Secondary Prophylaxis With Inhaled Colistin to Prevent Recurrence of Pseudomonas aeruginosa and Extended-spectrum β-lactamase-producing Enterobacterales Pneumonia in ICU After Lung Transplantation: A Before-and-after Retrospective Cohort Analysis : Transplantation

Journal Logo

Original Clinical Science—General

Secondary Prophylaxis With Inhaled Colistin to Prevent Recurrence of Pseudomonas aeruginosa and Extended-spectrum β-lactamase-producing Enterobacterales Pneumonia in ICU After Lung Transplantation: A Before-and-after Retrospective Cohort Analysis

Tran-Dinh, Alexy MD, PhD1,2; Slassi, Lina MD1; De Tymowski, Christian MD, PhD1; Assadi, Maksud MD1; Tanaka, Sébastien MD, PhD1,3; Zappella, Nathalie MD1; Lortat Jacob, Brice MD1; Jean-Baptiste, Sylvain MD1; Atchade, Enora MD1; Castier, Yves MD, PhD4,5; Mal, Hervé MD, PhD5,6; Mordant, Pierre MD, PhD4,5; Armand-Lefèvre, Laurence MD, PhD7,8; Messika, Jonathan MD, PhD5,6,9; Grall, Nathalie MD, PhD7,8; Montravers, Philippe MD, PhD2,5

Author Information
doi: 10.1097/TP.0000000000004187
  • Free

Abstract

INTRODUCTION

Lung transplantation (LTx) is a life-saving therapy for end-stage chronic respiratory diseases1,2; however, the overall median survival of 6.7 y is still lower than that of any of the other solid organ transplants.3 Infections, of which pneumonia is the most common cause, are a major cause of early mortality during the first year after LTx, accounting for 37% of deaths.4 In a multicenter prospective study, Aguilar-Guisado et al5 showed that 72% of lung transplant recipients had at least 1 episode of pneumonia during the first year, with almost half of the episodes occurring within the first month. The pneumonia was principally of bacterial origin (83%), mainly gram-negative bacilli (GNB; 72%), with Pseudomonas aeruginosa as the most common isolate (25%). Moreover, the authors showed that pneumonia was an independent risk factor for 1-y mortality. Preventing the recurrence of pneumonia due to infection with difficult-to-treat pathogens such as P aeruginosa may be beneficial after LTx, and it might also improve chronic lung allograft dysfunction-free survival and graft survival.6

Colistin is an antibiotic that has been used for many years, but it has recently gained renewed interest because of the increasing incidence of infections due to multidrug-resistant GNB.7-9 In nontransplant patients, inhaled colistin (IC) monotherapy has been shown to have a similar therapeutic efficacy to intravenous (IV) colistin in treating pneumonia due to multidrug-resistant pathogens.8,10-13 IC is also frequently used to eradicate P aeruginosa in patients with chronic respiratory diseases, such as noncystic fibrosis bronchiectasis14,15 and cystic fibrosis.16 Moreover, IC was shown to prevent or at least delay respiratory colonization by P aeruginosa in cystic fibrosis lung transplant patients who were not previously colonized.17

In our institution, since January 2018, we have implemented secondary prophylaxis with IC to prevent the recurrence of P aeruginosa or extended-spectrum β-lactamase-producing Enterobacterales (ESBL-PE) pneumonia during the postoperative stay in the intensive care unit (ICU) after LTx. The aim of our study was to compare the prevalence of recurrent P aeruginosa and ESBL-PE pneumonia in the ICU after LTx before-and-after IC protocol implementation.

MATERIALS AND METHODS

Study Design

We conducted a retrospective, single-center, before-and-after study by including all patients who underwent LTx between January 2015 and December 2020. The period from January 2015 to December 2017 preceding the introduction of the secondary prophylaxis protocol with IC was defined as the observation period, and the period from January 2018 to December 2020 was defined as the intervention period. We compared the recurrence rates of P aeruginosa or ESBL-PE pneumonia between the observation and intervention periods.

Secondary Prophylaxis With IC

In January 2018, we instituted a protocol of secondary prophylaxis with IC to prevent the recurrence of P aeruginosa and ESBL-PE pneumonia during the posttransplant ICU stay. At the first occurrence of P aeruginosa or ESBL-PE pneumonia, IC monotherapy (colistin methanesulfonate 3 million international units [MIU] powder reconstituted with 6 mL sterile water for nebulization twice daily, Sanofi-aventis, Paris, France) was started concomitantly with IV antibiotic therapy. The standard duration of IV antibiotic therapy was 7 d, whereas IC was maintained for at least the duration of the ICU stay as secondary prophylaxis. For ventilated patients, IC was administered using vibrating-mesh nebulizers (Aerogen, Galway Business Park, Dangan, Galway, Ireland) positioned 15 cm before the Y piece, generating particles sufficiently small to reach the lung parenchyma. A filter was inserted on the expiratory branch to protect the ventilator flow device and changed between each nebulization to avoid obstruction of the expiratory flow.

Definition of Pneumonia and Recurrence

Pneumonia was defined as in the recommendations for cardiothoracic transplant patients.18 We included pneumonia in both ventilated and nonventilated patients. A diagnosis of pneumonia was established when clinical, biological, radiographic, and microbiological criteria were met by a collegial discussion with the daily staff in the ICU with all the intensivists and once a week during a transplant staff with the pulmonologists and the surgeons. Clinical, biological, and radiographic criteria were fever (temperature >38 °C), cough if not ventilated, dyspnea, purulent secretions, gas exchange degradation, elevated white blood cell count, and chest imaging revealing a new or progressive alveolar or interstitial or cavitation that could not be explained by any other noninfectious cause. Microbiological criteria were the detection of microorganisms in representative respiratory samples (plugged telescoping catheter, ≥103 CFU/mL or bronchoalveolar lavage, ≥104 CFU/mL).19,20

The recurrence of P aeruginosa or ESBL-PE pneumonia was defined as the occurrence of pneumonia with the same bacterial species but not necessarily with the same antibiotic susceptibility profile, occurring >7 d after the initial pneumonia was treated with appropriate antibiotic therapy.

