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Use of Inhaled Tobramycin for the Treatment of Severe Nosocomial Pneumonia

Objective: The objective of the study was to estimate the efficacy and safety of Inhaled Tobramycin (IT) as an adjunct to systemic antibiotics in the treatment of severe Nosocomial Pneumonia (NP). Patients and methods: 25 mechanically ventilated patients (out of 165 screened) were enrolled in the current observational single-center study. They were randomized to receive either IT (300mg, BID; group 1, n=15) as an adjunct to systemic antibiotics or for a correction of the regimen of systemic antibiotics (group 2, n=10). The primary outcome measure was resolution of NP and acute respiratory insufficiency. The CPIS, signs of Systemic Inflammatory Response Syndrome (SIRS) and oxygenation index were used as objective indicators of the clinical progress. Results: The following signs of IT efficacy were detected in 87% of group 1 patients: a decrease of SIRS and CPIS scores within 2, 3 ± 1, 2 days of IT therapy (p<0,05); decrease of microbes titer to 103-104 CFU/ml (p<0,05); increase of microbes sensitivity to systemic antibiotics in 40% of patients; positive X-ray dynamics in 60% of patients within 9, 0 ± 2, 5 days of IT therapy. No serious side effects of IT were observed. Conclusion: Administration of IT as an adjunct to systemic antibiotics is efficient and safe in 87% of patients with severe NP caused by multi resistant gram-negative bacteria. *Corresponding author: Artem N Kuzovlev, V.A Negovsky Scientific Research Institute of General Reanimatology RAMS, build 2, 25 Petrovka str., Moscow 107031, Russia, Tel: 0079261887641; Email: artem_kuzovlev@mail.ru Received August 20, 2012; Accepted September 25, 2012; Published September 27, 2012 Citation: Kuzovlev AN, Moroz VV, Goloubev AM, Polovnikov SG, Stec VV, et al. (2012) Use of Inhaled Tobramycin for the Treatment of Severe Nosocomial Pneumonia. J Pulmon Resp Med 2:130. doi:10.4172/2161-105X.1000130 Copyright: © 2012 Kuzovlev AN, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Nosocomial Pneumonia (NP) remains one of the significant problems of the intensive care units worldwide. Multiresistant gramnegative and gram-positive bacteria are prevalent agents of NP. Rational antibiotic therapy is the cornerstone of the treatment of NP. An early onset of antibiotic therapy improves the prognosis dramatically, but still the mortality and bacterial resistance are high. Pseudomonas aeruginosa, Acinetobacter spp., Burkholderia spp., Stenotrophomonas spp. present with a property to form biofilms which protect them against antibiotics and immune cells [1][2][3][4].
Intravenous antibiotics do not reach a bactericidial concentration in the tissue of lungs: intravenously administered antibiotics are primarily detected in the tracheobronchial tree of the lungs, but not in sputum. Increase of daily dose and combining different antibiotics often poses patients to side effects, superinfection and the selection of multiresistant bacteria [3,[5][6][7][8]. Inhaled colistin, tobramycin, cephalosporins, amphotericin B, pentamidin have been used for prophylaxis and treatment of chronic and acute pseudomonal infections in patients with cystic fibrosis and bronchiectases for more than 50 years [9][10][11][12][13][14]. A 28 days course of the IT was proved to be effective in eradication of Pseudomonas aeruginosa in patients with cystic fibrosis [15].
Inhaled antibiotics are not administered without systemic drugs because the degree of their adsorbtion is low (2-4%) and insufficient for the treatment of infections associated with NP which is common in intensive care unit patients. The incidence of the side effects of inhaled antibiotics is low. One of the pitfalls of modern inhaled aminoglycosides is the small size of particles which speeds up their clearance from lungs [9,26,[28][29][30][31][32].
Only few clinical trials and case reports on IT in nosocomial pneumonia in critically ill patients were carried out [16, 32,33]. The objective of the current study was to estimate the efficacy of IT as an adjunct to systemic antibiotics in the treatment of severe NP in critically ill patients.

