted microdialysates were directly injected onto a Novapack C18 column (150 by 3.9 mm [inner diameter]; Waters, France). The chromatographic system consisted of a Shimadzu (Croissy Beaubourg, France) LC-10AT pump and a Waters 717 plus autosampler connected to a UV detector (SPD 10A Shimadzu UV detector) at 313 nm. Data were recorded and analyzed on a Kromasystem integrator (Bio-Tek, St. Quentin en Yvelines, France). The mobile phase consisted of 0.2 M aqueous borate buffer, pH 7.2; and the flow rate was 1 ml · min–1. The between-day variability of the IPM concentration was characterized at 10 µg · ml–1, with a coefficient of variation equal to 4.1% (n = 14) and an accuracy equal to 102.6% (n = 14).

Noncompartmental pharmacokinetic analysis. Pharmacokinetic parameters were determined in each individual rat by a noncompartmental approach according to standard procedures and with the software WinNonLin 4.0.1 (Pharsight Corporation, Mountain View, Calif.). Total body clearance (CL) was calculated as CL = dose/AUCblood, where AUCblood is the total area under the free blood concentration-versus-time curve, calculated by using the trapezoidal rule. The area remaining under the curve after the last measured concentration, C(last)blood, was determined from C(last)blood/kel,blood. The elimination rate constant (kel,blood) and its corresponding half-life (t1/2,blood) were estimated by least-squares fit of the datum points (log concentration-time) in the terminal phase of the decline. The volume of distribution (V) was obtained from CL/kel,blood. The area under the curve (AUC) and t1/2 in tissues were also estimated by the same procedure and are referred as AUCmuscle, AUClung, t1/2,muscle, and t1/2,lung. Note that although microdialysis allows determination of the unbound drug concentrations in plasma water or tissue extracellular fluid, for simplicity, the subscripts (blood, muscle, and lung) refer to the medium in which the probe was implanted.

Statistical analysis. Concentrations were expressed as means ± SDs. Comparisons of AUC, t1/2, and the maximum concentration (Cmax) obtained for blood, muscle, and lung tissue between rats in the same group were performed by the nonparametric Kruskall-Wallis test, with significance being a P level of <0.05. The ratio of AUCmuscle/AUCblood, the ratio of AUClung/AUCblood, CL, and V between the two groups were compared by a Mann-Whitney test, with significance being a P level of <0.05.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Stability of imipenem probe recoveries with time. The relative recovery by loss (RL) of IPM over a period of 150 min determined in the three dedicated rats varied between 24.1% ± 1.1% and 49.6 ± 2.7% in blood, between 15.4% ± 4.0% and 16.3% ± 1.7% in muscle, and between 5.9% ± 1.5% and 16.0% ± 4.6% in lung tissue. The recovery by loss of IPM differed in blood, muscle, and lung in a particular rat and for a particular probe between experiments but was stable during the duration of any particular experiment (150 min) (Fig. 1).



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  		FIG. 1. Relative recovery by loss of imipenem (%) in blood, muscle, and lung in a representative rat obtained after probe perfusion with imipenem solution (10 µg · ml–1) at a flow rate of 1 µl · min–1 for 150 min.

 
Imipenem distribution study. (i) Nonhydrated group. The decay of free concentrations in blood, muscle, and lung tissue with time were monoexponential; and the concentration profiles in these three media were almost superimposed (Fig. 2), with the concentrations at the end of infusion equal to 253 ± 27, 292 ± 25, and 285 ± 80 µg · ml–1, respectively. Greater between-rat variability was observed in lung tissue than in muscle or blood. The values of the pharmacokinetic parameters obtained for the nonhydrated group are presented in Table 1. Half-lives and AUCs were not statistically different between blood, muscle, and lung, with the AUC ratios being close to 1 (Table 1).



