Pulmonary versus Systemic Delivery of Antibiotics: Comparison of Vancomycin Dispositions in the Isolated Rat Lung

Vancomycin dispositions in the respiratory system were comparedafter systemic and inhalatory administration under two respiratoryconditions using the isolated-lung model. Inhalatory deliveryled to much higher drug levels in pulmonary tissue and fluids.The respiratory pattern affects vancomycin disposition in thepulmonary system regardless of the administration route.

INTRODUCTION

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INTRODUCTION

Pulmonary drug delivery is an efficient method for the passivetargeting of drugs used in the treatment of pulmonary diseasessuch as asthma, bronchitis, emphysema, and respiratory infections.Nebulization of antibiotics has relevant advantages comparedto other administration modes: drug access to all regions ofthe respiratory system, prolonged delivery periods, and theavoidance of extensive systemic exposure to drugs are some ofthe most interesting features of this practice (6, 9). Vancomycinis a glycopeptide drug indicated for the treatment of serious,life-threatening infections caused by gram-positive bacteriathat are unresponsive to other, less toxic antibiotics (11,17), and this is the drug of choice for the treatment of bronchopneumoniadue to methicillin-resistant Staphylococcus aureus (MRSA), particularlyin the case of patients undergoing mechanical ventilation (3).Renal impairment and ototoxicity are the most significant sideeffects, being the consequences of excessive drug accumulation(15). Owing to the interest in obtaining information about vancomycindisposition after pulmonary delivery, the aims of the presentstudy were to compare the kinetics of this glycopeptide in thepulmonary system after systemic and inhalatory delivery andto evaluate the influence of the respiratory pattern on administrationby both routes.

Experimental protocol.

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Experimental protocol.

Twenty-four male Wistar rats with a mean body weight of 239.89± 19.96 g were used. Twelve hours prior to the experiments,the animals were isolated in cages and allowed access to tapwater ad libitum. The housing and experimental treatment ofanimals were in accordance with the current Spanish legislationand complied with the principles of laboratory animal care.The animals were randomly distributed into four groups: (i)systemic administration, 60 respirations per minute (rpm), 8.4-ml/kgtidal volume; (ii) systemic administration, 30 rpm, 16.7-ml/kgtidal volume; (iii) inhalatory administration, 60 rpm, 8.4-ml/kgtidal volume; and (iv) inhalatory administration, 30 rpm, 16.7-ml/kgtidal volume. The inspiration/expiration ratio was 0.8. Themethod used to isolate lungs and to keep them artificially perfusedand mechanically ventilated has been described in depth previously(13). A dose of 500 µg of vancomycin was administeredby the systemic or inhalatory route. For pulmonary administration,700 µg of drug was dissolved in 7 ml of distilled water.Nebulization was performed using a nebulizer device (ultrasonicaerosol generator 700700-UV TSE system) connected to the artificialventilation system in such a way that 5 ml reached the lungsthrough the cannula for 20 min (nebulization flow rate, 15 ml/h;droplet size range, 1 to 2 µm). Efferent fluid (EF) collectionstarted at the same time as drug administration using a fractioncollector (Gilson FC 203B) programmed at different sample times.Bronchoalveolar lavage (BAL) was carried at the end of experimentsusing 1.2 ml/kg of 0.9% saline solution. Then, the lung wasexcised, weighed, and used for vancomycin quantification. Drugconcentrations in all samples were measured by high-pressureliquid chromatography showing a quantification limit of 0.1µg/ml with a variation coefficient under 9%.

Pharmacokinetic analysis.

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Pharmacokinetic analysis.

Area under the curve and mean transit time (MTT) were estimatedfrom EF drug levels by statistical moment theory (21). Additionalassays under the same experimental conditions but without thetissue were carried out to correct for the influence of thedevice. The distribution volume of the drug in the lung (V)was calculated as the product of the MTT and the perfusion flowrate (5 ml/min) (20).

The distribution coefficient (V/L_w) was also determined, L_wbeing the weight of the isolated lung. Partition coefficientswere estimated from simultaneous concentrations in the threetypes of samples analyzed.

The nonparametric Kruskal-Wallis (10) test was used to compareresults.

Figure 1 shows mean concentration curves of vancomycin in EFafter systemic administration; Table 1 shows the correspondingstatistical moments and derived parameters. The respiratorymode significantly affected the kinetic profile and parametervalues of vancomycin in the isolated lung for systemic and inhalatoryadministration. Figure 2 depicts curves of mean vancomycin concentrationsin EF for the latter route.

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FIG. 1. Mean vancomycin concentrations (± standard deviations) in efferent fluid after systemic administration.

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TABLE 1. Pharmacokinetic parameters of vancomycin in lungs after systemic administration^a

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FIG. 2. Mean vancomycin concentrations (± standard deviations) in efferent fluid after pulmonary administration.

Comparison of systemic and pulmonary administration of vancomycinrevealed limited access of the drug to the systemic space whenadministered by inhalation, regardless of the respiratory pattern.In contrast, as shown in Fig. 3, pulmonary delivery led to highlevels in BAL fluid (BALF) as well as in lung tissue, whilesystemic administration elicited undetectable concentrationsin BALF (<0.1 µg/ml) and very low drug levels in lungtissue (0.10 ± 0.04 and 0.11 ± 0.05 µg/g).Table 2 shows mean partition coefficients of vancomycin forthe two administration modes and both respiratory patterns.