Materials and Methods
Twenty five mechanically ventilated patients out of a cohort of 165 surgical Intensive Care Unit (ICU) patients were enrolled in the current observational single-center study within the period of 2009-2012 at the V.A. Negovsky scientific research institute of general reanimatology of the Russian academy of medical sciences (Moscow, Russia). The current study received the formal approval from the local Ethical Committee and written informed consents were obtained from all the enrolled subjects or their legal representatives. The research was conducted in accordance with the Declaration of Helsinki, national and institutional standards.
Twenty five patients were randomized in two groups: group 1 (interventional) and group 2 (control). The randomization was performed by the independent medical doctors using closed envelopes with a number of the investigation group inside. Group 1 received IT (group 1, n=15) as an adjunct to systemic antibiotics; the basic antibiotic regimen remained unchanged. Group 2 experienced a correction of the regimen of systemic antibiotics (group 2, n=10) according to bacterial sensitivity to IV tigecycline (n=3, 30%); iv amikacin 1-1, 5 g/day was added to therapy (n=4, 40%); daily dosage of iv meropenem was increased up to 6 g (n=3, 30%).
The primary outcome measure was resolution of NP and acute respiratory insufficiency. The CPIS, signs of SIRS and oxygenation index were used as objective indicators of the clinical progress. Nosocomial pneumonia was diagnosed according to the Russian national guidelines [34] and CPIS [35]. Pneumonias were bilateral and polysegmental in 100% of patients (confirmed by the X-rays (performed on enrollment, on days 5, 7, 14) and computed tomography scans). Sepsis was diagnosed in 100% of patients on enrollment using the standard criteria [36][37][38][39].
All patients experienced a withdrawal of the biological samples for the microbiological essay (analyzer "VITEK Compact", Biomerieux, France) on enrollment, on days 5 and 7. BAL samples were taken during the bronchoscopy in the operation room or in the ICU. Transport media "MEUS S.r.l. " (Piove di Sacco, Italy) was used. Associations of 2-4 multiresistant gram-negative microbes 10 7 -10 8 CFU/ml were detected in all patients. No reliable differences in the incidence of microbes were detected (Table 1).
Inhaled Tobramycin was administered in group 1 in case of inefficacy of the systemic antibiotics (no positive clinical dynamics and deterioration of the acute respiratory insufficiency and SIRS due to NP), simultaneously with systemic antibiotics on day 6, 5 ± 1, 4 of the treatment of NP, 300 mg BID. The daily dosage of IT was reduced to 300 mg/day in case of creatinine clearance less than 50 ml/min (n=2, 20%). Tobramycin was inhaled by "Aeroneb Pro" (Aeroneb, Ireland) nebulizer. The duration of IT therapy was 7, 5 ± 2, 4 days. The following criteria were used for the discontinuation of IT: positive clinical dynamics (decrease of SIRS and acute respiratory insufficiency signs). Systemic antibiotics were normally continued in group 1 for the treatment of the underlying infections.
Adverse events reporting, audiometry, and renal function were monitored to evaluate the tolerability and safety of the IT regimen. No patients were withdrawn from the study for adverse events.

Results and Discussion
All patients enrolled in the study were males, aged 49 ± 7, 3 yr. old No reliable differences in severity were detected between the groups prior the randomization: APACHE II on the day of enrollment was 18, 0 ± 3, 2 in group 1 and 17, 7 ± 3, 5 in group 2; Clinical Pulmonary Infection Score (CPIS) was 8, 5 ± 2, 4 in group 1 and 8, 2 ± 2, 0 in group 2.
Nosocomial pneumonias were ventilator-associated in 100% of patients. NP developed in patients with severe intraabdominal infections (group 1 n=8, 54%; group 2 n=6, 60%), purulent mediastinitis (group 1 n=4, 27%; group 2 n=3, 30%), intracerebral abscesses (group 1 n=2, 14%; group 2 n=1, 10%), tracheoesophageal fistulas (group 1 n=1, 5%; group 2 n=0).   Table 2 deals with the dynamics of the key physiological parameters in groups 1 and 2. No statistically reliable differences (intergroup or between days) were obtained within 8 days of investigation, which can probably be explained by the small sample size and influences of the underlying diseases (peritonitis, mediastinitis, etc.) Administration of IT in group 1 was clinically effective and decreased the signs of SIRS (decrease of body temperature, leukocytosis and amount of purulent discharge from the airways) and acute respiratory insufficiency (increase of the oxygenation index, decrease of the CPIS scores) within 2, 3 ± 1, 1 days from the treatment start in 13 patients in group 1 (87%). The decrease of SIRS signs in group 2 in comparison to group 1 was detected significantly later,6, 3 ± 1, 5 days after the shift of antibiotics (p<0, 05).

Microbes
A significant decrease (p<0, 05) of the titer of pathogenic microbes in BAL on days 5 and 7 in comparison of the titer on enrollment was detected: down to 10 3-4 CFU/ml in group 1 (87% of patients) and in group 2 (50% of patients). Microbes in BAL of 13 patients of group 1 were in vitro sensitive to tobramycin; 2 patients of group 1 (13,4%) presented with in vitro resistance to tobramycin, but still the clinical efficacy of IT was shown in them -probably due to a high local concentration of the inhaled antibiotic [9,31]. An increase of the sensitivity of microbes to antibiotics they were resistant to, prior the IT therapy, was detected in group 1 (40%), which is probably due to the action of IT on biofilms [26].
Positive X-ray and chest computed tomography dynamics was detected in 6 patients (40%) of group 1 within 9, 0 ± 2, 5 days ( Figure  1); there were no such dynamics in group 2. Three patients of group 1 were switched to the continuous positive airway pressure ventilation with pressure support on day 5, 2 ± 1, 7 of IT treatment.
In 2 patients of group 1 (13, 4%, underlying pathologyintraabdominal infections) IT was ineffective and the antibiotic regimen was switched to IV tigecycline in standard doses, which finally provided us with a favourable outcome of NP. The failure of IT regimen was probably due to multi-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumanii/calcoaceticus detected in these patients.
The mortality in group 1 was 27% (n=4), in group 2-30% (n=3). None of the deaths were associated with the progression of NP. Partial hearing loss and tinnitus were registered in 2 patients (14%) of group 1 after the administration of IT. These symptoms resolved spontaneously 3 months after the discontinuation of IT. It is noteworthy that these patients had a very prolonged period of ICU stay (100-120 days) due to the severity of the underlying infections. Therefore, the influence of sepsis and other treatment modalities on the development of hearing loss and tinnitus cannot be excluded. There were no cases of bronchospasm or kidney damage registered, which corresponds well with the data of the other investigations [9,[29][30][31][32].
Future studies of our research group will focus on a mulitcenter trial in a larger population of ICU patients.

Conclusions
Administration of the inhaled tobramycin 300 mg BID as an adjunct to systemic antibiotics is efficient and safe in 87% of patients in treatment of severe nosocomial pneumonia caused by multiresistant gram-negative bacteria.