Association between the lung microbiome and perioperative prognosis in lung transplant recipients.

RATIONALE: Studies have confirmed that the lung microbiome of lung transplant recipients is altered and serves as a prognostic indicator for long-term mortality. Other studies reported that the lung microbiome affects host immunity and the transcriptome. However, the lung microbiome composition at the early post-transplant period following lung transplantation is unclear, and the relationship of the lung microbiome with pulmonary immunity and the host transcriptome is also not well understood. OBJECTIVES: We hypothesize that changes in the lung microbiome composition in the early post-transplant period may have a predictive value for perioperative outcomes following lung transplantation and that the lung microbiome is correlated with pulmonary immunity and the host transcriptome. Thus, this prospective study aimed at observing the lung microbiome composition in the early post-transplant period and the impact of the lung microbiome on pulmonary cytokines and the host transcriptome. Our findings will help us gain a comprehensive understanding of the distribution and significance of the lung microbiome in the early post-transplant period. METHODS: An observational study was conducted to identify the lung microbiome and the host transcriptome characteristics using next-generation sequencing. Luminex was employed for quantifying alveolar cytokines. Spearman's correlation analysis was utilized to assess the impact of the lung microbiome on pulmonary immunity and differentially expressed genes in patients who died perioperatively after lung transplantation. RESULTS: Patients with poor perioperative outcomes showed an increase in Mycoplasma and Arcobacter, a decrease of Gemella, and increased interleukin (IL)-10, IL-1ß, and tumor necrosis factor (TNF)-α concentration. The lung microbiome correlates with lung immunity in lung transplant recipients. In the death group, the function of differentially expressed genes is associated with cell apoptosis, and promoting TNF production is upregulated. The lung microbiome is related to differentially expressed genes between the two groups. CONCLUSIONS: The lung microbiome and cytokines can be considered as potential biomarkers for early prognosis in lung transplant recipients. The lung microbiome is associated with both lung immunity and differentially expressed genes in lung transplant recipients.

The role of lung microbiota in primary graft dysfunction in lung transplant recipients.

BACKGROUND: Recent studies have shown that the lung microbiota is altered in critically ill patients and predicts clinical outcomes. Primary graft dysfunction (PGD) is a common complication and a leading cause of death within 1 month of lung transplantation, but the clinical significance of changes in the lung bacterial community during PGD is unclear. The aim of this study was to determine the contribution of the lung microbiota to the development and course of severe PGD. METHODS: We conducted a retrospective study to characterize the lung microbiota of 32 lung transplant patients with combined PGD using next-generation sequencing of bronchoalveolar lavage samples. The relationship between lung flora dysbiosis and lung immunity in PGD was assessed by quantification of alveolar cytokines. The contribution of microbiota characteristics to patient outcomes was assessed by estimating overall survival. RESULTS: Patients diagnosed with PGD grade 3 showed a reduction in alpha diversity, driven by a significant increase in the abundance of the genera Modestobacter, Scardovia and Selenomonas, and a reduction in the proportion of the genera Klebsiella and Oribacterium. Alpha diversity of the lung microbiota in PGD3 patients was negatively correlated with BALF interleukin (IL)-2 (r = -.752, p < .05). In addition, bacterial diversity in the lung microbiota of non-survivors was lower than that of survivors (p = .041). CONCLUSIONS: There is variation in the lung microbiota of PGD grade 3 patients and dysbiosis of the lung microbiota is associated with lung immunity. The lung microbiota has potential in the diagnosis and treatment of PGD grade 3.

Risk factors for bloodstream infection (BSI) in patients with severe acute respiratory distress syndrome (ARDS) supported by veno-venous extracorporeal membrane oxygenation (VV-ECMO).

