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Introduction Pneumonia remains the leading cause of death in intensive care unit (ICU) patients, with an attributed mortality of around 30%. Moreover, it affects the length and cost of the ICU stay. (1) Gram-negative enteric bacilli often multidrug resistant (MDR) to antibiotics are the most frequent causative antimicrobial pathogens. resistance in the (2) ICUs Thus, increasing has challenged intensivists to search for alternative therapeutic options. (3) Since the tissue concentration at the site of infection is a major determinant of the bacterial killing efficiency and clinical response, the use of adjunctive therapy with aerosolized antibiotics (e.g. aminoglycosides, polymixins and colistin) represents one of these. (4, 5) Aerosolized antimicrobial agents have been used in clinical practice since the 1950s. (6) Their administration remains theoretically attractive for the prevention and treatment of hospital-acquired pneumonia (HAP) because of the ability to generate high drug concentrations at the site of 1 infection. There is renewed interest in this area because of the shortcoming of current therapies, increasing MDR gramnegative organisms and the established use of nebulized antibiotics for treatment of chronic infection with pseudomonas areugenosa, particularly in cystic fibrosis and bronchiectasis but with variable clinical efficacy. (7) Clinical trials of aerosolized or endotracheally administered antibiotics for HAP prevention or the ventilator-associated pneumonia (VAP) treatment in adults have generally been positive. (8, 9) Compared to systemic routes of administration (both enteral and parenteral), inhalation achieves higher pulmonary concentrations of antibiotics, with the potential to reduce systemic toxicity. (5, 10, 11, 12) But, it is important to know that the penetration of antimicrobial drugs into the respiratory tract is influenced by both host-related factors, such as inflammation or mechanical injury, and drug-related factors, such molecular 2 weight, product formulation and the nebulizer used (ultrasonic or jet). (13) The hazards of nebulized antibiotics depend on the formula used and the dose administered. The highest local concentrations are associated with the highest peak values in serum and hence more systemic toxicity. (14) The use of intravenous formulations via a nebulizer can lead to exposure to potentially irritant or toxic additives and inappropriate pH or osmolality ranges, with the risk of bronchospasm. (15, 16, 17) In addition, inhaled antibiotic may be deposited poorly or may be virtually absent in regions of the lung where airflow is minimal and where infection is presumably greatest. (18) Labiris and colleagues found that aminoglycosides, including gentamycin, are considered among the most useful classes of antibiotics for treatment of Gram-negative infections. The major drawback was that in its maximum safe intravenous dose, only low sputum concentrations are achievable. Inhalation of the intravenous formula of 3 gentamycin offered the potential benefit of producing high concentrations at the site of infection in the airways, without the risk of systemic toxicity. (19) All these potential risks regarding the use of inhaled aminoglycosides were found negligible when actually studied before. (5, 17, 20) Based on those previous experiences in the use of inhaled antibiotics, our goal in this study was to assess the safety and effectiveness of aerosolized gentamycin as an adjunct to intravenous antimicrobial therapy for treatment of pneumonia in pediatric intensive care unit (PICU). Patients and Methodology: This is a randomized controlled clinical trial. Population: All children, admitted to university hospital based pediatric ICU from September 2009 till September 2010, were enrolled if they met the following criteria: Presence of clinical and/or radiological evidence of pneumonia on admission. Age from 2 months till 14 years. 4 Exclusion criteria: - Known asthmatic children. - Moderate to severe renal insult (serum creatinine above 1.5 times the upper level for age). Patients were subjected to initial evaluation in the form of history and clinical examination, routine laboratory investigations and assessment of severity of illness on admission using the need of mechanical ventilation or the need of inotropes within first 24 hours. Special emphasis was paid to the level of respiratory support needed, white blood cell counts, cultures (blood, sputum and endotracheal) and chest X-ray. Intervention: The patients were randomly assigned to Control group (CG) or Study group (SG) by using sealed envelopes chosen blindly for each patient upon enrollment. Controls culture and received systemic sensitivity if antibiotics cultures were according to available on admission. The routine protocol of the ICU, in the form of 5 double antibiotics as 1st line (Floxacillin, Amoxicillin/clavulonic or Ampicillin/sulbactum plus Amikacin or Cefotaxime) was otherwise given. Study group received the systemic antibiotics by the same concept plus nebulized gentamycin for a period of 7 days at a dose of: 20 mg every 12 hrs in children less than 1year old. 40 mg every 12 hrs in children from 1 year till 5 years old. 60 mg every 12 hrs in children more than 5 years old. (21, 22, 23) We used the intravenous formula of the Gentamycin according to the above dose added to 2.5ml of normal saline. The aerosolized gentamycin was administered by means of small-volume ultrasonic nebulizers (Atom brand). In ventilated patients it was used by the mean of the ventilator nebulizer cup. This form of administration has been officially sanctioned by the U.S. Food and Drug 6 Administration. Each patient in the study group was monitored after the first dose of inhaled gentamycin to