1 UVIR Institut Clínic de Pneumologia i Cirurgia Toràcica; 2 Servei de Farmàcia; 3 Laboratori de Farmacologia Clínica, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Villarroel, 170, 08036 Barcelona, Spain
Received 26 February 2004; returned 5 April 2004; revised 26 April 2004; accepted 15 May 2004
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Abstract |
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Aim: To assess bronchial and serum concentrations of imipenem or tobramycin obtained by nebulization or instillation in critically ill mechanically ventilated patients.
Methods: Prospective randomized open trial. Eighteen patients ventilated for more than 48 h were included. Two doses of imipenem/cilastatin (1000/500 mg) separated by 8 h, or two doses of tobramycin 200 mg separated by 12 h were randomly nebulized or instilled into the tracheal tube. Five bronchoaspirates (two bronchoscopic, three blind) and five blood samples were collected on a timed schedule after the second dose. Respiratory and serum samples were analysed by HPLC, and a subset of blood samples was also evaluated by enzyme-immunoassay.
Results: When instilled, imipenem/cilastatin obtained higher concentrations in respiratory secretions than when nebulized (P=0.022, 1 h after the last dose; P=0.029, 2 h after the last dose). Tobramycin showed equally high concentrations when nebulized or instilled. Instillation of tobramycin may result in significant accumulation in patients with renal failure.
Conclusions: High bronchial concentrations of imipenem could only be achieved by instillation, whereas tobramycin seems suitable for both modes of administration. Instillation of these antibiotics is a safe procedure that achieves high drug concentrations in respiratory secretions.
Keywords: administration, dosage , antibiotics , bronchial secretions , inhalation , intensive care , nosocomial pneumonia
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Introduction |
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Materials and methods |
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Between June and December 2001, 18 patients on mechanical ventilation for more than 48 h at inclusion and with suspected or documented respiratory infection were studied. Suspected respiratory infection was defined as the presence of two of the following: radiological infiltrates on chest X-ray, purulent tracheobronchial secretions, fever over 38°C and leucocyte count greater than 12 000 cells/mm3. Exclusion criteria included: known immediate sensitivity to metabisulphite, presence of atelectasis, pulmonary thromboembolism, endobronchial neoplasm or any other conditions that could reasonably directly influence antibiotic deposition or absorption. Patients did not receive parenteral imipenem/cilastatin or tobramycin, but use of other antibiotics was not restricted. Concurrent use of other aminoglycosides or carbapenems was not an exclusion criterion, as the tests applied to measure antibiotic levels are drug specific.
The Hospital Ethics Committee approved the study and informed consent was obtained from the next of kin before enrolment.
Antibiotics and procedures
The assignment to nebulization or instillation was carried out by means of a computer-generated randomization list in two independent blocks, one for each antibiotic treatment. They received two doses of 1500 mg of imipenem/cilastatin (1000/500 mg) at an 8 h interval or two doses of tobramycin 200 mg separated by 12 h either nebulized or instilled. Standard intravenous formulations of tobramycin (Tobramicina Braun; Braun Medical, Barcelona, Spain) and imipenem/cilastatin (Tienam; Merck, Sharp & Dohme, Madrid, Spain) were used. Instilled treatment was prepared as follows: 200 mg (4 mL) of tobramycin with 6 mL of normal saline or 1000/500 mg (powder) of imipenem/cilastatin reconstituted with 10 mL of normal saline. This preparation was slowly injected with a standard syringe into the tracheal tube. Nebulized antibiotics were prepared in a similar manner. The solution of tobramycin or imipenem/cilastatin was administered by means of an ultrasonic nebulizer (NeU-12; Omron Corporation, Tokyo, Japan) at a flow rate of 8 L/min for 30 min. According to the specifications of the manufacturer, this device generates particles of a size ranging from 1 to 5 µm. All patients were in semi-recumbent position and mechanically ventilated in volume control mode with a tidal volume between 8 and 10 mL/kg without concomitant application of positive end expiratory pressure. The nebulization system was connected immediately after the orotracheal tube and in the inspiratory arm of the breathing circuit. The only humidifier systems applied in the breathing circuit were standard heat and moisture exchangers that were removed during nebulization and replaced once the procedure was complete.