BACKGROUND: There were relatively few studies about the incidence and risk factors for bloodstream infection (BSI) in patients with severe acute respiratory distress syndrome (ARDS) supported by veno-venous extracorporeal membrane oxygenation (VV-ECMO). METHODS: Patients who were diagnosed with severe ARDS and received VV-ECMO treatment in the medical intensive care unit of China-Japan Friendship Hospital from August 2013 to March 2019 were retrospectively studied. The pathogens isolated from blood culture (BC) were identified and analyzed for drug sensitivity. The risk factors for BSI were analyzed by logistic regression. RESULTS: A total of 105 patients were included in this single-center retrospective cohort study. Among them, 23 patients (22%) had BSIs. 19 cases were identified as primary BSI; while the other 4 cases were as secondary BSI. A total of 23 pathogenic strains were isolated from BCs, including gram-negative (G-) bacilli in 21 (91%) cases, gram-positive (G+) cocci in 1 case, fungus in 1 case, and multidrug-resistant (MDR) organisms in 8 cases. Compared with patients without BSI, patients with BSI had a higher Murray score (odds ratio = 6.29, P = 0.01) and more blood transfusion (odds ratio = 1.27, P = 0.03) during ECMO. CONCLUSIONS: The incidence of BSI in patients with severe ARDS supported by VV-ECMO was 22%. G- bacilli was the main pathogen, and most of them were MDR-G- bacilli (MDR-GNB). Higher Murray score and more blood transfusion may be the independent risk factors for BSI.

Diagnostic value of galactomannan test in non-immunocompromised critically ill patients with influenza-associated aspergillosis: data from three consecutive influenza seasons.

To explore the diagnostic value of a galactomannan (GM) detection for non-immunocompromised critically ill patients with influenza-associated aspergillosis (IAA). In this retrospective case-control study, we explored the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic (ROC) curve (AUC) of serum and bronchoalveolar lavage fluid (BALF) GM tests by four detection strategies at different detection time points and with different compound modes. In total, 90 patients were evaluated. The AUC values of the second serum GM test, the first and second BALF GM tests, were significantly higher (0.839 (95% CI 0.716 to 0.963), P < 0.01; 0.904 (95% CI 0.820 to 0.988), P < 0.01; 0.827 (95% CI 0.694 to 0.961), P = 0.043) than that of the first serum GM test (0.548 (95% CI 0.377 to 0.718)). We found that at least one positive result on two consecutive serum GM tests (0.719 (95% CI 0.588 to 0.849)) was the best compared with the first positive test (0.419 (95% CI 0.342 to 0.641), P < 0.01) and positives on two consecutive tests (0.636 (95% CI 0.483 to 0.790), P = 0.014). However, there were no differences between those three detection strategies of BALF GM. The BALF GM test might have a better diagnostic value for IAA in the ICU than the serum GM test. A possible cutoff value of 1.0 to 1.3 was set for GM from BALF specimens for IAA. A single serum GM test is not routinely recommended, but at least one positive result on two consecutive tests appeared to be useful.

Circulating Rather Than Alveolar Extracellular Deoxyribonucleic Acid Levels Predict Outcomes in Influenza.

BACKGROUND: High levels of circulating neutrophil extracellular traps (NETs) are associated with a poor prognosis in influenza A infection. It remains unclear whether NETs in the plasma or bronchoalveolar lavage fluid (BALF) can predict clinical outcomes in influenza. METHODS: One hundred eighteen patients who were diagnosed with H1N1 influenza in 2017-2018 were recruited. The NETs were assessed in plasma and BALF samples by quantifying cell-free deoxyribonucleic acid (cfDNA) and protein-DNA complexes. Predictions of severe illness and 60-day mortality were analyzed with receiver operating characteristic curves. RESULTS: The NET levels were significantly elevated in the BALF and contributed to the pathology of lungs, yet it was not associated with disease severity or mortality in patients severely infected with H1N1. Plasma NET levels were significantly increased in the patients with severe influenza and positively correlated with the oxygen index and sequential organ failure assessment scores. High levels of plasma cfDNA (>286.6 ng/mL) or histone-bound DNA (>9.4 ng/mL) discriminated severe influenza from mild, and even higher levels of cfDNA (>306.3 ng/mL) or histone-bound DNA (>23.1 ng/mL) predicted fatal outcomes in severely ill patients. CONCLUSIONS: The cfDNA and histone-bound DNA in plasma represent early predictive biomarkers for the prognosis of influenza.