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FIG. 3. Mean vancomycin levels in lung tissue (A) and bronchoalveolar fluid (B) after systemic and pulmonary administration. *, P < 0.05. ND, not detected.

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TABLE 2. Partition coefficients of vancomycin

The results indicate that vancomycin has a limited ability tocross the alveolar-capillary membrane, regardless of the sidethe drug is located on. For both administration routes, vancomycinlargely remained on the administration side, as it was undetectableon the other side of the barrier after systemic delivery anddetectable at extremely low levels after inhalation. Since vancomycinis a hydrophilic molecule with a high molecular weight, itsdistribution is probably controlled by membrane permeabilityinstead of by tissue flow. For this kinetic situation, maintenanceof serum levels for as long a period as possible is the beststrategy to improve drug transference. This would explain whysome clinical studies have related the continuous infusion ofvancomycin to better outcome rates in cases of pneumonia (1,7, 8). Unfortunately, no data on BALF/serum ratios were providedin those studies, although Byl et al. (2) found more sustainedlevels in pleural exudates after continuous infusion comparedto intermittent administration. Although maintenance of highserum levels would be recommended to improve alveolar-capillarymembrane transference for this drug, such an approach couldlead to an increased risk of renal impairment and ototoxicity;pulmonary delivery would be an alternative, with minor riskof drug-induced oto- and nephrotoxicity, since this administrationroute leads to lower systemic exposure.

The present study also confirms the effect of the respiratorypattern on the pulmonary disposition of vancomycin, as EF drugprofiles and parameters showed significant differences regardlessof the administration route. The respiratory mode correspondingto 30 rpm and a 4-ml tidal volume led to higher alveolar-capillarymembrane transference not only for pulmonary delivery but alsofor systemic administration, likely due to the increase of residencetime of the drug and the extension of the transference area.Previous data from Martonen and Katz (14) show that increasedtidal volumes and breath-holding times improve deposition inthe pulmonary region. Although that work was performed for drypowder instead of nebulized solution, their finding might alsoapply to our case.

The interest in the use of pulmonary delivery of vancomycinto reach high concentrations in pulmonary secretions is unquestionable.The results of our study show a BALF/EF partition coefficientvalue of 17.89 for pulmonary delivery (30 rpm and a 4-ml tidalvolume), while this parameter cannot be estimated for the systemicroute owing to the low concentration reached in the BALF. Forthe more unfavorable transport condition, the influence of theroute seemed to be even greater. Not only is the BALF/EF partitioncoefficient favorable for this administration route, but thelung tissue/EF ratio is too, since this had a value of 9.44after inhalation delivery versus 0.49 or 0.50 for systemic route.According to our results, the dose administered (500 µg,corresponding to 2 to 3 mg/kg) affords an excellent partitioncoefficient, but higher doses (10 to 20 mg/kg) would be neededin humans to achieve BALF and lung tissue levels as high aspossible. Nebulization of a more concentrated solution wouldalso be a recommended practice to improve lung tissue and fluidlevels.

The experimental approach using the isolated rat lung may bea useful model for pulmonary drug delivery studies, althoughit has shortcomings related to the difficulty involved in obtainingaccurate estimates of the dose delivered to the lung and bioavailabilitytogether with limitations due to the artificial perfusion mediumused, which lacks some nutrients. This circumstance may be linkedto our findings of low systemic levels reached after pulmonarydelivery, since data from Franz et al. (4) have shown that systemiclevels after the pulmonary delivery of gentamicin and vancomycinare lower for surfactant-depleted animals. Also, Veldhuizenet al. (18) found that pulmonary surfactant is altered duringmechanical ventilation, so this point should be controlled whenthis experimental model is used.

The few available data in clinical practice (19, 5, 12, 16)indicate that pulmonary administration of vancomycin is safeand well tolerated, contributing to the elimination of MRSAfrom the sputum and improving the clinical conditions of cysticfibrosis patients suffering from chronic lung infection. Clinicalassays aimed at determining the most appropriate delivery conditionsas well as the suitability of systemic coadministration, thepotential increase in patient sensitivity, and the influenceof the respiratory pattern on drug disposition would be of greatinterest to determine the usefulness of the pulmonary inhalationof vancomycin. In conclusion, pulmonary administration of vancomycinappears to be an alternative for the treatment of MRSA lunginfections, since it allows high drug levels to be obtainedin respiratory tissue and fluids with no need of sustained serumlevels that increase the incidence of oto- and nephrotoxicity.

ACKNOWLEDGMENTS

We acknowledge the Consejería de Educación dela Junta de Castilla y León for a Ph.D. grant (OrdenEDU/1490/2003).

FOOTNOTES

* Corresponding author. Mailing address: Pharmacy Department, University of Salamanca, Licenciado Méndez Nieto, s/n 37007, Salamanca, Spain. Phone: 34 923 294536. Fax: 34 923 294515. E-mail: asn{at}usal.es

Published ahead of print on 6 August 2007.

REFERENCES

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