detect any change in his airway resistance. Patient’s outcome was assessed by comparing the two groups regarding the length of stay in the ICU, days of systemic antibiotic needs, persistence of same organism with acquiring resistance or the development of new organism, development of adverse effect (as bronchospasm or renal toxicity) and mortality rate. Statistical Analysis: Nominal data were expressed as frequency and were compared using Chi square test. Numerical data were expressed as mean and range and were compared using T test. Non-parametric data were compared using Mann Whitney test. P values < 0.05 were considered significant. Results: 7 After excluding asthmatic patients, those with renal impairment and those without evidence of chest infection, we studied 90 child admitted to the PICU during the duration of the study. (Fig, 1) After randomization using sealed envelopes, both groups were almost the same pattern. (Table, 1) The age of both groups ranged from 2 months till 13 years. The outcome of both groups regarding the length of stay, duration of respiratory support and antibiotics used showed no significant difference. (Table, 2) Leucocytosis on day 7 was more common among Study group17 patients (37.7%) compared with 8 patients (17.7%) of Control group. Fifty five percent of the Study Group patients had day 1 positive cultures compared to 42% in Control Group, with more gram –ve organisms 16 patients (42.2%) than gram +ve organisms 7 patients (15.5%). The dominant organism was pseudomonas areugenosa in 10 patients (22.2%). 8 Regarding microbiological progress between cultures day 1 and day 7, SG had almost same number of +ve cultures becoming –ve when compared with CG 15 (33.3%); 14 (31.1%), respectively. The persistence of same organism in 2nd culture was found only in one patient of the CG (2.2%). (Table, 3) Considering the final outcome of both groups, Control Group had 24(53.3%) discharged patients and 21(46.6%) deaths compared with study group 33(73.3%) discharged patients and 12(26.6%) deaths. This difference in favor of the SG was statistically significant, p=0.024 (figure, 2). Discussion: The principal goals of management of pneumonia in any PICU emphasize early, appropriate antibiotics in adequate doses, adjustment of therapy according to the clinical response and susceptibility data, culture, and an appropriate duration of therapy. These goals are increasingly difficult to achieve, because of hospital-acquired gram9 negative bacteria have acquired resistance to all of the major antibiotic classes. (24, 25) The traditional approach is to administer antibiotics via systemic circulation. Because the airways provide a direct pathway to the lung cells and tissues, aerosolized delivery offers an alternative route, with antibiotic delivery directly to the air/liquid interface in the lung. New and improved delivery devices have made it possible to administer precise doses of inhaled drugs, with pulmonary delivery of 50-70% of the nominal dose. (26, 27) Our study shows that inhaled gentamycin as an adjunct to systemic therapy for the treatment of pneumonias in the PICU, did not help in decreasing the days of antibiotics, the length of stay or the mechanical ventilation days. Those results are similar to those found in study done by Palmer et al, 2008 (28), apart from they had significant results in the decreased weaning days from mechanical ventilation. Our study also demonstrates that the use of aerosolized gentamycin along with systemic therapy is associated with clinical resolution of pneumonia similar to 10 Mohr et al, 2007 (20), but with an insignificantly longer length of stay and duration of antibiotics between SG and CG (p= 0.4048 and 0.4677; respectively. Chastre et al, 2003 (29) found that neither white blood cells (WBCs) nor temperature had normalized; these parameters did not normalize until day 28 of their study. Similar findings were described by Dennesen et al, 2001 (30) who observed that neither WBCs nor temperature returned to normal after 14 days of therapy and by Kollef et al, 2006 who suggested that WBCs may not normalize after successful treatment of pneumonia as a result of multiple inflammatory stimuli from the underlying critical illness. (31) Our treatment approach observes that the use of inhaled gentamycin is associated with normalization of WBCs after 7 days in 62.3% of patients compared to 82.7% of the Control group. The most significant result in this study is the better outcome (discharge versus death) noticed with the inhaled gentamycin group compared with Control group. On the 11 contrary to our findings, the results of Palmer et al, 2008 (28) demonstrates that the mortality rate in both groups was similar. This study demonstrates the safety of inhaled aminoglycosides, without adverse effects reported for either groups (SG and CG). In particular, there is no demonstrated renal toxicity and no reported pulmonary complications. The development of ototoxicity in our patients is not assessed as long-term follow up is lacking. Our study has several limitations, including the small size of the studied groups and the absence of a scoring system to compare the severity of the patient’s conditions on admission. In conclusion, inhaled gentamycin are safe in conjugation with parenteral antibiotics. Moreover, inhaled gentamycin do not foster bacterial resistance and appear to play a role in eradication of pneumonia and better outcome in PICU. 12 References: 1. Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z, Falagas ME. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrugresistant gram-negative bacteria: a prospective study. Respir Med 2008; 102: 407-12. 2. MiChalopoulos A, Kasiakou SK, Mastora Z, Rellos K, Kapaskelis AM, Falagas ME. 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