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Volume: 22 Issue: 4 April 2024

FULL TEXT

ARTICLE
Carbapenem-Resistant Pseudomonas aeruginosa Infection and Mixed Infections Are Risk Factors for Poor Outcome After Lung Transplant

Objectives: In this study, we analyzed the effects of carbapenem-resistant Pseudomonas aeruginosa infection and mixed infection on the perioperative prognosis of lung transplant recipients and studied statistics on antibiotic resistance in P aeruginosa.

Materials and Methods: This was a retrospective case-control study. We collected data on lung transplant recipients with combined lower respiratory tract P aeruginosa infection within 48 hours after lung transplant at the China-Japan Friendship Hospital from August 2018 to April 2022. We grouped recipients according to P aeruginosa resistance to carbapenem antibiotics and summarized the clinical characteristics of carbapenem-resistant P aeruginosa infection. We analyzed the effects of carbapenem-resistant P aeruginosa infection and mixed infections on all-cause mortality 30 days after lung transplant by Cox regression. We used the Kaplan-Meier method to plot survival curves.

Results: Patients in the carbapenem-resistant P aeruginosa group had a higher all-cause mortality rate than those in the carbapenem-sensitive P aeruginosa group at both 7 days (6 patients [22.3%] vs 2 patients [4.5%]; P = .022) and 30 days (12 patients [44.4%] vs 7 patients [15.9%]; P = .003) after lung transplant. In multivariate analysis, both carbapenem-resistant P aeruginosa infection and P aeruginosa combined with bacterial infection were independent risk factors for death 30 days after transplant in lung transplant recipients (P < .05). In subgroup analysis, carbapenem-resistant P aeruginosa combined with bacterial infection increased the risk of death 30 days after transplant in lung transplant recipients compared with carbapenem-sensitive P aeruginosa combined with bacterial infection (12 patients [60%] vs 6 patients [19.4%]; P < .001).

Conclusions: Combined lower respiratory tract carbapenem-resistant P aeruginosa infection and P aeruginosa combined with bacterial infection early after lung transplant increased the risk of 30-day mortality after lung transplant.


Key words : Antibiotic resistance, Lower respiratory tract infection, Prognosis

Introduction

Lung transplant is currently the only viable treatment for end-stage respiratory disease worldwide.1 Although the life expectancy of lung transplant recipients (LTRs) has improved as a result of advances in surgical techniques, improved care, and new therapies, ~5% of LTRs still die within 30 days of lung transplant.2 Infection is the second leading cause of death 30 days after lung transplant, according to the 2016 International Society for Heart and Lung Transplant (ISHLT) report.3

Pseudomonas aeruginosa is an important oppor-tunistic pathogen, one of the most common Gram-negative bacteria in nosocomially acquired pneumonia,4,5 and one of the most common pathogens in the early period after lung transplant.6 Inherent and acquired resistance mechanisms make

P aeruginosa resistant to most antibiotics. Carba-penems are the most effective antimicrobial agents against P aeruginosa infections, which produce the cephalosporinases AmpC and ultra-broad-spectrum beta-lactamases.7 However, with the increase in resistance of P aeruginosa to carbapenem antibiotics, the rate of carbapenem-resistant P aeruginosa (CRPA) infection has been increasing every year, posing a major threat to patient health. Carbapenem-resistant P aeruginosa is common in LTRs because of the carriage of CRPA from donor lungs, immunosup-pression, and the use of broad-spectrum antibiotics.8 However, it is uncertain whether combined lower respiratory tract CRPA infection early after lung transplant increases perioperative mortality in LTRs. Therefore, we designed a retrospective case-control study to evaluate the clinical characteristics of patients with combined lower respiratory tract CRPA infections within 48 hours after lung transplant and to assess the effect of CRPA infections and mixed infections on 30-day mortality after lung transplant in LTRs.

Materials and Methods

Ethics approval and consent to participate

This retrospective study was approved by the Ethics Committee of the Beijing China-Japan Friendship Hospital (ethics number: 2022-HX-53), and the need for informed consent was waived. The protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.

Study patients and study design

We retrospectively collected information on patients who underwent lung transplant at the China-Japan Friendship Hospital between August 2018 and April 2022. Inclusion criteria were (1) intensive care unit (ICU) admission for lung transplant, (2) age ?18 years, (3) bronchoalveolar lavage fluid (BALF) collected within 48 hours after lung transplant for pathogenetic examination, (4) postoperative survival time >48 hours, (5) pathogenetic culture positive for P aeruginosa and fulfillment of the criteria for lower respiratory tract infection (LRTI),9 and (6) complete clinical data. Patients who did not meet the inclusion criteria were excluded.