DNA Triplex and Quadruplex Assembled Nanosensors for Correlating K+ and pH in Lysosomes.

It remains an unanswered question whether the flux of K+ and H+ in lysosomes are correlated due to difficulties in simultaneously imaging these two ions. This question is of great value for understanding lysosomal acidification. Herein, we designed DNA quadruplex and triplex based luminescent nanosensors that can, respectively monitor K+ and pH in lysosomal lumen. Each sensor contained an upconversion nanoparticle luminophore and a gold nanoparticle quencher, producing green and blue luminescence signals for K+ and H+ , respectively. The sensors were tested in buffers showing dynamic ranges of 5 to 200 mM K+ and pH 5.0 to 8.2. Co-imaging using these two sensors in cells indicated that the influx of H+ was accompanied with the efflux of K+ , solving this long-standing question of the lysosomal biochemistry.

Insight into the Effect of Ligands on the Optical Properties of Germanium Quantum Dots and Their Applications in Persistent Cell Imaging.

Germanium quantum dots (GeQDs) show unique advantages in fluorescence applications due to their large quantum confinement effect and excellent biocompatibility. However, GeQDs are confronted with difficulty in accurately controlling the fluorescence emission. This defect brings challenges to understanding the fluorescence mechanism and limits the potential applications of GeQDs. In this paper, a series of GeQDs with the average diameter of about 2.6 nm modified with different ligands were synthesized by the chemical reduction method. The fluorescence emission of GeQDs can be changed from blue to yellow-green through adjusting the surface ligands. The influence of surface ligands on the fluorescence emission of GeQDs was thoroughly investigated by experimental and theoretical calculations. Furthermore, the synthesized GeQDs exhibit good biocompatibility and photostability and can act as high-performance fluorescence probes for long-term fluorescent bioimaging. This work provides a good and deep understanding of the fluorescence mechanism of GeQDs and will facilitate diverse promising applications of GeQDs in the near future.

Acute Kidney Injury in Patients with the Coronavirus Disease 2019: A Multicenter Study.

INTRODUCTION: Severe acute respiratory viral infections are frequency accompanied by multiple organ dysfunction, including acute kidney injury (AKI). In December 2019, the coronavirus disease 2019 (COVID-19) outbreak began in Wuhan, Hubei Province, China, and rapidly spread worldwide. While diffuse alveolar damage and acute respiratory failure are the main features of COVID-19, other organs may be involved, and the incidence of AKI is not well described. We assessed the incidence and clinical characteristics of AKI in patients with laboratory-confirmed COVID-19 and its effects on clinical outcomes. METHODS: We conducted a multicenter, retrospective, observational study of patients with COVID-19 admitted to two general hospitals in Wuhan from 5 January 2020 to 21 March 2020. Demographic data and information on organ dysfunction were collected daily. AKI was defined according to the KDIGO clinical practice guidelines. Early and late AKI were defined as AKI occurring within 72 h after admission or after 72 h, respectively. RESULTS: Of the 116 patients, AKI developed in 21 (18.1%) patients. Among them, early and late AKI were found in 13 (11.2%) and 8 (6.9%) patients, respectively. Compared with patients without AKI, patients with AKI had more severe organ dysfunction, as indicated by a higher level of disease severity status, higher sequential organ failure assessment (SOFA) score on admission, an increased prevalence of shock, and a higher level of respiratory support. Patients with AKI had a higher SOFA score on admission (4.5 ± 2.1 vs. 2.8 ± 1.4, OR 1.498, 95% CI 1.047-2.143 ) and greater hospital mortality (57.1% vs. 12.6%, OR 3.998, 95% CI 1.088-14.613) than patients without AKI in both the univariate and multivariate analyses. Patients with late AKI, but not those with early AKI, had a significantly prolonged length of stay (19.6 vs. 9.6 days, p = 0.015). CONCLUSION: Our findings show that admission SOFA score was an independent risk factor for AKI in COVID-19 patients, and patients with AKI had higher in-hospital mortality. Moreover, AKI development after 72 h of admission was related to prolonged hospitalization time.