The study was approved by the ethics committee CEERB Paris Nord (Institutional Review Board -IRB 00006477- University of Paris, AP-HP.Nord).

Data Collection

The following data were recorded: (1) pretransplant characteristics (age, sex, body mass index, cause of pulmonary disease, cytomegalovirus serologic status, high-emergency LTx, extracorporeal membrane oxygenation (ECMO) as bridge-to-transplant, coronary artery disease with angioplasty and stent, estimated glomerular filtration rate and mean pulmonary arterial pressure, estimated glomerular filtration rate, known history of P aeruginosa or ESBL-PE infection/colonization within 1 y before LTx); (2) LTx characteristics (type of LTx, ie, single or bilateral, maximum graft ischemic time, intraoperative ECMO); (3) postoperative ICU stay features (simplified acute physiology score II [SAPS II], sequential organ failure assessment [SOFA] score, acute kidney injury stage 3 of Kidney Disease: Improving Global Outcomes (KDIGO), renal replacement therapy, duration of mechanical ventilation, duration of norepinephrine support, ECMO in the ICU, tracheostomy, ICU length of stay, P aeruginosa and ESBL-PE pneumonia, grade 3 primary graft dysfunction, side effects related to IC; and (4) mortality rates in the ICU at 30 and 90 d.

Perioperative Management

Surgical transplantation procedures and perioperative care, including postoperative management, were standardized for all patients according to our local protocol.21 The immunosuppressive regimen included mycophenolate mofetil (1000 mg intraoperatively, then 1000 mg every 12 h postoperatively), prednisolone (1000 mg intraoperatively and 125 mg/d for 48 h, followed by 1 mg/kg/d and decreasing by 5 mg/wk to a minimum dose of 0.25 mg/kg), and tacrolimus with a residual blood concentration target of 10 to 12 ng/mL. Perioperative antibiotics were routinely administered for 48 h after LTx. Cefazolin (or the antibiotic that was administered to the donor before LTx) was the standard prophylactic antibiotic therapy. During the intervention period, patients with a known history with P aeruginosa or ESBL-PE infection/colonization within 1 y before LTx received prophylactic antibiotic therapy tailored to account for this history, and colistin prophylaxis was introduced immediately after surgery during postoperative ICU admission.

Objectives

Primary Objective

The primary objective was to compare the proportion of patients who had at least 1 recurrence of P aeruginosa or ESBL-PE pneumonia in the observation and intervention periods.

Secondary Objectives

The secondary objectives were to compare the ICU, 30-, and 90-d posttransplant mortality rates and the duration of mechanical ventilation between the observation and intervention periods. We also evaluated the impact of P aeruginosa and ESBL-PE pneumonia and their recurrence on the outcome of lung transplant recipients, irrespective of time period.

Statistical Analysis

Baseline characteristics within each group were described with numbers and percentages for qualitative variables and medians and interquartile ranges for quantitative variables. Baseline characteristics and primary and secondary end points were compared between the 2 periods by univariate analysis using χ2 or Fisher exact test for categorical variables and the Mann-Whitney U test for quantitative variables. To assess the impact of the intervention period on the recurrence rate of P aeruginosa or ESBL-PE pneumonia, multivariate associations were calculated using a binary logistic regression model; variables with 2-sided nominal P < 0.1 were included in the multivariate model, with the exception of variables with collinearity. We used a threshold of 0.05 to identify statistical significance. All statistical analyses were performed using IBM SPSS Statistics, version 20 (IBM Corp, Armonk, NY).

RESULTS

Impact of Secondary Prophylaxis With IC on Preventing P aeruginosa or ESBL-PE Pneumonia

Population Description

From January 2015 to December 2020, 271 lung transplant recipients were included (125 in the observation period and 146 in the intervention period). A comparison of the pretransplant recipient characteristics, intraoperative features, and postoperative outcomes between the 2 periods is presented in Table 1.

