Non-cystic Fibrosis Patients Research Articles

High rate of macrolide resistance and closely genetically related Mycobacterium abscessus complex strains identified among both cystic fibrosis and non-cystic fibrosis patients within two countries.

This study highlights the importance of understanding Mycobacterium abscessus transmission because it poses a growing threat to vulnerable populations, especially young cystic fibrosis patients. Investigating how it spreads and which antibiotics work best is crucial for effective treatment. This research used whole genome sequencing to track M. abscessus and found evidence of potential transmission between patients, including across borders. The findings suggest that dominant strains are circulating and some patients may be infected through direct or indirect contact. This knowledge can inform infection control and treatment strategies.

Integrating 16S rRNA profiling and in-silico analysis for an epitope-based vaccine strategy against Achromobacter xylosoxidans infection

Achromobacter xylosoxidans is an aerobic, catalase-positive, non-pigment-forming, Gram-negative, and motile bacterium. It potentially causes a wide range of human infections in cystic fibrosis and non-cystic fibrosis patients. However, developing a safe preventive or therapeutic solution against A. xylosoxidans remains challenging. This study aimed to construct an epitope-based vaccine candidate using immunoinformatic techniques. A. xylosoxidans was isolated from an auto workshop in Lahore, and its identification was confirmed through 16S rRNA amplification and bioinformatic analysis. Two protein targets with GenBank accession numbers AKP90890.1 and AKP90355.1 were selected for the vaccine construct. Both proteins exhibited antigenicity, with scores of 0.757 and 0.580, respectively and the epitopes were selected based on the IC50 value using the ANN 4.0 and NN-align 2.3 epitope prediction method for MHC I and MHC II epitopes respectively and predicted epitopes were analyzed for antigenicity, allergenicity and pathogenicity. The vaccine construct demonstrated structural stability, thermostability, solubility, and hydrophilicity. The vaccine produced 250 B-memory cells per mm3 and approximately 16,000 IgM + IgG counts, indicating an effective immune response against A. xylosoxidans. Moreover, the vaccine candidate interacted stably with toll-like receptor 5, a pattern recognition receptor, with a confidence score of 0.98. These results highlight the potency of the designed vaccine candidate, suggesting its potential to withstand rigorous in vitro and in vivo clinical trials. This epitope-based vaccine could serve as the first preventive immunotherapy against A. xylosoxidans infections, addressing this bacterium’s health and financial burdens. The findings demonstrate the value of employing immunoinformatic tools in vaccine development, paving the way for more precise and tailored approaches to combating microbial threats.

Epidemiology, microbiological, clinical characteristics, and outcome of Burkholderia cepacia complex infections in non-cystic fibrosis adult patients from Qatar

ObjectivesBurkholderia species infections are associated with diverse and challenging clinical presentations because of distinct virulence and antimicrobial resistance factors. The study aims to evaluate the epidemiology, microbiological, and clinical outcomes of Burkholderia cepacia complex (Bcc) infections in non-cystic fibrosis (CF) patients from Qatar. MethodsA retrospective study was conducted on adult patients across all hospitals at Hamad Medical Corporation between January 2012 and December 2018 to evaluate clinically relevant Bcc in non-CF adult patients. ResultsOver 7 years, 72 episodes of Burkholderia species infections were recorded, 64 were secondary to Bcc primarily affecting males (78.12%) with a mean age of 53 years, from the Middle and Southeastern region (92.2%) affected predominantly by diabetes mellitus (34.4%), chronic kidney (23.4%), coronary heart (20.3%), and hypertensive diseases (17.2%) while recent hospitalization and admission to critical care were evident in 45.3% and 93.8% of cases, respectively. Main infection sites were urinary (43.8%) and respiratory (29.7%) with associated bacteremia recorded in 26.6% of cases. Microbiological characteristics demonstrated high-level resistance profiles leading to delayed microbiological clearance in case of bacteremia (61%) and management with multiple therapeutic agents (range 4-6) resulting in disease resolution in 90.6% of cases with observed 30-day mortality of 7.8%. ConclusionsB. cepacia infections are infrequent, recorded mainly in middle-aged males with chronic comorbidities presenting as urinary, respiratory, and bacteremia associated with hospitalization, admission to critical care, and invasive procedures. High-level antimicrobial resistance is observed necessitating multiple therapeutic agents and suboptimal bacteriological clearance.