Vanrija jinghongensis sp. nov., an asexual basidiomycetous yeast from rotting wood.

Three strains of a novel basidiomycetous yeast were isolated from the Xishuangbanna Tropical Rainforest, Yunnan Province, PR China. Sequence analysis of the D1/D2 domains of the large subunit (LSU) rRNA gene and the internal transcribed spacer (ITS) regions indicated that the novel species represents a member of the genus Vanrija. It differed from the most closely related known species, Vanrija albida CBS 2839T, by 1.5 % sequence divergence (seven substitutions and two gaps out of 597 bp) in the D1/D2 domains and by 7.4 % sequence divergence (17 substitutions and 20 gaps over 495 bp) in the ITS regions, respectively. The three strains of the novel species reproduced asexually, and no mating could be found. In contrast to V. albida, the novel yeast species was able to assimilate d-glucosamine, inulin, erythritol and galactitol and unable to assimilate raffinose. The name Vanrija jinghongensis sp. nov. is proposed to accommodate these strains, with NYNU 17910T (=CICC 33269=CBS 15229) as the type strain.

Metschnikowia baotianmanensis f.a., sp. nov., a new yeast species isolated from the gut of the rhinoceros beetle Allomyrina dichotoma.

Four strains, NYNU 15610, NYNU 15612, NYNU 15613 and NYNU 15615, of a novel ascomycetous yeast were isolated from the gut of Allomyrina dichotoma (Coleoptera: Scarabeidae) collected from two different localities in Henan Province, Central PR China. The four strains shared identical sequences in both of the D1/D2 domains of the large subunit rRNA gene and the internal transcribed spacer regions. Sequence analyses revealed that this novel species represents a member of the genus Metschnikowia. It differed from its closest known species Metschnikowia zobellii, Metschnikowiaaustralis and Metschnikowia bicuspidata, by 8.4-9.2 % sequence divergence (33-40 nt substitutions and 7-12 gaps over 509 bases) in the D1/D2 sequences. The formation of ascospores was not observed on various sporulation media. In contrast to M. zobellii, M. australis and M. bicuspidata, the novel yeast species was unable to assimilate succinate, ethanol, ethylamine, cadaverine and 10 % NaCl plus 5 % glucose, but was able to grow in vitamin-free medium. The name Metschnikowia baotianmanensis f.a., sp. nov. is proposed to accommodate these strains, with NYNU 15613 as the holotype.

Wickerhamomyces menglaensis f.a., sp. nov., a yeast species isolated from rotten wood.

Five strains, NUNU 16637, NYNU 16645, NYNU 1673, NYNU 1680 and NYNU 1689, of a novel ascomycetous yeast were isolated from the Xishuangbanna tropical rainforest, Yunnan Province, PR China. The five strains shared identical sequences in both of the D1/D2 domains of the large subunit rRNA gene and the internal transcribed spacer (ITS) regions. Sequence analysis showed that they represent undescribed yeast species belonging to the genus Wickerhamomyces. They differed from their closest known species, Wickerhamomyces xylosivorus NBRC 111553T, by 3.4 % sequence divergence (14 substitutions and six gaps out of 584 bp) in the D1/D2 domains and by 9.6 % sequence divergence (28 substitutions and 24 gaps over 543 bp) in the ITS regions, respectively. The five strains of novel species reproduced asexually; no sexual reproduction could be found. In contrast to W. xylosivorus, the novel yeast species were able to assimilate l-arabinose, inulin, soluble starch, d-mannitol and citrate, and unable to assimilate trehalose, raffinose, 5-keto-d-gluconate, d-gluconate, ethanol, ethylamine and cadaverine. Growth was observed at 35 °C. The name Wickerhamomyces menglaensis f.a., sp. nov. is proposed to accommodate these strains, with NYNU 1673 as the holotype.