TABLE 1. - Comparison of characteristics and outcomes of lung transplant recipients before (observation period) and after (intervention period) the implementation of secondary prophylaxis with inhaled colistin
All patients (n = 271) Observation period (n = 125) Intervention period (n = 146) P
Pretransplant conditions
 Age, y 57 (50–62) 56 (50–62) 57 (50–62) 0.38
 Female sex 97 (35.8) 44 (35.2) 53 (36.3) 0.85
 Cause
  Emphysema 98 (36.2) 47 (37.6) 51 (34.9) 0.65
  Interstitial lung disease 131 (48.3) 62 (49.6) 69 (47.3) 0.70
  Others 43 (16) 16 (12.8) 27 (18.9) 0.18
 Pretransplant coronary angioplasty and stent 11 (4.1) 6 (4.8) 5 (3.4) 0.57
 eGFR, mL/min/1.73 m2 90 (88–90) 90 (90–90) 90 (84–90) 0.11
 Pretransplant mPAP, mm Hg 25 (20–30) 26 (22–30) 25 (19.5–30) 0.16
 ECMO as bridge-to-transplant 19 (7.0) 9 (7.2) 10 (6.8) 0.91
 High-emergency lung allocation 50 (18.5) 23 (18.4) 27 (18.6) 0.96
 Pretransplant P aeruginosa or ESBL-PE infection/ colonization 5 (1.8) 4 (3.2) 2 (1.4) 0.32
Lung transplant surgery
 Type of LTx
  Single LTx 87 (32.1) 44 (35.2) 43 (29.5) 0.78
  Double LTx 184 (67.9) 81 (64.8) 103 (70.5) 0.31
 Maximum graft ischemic time, min 330 (270–400) 310 (270–380) 360 (280–420) 0.001
 Intraoperative ECMO 190 (70.1) 89 (71.2) 101 (69.2) 0.72
Postoperative ICU stay
 SAPS II at admission 43 (38–50) 43 (38–46) 46 (38–57) 0.001
 SOFA score at admission 7 (6–9) 8 (7–9) 7 (5–9) 0.04
 Acute kidney injury (KDIGO 3) 38 (14) 19 (15.2) 19 (13) 0.61
 Renal replacement therapy 30 (11.1) 15 (12) 15 (10.3) 0.65
 Duration of mechanical ventilation, d 3 (1–20) 3 (1–12.5) 4 (1–23.3) 0.09
 Duration of vasopressor support, d 2 (1–4) 1 (1–3) 2 (1–4.75) 0.01
 ECMO in ICU 76 (28) 34 (27.2) 42 (28.8) 0.78
 Duration of ECMO in ICU, d 0 (0–1) 0 (0–1) 0 (0–1) 0.46
 Tracheotomy 69 (25.5) 26 (20.8) 43 (29.5) 0.10
 Pneumonia due to P aeruginosa or ESBL-PE 52 (19.2) 23 (18.4) 29 (19.9) 0.88
  Pneumonia due to P aeruginosa 42 (15.5) 19 (15.2) 23 (15.8) 0.90
  Pneumonia due to ESBL-PE 14 (5.2) 8 (6.4) 6 (4.2) 0.27
 Recurrence of pneumonia due to P aeruginosa  or ESBL-PE 10 (3.7) 9 (7.2) 1 (0.7) 0.007
  Recurrence of pneumonia due to P aeruginosa 8 (3.0) 7 (5.6) 1 (0.7) 0.03
  Recurrence of pneumonia due to ESBL-PE 4 (1.5) 4 (3.2) 0 (0) 0.04
 Grade 3 primary graft dysfunction 48 (17.7) 24 (19.2) 24 (16.4) 0.55
 Length of stay, d 17 (10–34) 14 (9–24) 18 (11–38) 0.08
Mortality
 ICU mortality 40 (14.8) 16 (12.8) 24 (16.4) 0.40
 30-d mortality 22 (8.1) 8 (6.4) 14 (9.6) 0.38
 90-d mortality 40 (14.8) 17 (13.6) 23 (15.8) 0.73
ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ESBL-PE, extended-spectrum β-lactamase-producing Enterobacterales; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; LTx, lung transplantation; mPAP, mean pulmonary arterial pressure; SAPS II, simplified acute physiology score II; SOFA, sequential organ failure assessment.

The lung transplant recipients were predominately male (64.2%) with a median age of 57 y. They primarily received double LTx (67.9%) for chronic obstructive pulmonary disease/emphysema (36.2%) or interstitial lung disease (48.3%). Overall, we did not observe any differences in the pretransplant characteristics of the patients between the 2 periods. Twenty-three patients had respiratory diseases causing bronchiectasis (cystic fibrosis [n = 4], alpha-1 antitrypsin deficiency [n = 2], others [n = 17]). Four patients had a history of P aeruginosa (n = 3) or ESBL-PE (n = 1) infection/colonization in the year preceding LTx in the observation period and 2 patients in the intervention period (P aeruginosa n = 1 and ESBL-PE n = 1).

Whereas there was no difference in intraoperative ECMO duration of mechanical ventilation, length of ICU stay, and ICU, 30-, and 90-d mortality rates between the 2 periods, patients transplanted during the intervention period had a longer maximum cold graft ischemic time, higher SAPS II and SOFA severity scores at ICU admission, and a longer duration of norepinephrine treatment.

Regarding the potential side effects of nephrotoxicity and bronchoconstriction related to colistin toxicity, the rate of acute kidney injury stage 3 of KDIGO was similar between the observation period and the intervention period. No patient experienced bronchospasm after IC.

Pneumonia

Fifty-two patients (19.2%) experienced at least 1 episode of P aeruginosa or ESBL-PE pneumonia throughout the study period (Table 1), with 40 (76.9%) ventilator-associated pneumonia cases and 12 (23.1%) nonventilated-associated pneumonia cases. The prevalence of P aeruginosa and ESBL-PE pneumonia was 15.2% and 7.2%, respectively, in the observation period and 15.8% and 4.1%, respectively, in the intervention period. The median duration (interquartile range) of the first P aeruginosa or ESBL-PE pneumonia episode was 7 (5–17) d in the observation period and 8 (4–17) d in the intervention period. Among patients with P aeruginosa pneumonia, 13 (31%) were related to wild strains. The bacterial species responsible for ESBL-PE pneumonia were Klebsiella pneumoniae (n = 7), Escherichia coli (n = 6), and Klebsiella aerogenes (n = 1). Pretransplant conditions, transplant surgery features, and postoperative outcomes after LTx were similar in the 2 periods among patients who had P aeruginosa or ESBL-PE pneumonia (Table 2).