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  		FIG. 2. Unbound imipenem concentrations in nonhydrated rats (n = 4) after a 30-min intravenous infusion of 120 mg · kg–1 of imipenem: superimposed mean concentrations in the three media (blood, muscle, and lung) (a), mean ± SD concentrations in blood (b), mean ± SD concentrations in muscle (c), and mean ± SD concentrations in lung (d).

 

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  		TABLE 1. Values of pharmacokinetic parameters obtained for blood, muscle, and lung of nonhydrated rats (n = 4) after a 30-min intravenous infusion of imipenem at a dose of 120 mg · kg–1

 
(ii) Hydrated group. The decay of free concentrations in blood, muscle, and lung tissue with time were monoexponential; and the concentration profiles in these three media were also virtually superimposed (Fig. 3). The values of the pharmacokinetic parameters obtained in the hydrated group are presented in Table 2. Half-lives and AUCs were not statistically different between blood, muscle, and lung tissue, with AUC ratios still being close to 1 (Table 2). However, the AUCs and half-lives of IPM in each tissue were significantly lower in the hydrated group than in the nonhydrated group (Table 1 and Table 2). CL was increased by a factor of 1.3 between the hydrated group and the nonhydrated group (10.4 ± 0.6 ml · min–1 kg–1 versus 8.0 ± 0.9 ml · min–1 kg–1), and this difference was statistically significant. V was not significantly different between the two groups (326 ± 35 ml · kg–1 in the nonhydrated group versus 330 ± 25 ml · kg–1 in the hydrated group).



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  		FIG. 3. Unbound imipenem concentrations in hydrated rats (n = 6) after a 30-min intravenous infusion of 120 mg · kg–1 of imipenem: superimposed mean concentrations in the three media (blood, muscle, and lung) (a), mean ± SD concentrations in blood (b), mean ± SD concentrations in muscle (c), and mean ± SD concentrations in lung (d).

 

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  		TABLE 2. Values of pharmacokinetic parameters obtained for blood, muscle, and lung of hydrated rats (n = 6) after a 30-min intravenous infusion of imipenem at a dose of 120 mg · kg–1

 

   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Numerous studies have recently been conducted with microdialysis to investigate tissue antibiotic distributions in rats (7, 11, 19, 22, 25). However, although the unbound concentrations were determined in the tissue interstitial space by using microdialysis, the total concentrations were measured in plasma, followed by correction with an averaged unbound fraction value. Intravascular microdialysis is a technique of choice for the direct determination of free drug concentrations in blood (15, 31). It does not require repeated blood sampling, which eventually alters hematocrit and plasma protein concentrations and, therefore, possibly, drug disposition characteristics (10), which was preferred for this study.

Only two articles on the kinetics of antibiotics in rat lungs determined by microdialysis have been published: one with cefaclor and CMA/10 probes (11) and the other with cefpodoxime and CMA/20 probes (22). Our attempts with these probes were not successful because of tissue damage, which was suppressed because of the use of a 5-mm linear flexible probe. Yet, under these conditions IPM recovery in lung tissue ranged from 5.03% ± 0.05% to 16.8% ± 0.2%, which is much less than that in muscle (19.9% ± 3.2% to 53.4% ± 2.8%) or blood (21.9% ± 2.1% to 55.9% ± 1.1%) because of the reduced length and/or the different polymer type of the probe. As a consequence, a small experimental error in recovery estimate results in a relatively larger error in drug concentration estimates (4), which is probably responsible for the greater interanimal variability observed in lung tissue than in the other media (Fig. 2 and Fig. 3).