Saturnispora galanensis sp. nov., a yeast species isolated from rotting wood.

Three strains of a novel yeast species were isolated from rotting wood in the Xishuangbanna Tropical Rainforest, Yunnan Province, PR China. Sequence analysis of the D1/D2 domains of the large subunit rRNA gene and the internal transcribed spacer (ITS) regions showed that the novel species represents a member of the genus Saturnispora. It differed from its closest known species, Saturnispora sekii CBS 10931T, by 1.3 % nucleotide substitutions in the D1/D2 domains and by 2.2 % nucleotide substitutions in the ITS regions, respectively. In contrast to Saturnispora sekii, the novel yeast species was unable to assimilate glycerol, dl-lactate, succinate and citrate, and grow at 37 °C. The name Saturnispora galanensis sp. nov. is proposed to accommodate these strains, with NYNU 1797 as the holotype.

Candida yunnanensis sp. nov. and Candida parablackwelliae sp. nov., two yeast species in the Candida albicans/Lodderomyces clade.

During studies on the yeast communities associated with rotting wood in the Xishuangbanna Tropical Rainforest in PR China, four novel yeast strains were found. Phylogenetic analysis based on the concatenated sequences of the D1/D2 domains of the large subunit rRNA gene and the ITS regions showed that these strains represented two novel species in the Candida albicans/Lodderomyces clade. The novel species, represented by strains NYNU 17948 and NYNU 17981, formed a clade with Candida maltosa and Candida baotianmanensis, with 1-1.8% sequence divergence in the D1/D2 domains and 8.9-10% sequence divergence in the ITS regions. The other novel species, represented by NYNU 17105 and NYNU 17763, is most closely related to Candida blackwelliae with 0.7 % sequence divergence in the D1/D2 domains and 6.9 % sequence divergence in the ITS regions. The two novel species could be distinguished from their closest described species in terms of physiological traits. The two novel species are described as Candida yunnanensis sp. nov. (holotype NYNU 17948) and Candida parablackwelliae sp. nov. (holotype NYNU 17763).

Circulating and Pulmonary T-cell Populations Driving the Immune Response in Non-HIV Immunocompromised Patients with Pneumocystis jirovecii Pneumonia.

Background: Previous studies in human subjects have mostly been confined to peripheral blood lymphocytes for Pneumocystis infection. We here aimed to compare circulating and pulmonary T-cell populations derived from human immunodeficiency virus (HIV)-uninfected immunocompromised patients with Pneumocystis jirovecii pneumonia (PCP) in order to direct new therapies. Methods: Peripheral blood and bronchoalveolar lavage samples were collected from patients with and without PCP. Populations of Th1/Tc1, Th2/Tc2, Th9/Tc9, and Th17/Tc17 CD4+ and CD8+ T cells were quantified using multiparameter flow cytometry. Results: No significant differences were found between PCP and non-PCP groups in circulating T cells. However, significantly higher proportions of pulmonary Th1 and Tc9 were observed in the PCP than in the non-PCP group. Interestingly, our data indicated that pulmonary Th1 was negatively correlated with disease severity, whereas pulmonary Tc9 displayed a positive correlation in PCP patients. Conclusions: Our findings suggest that pulmonary expansion of Th1 and Tc9 subsets may play protective and detrimental roles in PCP patients, respectively. Thus, these specific T-cell subsets in the lungs may serve as targeted immunotherapies for patients with PCP.

Scopulariopsis/Microascus isolation in lung transplant recipients: A report of three cases and a review of the literature.