TABLE 2. - Comparison of characteristics and outcomes of patients with P aeruginosa or ESBL-PE pneumonia before (observation period) and after (intervention period) the implementation of secondary prophylaxis with inhaled colistin
Patients with P aeruginosa or ESBL-PE pneumonia (n = 52) Observation period (n = 23) Intervention period (n = 29) P
General characteristics
 Age, y 57 (48–62) 57 (47.5–60) 56 (49–61) 0.59
 Female sex 14 (26.9) 5 (21.7) 9 (31) 0.54
 Cause
  Emphysema 19 (36.5) 9 (39.1) 10 (34.5) 0.73
  Interstitial lung disease 26 (50) 12 (52.2) 14 (48.3) 0.78
  Others 7 (13.5) 2 (8.7) 5 (17.2) 0.44
 Pretransplant coronary angioplasty  and stent 11 (4.1) 6 (4.8) 5 (3.4) 0.57
 eGFR, mL/min/1.73 m2 90 (80–90) 90 (80–90) 90 (80–90) 0.85
 Pretransplant mPAP, mm Hg 26 (21.5–26) 28 (25–32) 25 (19.5–28.5) 0.06
 ECMO as bridge-to-transplant 5 (9.6) 1 (4.3) 4 (13.8) 0.37
 High-emergency lung allocation 10 (19.2) 2 (8.7) 8 (27.6) 0.16
Lung transplant surgery
 Type of LTx
  Single LTx 17 (32.7) 9 (39.1) 8 (27.6) 0.38
  Double LTx 35 (67.3) 14 (60.9) 21 (72.4) 0.55
 Maximum graft ischemic time, min 332 (272–414) 330 (278–390) 334 (270–435) 0.37
 Intraoperative ECMO 40 (76.9) 18 (78.3) 22 (75.9) 0.84
Postoperative ICU stay
 SAPS II at admission 46.5 (38.5–54) 43 (39–48) 48 (42–60) 0.13
 SOFA score at admission 8 (6–10) 9 (7–10) 8 (6–10) 0.25
 Acute kidney injury (KDIGO 3) 15 (28.8) 9 (39.1) 6 (20.7) 0.15
 Renal replacement therapy 10 (19.2) 6 (26.1) 4 (13.8) 0.31
 Duration of mechanical ventilation, d 26.5 (6–42) 27 (10.5–42) 25 (5–55) 0.68
 Duration of vasopressor, d 3 (2–8) 3 (1–6.5) 4 (2–9) 0.15
 ECMO in ICU 24 (46.2) 9 (39.1) 15 (51.7) 0.41
 Duration of ECMO in ICU, d 0 (0–3) 0 (0–2) 1 (0–3) 0.38
 Tracheotomy 31 (59.6) 13 (56.5) 18 (62.1) 0.69
 Recurrence of pneumonia due to  P aeruginosa and ESBL-PE 10 (19.2) 9 (39.1) 1 (3.4) 0.003
  Recurrence of pneumonia due to   P aeruginosa 8 (15.4) 7 (30.4) 1 (3.4) 0.01
  Recurrence of pneumonia due to   ESBL-PE 4 (7.7) 4 (17.4) 0 (0) 0.03
 Grade 3 primary graft dysfunction 20 (38.5) 10 (43.5) 10 (34.5) 0.51
 Length of stay, d 44 (20–72) 37 (19–89) 45 (26–55) 0.90
Mortality
 ICU mortality 10 (19.2) 5 (21.7) 5 (17.2) 0.68
 30-d mortality 1 (1.9) 0 (0) 1 (3.4) 1
 90-d mortality 7 (13.5) 3 (13) 4 (13.8) 1
ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ESBL-PE, extended-spectrum β-lactamase-producing Enterobacterales; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; LTx, lung transplantation; mPAP, mean pulmonary arterial pressure; SAPS II, simplified acute physiology score II; SOFA, sequential organ failure assessment.

Recurrence

The proportion of patients who experienced at least 1 recurrence of P aeruginosa or ESBL-PE pneumonia was significantly lower after the initiation of secondary prophylaxis with IC than the observation period in overall population (0.7% versus 7.2%, P = 0.007; Table 1) and among patients with P aeruginosa or ESBL-PE pneumonia (10% versus 66.7%, P = 0.003; Table 3). In multivariate analysis, the intervention period was independently associated with fewer recurrences in patients with P aeruginosa or ESBL-PE pneumonia (odds ratio = 0.06 [95% confidence interval, 0.001-0.49], P = 0.025). The differences observed in maximum graft ischemic time, SAPS II and SOFA score upon ICU admission, and duration of norepinephrine support between the 2 periods were not associated with recurrences of P aeruginosa or ESBL-PE pneumonia (Table 3).