Protocol and antibiotic concentration measurements
Protocol and sample collection schedules are shown in Figure 1. Five bronchoaspirates (first two by fibre-optic bronchoscopy) and blood samples were obtained simultaneously at 1, 2, 4, 6 and 8 h after the last dose of imipenem/cilastatin or at 1, 2, 4, 6 and 12 h after the last dose of tobramycin. Fibre-optic bronchoaspirates were collected from segmentary and/or subsegmentary bronchi from the left lower lobe. Blood samples were centrifuged at 3000 rpm and the supernatant, as well as all bronchial secretion samples, were preserved at 70°C until processed. Later, antibiotic concentrations were measured by HPLC. The HPLC system was a HP1100 (Hewlett-Packard, Boise, ID, USA) equipped with an autosampler, a quaternary pump, a spectrophotometric ultraviolet/visible (UV) detector and a computer-based chromatographic data processor workstation.
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A calibration curve was prepared fresh every day of analysis before each use as follows: a standard solution of imipenem (1 mg/mL) made by dissolving 25 mg of the drug (imipenem/cilastatin sodium) in 25 mL of stabilizer solution was arranged in drug-free sputum by adding known amounts of imipenem/cilastatin to give final concentrations ranging from 0.5 to 25 mg/L. The calibration curve was obtained from the peak height values using a linear least square regression analysis. Within this range, the recovery for imipenem was over 99%. Precision was expressed as a coefficient of variation, which was <10% at each of five imipenem concentrations in the range 0.525 mg/L.
Tobramycin HPLC analysis
Analysis was carried out at room temperature using a C18 reversed-phase column (µBondapack C18; 3.9 mmx300 mm; 5 µm particle size; Waters Cromatografía, S.A., Barcelona, Spain). The mobile phase was water/acetonitrile (83:17, v/v) at a flow rate of 1.3 mL/min and the UV detector was set at 214 nm.
Gentamicin (Shering-Plough S.A., Barcelona, Spain) was used as the internal standard (IS) at a concentration of 5 mg/mL in water. It was added to several drug-free sputum specimens to prepare a calibration curve with final concentrations ranging from 20 to 320 mg/L. The calibration curve was obtained from the peak height ratio of the internal standard to the tobramycin, by using a linear least square regression analysis. Within this range, the recovery for tobramycin was over 97%. Precision (expressed as a coefficient of variation) was <9% at each of five tobramycin concentrations in the range 20320 mg/L. Under these conditions, the limit of detection for tobramycin was 20 mg/L when 15 µL of ultrafiltrated sample was injected.
A subset of tobramycin measured in blood samples was also analysed by enzyme-immunoassay20 (ACA analyzer, Dade; Behring, USA,21 limit of detection: 0.5 mg/L).
Statistical analysis
The number of subjects receiving tobramycin was estimated to identify differences in antibiotic concentration in bronchoaspirates over 10 mg/L, assuming an average value of tobramycin concentration of 20±6 mg/L. Sample size for imipenem was calculated to identify a change equal to or greater than 70 mg/L, assuming an average value of imipenem concentration in respiratory secretions of 140±25 mg/L, with an 80% power and significance level=0.05. These expected levels were identified in a previous pilot study.22 Antibiotic concentrations were log-transformed to test for a symmetric distribution and comparisons were studied using Student's t-test. Data were analysed with the SPSS statistical program, version 10.0 (SPSS Inc., Chicago, IL, USA).
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Results |
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Discussion |
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Antibiotic levels in plasma were non-detectable or marginal except for three patients receiving instilled tobramycin who presented with renal failure. We did not observe side effects attributable to antibiotic delivery through the artificial airway by either method. Since instillation of imipenem/cilastatin and tobramycin achieved higher or similar active antibiotic levels to nebulization, the first could be the method of choice when planning adjunctive antibiotic therapy in mechanically ventilated patients.