The current knowledge of invasive Scopulariopsis/Microascus infection in lung transplantation has been derived from only four case reports. Although these fungi are uncommon compared with Aspergillus, they are highly resistant to the current antifungal agents, and the mortality is extremely high. To explore the risk factors, clinical manifestations, notable diagnostic characteristics and outcomes of positive Scopulariopsis/Microascus isolation in lung transplantation patients. We included all cases with positive Scopulariopsis/Microascus isolation from lower respiratory tracts or bronchial mucosa biopsies in our lung transplantation centre. Proven cases from the literature were added. Positive isolation occurred in 2% (3/157) in our centre. Four cases from the literature were added. The mortality could be considered as high as 80%, once the two cases of colonisation were excluded. The average interval between transplantation and positive isolation was 106 (19-131) days. A total of 57.1% of patients had experienced a combination of infection with Aspergillus or other fungi as well as long-term azole antifungal agent treatment before the positive isolation, which may be possible risk factors. The combination of micafungin, posaconazole and terbinafine may be an effective treatment. The peak time of positive isolation was consistent with that of some opportunistic pathogens, and the possible risk factors were the infection of other fungi as well as prior long-term azole antifungal administration. In addition to its high mortality, Scopulariopsis/Microascus was also highly resistant to common antifungal agents and the combination of two or three drugs for therapy was recommended.

Sugiyamaella xiaguanensis f.a., sp. nov., a yeast species isolated from rotting wood.

Three strains representing a novel yeast species, Sugiyamaella xiaguanensis f.a., sp. nov. (type strain NYNU 161041T=CICC 33167T=CBS 14696T), were isolated from rotting wood samples collected in Henan and Yunnan Provinces, PR China. The novel species is able to assimilate cellobiose, salicin and d-xylose, which was typical of the species of the genus Sugiyamaella. Analysis of the D1/D2 domains of the large subunit rRNA gene and internal transcribed spacer regions of these strains showed that this species was related to Sugiyamaella lignohabitans and Sugiyamaella marionensis, its closest relatives. Su. xiaguanensis sp. nov. differed by 1.4 % nucleotide substitutions from Su. lignohabitans, and by 1.9 % nucleotide substitutions from Su. marionensis in the D1/D2 sequences. The ITS sequences of Su. xiaguanensis sp. nov. displayed more than 6.5 % nucleotide substitutions from the latter two species, showing that it is a genetically separate species.

An Unusual Triple-Decker Variant of the Tetragonal BaAl4-Structure Type: Synthesis, Structural Characterization, and Chemical Bonding of Sr3Cd8Ge4 and Eu3Cd8Ge4.

Reported are the synthesis and the crystal structures of the new ternary phases Sr3Cd8Ge4 and Eu3Cd8Ge4. The structures of both compounds have been established by single-crystal and powder X-ray diffraction methods. They crystallize in the tetragonal space group I4/mmm (No. 139, own structure type, Pearson symbol tI30) with Z = 2, and lattice parameters as follows: a = 4.4941(14) Å; c = 35.577(7) Å for Sr3Cd8Ge4, and a = 4.4643(12) Å; c = 35.537(9) Å for Eu3Cd8Ge4, respectively. The most prominent feature of the structure is the complex [Cd2Ge] polyanionic framework, derived by unique ordering of the Cd and Ge atoms in fragments that bear resemblance to the BaAl4 structure type. Temperature dependent DC magnetization measurements indicate that Eu3Cd8Ge4 displays Curie-Weiss paramagnetic behavior with no sign of magnetic ordering in the measured range. Theoretical considerations of the electronic structure on the basis of the tight-binding linear muffin-tin orbital (TB-LMTO-ASA) method are also presented and discussed.

Is Bulpa criteria suitable for the diagnosis of probable invasive pulmonary Aspergillosis in critically ill patients with chronic obstructive pulmonary disease? A comparative study with EORTC/ MSG and ICU criteria.