Patients were divided into CRPA and carbapenem-sensitive P aeruginosa (CSPA) groups according to whether P aeruginosa was resistant to carbapenem antibiotics. The clinical characteristics of CRPA infection were analyzed by intergroup comparison. We analyzed the effects of CRPA infection and mixed infection on all-cause mortality 30 days after lung transplant by Cox regression. We used the Kaplan-Meier method to plot survival curves. We defined perioperative prognosis of lung transplant as death or survival status within 30 days after lung transplant.

After surgery, broad-spectrum antibiotics were routinely used to prevent Gram-negative bacterial infections (?-lactams/enzyme inhibitors or carbapenems) and Gram-positive bacterial infections (vancomycin or linezolid), caspofungin and ampho-tericin B were used to prevent fungal infections,10 and ganciclovir was used to prevent viral infections. Patients received methylprednisolone and tacrolimus to counteract rejection.

Sample collection, processing, and analyses

Experienced physicians collected BALF within 48 hours after surgery; during BALF collection, patients received local anesthesia with lidocaine in accordance with the ISHLT consensus statement on standardization of BALF in lung transplant.11 Normal saline (30-40 mL) was injected at a targeted recovery rate of 50% to 60%. Collected BALF was transported to the microbiology laboratory of our hospital for conventional microbiological tests.

Conventional microbiological tests included smears and cultures of bacteria or fungus, pneumocystis smears (Grocott methenamine stain), acid-resistant staining, Xpert MTB/RIF assay, and real-time polymerase chain reaction (PCR).

Guidelines and methodologies for antimicrobial susceptibility testing

Antimicrobial susceptibility testing was performed in accordance with the Clinical and Laboratory Standards Institute recommendations.12 The Kirby-Bauer method of susceptibility testing was used for amtriannan and piperacillin/tazobactam, and the minimum inhibitory concentration method was used for the remaining antibiotics.

Diagnostic criteria for combined P aeruginosa infection of the lower respiratory tract

In cardiothoracic transplant recipients,9 P aeruginosa infection was defined as BALF culture positive for P aeruginosa, bronchoscopic visualization showing moderate to large amounts of sputum/new yellowish-white sputum, or chest imaging suggestive of new/progressive lower respiratory tract infiltrative shadows, with exclusion of primary graft failure, pulmonary edema, and acute presentation and presentation with or without fever, elevated or decreased leukocyte levels, and coughing up of yellowish/white sputum. Mixed infections were defined as infections caused by the presence of more than 1 pathogen.

Tests for proven and probable fungal infection of the lower respiratory tract were performed according to the European Organisation for Research and Treatment of Cancer guideline13 and ISHLT consensus statements.9 Proven infection included a biopsy of new lung lesions within 3 months that showed histopathological or cytological evidence of fungal presence and tissue destruction or positive culture from sterile tissue alone or with signs or symptoms of infection plus presentation on radiology and laboratory tests. Probable infection included presentation of signs or symptoms plus presentation on radiology and laboratory tests. Signs and symptoms included ?1 of the following: fever >38 °C or hypothermia <36.5 °C with no other recognized cause, leukopenia (<4000 white blood cells/mm3) or leukocytosis (?12?000 white blood cells/mm3), new onset of purulent sputum or change in character or quantity of sputum, worsening gas exchange, and pleural effusion. Presentation on radiology meant presentation of ?1 of the following: new or progressive and persistent infiltrate, consolidation, cavitation, and nodules. Presentation on laboratory tests meant presentation of single positive culture for mold in BALF/blood, or single positive PCR for mold in BALF/blood, or positive galactomannan in the BALF, or ?2 positive sputum cultures/PCRs of fungal organisms (excluding Candida species). In contrast, colonization implies presence of fungi in respiratory materials in the absence of symptoms.14

Observational indicators

We collected the following preoperative baseline characteristics of LTRs: sex, age, body mass index (BMI; in kilograms divided by height in meters squared), immune status, diagnostic classification, and underlying diseases and infections. We collected the immunosuppressants and hormones used by LTRs intraoperatively.

We analyzed the following postoperative baseline conditions on the day of transfer to the ICU: vital signs, level of consciousness, laboratory tests, acute physiology and chronic health evaluation scoring system (Apache) II results, Sequential Organ Failure Assessment (SOFA) results, and use of vasoactive medications. We also collected vital signs, consciousness, laboratory tests, bronchoscopy, and chest imaging results that were taken within 48 hours postoperatively, as well as dosages of postoperative hormones and immunological agents. We collected the options of postoperative ICU organ support in patients, which included duration of invasive positive pressure ventilation (IPPV) and duration of extracorporeal membrane oxygenation (ECMO). We also collected the number of LTRs with need for continuous renal replacement therapy (CRRT), length of ICU stay, and all-cause mortality at 7 days and 30 days after lung transplant.