Tobramycin attained high concentrations in bronchial secretions when either nebulized or instilled through the tracheal tube. However, imipenem concentrations were significantly lower when nebulization was applied. As the preparation of imipenem/cilastatin was reconstituted immediately before administration, it seems unlikely that this can be due to degradation of the drug. The most plausible explanation relates to the physical properties of the solution of this antibiotic. The preparation tends to precipitate in the nebulization device as the solubility limit is exceeded. Thus, less reaches the lower airway. Although we have not studied this issue specifically, it is highly possible that a higher dilution of the drug solution could improve these results. However, this would probably prolong the nebulization period. Administration of a lower dose of imipenem (i.e. 500 mg instead of 1000 mg every 8 h) in the same volume might solve the problem of drug solubility, but it would probably yield even lower drug concentrations in respiratory secretions. In this study, we used imipenem/cilastatin but only determined the carbapenem (imipenem) concentration, as it is the antimicrobial component. Using a cilastatin-free preparation might be more suitable but also less applicable, since no preparation containing imipenem alone is available on the market.
Serum levels of antibiotic were undetectable with nebulization. In one case we found minimal antibiotic levels after instilling imipenem/cilastatin. Most importantly, in three cases we found tobramycin trough serum levels in the range of potential risk of nephrotoxicity with instillation. These three patients presented with acute renal failure. These results indicate that tobramycin undergoes significant bronchial absorption and thus a normal renal clearance is required to avoid possible drug accumulation. It seems that antibiotics may be cleared from the lower respiratory airways by other routes such as the mucociliary transport mechanism.24,25 To date, there is a single published case with trough tobramycin concentrations above the optimal therapeutic range (0.52 mg/L), in a young patient with renal failure after antibiotic endotracheal administration during mechanical ventilation.26 In our study, in patients with stable renal function, toxicity due to drug accumulation after tobramycin administration seemed to be negligible.
To confirm our results, tobramycin samples were also analysed by an enzyme-immunoassay method with a quantification limit lower than the HPLC method used in this study. In a subset of patients, we carried out additional measurements with this technique confirming that absorption was significant in particular cases (patients number 6, 8, and 11; see Table 3). A single patient presented evidence of low-level systemic imipenem absorption. The clinical implications of these findings are: (i) this therapy can only be considered adjunctive to intravenous or oral antibiotic treatment in respiratory infections, and (ii) instillation of tobramycin does not entail the development of side effects due to systemic absorption in patients with normal renal function but, possibly, serum levels should be monitored in patients with impaired renal function. Notably, these procedures proved to be well tolerated and we did not observe any significant change either in physical examination and respiratory sounds or in ventilatory pattern or respiratory mechanics in any patient. Peak and plateau pressures did not exhibit significant variations after nebulization or instillation of antibiotic, thus indicating that respiratory resistance or intrinsic positive end expiratory pressure (PEEP) did not change substantially. In contrast, experience published by other authors, mainly in cystic fibrosis patients, suggests that nebulization of antibiotics can indeed trigger bronchoconstriction phenomena.1518
In fact, a variable degree of bronchoconstriction is occasionally seen in clinical practice in non-ventilated patients. As antibiotic levels obtained with both methods are analogous (and even better for imipenem with instillation), it seems reasonable to consider instillation as an eligible first choice in the clinical setting as adjunctive treatment. Regarding practical issues of application, nebulization cannot be considered complex at all as it can be readily applied, especially in mechanically ventilated patients, in an intensive care setting. However, instillation is the simplest approach and does not require additional equipment.
An important question arises as to whether the differences in both methods of administering antibiotics may be clinically relevant. In principle, it appears reasonable to consider that nebulization could achieve a more uniform and homogeneous distribution along the airway than instillation. Experimental studies, both in ventilated healthy piglets and in animals with pneumonia, have shown that nebulized amikacin achieves high concentrations even in the more peripheral airways and alveoli.27,28 In our work, the first two samples were collected by fibre-optic bronchoscopy from subsegmental bronchi and the last three samples were blind bronchoaspirates. The site of sample collection could theoretically have influenced the concentrations of antibiotic obtained, especially when instilled through the tracheal tube (i.e. higher concentrations in right lower lobe due to gravity and normal bronchial anatomy). In practice, this does not appear to be a critical point as we have found tobramycin concentrations several times higher than the MIC for common pathogens at 1 h and 2 h in all cases without differences in mean concentrations between both methods. In fact, most clinical trials available in ventilated patients have been carried out with intratracheal antibiotic instillation of aminoglycosides or colistin.912
Information on clinical efficacy of nebulization of antibiotics in the ventilated patient is extremely limited. In our view, currently there are not enough published data to elucidate possible differences between both methods in the prevention of ventilator-acquired pneumonia or treatment of infection. The results of our study show equally high drug concentrations with both methods, with the exception of nebulized imipenem/cilastatin as discussed previously. Nevertheless, whether the use of local antibiotics is effective for treatment or prevention of lower respiratory tract infections remains an open question that can only be answered by means of large, randomized, controlled clinical trials.
