P - ISSN : 2349-6592    |    E - ISSN : 2455-7099
Year : 2019 | Volume : 6 | Issue : 3 | Page : 15 - 20
Source of Funding:None Conflict of Interest:None
Background and Objective:
The treatment of ventilator-associated pneumonia (VAP) caused by multidrug resistant organisms is challenging even with appropriate intravenous antibiotics. The study was conducted to evaluate the effi cacy and safety of nebulised Colistimethate sodium (CS) in the treatment of Gram negative VAP.
For this prospective, interventional, open label, intention-to-treat, randomized trial, 40 consecutive patients were enrolled on the suspicion of VAP. After exclusion, 13 patients in CS nebulisation group and 15 patients in normal saline (NS) nebulisation group were randomized and completed the study. All patients were on systemic antibiotics. The clinical cure was the primary outcome and secondary outcomes included were microbiological cure, durations of mechanical ventilation and stay in PICU and adverse events related with nebulization therapy.
Two study groups had comparable clinical characteristics. Clinical and microbiological cures occurred in all patients of CS nebulisation group (100%) but in 11 out of 15 (73.3%) patients in NS nebulisation group (p-0.06). The total duration of mechanical ventilation and PICU stay were not signifi cantly different in two groups. No statistically signifi cant differences were observed with regard to adverse events.
Aerosolized CS seems to be safe with no major adverse effects and with no clinical and microbiological benefits. There is need for adequately powered, multicentre study.
Aerosol antibiotics, Gram negative pneumonia, Nebulized Colistimethate sodium, Randomised control trial, Ventilator associated pneumonia
One of the cornerstones of ventilator-associated pneumonia (VAP) management is antibiotic treatment, which currently presents a major challenge because of the emergence of multi-drug resistant (MDR) pathogens. Nebulized antibiotics have been used to treat respiratory tract infections for the last 70 years .1,2 Many theoretical advantages of nebulized antibiotic therapy have been proposed, such as higher drug levels at the infection site and fewer systemic side effect s, enhanced antimicrobial therapy and maximized results.3 70% clinicians have a positive view of adjunctive nebulized antibiotics for VAP treatment.4
Recent studies in adults showed benefi cial effects of Colistimethate sodium (CS) nebulisation in patients with VAP.4-7 To the best of our knowledge no such study has been conducted in children. We hypothesized that nebulized CS would improve the clinical response success rate in the treatment of VAP. The primary objective of this study was to evaluate the effi cacy of adjuvant use of Colistimethate sodium(CS) nebulization leading to clinical cure in patients with VAP and to study the associated adverse effects.
Materials and Methods|
This was an open label, intention-to-treat randomized trial conducted for a period of 1 year in the 12-bed multidisciplinary PICU at an urban, academic, tertiary care, multispecialty hospital. A written informed consent or assent was obtained for the study after explaining the purpose and the need to do such a study. Institutional research and ethical committee approved the study.
All children age 1 month to 16 years, on invasive mechanical ventilation were assessed for VAP using clinical pulmonary infection score (CPIS). Children with CPIS ≥6 and fulfi lling the inclusion criteria were enrolled and randomized.8 The diagnosis of VAP was considered when a child on mechanical ventilation for ≥48 h developed fever, leucocytosis, purulent tracheal secretions, low PO2/FiO2 ratio and new or progressive pulmonary infiltrates in chest radiograph.9 Blind bronchial sampling (BBS) was performed in all enrolled patients and allocated treatment was initiated. Isolation of Gram negative organisms from BBS (colony count 10 4 CFU/ml) was defi ned as defi nite Gram negative VAP. The patients were excluded from the study in the absence of informed consent, presence of renal failure, allergy to CS and those who developed VAP while on CS therapy.
Randomization and drug delivery
Patients were randomized into two groups (A and B) by block randomization, performed by a computer generated randomization algorithm. Group A received systemic antibiotics along with CS nebulization. Group B received systemic antibiotic along with normal saline (NS) nebulization.
