Low-dose intravenous plus inhaled versus intravenous polymyxin B for the treatment of extensive drug-resistant Gram-negative ventilator-associated pneumonia in the critical illnesses: a multi-center matched case-control study

Abstract

Background: The mortality of extensively drug-resistant Gram-negative (XDR GN) bacilli-induced ventilator-associated pneumonia (VAP) is extremely high. The purpose of this study was to compare the efficacy and safety of inhaled (IH) plus intravenous (IV) polymyxin B versus IV polymyxin B in XDR GN bacilli VAP patients.

Methods: A retrospective multi-center observational cohort study was performed at eight ICUs between January 1^st 2018, and January 1^st 2020 in China. Data from all patients treated with polymyxin B for a microbiologically confirmed VAP were analyzed. The primary endpoint was the clinical cure of VAP. The favorable clinical outcome, microbiological outcome, VAP-related mortality and all-cause mortality during hospitalization, and side effects related with polymyxin B were secondary endpoints. Favorable clinical outcome included clinical cure or clinical improvement.

Results: 151 patients and 46 patients were treated with IV polymyxin B and IH plus IV polymyxin B, respectively. XDR Klebsiella pneumoniae was the main isolated pathogen (n = 83, 42.1%). After matching on age (± 5 years), gender, septic shock, and Apache II score (± 4 points) when polymyxin B was started, 132 patients were included. 44 patients received simultaneous IH plus IV polymyxin B and 88 patients received IV polymyxin B. The rates of clinical cure (43.2% vs 27.3%, p = 0.066), bacterial eradication (36.4% vs 23.9%, p = 0.132) as well as VAP-related mortality (27.3% vs 34.1%, p = 0.428), all-cause mortality (34.1% vs 42.0%, p = 0.378) did not show any significant difference between the two groups. However, IH plus IV polymyxin B therapy was associated with improved favorable clinical outcome (77.3% vs 58.0%, p = 0.029). Patients in the different subgroups (admitted with medical etiology, infected with XDR K. pneumoniae, without bacteremia, with immunosuppressive status) were with odd ratios (ORs) in favor of the combined therapy. No patient required polymyxin B discontinuation due to adverse events. Additional use of IH polymyxin B (aOR 2.63, 95% CI 1.06, 6.66, p = 0.037) was an independent factor associated with favorable clinical outcome.

Conclusions: The addition of low-dose IH polymyxin B to low-dose IV polymyxin B did not provide efficient clinical cure and bacterial eradication in VAP caused by XDR GN bacilli. Keypoints Additional use of IH polymyxin B was the sole independent risk factor of favorable clinical outcome. Patients in the different subgroups were with HRs substantially favoring additional use of IH polymyxin B. No patients required polymyxin B discontinuation due to adverse events.

Keywords: Critical illnesses; Extensively drug-resistant Gram-negative bacilli; Inhalation; Polymyxin B; Ventilator-associated pneumonia.

Fig.1

Flowchart of the study inclusion process. VAP: ventilator-associated pneumonia; IH + IV, inhaled and intravenous; IV, intravenous

Fig.2

Comparison of clinical cure and improvement in the different subgroups. SOFA, Sequential Organ Failure Assessment; XDR, extensively drug-resistant; A. baumannii, Acinetobacter baumannii; E. coli, Escherichia coli; K. pneumoniae, Klebsiella pneumoniae; P. aeruginosa, Pseudomonas aeruginosa

Fig.3

Mortality in two treatment groups in the matched population. A All-cause in-hospital mortality; (B) VAP-related in-hospital mortality. IH + IV, inhaled plus intravenous; IV, intravenous. Day 0 represent VAP onset

Fig.4

Comparison of all-cause in-hospital mortality in the different subgroups. SOFA, Sequential Organ Failure Assessment; XDR, extensively drug-resistant; A. baumannii, Acinetobacter baumannii; E. coli, Escherichia coli; K. pneumoniae, Klebsiella pneumoniae; P. aeruginosa, Pseudomonas aeruginosa