TABLE 3. - Comparison of the characteristics and outcomes of lung transplant recipients with P aeruginosa or ESBL-PE pneumonia according to the occurrence of recurrence
Patients with P aeruginosa and ESBL-PE pneumonia (n = 52) No recurrence of pneumonia (n = 42) Recurrence of pneumonia due to P aeruginosa or ESBL-PE (n = 10) P
General characteristics
 Age, y 57 (48–62) 56.5 (48–61) 57.5 (47–60) 0.94
 Female sex 14 (26.9) 30 (71.4) 8 (80) 0.71
 Cause
  Emphysema 19 (36.5) 15 (35.7) 4 (40) 0.80
  Interstitial lung disease 26 (50) 21 (50) 5 (50) 1
  Others 7 (13.5) 6 (14.3) 1 (10) 1
 Pretransplant coronary angioplasty  and stent 11 (4.1) 1 (2.4) 0 (0) 1
 eGFR, mL/min/1.73 m2 90 (80–90) 90 (80–90) 90 (84–90) 0.71
 Pretransplant mPAP, mm Hg 26 (21.5–26) 25.5 (20.5–30.5) 29 (25–30) 0.28
 ECMO as bridge-to-transplant 5 (9.6) 5 (11.9) 0 (0) 0.57
 High-emergency lung allocation 10 (19.2) 9 (21.4) 1 (10) 0.66
Lung transplant surgery
 Type of LTx
  Single LTx 17 (32.7) 15 (35.7) 2 (20) 0.47
  Double LTx 35 (67.3) 27 (64.3) 8 (80) 0.47
 Maximum graft ischemic time, min 332 (272–414) 337 (285–420) 304.5 (210–390) 0.24
 Intraoperative ECMO 40 (76.9) 31 (73.8) 9 (90) 0.42
Postoperative ICU stay
 Intervention period 29 (55.8) 28 (66.7) 1 (10) 0.003
 SAPS II at admission 46.5 (38.5–54) 47.5 (38–54) 46 (43–48) 0.86
 SOFA score at admission 8 (6–10) 8 (6–10) 9 (6–10) 0.46
 Acute kidney injury (KDIGO 3) 15 (28.8) 10 (23.8) 5 (50) 0.10
 Renal replacement therapy 10 (19.2) 7 (16.7) 3 (30.0) 0.34
 Duration of mechanical ventilation, d 26.5 (6–42) 24 (5–42) 36 (26–64) 0.09
 Duration of vasopressor, d 3 (2–8) 3 (2–8) 3 (1–7) 0.77
 ECMO in ICU 24 (46.2) 18 (42.9) 6 (60) 0.48
 Duration of ECMO in ICU, d 0 (0–3) 0 (0–3) 1 (0–4) 0.27
 Tracheotomy 31 (59.6) 22 (52.4) 9 (90) 0.04
 Grade 3 primary graft dysfunction 20 (38.5) 16 (38.1) 4 (40) 0.91
 Length of stay, d 44 (20–72) 42.5 (18–55) 63.5 (31–96) 0.10
ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ESBL-PE, extended-spectrum β-lactamase-producing Enterobacterales; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; LTx, lung transplantation; mPAP, mean pulmonary arterial pressure; SAPS II, simplified acute physiology score II; SOFA, sequential organ failure assessment.

The time from the onset of the first P aeruginosa or ESBL-PE pneumonia to the first recurrence was 18.5 (11–25) d.

Among patients with a known history with P aeruginosa or ESBL-PE infection/colonization within 1 y before LTx, 2 had postoperative recurrence of P aeruginosa pneumonia during the observation period.

Impact of P aeruginosa or ESBL-PE Pneumonia and Their Recurrence on Postoperative Outcomes

Overall, recipients who experienced P aeruginosa or ESBL-PE pneumonia had similar pretransplant and transplant surgery features but worse early outcomes without an impact on survival (Table 4). P aeruginosa or ESBL-PE pneumonia was associated with higher ICU morbidity in terms of the duration of mechanical ventilation, duration of norepinephrine support, acute kidney injury stage 3 of KDIGO, renal replacement therapy, ECMO in the ICU, tracheotomy, and length of ICU stay. Grade 3 primary graft dysfunction was a risk factor for P aeruginosa or ESBL-PE pneumonia in the univariate analysis. The ICU, 30, and 90-d mortality rates were not different between patients with and without pneumonia (Table 4). The recurrence of P aeruginosa or ESBL-PE pneumonia was associated with tracheostomy (Table 3).

TABLE 4. - Comparison of characteristics and outcomes of lung transplant recipients according to the occurrence of P aeruginosa or ESBL-PE pneumonia
All patients (n = 271) No pneumonia (n = 219) Pneumonia due to P aeruginosa or ESBL-PE (n = 52) P
General characteristics
 Age, y 57 (50–62) 57 (51–62.5) 57 (48–60.5) 0.64
 Female sex 97 (35.8) 83 (37.9) 14 (26.9) 0.15
 Cause
  Emphysema 98 (36.2) 79 (36.1) 19 (36.5) 0.95
  Interstitial lung disease 131 (48.3) 105 (47.9) 26 (50) 0.79
  Others 43 (16) 36 (16.7) 7 (13.5) 0.68
 Pretransplant coronary angioplasty  and stent 11 (4.1) 10 (4.6) 1 (1.9) 0.70
 eGFR, mL/min/1.73 m2 90 (88–90) 90 (90–90) 90 (80–90) 0.05
 Pretransplant mPAP, mm Hg 25 (20–30) 25 (20–30) 26 (22–30) 0.41
 ECMO as bridge-to-transplant 19 (7) 14 (6.4) 5 (9.6) 0.41
 High-emergency lung allocation 50 (18.5) 40 (18.3) 10 (19.2) 0.88
Lung transplant surgery
 Type of LTx
  Single LTx 87 (32.1) 70 (32) 17 (32.7) 0.78
  Double LTx 184 (67.9) 149 (68) 35 (67.3) 0.92
 Maximum graft ischemic time, min 330 (270–400) 330 (270–400) 332 (273–408) 0.87
 Intraoperative ECMO 190 (70.1) 150 (68.5) 40 (76.9) 0.31
Postoperative ICU stay
 SAPS II at admission 43 (38–50) 43 (38–50) 46.5 (39–54) 0.17
 SOFA score at admission 7 (6–9) 7 (6–9) 8 (6–10) 0.047
 Acute kidney injury (KDIGO 3) 38 (14) 23 (10.5) 15 (28.8) 0.001
 Renal replacement therapy 30 (11.1) 20 (9.1) 10 (19.2) 0.04
 Duration of mechanical ventilation, d 3 (1–20) 2 (1–7) 26.5 (6.5–42) 0.001
 Duration of vasopressor support, d 2 (1–4) 1 (1–3) 3 (2–7.5) 0.001
 ECMO in ICU 76 (28) 52 (23.7) 24 (46.2) 0.001
 Duration of ECMO in ICU, d 0 (0–1) 0 (0–0) 0 (0–3) 0.001
 Tracheotomy 69 (25.5) 38 (17.4) 31 (59.6) 0.001
 Grade 3 primary graft dysfunction 48 (17.7) 28 (12.8) 20 (38.5) 0.001
 Length of stay, d 17 (10–34) 14 (9–22.5) 44 (20–71.5) 0.001
Mortality
 ICU mortality 40 (14.8) 30 (13.7) 10 (19.2) 0.38
 30-d mortality 22 (8.1) 21 (9.6) 1 (1.9) 0.09
 90-d mortality 40 (14.8) 33 (15.1) 7 (13.5) 1
ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ESBL-PE, extended-spectrum β-lactamase-producing Enterobacterales; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; LTx, lung transplantation; mPAP, mean pulmonary arterial pressure; SAPS II, simplified acute physiology score II; SOFA, sequential organ failure assessment.