5,00,000 IU of CS was reconstituted in 4 mL of normal saline and was delivered immediately after reconstitution via vibrating mesh nebulizer (Aerogen, Ireland), with connection in ventilator circuit, for 10 min or until the nebulized solution container got empty. Group B received only 4 ml NS in the same way.10 Patients with history of hyper-reactive airway disease was nebulized with salbutamol prior to CS nebulization. Nebulized CS or NS was given every 8 hourly and continued through the duration of systemic antibiotics.The regimen and duration of the systemic antibiotic(s) was decided by patient’s attending physician. As a unit policy, all children with multidrug resistant Gram negative VAP are treated with systemic antibiotics for 14 days. All patients in both groups continued to receive all other treatment modalities as per the decision of the attending intensivists.
Respiratory secretions were obtained by BBS on the enrolment to study before instituting new antimicrobials. The BBS as a diagnostic test and its safety profi le had been validated in children with VAP in previous studies from our institution. 9,11 Bacterial growth of ≥ 104 CFU/ml was considered diagnostic. Repeat sample was taken on day 3 and day 7 of starting nebulized CS or normal saline, if patient remained on mechanical ventilation. The decision to wean or to extubate was taken by the attending intensivist who was not participating in the study.
Any adverse effects during nebulization were recorded by the trained qualifi ed staff nurse in every patient. The PICU nurses were trained by the researcher about nebulization techniques, monitoring the patient during nebulization and recording the adverse effects.A renal function test was performed at the time of inclusion in the study, once in 3 days thereafter and as instructed by the attending intensivist.
Other demographic and clinical data of enrolled patients was gathered, including socio-demographic parameters, clinical diagnosis, PRISM score 12 and 24, details of antibiotics received before enrolment in the study, baseline blood investigation, duration of mechanical ventilation and PICU stay.
Defi nition of the outcomes
Clinical outcomes were recorded 72 hours onwards after enrolment in the study. It was classified as clinical cure or clinical failure. Clinical cure was defi ned as complete resolution of all signs and symptoms of pneumonia, with normalization of total leucocyte count and temperature at the end of CS therapy. Clinical failure was defi ned as persistent or worsening of presenting signs and symptoms.
First microbiological culture sample was taken at the time of enrolment. Repeat BBS was taken on day 3 and day 7 after enrolment in study if patient remains on mechanical ventilation. If the patient continues to have persistent growth of same pathogen in repeated samples and patient remained on mechanical ventilation, repeat sample was taken at day 14.
Microbiological culture result of BBS was defi ned as following: eradication, if no growth of the same pathogen as in the last culture of a respiratory specimen; persistent, if yield of same microbe was obtained from BBS along with signs and symptoms of VAP infection; colonization was considered when yield of same pathogen was not associated with clinical signs and symptoms of infection. If patient developed respiratory wheeze within 1 hour after receiving nebulized solution, it was attributed to the nebulization.
Renal impairment was defined according to p RIFLE criteria, if increase in the serum creatinine level of patients occurred with previously normal renal function or a doubling of the baseline serum creatinine level in patients with pre-existing renal insufficiency.
Statistical testing was conducted with the statistical package for the social science system version SPSS 20. Continuous variables are presented as mean ± SD for normally distributed variables or median (Interquartile range (IQR) 25th – 75th centile) for non-normally distributed data. Categorical variables are expressed as frequency and percentages. The comparison of normally distributed continuous variables between the groups was performed using student’s test whilst non-normally distributed continuous variable was compared using Mann Whitney U test. Nominal categorical data between the groups was compared using chi- squared test or Fisher’s exact test as appropriate. Intention to treat analysis was performed to study the effi cacy of interventional drug. For all statistical tests, P value < 0.05 was considered signifi cant.
A sample size and power analysis revealed that 152 participants were required in each arm to show an increment in clinical cure rate from 95 to 100% with use of adjuvant use of nebulized CS with systemic CS. (Power=0.80, α = 0.05 two sided and β=0.2). Since this was a time bound study, less number of patients were enrolled.