Phenotypes of a Pseudomonas aeruginosa hypermutator lineage that emerged during prolonged mechanical ventilation in a patient without cystic fibrosis.

Hypermutator lineages of Pseudomonas aeruginosa arise frequently during the years of airway infection experienced by patients with cystic fibrosis and bronchiectasis but are rare in the absence of chronic infection and structural lung disease. Since the onset of the COVID-19 pandemic, large numbers of patients have remained mechanically ventilated for extended periods of time. These patients are prone to acquire bacterial pathogens that persist for many weeks and have the opportunity to evolve within the pulmonary environment. However, little is known about what types of adaptations occur in these bacteria and whether these adaptations mimic those observed in chronic infections. We describe a COVID-19 patient with a secondary P. aeruginosa lung infection in whom the causative bacterium persisted for >50 days. Over the course of this infection, a hypermutator lineage of P. aeruginosa emerged and co-existed with a non-hypermutator lineage. Compared to the parental lineage, the hypermutator lineage evolved to be less cytotoxic and less virulent. Genomic analyses of the hypermutator lineage identified numerous mutations, including in the mismatch repair gene mutL and other genes frequently mutated in individuals with cystic fibrosis. Together, these findings demonstrate that hypermutator lineages can emerge when P. aeruginosa persists following acute infections such as ventilator-associated pneumonia and that these lineages have the potential to affect patient outcomes.IMPORTANCEPseudomonas aeruginosa may evolve to accumulate large numbers of mutations in the context of chronic infections such as those that occur in individuals with cystic fibrosis. However, these "hypermutator" lineages are rare following acute infections. Here, we describe a non-cystic fibrosis patient with COVID-19 pneumonia who remained mechanically ventilated for months. The patient became infected with a strain of P. aeruginosa that evolved to become a hypermutator. We demonstrate that hypermutation led to changes in cytotoxicity and virulence. These findings are important because they demonstrate that P. aeruginosa hypermutators can emerge following acute infections and that they have the potential to affect patient outcomes in this setting.

Comparative Genomics Identified PenR E151V Substitution Associated with Carbapenem-Resistance Burkholderia cepacia Complex and a Novel Burkholderia cepacia Complex Specific OXA-1043 Subgroup.

Burkholderia cepacia complex (Bcc) is a known significant opportunistic pathogen causing morbidity and mortality, particularly in those with cystic fibrosis, chronic granulomatous disease, or immunocompromising host. Mortality of Bcc bloodstream infections among non-cystic fibrosis patients remained high. The antibiotic treatment for Bcc infection is quite challenging due to its intrinsic resistance to most antibiotics, and the resistance to carbapenems was the biggest concern among them. We aimed to realize the mechanism of carbapenem resistance in Bcc. Ten strains of Bcc were identified by the MALDI-TOF MS, and the drug susceptibility test was using VITEK 2 system. The Burkholderia cepacia complex genomes were sequenced via Nanopore GridIon. We also downloaded another ninety-five strains of Bcc from the National Center for Biotechnology Information database to evaluate the divergence between carbapenem-resistance and carbapenem-sensitive strains. The genetic organization between carbapenem-sensitive and carbapenem-resistant strains of Bcc showed no difference. However, in the carbapenem-sensitive strain, E151V substitution in PenR was detected. In addition, a novel specific OXA family subgroup, blaOXA-1043 in Burkholderia cenocepacia was discovered. The E151V substitution in PenR may be associated with carbapenem-sensitive in Bcc. Moreover, the V151E mutation in PenR may be related to the activation of PenB, leading to Bcc resistance to carbapenems. Besides, a novel OXA family subgroup, blaOXA-1043, was found in Burkholderia cenocepacia, which differs from the previous OXA family.

