According to many studies, Ventilator-Associated Pneumonia (VAP) is the most awful nosocomial infection among critically ill patients admitted to Intensive Care Unit (ICU) which usually demands for using broad-spectrum parenteral antibiotics [1-4]. Once the critical ill patients are intubated, the risk of VAP increases by approximately 10 folds in average which is accompanied by at least 30% extra-mortality rate which is further increased in case of multi-drug-resistant gram-negative bacteria (MDR-GNB), including but not excluded to, Enterobacteriaceae. Spp. producing carbapenemase and multidrug-resistant (MDR) Pseudomonas spp. and Acinetobacter spp., after prolonged intubation [5-7]. Globally, the prevalence of MDR-GNB is increasing in an exaggerated manner making the importance of conserving salvaging antibiotics such as Colistin is of our urgent priority [8-10].

Several studies have suggested the use of certain aerosol antibiotics to treat refractory VAP caused by MDR-GNBs. One of the most interesting antibiotics in these scenarios is colistin. Colistin has favourable properties that make it attractive in pharmaco-nebulization treatment strategies that focuses on active bactericidal activity, high barrier resistance, maintenance of activity against MDR-GNB, unique mechanism of action and synergy with other common systemic antibiotics, supported by large controlled studies and many rationales that support its use via nebulization. Rationales for using Colistin nebulizer as an adjunct to systemic antibiotics including colistin IV, including but not excluded to, drug hydrophilicity which belongs to polypeptide antibiotics, poor parenchymal penetration, altered pharmacokinetics in patients undergoing mechanical ventilation in a way that reduces the effectiveness of systemic colistin [11-13].

Our objectives in this study are to investigate the clinical impacts of Colistin nebulizer when adjunctively used at dose regimen of 1 MIU TID with Colistin IV regarding changes in white blood cells, neutrophil and monocyte to lymphocyte ratios, hemodynamic parameters, vasopressor rate, core body temperature, c-reactive protein to albumin ratio, ICU and overall length of stay, early, late and overall mortality (∆WBCs, ∆NLR, ∆MLR, ∆MAP, ∆HR ∆NE, ∆T, ∆ CRP:ALB, LOS and MORT (14<d, ≥14 d, 28 d), respectively.

An observational retrospective study was conducted on eligible 122 adult mechanically ventilated critically ill refractory VAP infected patients admitted to adult ICU of King Hussein Medical Hospital (KHMH) at the Royal Medical Services (RMS) in Jordan between April 2017 and January 2019 after it was approved by our institutional ethical committee. Owing to its retrospective design, a signed consent form was waived. All eligible studied ICU patients were admitted from other surgical or medical wards.

In this study we excluded VAP affected patients if there was a positive history of Colistin hypersensitivity, the patient had a culture based Carbapenem sensitivity, the patient was either died, extubated or discharged before at least 3 days of Colistin IV and nebulizer were overlapped and there were a shortage of patient’s data. Critically ill patients were considered eligible if any ICU admitted patient was intubated for at least 5 days, had a recent culture of MDR-Pseudomonas, MDR-Acinetobacter or Carbapenem Resistant Enterobacteriaceae (CRE).

All eligible mechanically ventilated critically ill VAP affected patients were allocated into either Group I (Colistin IV + Colistin Neb) or Group II (Colistin IV). Analytical variables were firstly evaluated for normality of distribution by using Kolmogorov-Smirnov Test. Normally distributed continuous variables were expressed as Mean±SD by using independent T-Test while non-parametric categorical and ordinal variables were expressed as either Mean (Range) or Number (Percentage) by using Mann-Whitney U Test and Chi Square Test, respectively. All statistical analyses were performed using IBM SPSS ver. 25 (IBM Corp., Armonk, NY, USA) and a p-value ≤ 0.05 is considered sta­tistically significant.

One hundred and twenty-two (N=122) mechanically ventilated critically ill VAP affected patients were included in this study and they were distributed into two studied groups; Group I which included the interventional Colistin Neb at dose regimen of 1 MIU TID in addition to renal adjusted Colistin IV and Group II which included VAP affected studied patients who were on only renal adjusted Colistin IV. Sixty (N=60) eligible patients were allocated to Group I while Sixty-Two (N=62) eligible patients were allocated to Group II. The mean age of the whole study cohort was 59.90±10.85 years and Group II cohort were insignificantly older than Group I cohort (60.10±11.65 years vs 59.70±10.05 years, respectively, p >0.05). Males were significantly distributed in our study at ratio approximately 2:1 compared to females (86 (70.5%) vs 36 (29.5%), respectively, p <0.05) in which 66.7% (40 VAP infected ICU admitted males) were grouped to Group I compared with 25.8% (VAP infected ICU admitted females) were grouped to Group II.