The main limitation of our study is probably the variability of the sample collection site within the airways. In this study, the first two samples were collected by bronchoscopy and the last three were blind bronchoaspirates. Thus, we are evaluating antibiotic levels of samples obtained with different sample collection methodology. Probably the best method to collect respiratory samples to assess drug concentrations may be fibre-optic bronchoalveolar lavage. However, we did not consider it reasonable to carry out five consecutive bronchoscopies in each patient. The methodology applied appears balanced in order to obtain at least two reliable and representative samples of lower respiratory secretions and three additional bronchoaspirates over time that may be comparable to some extent. We have assessed the antibiotic deposition in bronchial secretions. However, these concentrations are probably not fully representative of those present in lung parenchyma, distal airway and alveoli. The concentration of antibiotic that reaches these sites cannot be easily estimated as it depends on a large number of variables including ventilator settings, patient position, heterogeneity of lung aeration, type of infection and pathogens, density of polymorphonuclear inflammation and mucus plugging of distal bronchioles among other factors. Studies measuring instilled or nebulized antibiotic concentrations in bronchoalveolar lavage fluid in humans are warranted.
In conclusion, instillation of imipenem/cilastatin or tobramycin achieves high antibiotic concentrations in lower respiratory tract secretions and has a potential role in the treatment of mechanically ventilated patients with respiratory infections. We believe that nebulization or instillation of antibiotics must be considered currently only as a possible adjunctive therapy in the treatment of established pneumonia. In view of our results, instillation (a very simple method) should be preferred over nebulization. Further clinical studies should address the role and efficacy of these methods in the prevention of ventilator-acquired pneumonia.
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Acknowledgements |
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Footnotes |
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References |
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2 . Fagon, J. Y., Chastre, J., Vuagnat, A. et al. (1996). Nosocomial pneumonia and mortality among patients in intensive care units. Journal of the American Medical Association 275, 8669.[Abstract]
3 . Torres, A., Aznar, R., Gatell, J. M. et al. (1990). Incidence, risk, and prognosis factors of nosocomial pneumonia in mechanically ventilated patients. American Review of Respiratory Disease 142, 5238.[ISI][Medline]
4 . Rello, J., Ausina, V., Ricart, M. et al. (1994). Risk factors for infection by Pseudomonas aeruginosa in patients with ventilator-associated pneumonia. Intensive Care Medicine 20, 1938.[ISI][Medline]
5 . Palmer, L. B., Smaldone, G. C., Simon, S. et al. (1998). Aerosolized antibiotics in mechanically ventilated patients: delivery and response. Critical Care Medicine 26, 319.[ISI][Medline]
6
.
Fiel, S. B. (1995). Aerosol delivery of antibiotics to the lower airways of patients with cystic fibrosis. Chest 107, 61S4S.
7
.
Ramsey, B. W., Dorkin, H. L., Eisemberg, J. D. et al. (1993). Efficacy of aerosolized tobramycin in patients with cystic fibrosis. New England Journal of Medicine 328, 17406.
8
.
Ramsey, B. W., Pepe, M. S., Quan, J. M. et al. (1999). Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. New England Journal of Medicine 340, 2330.