Genomic features, antimicrobial susceptibility, and epidemiological insights into Burkholderia cenocepacia clonal complex 31 isolates from bloodstream infections in India.

Burkholderia cepacia complex (Bcc) clonal complex (CC) 31, the predominant lineage causing devastating outbreaks globally, has been a growing concern of infections in non-cystic fibrosis (NCF) patients in India. B. cenocepacia is very challenging to treat owing to its virulence determinants and antibiotic resistance. Improving the management of these infections requires a better knowledge of their resistance patterns and mechanisms. Whole-genome sequences of 35 CC31 isolates obtained from patient samples, were analyzed against available 210 CC31 genomes in the NCBI database to glean details of resistance, virulence, mobile elements, and phylogenetic markers to study genomic diversity and evolution of CC31 lineage in India. Genomic analysis revealed that 35 isolates belonging to CC31 were categorized into 11 sequence types (ST), of which five STs were reported exclusively from India. Phylogenetic analysis classified 245 CC31 isolates into eight distinct clades (I-VIII) and unveiled that NCF isolates are evolving independently from the global cystic fibrosis (CF) isolates forming a distinct clade. The detection rate of seven classes of antibiotic-related genes in 35 isolates was 35 (100%) for tetracyclines, aminoglycosides, and fluoroquinolones; 26 (74.2%) for sulphonamides and phenicols; 7 (20%) for beta-lactamases; and 1 (2.8%) for trimethoprim resistance genes. Additionally, 3 (8.5%) NCF isolates were resistant to disinfecting agents and antiseptics. Antimicrobial susceptibility testing revealed that majority of NCF isolates were resistant to chloramphenicol (77%) and levofloxacin (34%). NCF isolates have a comparable number of virulence genes to CF isolates. A well-studied pathogenicity island of B. cenocepacia, GI11 is present in ST628 and ST709 isolates from the Indian Bcc population. In contrast, genomic island GI15 (highly similar to the island found in B. pseudomallei strain EY1) is exclusively reported in ST839 and ST824 isolates from two different locations in India. Horizontal acquisition of lytic phage ST79 of pathogenic B. pseudomallei is demonstrated in ST628 isolates Bcc1463, Bcc29163, and BccR4654 amongst CC31 lineage. The study reveals a high diversity of CC31 lineages among B. cenocepacia isolates from India. The extensive information from this study will facilitate the development of rapid diagnostic and novel therapeutic approaches to manage B. cenocepacia infections.

Retrospective analysis of Achromobacter species isolated from cystic fibrosis and non-cystic fibrosis patients

Achromobacter türleri Gram negatif, katalaz, oksidaz ve sitrat pozitif, fermentatif olmayan bakterilerdir. Toplum kökenli ya da hastane kaynaklı enfeksiyonlara sebep olabilmektedir. Hem immünokompetan hem de immün yetmezlikli kişilerde enfeksiyonlara sebep olabilmekle birlikte kistik fibrozis (KF) hastalarını enfekte etmeleri durumunda, KF hastalarının akciğer fonksiyonlarını kötüleştirdiğinden ve daha sık pulmoner alevlenmeye neden olduğundan bu hasta grubunda özellikle önem taşımaktadır. Bu retrospektif çalışmada, Marmara Üniversitesi Eğitim ve Araştırma Hastanesi’nde 2017-2021 yıllarında Achromobacter türleri izole edilen hastaların verileri analiz edilmiştir. Altta yatan hastalıkların varlığına göre Achromobacter türlerinin izolasyon sıklığı, hastalara ait demografik veriler ve antimikrobiyal duyarlılık sonuçları irdelenmiştir. İzolatların tür düzeyinde tanımlaması, matriks ile desteklenmiş lazer desorpsiyon/iyonizasyon uçuş zamanı kütle spektrometresi (MALDI-TOF MS, VITEK MS, BioMérieux, Fransa) ile yapılmıştır. Antimikrobiyal duyarlılık testleri, disk difüzyon metodu ile çalışılmıştır. İstatistiksel analizler için SPSS (Statistical Package for Social Sciences) for Windows 24.0 programı kullanılmıştır.
 Toplam 148 hastadan 318 Achromobacter izolatı elde edilmiştir. Hastaların %29.7’si kistik fibrozis (KF); %70.3’ü ise KF dışı hastalar olmasına rağmen izolatların %51.6’sı KF hastalarına aittir (P=0.63). En sık gönderilen örnek türü, solunum yollarına ait örnekler olup (%78), KF hastalarında gönderilen örneklerin tümü solunum örneği iken; KF dışı hastalarda bu oran %54.5’tir (P