DISCUSSION

In this study, we identified the potential value of secondary prophylaxis with IC monotherapy to prevent the recurrence of P aeruginosa or ESBL-PE pneumonia in the ICU after LTx. Compared with the IV route, IC achieves higher concentrations in the lungs, above the minimum inhibitory concentration and the mutation prevention concentration at the site of infection, with reduced systemic toxicity such as nephrotoxicity.10,13 Only 1 study including 70 lung transplant recipients for cystic fibrosis has evaluated IC monotherapy after LTx. The authors found that, among 15 patients who were not colonized by GNB in the immediate posttransplant period, 3 out of 9 patients treated with IC did not have any colonization at 12 mo, whereas all of the other 6 patients who were not treated with IC had colonization with difficult-to-treat bacteria; however, IC was ineffective in eradicating these microorganisms among patients who were colonized after transplant surgery.17 Eight studies have previously shown promising results for IC monotherapy in the treatment of pneumonia due to multidrug-resistant pathogens in nontransplant patients; however, only 3 of the studies included >100 patients. Lu et al11 studied the clinical recovery and ICU mortality rates of 122 patients with ventilator-associated pneumonia caused by P aeruginosa and Acinetobacter baumannii susceptible to β-lactams, aminoglycosides, or quinolones who were treated with IV antibiotics for 14 d (=sensitive group) and compared them with 43 patients with ventilator-associated pneumonia caused by multidrug-resistant P aeruginosa and Acinetobacter baumannii and treated with IC either in monotherapy (n = 28) or combined with 3 d of IV aminoglycosides (n = 15) for a total antibiotic therapy time of 7 to 19 d (=multidrug-resistant group). The efficacy of IC was similar to that of IV antibiotic therapy, with clinical recovery and ICU mortality rates of 66% and 23% in the sensitive group versus 67% and 16% in the multidrug-resistant group, respectively. Wang et al22 conducted a retrospective study including 135 patients with multidrug-resistant pneumonia or colonization who were treated with IC monotherapy (n = 54) or IC associated with either IV antibiotic therapy (n = 27), tigecycline (n = 40), or ampicillin/sulbactam (n = 12). They showed a significantly higher eradication rate in patients receiving IC monotherapy than patients receiving IV therapy only (61.1% versus 29%, P = 0.0001) but no difference in the 28-d and in-hospital mortality rates.22 Another retrospective, case-control study showed no difference in the 30-d mortality of 212 patients with extensively drug-resistant A baumannii pneumonia who received either IC alone (n = 106) or combined with tigecycline (n = 106).23

Regarding pathophysiological hypotheses, polymyxins rapidly kill bacteria by disrupting the outer and inner membranes of GNB24 and exert a potent antiendotoxin effect by inhibiting the activity of lipid A.25 In ventilated piglets with massive P aeruginosa inoculation pneumonia who were treated with colistin nebulization, high colistin concentrations measured in postmortem subpleural lung samples were observed.26 IC could potentially control P aeruginosa biofilms,27,28 although nebulized combination antibiotics may be more effective than monotherapy29 and tolerance to colistin may develop.30

Secondary prophylaxis with IC appears to be effective in reducing the recurrence of P aeruginosa and ESBL-PE pneumonia, but it does not reduce short-term ICU morbidity and mortality. The duration of mechanical ventilation and ICU stay and the ICU, 30-, and 60-d mortality rates were similar between observation and intervention periods, raising the question of the true utility of secondary prophylaxis with IC; however, we observed an additional risk of tracheotomy for patients who experienced a recurrence of P aeruginosa or ESBL-PE pneumonia, although this result should be interpreted with caution, as the indication for tracheotomy after LTx is multifactorial. Furthermore, P aeruginosa or ESBL-PE pneumonia occurring during the posttransplant ICU stay was associated with higher ICU morbidity but did not reduce early survival. This result was not expected, as Aguilar-Guisado et al5 observed that pneumonia was an independent risk factor for 1-y mortality; however, we could assess mortality only at 3 mo. Finally, the cost of a 1-d treatment with IC of 36 euros seems acceptable considering the potential benefits on P aeruginosa and ESBL-PE pneumonia.