The primary outcome of this study (An overall 28-day ICU mortality) was detected in fifty-two (N=52) with an overall incidence of 46.62% during an average of 10.89±5.34 days and 12.66±5.91 days of ICU and overall hospital LOS days, in which it was significantly lower in studied patients who received the Colistin Neb 1 MIU TID in adjunctive to renal adjusted systemic Colistin IV compared to the contrary group (Group II) at early phase (<14 days), late phase (≥14 days) and overall 28-days (5 (8.33%) vs 10 (16.13%), 15 (25%) vs 22 (35.48%) and 20 (33.33%) vs 32 (51.61%), respectively, p <0.05]. Baseline pre-ICU admission days, ICU stay and overall hospital stay were significantly lower in group I than in group II [1.00±0.00 day, 8.00±0.00 days and 9.00±0.00 days vs 2.29±0.46 days, 13.68±6.36 days and 16.19±6.59 days, respectively, p <0.05).

For infectious variables, ∆WBCs, ∆NLR and ∆MLR between Group I and Group II were also significant decreased, when the Colistin Neb 1 MIU TID were added to the systemic Colistin IV for at least three overlapped days, by Mean differences±SEM of (-3822±264 cells/µL, -4.11±0.34:1 and -0.44±0.04:1, p <0.001). Moreover, the hemodynamic parameters of MAP, NE and HR were significantly improved in Group I as compared with those in Group II by Mean differences±SEM of (+7.14±0.17 mmHg, -7.44±0.23 bpm, -1.07±0.03 µg/min, p <0.001). Mechanically ventilated critically ill VAP affected patients’ comparative variables and analytical outcomes data between Group I and Group II. are fully summarized in Tables 1 and 2.

Table 1: Mechanically ventilated critically ill VAP affected patients’ comparative variables and analytical outcome data between Group I (Colistin Neb + Colistin IV) and Group II (Colistin IV)

Table 2: Mechanically ventilated critically ill VAP affected patients’ comparative variables and analytical outcome data between Group I (Colistin Neb + Colistin IV) and Group II (Colistin IV).

A limited study discussed the clinical impacts of Colistin nebulizer when adjunctively used to Colistin IV in mechanically ventilated critically ill patients with ventilator associated pneumoniae. Here, we compared the clinical impacts in mechanically ventilated critically ill VAP affected patients caused by culture based MDR-GNB that sensitive to Colistin and resistant to all commonly available ABs in our institution. In this study, VAP affected patients who received Colistin IV adjusted according to CrCl (Group II) were compared with comparable VAP affected patients who used in addition to renal adjusted Colistin, Colistin nebulizer at dose regimen of 1 MIU TID for at least 3 days (Group II). The present study demonstrates that the Colistin IV dose was significantly higher in Group I than in Group II (9.94±2.65 MIU vs 6.05±1.08 MIU, p <0.001) because CrCl was significantly lower in Group II than in Group I (30.81±10.91 mL/min vs 64.62±20.28 mL/min, p <0.001). 

Carbapenem-Resistant Enterobacter. Spp. was the most culture isolated bacteria in Group II (19.4%) followed by Acinetobacter Baumannii (16.1%) while in Group I, Carbapenem-resistant Klebsiella pneumonia (KPC) had the highest prevalence in our study (23.3%). Although Group II patients had significantly higher ALB levels than Group I (3.46±0.38 g/dL vs 3.31±0.23 g/dL, p <0.05), Group I patients had a significantly lower overall 28-day ICU mortality as compared with those in the Group II cohort which we explained by the significantly higher CRP levels in Group II than in Group I (35.84±13.59 mg/dL vs 23.21±9.57 mg/dL, p <0.001), which ultimately resulted in a significant difference in ∆CRP:ALB between the two tested groups by Mean difference±SEM of (-3.74±0.77:1, p <0.001). 

While VAP affected critically ill patients are considered the leading cause of mortality in ICUs and the highest indication for using Colistin IV, which pharmacokinetics are altered significantly in these critical cohort when its prodrug form (CMS) is administered intravenously, the mandatory to mitigate the Colistin’s pharmacokinetic barriers by diverse strategies, most commonly by directly instillation Colistin into the lung parenchymal tissues, in hopeful of improving Colistin efficacy by achieving its desired PK/PD and minimizing toxicity through limiting systemic exposure [14,15]. This situation is particularly challenging when the target PKs/PDs of ABs against bacteria at an elevated minimum inhibitory concentration (MIC) which definitely leads to increased toxicity [16-19].

Colistin nebulizer at dose regimen of 1 MIU TID has a positive clinical impact when is adjunctively used with renal-adjusted Colistin IV in mechanically ventilated critically ill patients with ventilator associated pneumonia which caused by multi-drug-resistant gram-negative bacteria. Also, this dual Colistin delivery may mitigate the emergence of pan-resistant GNB by conserving Colistin activity via maximizing its PK/PD parameters. The present study is limited by its retrospective design and an overall lack of robust clinical data; nonetheless, our centre is an experienced and high-volume unit, thus our data may be useful for other centres. A larger, multisite and prospective study is required to control for multiple confounders in critically ill patients with VAP for the widespread adoption of nebulized ABs in clinical practice.

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