Ventilator-associated pneumonia was not included as the aim of the study; our aim was to observe patients with combined LRTI within 48 hours of lung transplant. Patients enrolled in the study did not have comorbid infections elsewhere.

Statistical analyses

We used SPSS version 22.0 software (IBM Corp) for statistical analyses. We presented continuous variables with a normal distribution as mean ± standard deviation, which were compared with the independent sample t test. We presented continuous variables with a skewed distribution as median and interquartile range (IQR), which we compared using the Mann-Whitney U test. We presented categorical variables as number (percent), which we compared using the chi-square test or the Fisher exact probability method. We used the Kaplan-Meier method to plot survival curves and the Breslow test to compare differences in survival distributions between the 2 groups (CRPA and CSPA). Variables identified in univariate analyses with P < .1 were subsequently included in the multivariate model for multivariate logistic regression analyses. P < .05 was statistically significant.

Results

General patient information

We screened 345 LTRs and subsequently included 71 patients: 27 in the CRPA group and 44 in the CSPA group. We excluded 256 LTRs because of negative P aeruginosa infection and 18 LTRs because of absence or suspicion of LRTI (Figure 1). Lung transplant recipients in the CRPA group had higher 7-day and 30-day mortality rates than LTRs in the CSPA group and required more CRRT support (P < .05) (Table 1).The CRPA group tended to require more ventilatory support and a longer ICU stay, although no differences were observed in the duration of IPPV use and ICU stay between the 2 groups. The proportion of mixed infections was high in both groups. In particular, the proportion of combined bacterial infections was >50%.

Carbapenem-resistant P aeruginosa infection and P aeruginosa combined with bacterial infection: risk factors for 30-day mortality after lung transplant

To investigate the effect of CRPA and P aeruginosa mixed infections on 30-day mortality in LTRs, risk factors for death within 30 days after lung transplant were analyzed by univariate and multivariate Cox regression. Unifactorial factors included age of LTRs, sex, underlying disease (eg, chronic obstructive pulmonary disease, interstitial lung disease, diabetes, coronary artery disease, heart failure), immunosup-pression status (preoperative use of immunosup-pressants, long-term preoperative hormone use, postoperative tacrolimus concentration), lung transplant mode, BMI, severe malnutrition (BMI <20), preoperative ICU admission for severe organ failure, preoperative use of IPPV or ECMO, baseline SOFA score, baseline Apache II score, CRRT use, duration of postoperative ECMO use, duration of postoperative IPPV use, CRPA or CSPA infection, and presence of multidrug-resistant P aeruginosa infection. Because LRTI in LTRs were mostly mixed infections, we included factors for P aeruginosa mixed infections: P aeruginosa infections combined with bacterial infections, and P aeruginosa infections combined with fungal infections.

In univariate and multivariate analyses, CRPA infection, P aeruginosa mixed with bacterial infection, and use of CRRT were independent risk factors for 30-day all-cause mortality in LTRs (P < .05) (Table 2).

Subgroup analysis: effect of mixed carbapenem-resistant and carbapenem-sensitive P aeruginosa infections on the prognosis of lung transplant recipients

Lung transplant recipients are prone to coinfection with multiple pathogens. To clarify the effect of CRPA coinfection versus CSPA coinfection on 30-day postoperative mortality in LTRs, we performed subgroup analyses. After we balanced the proportions of LTRs with Acinetobacter baumannii and Klebsiella pneumoniae between groups (P > .05), Kaplan-Meier analysis showed that the 30-day postoperative mortality rate of lung transplant was higher when CRPA was combined with bacterial infections than the rate shown in the CSPA group (12 LTRs [60%] vs 6 LTRs [19.4%]; P < .001). The mortality rate in the early postoperative period in LTRs with CRPA combined with fungal infections versus CSPA combined with fungal infections was not significantly different (2 LTRs [50%] vs 1 LTR [16.67%]; P = .207) (Figure 2).

Drug resistance profile of P aeruginosa

A total of 100 P aeruginosa strains were positive on culture during the study period: 39% (39/100) of P aeruginosa showed multidrug resistance, 9% (9/100) showed extensive resistance, and 4% (4/100) showed resistance only to carbapenem antibiotics. The antibiotics with the lowest rate of resistance were polymyxins (colistin 3%) and aminoglycosides (amikacin 3%), followed by tobramycin (14%). The rate of resistance of P aeruginosa to levofloxacin, cefoperazone sulfadoxine sodium, and ticarcillin barotropic acid was >40%, with ticarcillin barotropic acid having the highest rate of resistance at 54% (Table 3).

Discussion

Pseudomonas aeruginosa is a common opportunistic pathogen. Immunosuppressed patients are susceptible to P aeruginosa infection and have poor prognosis.15 In this study, in data collecting from LTRs with lower respiratory tract P aeruginosa infection in the early postoperative period, we confirmed that combined lower respiratory tract CRPA infection and P aeruginosa mixed bacterial infection in the early postoperative period after lung transplant severely affected early prognosis of LTRs.