BACKGROUND: Three diagnostic criteria have been proposed used for invasive pulmonary aspergillosis (IPA) diagnosis, namely EORTC/ MSG criteria, Bulpa criteria and intensive care unit (ICU) criteria. The Bulpa criteria were proposed to diagnose IPA in chronic obstructive pulmonary disease (COPD) patients specially. Our aim is to verify that whether the Bulpa criteria are the most suitable for diagnosing probable IPA in critically ill COPD patients compared with the other two criteria. METHODS: We included critically ill COPD patients admitted to the ICU from April 2006 to August 2013. Patients were classified into four populations: population one (n1 = 59) comprised all included patients; population two (n2 = 24) comprised patients with positive mycological findings (both positive cultures and positive serologic tests); population three (n3 = 18) comprised patients with positive lower respiratory tracts (LRTs) isolation; and population four (n4 = 5) comprised proven IPA patients with histopathology. Patients in four groups were diagnosed as probable IPA using three criteria respectively, and the "diagnostic rate" of each criteria were compared with each other. Then, the reasons for differences in "diagnostic rate" were analyzed in population two. Finally, the modified Bulpa criteria were proposed. RESULTS: Bulpa criteria yielded the highest "diagnostic rate" of probable IPA followed by the ICU criteria, while the EORTC/ MSG criteria provided the lowest rates in four populations (the "diagnostic rate" of probable IPA was 33.9%, 16.9% and 6.8% in population one, p = 0.001; 83.3%, 41.7% and 16.7% in population two, p < 0.001; 100%, 55.6% and 22.2% in population three, p < 0.001; 100%, 60% and 20% in population four, p = 0.036). The reasons for the highest "diagnostic rate" by Bulpa criteria were its less strict requirements regarding the doses/courses of steroid use and typical computed tomography (CT) findings. Finally, the modified Bulpa criteria for probable IPA were proposed for critically ill COPD patients admitted to ICU, mainly involving revised interpretations of microbiological findings. CONCLUSIONS: Among the existing three criteria, the Bulpa criteria are the most suitable for diagnosing probable IPA in critically ill COPD patients admitted to ICU. A modified criteria maybe proposed for better diagnosis,and its clinical validity need to be verified in future studies.

Renal Replacement Therapy as a New Indicator of Voriconazole Clearance in a Population Pharmacokinetic Analysis of Critically Ill Patients.

AIMS: The pharmacokinetic (PK) profiles of voriconazole in intensive care unit (ICU) patients differ from that in other patients. We aimed to develop a population pharmacokinetic (PopPK) model to evaluate the effects of using extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and those of various biological covariates on the voriconazole PK profile. METHODS: Modeling analyses of the PK parameters were conducted using the nonlinear mixed-effects modeling method (NONMEM) with a two-compartment model. Monte Carlo simulations (MCSs) were performed to observe the probability of target attainment (PTA) when receiving CRRT or not under different dosage regimens, different stratifications of quick C-reactive protein (qCRP), and different minimum inhibitory concentration (MIC) ranges. RESULTS: A total of 408 critically ill patients with 746 voriconazole concentration-time data points were included in this study. A two-compartment population PK model with qCRP, CRRT, creatinine clearance rate (CLCR), platelets (PLT), and prothrombin time (PT) as fixed effects was developed using the NONMEM. CONCLUSIONS: We found that qCRP, CRRT, CLCR, PLT, and PT affected the voriconazole clearance. The most commonly used clinical regimen of 200 mg q12h was sufficient for the most common sensitive pathogens (MIC ≤ 0.25 mg/L), regardless of whether CRRT was performed and the level of qCRP. When the MIC was 0.5 mg/L, 200 mg q12h was insufficient only when the qCRP was <40 mg/L and CRRT was performed. When the MIC was ≥2 mg/L, a dose of 300 mg q12h could not achieve ≥ 90% PTA, necessitating the evaluation of a higher dose.

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 casecontrol 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 carbapenemresistant 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 carbapenemresistant 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.