Patients with sustained P aeruginosa or ESBL-PE airway infections or colonizations before LTx or patients with a primary diagnosis of bronchiectasis, such as cystic fibrosis or alpha-1 antitrypsin deficiency, should probably be considered differently and may benefit from routine maintenance of IC in postoperative care if they were already treated with it or even from the introduction of primary prophylaxis with IC, to be evaluated in a future study. We used an arbitrary dosage of 3 MIU of colistin twice daily. Previous studies used doses ranging from 1 MIU twice daily31 to 5 MIU thrice daily,11 without significant observed side effects. Nephrotoxicity and bronchoconstriction are most common adverse events associated with colistin, especially with IV administration.12,32 Colistin exerts toxicity on renal tubular cells,33 but it has been shown that plasma concentrations of colistin after nebulization remain low (<2 µg/mL) because of its slow diffusion into the systemic circulation and rapid renal elimination.34 In our study, we could not identify acute kidney injury related to colistin toxicity because we did not monitor plasma concentrations of colistin and acute kidney injury during the postoperative ICU stay after LTx is multifactorial. Nonetheless, we observed no difference in the rate of acute kidney injury stage 3 of KIDIGO or renal replacement therapy between the observation period and the intervention period (Table 1). Bronchospasm is the most described adverse effect, but its prevalence remains quite low, from 2% to 7%, and is well managed with bronchodilators10,15; however, in view of the potential adverse effects, caution should be exercised until a prospective, randomized study confirms these results.

Our study has several limitations. First, owing to the retrospective and monocentric before-and-after analysis and the small number of patients with recurrent P aeruginosa and ESBL-PE pneumonia, caution is needed when interpretating the results. The efficacy of secondary prophylaxis with IC should be evaluated in a randomized controlled trial. Using our data, 232 or 310 patients would be needed to achieve 80% or 90% study power, respectively. Second, we did not evaluate long-term morbidity and mortality. This was because our cohort recently ended in December 2020, which did not allow us to assess outcomes beyond 3 mo after LTx. Third, we did not assess the risk of colistin resistance emergence because routine screening for colistin resistance in clinical specimens is not routinely performed by our microbiology laboratory; however, previous studies have shown that IC is not threateningly associated with an increased risk of colistin resistance in nontransplant patients.13,35 In addition, we have conducted a prospective study on the risk of colistin resistance emergence after secondary IC prophylaxis, which will soon be submitted for publication.

CONCLUSIONS

Our findings suggest the potential benefit of secondary prophylaxis with IC monotherapy to prevent the recurrence of P aeruginosa or ESBL-PE pneumonia in the ICU after LTx, without adverse effects. Although more robust evidence is needed, given the morbidity and mortality of difficult-to-treat GNB pneumonia, we believe that these results should encourage the use of secondary prophylaxis with IC in the postoperative ICU after LT.

ACKNOWLEDGMENTS

We warmly thank the list of investigators: Service d’Anesthésie-Réanimation: Dan Longrois, Alexandre Mignon, Aurélie Snauwaert, Parvine Tashk, Maksud Assadi, Jules Stern, Sacha Rozencwajg, Adnan El Kalai, Christian de Tymowski, Ali Jendoubi, Aurélie Gouel, Fabien Lion, Laura Soldan, Adela Harpan, Marie-Pierre Dilly, Yassine Rkik, Atanas Sabahov, Claire Depont, Elie Kantor, Laetitia Desplanque, Nils Carrara, Sonia Yung, Morgan Roue, Sophie Provenchère, Julia Voulgaropoulos, Alexandra Younes, Charles Moulin, Bozena Wachoswka, Corentin Gouezel, Elie Succar, Mohamed Foufa, Laila Guezouli, Lea Copelovici, Iulia Balcan, Jose Luis Carrasco, Julien Do vale, Lucie Mariani, Hadrien Portefaix, Vincent Mellano, Emmanuelle Busch; Service de Pneumologie B et Transplantation Pulmonaire: Cendrine Godet, Vincent Bunel, Gaelle Weisenburger, Tiphaine Goletto, Chahine Medraoui, Gilles Jebrak, Armelle Marceau, Domitille Mouren, Mathilde Salpin, Charlotte Thibaut de Menonville, Alice Savary, Malika Hammouda, Lucie Genet, Gwenn Frère, Laurie Torus, Agnès Abadie, Diego Ferreira, Sandrine Tissot, Linda Hajouji-Idrissi, Zohra Brouk; Service de Chirurgie Vasculaire, Thoracique et Transplantation Pulmonaire: Arnaud Roussel, Quentin Pellenc, Jean Senemaud, Jules Iquille, Pierre Cerceau, Regis Renard, Paul Labed.