There were 803 admissions in the PICU over period of 12 months. Out of these 363 (45.2%) children required assisted ventilation in the form of noninvasive ventilation, heated humidifi ed high fl ow nasal cannula or invasive mechanical ventilation. Two hundred two patients required endotracheal intubation for ventilation. After exclusion from 40 enrolled cases, 35 cases were randomized. (Figure 1) Sixteen patients in CS nebulisation group and 19 patients in NS nebulisation group were analysed. Due to early extubation one case in CS group and 2 patients in saline group, follow up BBS was not done.
The demographic and clinical characteristics of two groups of patients are compared in Table 1. The most common microorganisms isolated in two study groups were Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumonia. Majority of patients suffered with neurological diseases in both the study groups (7 patients in CS group and 8 in NS group). (Table 2)
Table 1 :
Demographic and clinical characteristics of patients
Data represented as numbers and percentages unless indicated. aMedian and interquartile range IQR (25th -75th centile), PRISM pediatric risk of mortality, MV mechanical ventilation, VAP ventilator-associated pneumonia.
Clinical cure was obtained in 93.7% of patients in CS group as compared to 73.6% in saline group (p value 0.12). There was 100% microbiological cure in CS group while it was in 76.5% in NS group (p value 0.06) (Table 3). There were no signifi cant differences in duration of mechanical ventilation and PICU stay after enrolment in two study groups.There were more deaths in the saline group as compared to CS group (P value 0.39
Table 2 :
Primary clinical diagnosis
(SLE systemic lupus erythematosus, RSV respiratory syncytial virus)
Table 3 :
Outcome and adverse events in study cohort and controls
The present pilot, randomized study was done to evaluate the effi cacy of nebulized CS as an adjunctive to standard intravenous antibiotics to treat VAP caused by Gram negative bacteria. We did not fi nd statistically signifi cant results in favour of use of CS nebulization.The proportion of patients receiving CS nebulization along with systemic antibiotics was higher as compared to patients in the saline nebulization group. This fi nding does not support the adjuvant use of aerosolized antibiotics in clinical practice in children. To the best of our knowledge, the present study is the fi rst randomised controlled trial in children that evaluated the effi cacy and safety of nebulised CS as adjunctive therapy in Gram negative VAP.
Many intravenous antibiotics used to treat VAP, including β-lactams, aminoglycosides and vancomycin, have poor penetration into the epithelial lining fl uid (ELF) of the lungs.12 The ELF concentrations for antibiotics are usually less than 50% of the concentrations achieved in the serum.
There are few studies on the pharmacokinetics of inhaled CS. Ratjen et al13 evaluated the CS pharmacokinetics post inhalation in patients with cystic fi brosis and showed higher concentration of drug in sputum even after 12 hours. Nakwan et al14study in mechanically ventilated neonates showed high local concentration of nebulized CS even after 12 hours of single nebulized dose of drug.
In our study, the demography and clinical parameters in two groups were comparable. Our study showed that clinical cure (93.7% vs 73.6%, p value 0.12) as well as microbiological cure (100% vs 76.5%, p value 0.06) were higher in CS nebulisation group as compared to NS nebulisation group. There are few adult studies comparing the results of systemic antibiotics alone with combination of systemic and aerosolized antibiotics. But the results are inconsistent and variable.6,7,15In a randomized controlled trial in adults by Rattanaumpawan et al to assess the effi cacy of adjuvant CS nebulisation in Gram negative VAP did not fi nd signifi cant difference in clinical cure (51% vs 53%, p value 0.84), however statistically signifi cant difference was found in microbiological cure (60.9% vs 38.2%, p value 0.03) between the two study groups. 6 Other cohort study done by Korbila et al7 suggested more clinical cure in CS nebulisation group in VAP (79.5% vs 60.5%, p value 0.02). However, this study did not assess the difference in microbiological cure. Retrospective nature of this study was the major limitation, so author argued for urgent need of randomised controlled trial. Another retrospective 1:1 matched case-control study conducted by Tumbarello et al15 to assess the effi cacy and safety of aerosolized CS in microbiologically documented VAP. This study concluded that compared with intravenous CS cohort, the combination of aerosolized and intravenous CS cohort had a higher clinical cure rate (68% vs 54.8%, p value 0.03) and required fewer days of mechanical ventilation after VAP onset (8 days vs 12 days, p value 0.001). Microbiological cure was not found to be signifi cant (63.4% vs 50%, p value 0.08).