Lung microdialysis required maintenance of the rats under anesthesia with a thoracotomy for the duration of the study (about 7 h), which could be responsible for the altered values of the pharmacokinetic parameters compared to the values reported previously by our group for awake rats (12, 20). A clearance reduction by half was observed in the initial group of nonhydrated rats (8.0 ± 0.9 ml · min–1 · kg–1 versus 16.4 ± 1.1 ml · min–1 · kg–1), resulting in the impaired renal excretion of IPM. A likely contribution to the clearance reduction was dehydration. It was therefore decided to continue the experiment with rats receiving an intravascular infusion of saline to prevent dehydration. A flow rate of 1.2 ml · h–1, adapted from the literature (27), was selected to account for the fluid volume injected (5 ml) during imipenem perfusion. The IPM clearance in anesthetized and hydrated rats (10.4 ± 0.6 ml · min–1 · kg–1) was closer to but still lower than that previously reported in awake rats (12, 20). The anesthetic agent may therefore have also contributed to the reduced IPM clearance, as isoflurane inhalation has been shown to induce a significant and dose-dependent decrease in blood pressure and cardiac output in dogs (2), with, presumably, decreases in renal blood flow and glomerular filtration, which could explain the reduced IPM clearance in isoflurane-anesthetized rats. However, by reducing the left ventricular stroke volume and, consequently, cardiac output, mechanical ventilation may also have contributed to this observation (16, 23). As opposed to elimination, the IPM distribution was not altered in the anesthetized rats. Carbapenem antibiotics are usually considered to be distributed within the extracellular body water (24). Accordingly, the IPM volume of distribution in rats was previously found (12, 20) to be almost equal to the mean value (297 ml · kg–1) of the extracellular fluid in rats (8). The lack of volume change in anesthetized rats suggests that the extracellular fluid volume was not altered, even in nonrehydrated animals.

The major finding of this study was the observation of virtually superimposed free IPM concentration-versus-time profiles in the three media investigated, with the values of the pharmacokinetic parameters, in particular, those of Cmax and AUC, being very close to each other and with none being statistically significantly different for both the nonhydrated (Table 1) and the hydrated (Table 2) groups. This result not only is in agreement with theory but also is consistent with most of the data in the literature. The first study that used microdialysis to investigate the tissue distributions of ß-lactam antibiotics in rats was conducted in 1992 by Deguchi and coworkers (9). Although probes recoveries were not estimated according to current standards, that study demonstrated that total tissue levels could vary by more than 100-fold with the type of tissue but that the free levels of drug determined in the interstitial fluid were similar for the various tissues studied (9). In other studies that have used microdialysis to measure free antibiotic concentrations in peripheral tissues, total plasma concentrations were presented, but after correction for plasma protein binding, the concentrations measured in these various media should be more or less identical (19, 25).

Yet, similar muscle and lung interstitial fluid concentrations profiles were observed with cefaclor (11) and cefpodoxime (22), but the free tissue concentrations were much less than the corresponding unbound plasma concentrations, in particular, with cefaclor, as assessed by the use of a penetration factor that corresponded to the unbound drug concentration in tissue-to-plasma AUC ratio of 0.26 (11). Because cefaclor is rather unstable, chemical degradation in muscle was a potential explanation for this low AUC ratio and apparently limited the tissue distribution. However, some of these authors found that a similar type of AUC ratio worked with the much more stable compound norfloxacin (14). Therefore, the existence of an unidentified active efflux transport system from tissue is another potential explanation, which was also proposed to explain the limited distribution of amoxicillin in the middle ears of chinchillas (15).

Another important parameter to be considered is the infection itself, since the unbound interstitial fluid concentrations of IPM were reduced in critical care patients compared to those in healthy volunteers (28), suggesting that infection was responsible for the impairment of the IPM tissue distribution. Similarly, the free concentrations of meropenem, another carbapenem antibiotic structurally related to IPM, were lower in infected lung than in presumably noninfected muscle (30).

In conclusion, intravascular microdialysis together with microdialysis of muscle and lung proved useful for investigation of the distribution of IPM and for demonstration that, at least in noninfected rats, the free concentrations in the interstitial fluid of tissues were almost identical and could be predicted from the corresponding free blood levels, in agreement with theory.


   ACKNOWLEDGMENTS
 
We thank Pharsight Corporation for supplying WinNonLin through the PAL program.


   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

{dagger} C.D. and S.M. contributed equally to this paper. Back


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Antimicrobial Agents and Chemotherapy, June 2005, p. 2356-2361, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2356-2361.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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