REFERENCES

1. Rodrigue JR, Baz MA, Kanasky WF Jr, et al. Does lung transplantation improve health-related quality of life? The University of Florida experience. J Heart Lung Transplant. 2005;24:755–763.
2. Vasiliadis HM, Collet JP, Poirier C. Health-related quality-of-life determinants in lung transplantation. J Heart Lung Transplant. 2006;25:226–233.
3. Khush KK, Cherikh WS, Chambers DC, et al.; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult heart transplantation report - 2019; focus theme: donor and recipient size match. J Heart Lung Transplant. 2019;38:1056–1066.
4. Yusen RD, Edwards LB, Dipchand AI, et al.; International Society for Heart and Lung Transplantation. The Registry of the International Society for Heart and Lung Transplantation: thirty-third adult lung and heart-lung transplant report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35:1170–1184.
5. Aguilar-Guisado M, Givaldá J, Ussetti P, et al.; RESITRA cohort. Pneumonia after lung transplantation in the RESITRA Cohort: a multicenter prospective study. Am J Transplant. 2007;7:1989–1996.
6. De Muynck B, Van Herck A, Sacreas A, et al.; Leuven Lung Transplant Group. Successful Pseudomonas aeruginosa eradication improves outcomes after lung transplantation: a retrospective cohort analysis. Eur Respir J. 2020;56:2001720.
7. Stein A, Raoult D. Colistin: an antimicrobial for the 21st century? Clin Infect Dis. 2002;35:901–902.
8. Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant gram-negative bacterial infections. Lancet Infect Dis. 2006;6:589–601.
9. Biswas S, Brunel JM, Dubus JC, et al. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther. 2012;10:917–934.
10. Abdellatif S, Trifi A, Daly F, et al. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann Intensive Care. 2016;6:26.
11. Lu Q, Luo R, Bodin L, et al.; Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology. 2012;117:1335–1347.
12. Vardakas KZ, Voulgaris GL, Samonis G, et al. Inhaled colistin monotherapy for respiratory tract infections in adults without cystic fibrosis: a systematic review and meta-analysis. Int J Antimicrob Agents. 2018;51:1–9.
13. Karvouniaris M, Makris D, Zygoulis P, et al. Nebulised colistin for ventilator-associated pneumonia prevention. Eur Respir J. 2015;46:1732–1739.
14. Blanco-Aparicio M, Saleta Canosa JL, Valiño López P, et al. Eradication of Pseudomonas aeruginosa with inhaled colistin in adults with non-cystic fibrosis bronchiectasis. Chron Respir Dis. 2019;16:1479973119872513.
15. Haworth CS, Foweraker JE, Wilkinson P, et al. Inhaled colistin in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. Am J Respir Crit Care Med. 2014;189:975–982.
16. Koerner-Rettberg C, Ballmann M. Colistimethate sodium for the treatment of chronic pulmonary infection in cystic fibrosis: an evidence-based review of its place in therapy. Core Evid. 2014;9:99–112.
17. Suhling H, Rademacher J, Greer M, et al. Inhaled colistin following lung transplantation in colonised cystic fibrosis patients. Eur Respir J. 2013;42:542–544.
18. Husain S, Mooney ML, Danziger-Isakov L, et al. A 2010 working formulation for the standardization of definitions of infections in cardiothoracic transplant recipients. J Heart Lung Transplant. 2011;30:361–374.
19. Torres A, Niederman MS, Chastre J, et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J. 2017;50:1700582.
20. Kalil AC, Metersky ML, Klompas M, et al. Executive summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63:575–582.
21. Desmard M, Benbara A, Boudinet S, et al. Post-operative kinetics of procalcitonin after lung transplantation. J Heart Lung Transplant. 2015;34:189–194.
22. Wang CC, Chao TY, Chen YM, et al. Influencing factors of successful eradication of multidrug-resistant Acinetobacter baumannii in the respiratory tract with aerosolized colistin. Biomed J. 2014;37:314.
23. Jean SS, Hsieh TC, Lee WS, et al. Treatment outcomes of patients with non-bacteremic pneumonia caused by extensively drug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolates: is there any benefit of adding tigecycline to aerosolized colistimethate sodium? Medicine (Baltimore). 2018;97:e12278.
24. El-Sayed Ahmed MAEG, Zhong LL, Shen C, et al. Colistin and its role in the era of antibiotic resistance: an extended review (2000-2019). Emerg Microbes Infect. 2020;9:868–885.
25. Domingues MM, Inácio RG, Raimundo JM, et al. Biophysical characterization of polymyxin B interaction with LPS aggregates and membrane model systems. Biopolymers. 2012;98:338–344.
26. Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intensive Care Med. 2010;36:1147–1155.
27. Haagensen JA, Klausen M, Ernst RK, et al. Differentiation and distribution of colistin- and sodium dodecyl sulfate-tolerant cells in Pseudomonas aeruginosa biofilms. J Bacteriol. 2007;189:28–37.
28. Lam J, Chan R, Lam K, et al. Production of mucoid microcolonies by Pseudomonas aeruginosa within infected lungs in cystic fibrosis. Infect Immun. 1980;28:546–556.
29. Herrmann G, Yang L, Wu H, et al. Colistin-tobramycin combinations are superior to monotherapy concerning the killing of biofilm Pseudomonas aeruginosa. J Infect Dis. 2010;202:1585–1592.
30. Pamp SJ, Gjermansen M, Johansen HK, et al. Tolerance to the antimicrobial peptide colistin in Pseudomonas aeruginosa biofilms is linked to metabolically active cells, and depends on the pmr and mexAB-oprM genes. Mol Microbiol. 2008;68:223–240.
31. Kwa AL, Loh C, Low JG, et al. Nebulized colistin in the treatment of pneumonia due to multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Clin Infect Dis. 2005;41:754–757.
32. Sorlí L, Luque S, Grau S, et al. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infect Dis. 2013;13:380.
33. Azad MA, Finnin BA, Poudyal A, et al. Polymyxin B induces apoptosis in kidney proximal tubular cells. Antimicrob Agents Chemother. 2013;57:4329–4335.
34. Bihan K, Zahr N, Becquemin MH, et al. Influence of diluent volume of colistimethate sodium on aerosol characteristics and pharmacokinetics in ventilator-associated pneumonia caused by MDR bacteria. J Antimicrob Chemother. 2018;73:1639–1646.
35. Rouby JJ, Poète P, Martin de Lassale E, et al. Prevention of gram negative nosocomial bronchopneumonia by intratracheal colistin in critically ill patients. Histologic and bacteriologic study. Intensive Care Med. 1994;20:187–192.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.