9 . Rouby, J. J., Poète, P., Martin de Lassale, E. et al. (1994). Prevention of Gram negative nosocomial bronchopneumonia by intratracheal colistin in critically ill patients. Histologic and bacteriologic study. Intensive Care Medicine 20, 18792.[ISI][Medline]
10 . Klastersky, J., Huysmans, E., Weerts, D. et al. (1974). Endotracheally administered gentamicin for the prevention of infections of the respiratory tract in patients with tracheostomy: a double-blind study. Chest 65, 6504.[ISI][Medline]
11 . Klastersky, J., Carpentier-Meunier, F., Kahan-Coppens, L. et al. (1979). Endotracheally administered antibiotics for gram-negative bronchopneumonia. Chest 75, 58691.[Abstract]
12 . Brown, R. B., Kruse, J. A., Counts, G. W. et al. (1990). Double-blind study of endotracheal tobramycin in the treatment of gram-negative bacterial pneumonia. Antimicrobial Agents and Chemotherapy 34, 26972.[ISI][Medline]
13 . O'Riordan, T. G., Greco, M. J., Perry, R. J. et al. (1992). Nebulizer function during mechanical ventilation. American Review of Respiratory Disease 145, 111722.[ISI][Medline]
14 . Dhand, A. R. & Tobin, M. J. (1998). Inhaled drug delivery in mechanically-ventilated patients. European Respiratory Monographs 8, 13961.
15 . Schoeffel, R. E., Anderson, S. D. & Altounyan, R. E. C. (1981). Bronchial hyperreactivity in response to inhalation of ultrasonically nebulised solutions of distilled water and saline. British Medical Journal (Clinical Research Ed.) 283, 12857.[Medline]
16 . Maddison, J., Dodd, M. & Webb, A. K. (1994). Nebulized colistin causes chest tightness in adults with cystic fibrosis. Respiratory Medicine 88, 1457.[CrossRef][ISI][Medline]
17 . Dodd, M. E., Abbott, J., Maddison, J. et al. (1997). Effect of tonicity of nebulised colistin on chest tightness and pulmonary function in adults with cystic fibrosis. Thorax 52, 6568.[Abstract]
18 . Nikolaizik, W. H., Jenni-Galovic, V. & Schöni, M. H. (1996). Bronchial constriction after nebulized tobramycin preparations and saline in patients with cystic fibrosis. European Journal of Pediatrics 155, 60811.[CrossRef][ISI][Medline]
19 . Duarte, A. G., Fink, J. B. & Dhand, R. (2001). Inhalation therapy during mechanical ventilation. Respiratory Care Clinics of North America 7, 23360.[Medline]
20
.
Wilson, J. F., Davis, A. C. & Tobin, C. M. (2003). Evaluation of commercial assays for vancomycin and aminoglycosides in serum: a comparison of accuracy and precision based on external quality assessment. Journal of Antimicrobial Chemotherapy 52, 7882.
21 . ACA Behring Analyser. [Online.] http://www.dadebehring.com. (13 May 2004, date last accessed).
22 . Soy, D., Corominas, N., Adrover, M. et al. (2000). Sputum and serum antibiotic concentrations after instilled or nebulized imipenem or tobramycin in ICU patients maintained on mechanical ventilation. In Program and Abstracts of the International Congress on Clinical Pharmacy, Monterey, CA, 2000. Abstract 46, p. 316. American College of Clinical Pharmacy & European Society of Clinical Pharmacy, Kansas City, MO, USA.
23 . Levy, J., Smith, A. L., Kenny, M. A. et al. (1983). Bioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum. Journal of Infectious Diseases 148, 106976.[ISI][Medline]
24 . Valcke, Y., Pauwels, R. & Van Der Straeten, M. (1990). Pharmacokinetics of antibiotics in the lungs. European Respiratory Journal 3, 71522.[Abstract]
25 . Pennington, J. E. (1981). Penetration of antibiotics into respiratory secretions. Review of Infectious Diseases 3, 6773.[ISI][Medline]
26 . Kahler, D. A., Schowengerdt, K., Fricker, F. J. et al. (2003). Toxic trough serum concentrations after administration of nebulized tobramycin. Pharmacotherapy 23, 5435.[CrossRef][ISI][Medline]
27 . Goldstein, I., Wallet, F., Robert, J. et al. (2002). Lung tissue concentrations of nebulized amikacin during mechanical ventilation in piglets with healthy lungs. American Journal of Respiratory and Critical Care Medicine 16, 1715.
28
.
Goldstein, I., Wallet, F., Nicolas-Robin, A. et al. (2002). Lung deposition and efficiency of nebulized amikacin during Escherichia coli pneumonia in ventilated piglets. American Journal of Respiratory and Critical Care Medicine 166, 137581.
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