Carbapenem-resistant P aeruginosa infection severely was shown to affect early prognosis of LTRs, with increased proportion of patients who require organ support, such as CRRT, prolonged ventilation support, and ICU treatment, compared with the effects of CSPA infection. This finding is consistent with previous results.16 The results of our study showed that combined lower respiratory tract CRPA infection was an independent risk factor for death in the early period after lung transplant (<30 days) in LTRs. A similar conclusion was shown in a meta-analysis that reported that patients infected with CRPA bacteremia have a higher risk of death than patients infected with CSPA bacteraemia.17 Vivo and colleagues also suggested that positive blood cultures for P aeruginosa in patients are associated with an increased likelihood of death at 90 days,18 whereas Lin and colleagues argued that lower respiratory tract CRPA infection is not associated with all-cause mortality in patients.19 The reason for this disagreement may be due to different patient populations studied, with LTRs being a severely immunocompromised population.

Our study showed that most LTRs with combined LRTI in the early postoperative period had mixed infections, which is consistent with previous results.14 We further evaluated mixed P aeruginosa infections and the effects of CRPA mixed infections on prognosis of LTRs. Our findings suggested that P aeruginosa mixed bacterial infections increased the risk of death 30 days after lung transplant. Clinicians should remain aware that combined lower respiratory tract CRPA infection with P aeruginosa mixed infection in the early postoperative period after lung transplant is dangerous for LTRs, which is a typical immunosup-pressed population, and may cause poor prognosis; this patient population should be actively treated by clinicians.

In detection of drug resistance of P aeruginosa in our study, the rate of multidrug-resistant P aeruginosa strains was generally consistent with previous retrospective results from the International Multicentre Multidrug-Resistant P aeruginosa Pneumonia group.20 The resistance rates of polymyxin and amikacin were the lowest, but the resistance rates of beta lactams, carbapenems, and quinolones, which are the main therapeutic agents for P aeruginosa, are still high, and clinical attention is needed with regard to the rational use of these agents.

The innovation of our study was to clarify the effects of CRPA infection on LTRs in the early postoperative period after lung transplant through a retrospective case-control study. The effect of mixed P aeruginosa infection on the early prognosis of LTRs was also investigated. At present, there are no relevant clinical studies. The results of this study further emphasize the need for early lung sampling and early identification of pulmonary pathogens.

Our study had several limitations. First, this was a single-center, retrospective study; although no significant differences in the baseline conditions of patients were shown between the 2 groups, there may have been some selection bias. Second, we only included the early prognosis results of LTRs and did not study long-term prognosis. Finally, previous literature reported that carbapenem antibiotics21 and long-term ICU stay22 are often high-risk factors for CRPA infection. We were not able to further analyze the risk factors for CRPA because of the short observation period and the lack of information on antibiotic use in donor lungs. In the future, more large-scale, prospective, multicenter studies are needed to further identify the risk factors for lower respiratory tract CRPA infection; such studies are needed to prevent CRPA infection as early as possible and improve the early prognosis of LTRs.

Conclusions

Early postoperative combined CRPA infection in LTRs and P aeruginosa combined with bacterial infection can seriously affect the early prognosis of LTRs. Clinical detection of CRPA infection should be vigilant, and intervention should be performed as early as possible.


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Volume : 22
Issue : 4
Pages : 300 - 306
DOI : 10.6002/ect.2023.0268


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From the 1Department of Respiratory and Critical Care Medicine, The Second Hospital of Harbin Medical University, Harbin, China; the 2Harbin Medical University, Harbin, China; the 3Department of Respiratory and Critical Care Medicine, Beijing Chest Hospital of Capital Medical University, Beijing, China; and the 4Department of Respiratory and Critical Care Medicine, China-Japan Friendship Hospital, Beijing, China
Acknowledgements: The authors thank colleagues from Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital for their assistance in diagnosis and management of patients. This study was supported by the Internal cross-cutting projects at China-Japan Friendship Hospital (2022-HX-53). The research was designed, conducted, and analyzed by the authors independently of the funding sources. The authors have no declarations of potential conflicts of interest. Data that support the findings of this study are available from Dr. Chen Wang and Dr. Qingyuan Zhan, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. However, data are available from the authors on reasonable request and with permission of Dr. Chen Wang and Dr. Qingyuan Zhan.
*Yuhan Wu and Jun Zhu contributed equally to this work and are equal first authors
Corresponding author: Qingyuan Zhan, drzhanqy@163.com; 2 Cherry Garden East Street, Chaoyang District, Beijing 100029, China; and Chen Wang, drchenwang123@163.com; 2 Cherry Garden East Street, Chaoyang District, Beijing 100029, China