With regard to safety profi le namely cough, bronchospasm and renal dysfunction, we did not observe statistically signifi cant difference between two study groups. Although we found more frequent bronchospasm in CS nebulisation group as compared to NS group (30.7% vs 6.6%) but that did not cause respiratory distress and higher mechanical ventilation settings. Our fi ndings are in concordance with the other studies.6, 7,15
The major limitations of our study include its design, an open label, randomised trial and not a double blind, randomized trial. Another limitation was small sample size as it was a time bound study. Last, this study was performed at a single center and results may not be generalizable to other institutions.
In conclusion, aerosolized CS seems to be safe with no major adverse effects with no clinical and microbiological benefi ts. There is need for adequately powered, multicentre study.
1. Kuhn RJ. Formulation of aerosolized therapeutics. Chest 2001;120: 94S-98S.
2. Ehrmann S, Roche-Campo F, Sferrazza Papa GF, Isabey D, Brochard L, Apiou-Sbirlea G. REVA research network. Aerosol therapy during mechanical ventilation: an international survey. Intensive Care Med 2013;39: 1048-56.
3. Boucher BA, Wood GC, Swanson JM. Pharmacokinetic changes in critical illness. Crit Care Clin 2006;22: 255-71.
4. Lin CC, Liu TC, Kuo CF, Liu CP, Lee CM. Aerosolized Colistimethate sodium for the treatment of multidrug-resistant Acinetobacter baumannii pneumonia: experience in a tertiary care hospital in northern Taiwan. J Microbiol Immunol Infect2010; 43: 323-31.
5. Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, et al. Aerosolized plus intravenous Colistimethate sodium versus intravenous Colistimethate sodium alone for the treatment of ventilatorassociated pneumonia: a matched case-control study. Clin Infect Dis 2010;51: 1238-44.
6. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, Angkasekwinai N, Thamlikitkul V. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother 2010;65: 2645-9.
7. Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas M. Inhaled Colistimethate sodium as adjunctive therapy to intravenous Colistimethate sodium for the treatment of microbiologically documented ventilatorassociated pneumonia: a comparative cohort study. ClinMicrobiol Infect 2010;16: 1230-6.
8. Sachdev A, Chugh K, Sethi M, Gupta D, Wattal C, Menon G. Clinical Pulmonary Infection Score to diagnose ventilatorassociated pneumonia in children. Indian Pediatr 2011; 48: 949-54.
9. Sachdev A, Chugh K, Sethi M, Gupta D, Wattal C, Menon G. Diagnosis of ventilator-associated pneumonia in children in resource-limited setting: a comparative study of bronchoscopic and nonbronchoscopic methods. Pediatr Crit Care Med 2010; 11: 258-66.
10. Pharmax Ltd. Colomycin package insert information. In: Colomycin 1,000,000 IU vial-Colistimethate sodium sulphomethate sodium. 1998; Bexley: Pharmax Ltd; Bexley.
11. Gupta N, Sachdev A, Gupta D, Gupta S. Safety profi le of blind bronchial sampling- A prospective study in pediatric intensive care unit. Pediatr Pulmonol 2018; 53: 942-7.
12. Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fl uid. Antimicrob Agents Chemother 2008;52: 24-36.
13. Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, et al. Pharmacokinetics of inhaled Colistimethate sodium in patients with cystic fi brosis. J Antimicrob Chemother 2006;57: 306-11.
14. Nakwan N, Lertpichaluk P, Chokephaibulkit K, Villani P, Regazzi M, Imberti R. (Pulmonary and Systemic Pharmacokinetics of Colistimethate sodium Following a Single Dose of Nebulized Colistimethate in Mechanically Ventilated Neonates. Pediatr Infect Dis J 2015;34: 961-3.
15. Tumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, et al. Effect of aerosolized Colistimethate sodium as adjunctive treatment on the outcomes of microbiologically documented ventilatorassociated pneumonia caused by Colistimethate sodium-only susceptible gram-negative bacteria. Chest 2013;144:1768-75.