424. Risk Factors for Infection or Colonization with Piperacillin-tazobactam (TZP) Resistant P. aeruginosa (PSA) with Increasing Degrees of β-lactam Resistance

Abstract Background Resistance to β-lactams amongst PSA is common with roughly 20% of isolates demonstrating resistance to TZP. This can lead to delays in the time to appropriate empiric therapy. While rapid diagnostics can identify PSA at earlier time points, they fail to detect common β-lactam resistance mechanisms in this pathogen. Though risk factors for TZP resistance (TZP-R) amongst PSA have been identified, co-resistance amongst traditional anti-PSA β-lactams is common, so decisions to turn to other traditional anti-PSA or novel agents in the presence of such predictors are unclear. This study aims to find predictors unique to varying degrees of β-lactam resistance amongst TZP-R PSA to inform these decisions. Methods This was a retrospective case-case-case-control study of all non-cystic fibrosis patients with PSA isolated from a culture from 2015-2021 at Michigan Medicine. Four study groups were created based on the susceptibility profile of PSA: TZP susceptible (TZP-S), resistance to TZP only (TZP-R ONLY), resistance to TZP in addition to 1 or 2 other traditional anti-PSA β-lactams (TZP-R PLUS), and resistance to all traditional anti-PSA β-lactams (pan β-lactam resistance, PBR). Bivariate and multivariate analyses were performed to compare each degree of TZP resistance to the TZP-S group. Results were then compared across models to assess uniqueness to a given resistant phenotype. Results 2365 patients were included, and results of the multivariate analyses are listed in the table. The sole predictor of TZP-R ONLY was recent ceftriaxone or cefotaxime use. Independent predictors unique to TZP-R PLUS were community acquired infection, recent ICU residence, and recent exposure to TZP or aztreonam. Most risk factors identified were either unique to PBR or shared between PBR and TZP-R PLUS including history of PSA, history of TZP-R PSA, and recent exposure to multiple antibiotics. Multivariate Models for TZP-R ONLY, TZP-R PLUS, and PBR Conclusion This analysis demonstrates that previously identified risk factors for TZP-R P. aeruginosa are predictors of PSA with greater degrees of resistance. Given these findings, consideration needs to be given to escalation to novel agents in the presence of risk factors at the time of PSA isolation, rather than to other traditional anti-PSA β-lactams. Disclosures Owen Albin, MD, Charles River Laboratory: Advisor/Consultant|Cipla Pharmaceuticals: Advisor/Consultant|Shionogi Inc: Advisor/Consultant Keith S. Kaye, MD, GSK: Advisor/Consultant|merck: Advisor/Consultant|merck: Stocks/Bonds|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant jason M. Pogue, PharmD, consultant to Venatorx, Merck, Shionogi, QPex Biopharma, Utility, GSK, and Entasis.: Advisor/Consultant.

Clinical characteristics and outcomes of non-cystic fibrosis patients with Burkholderia cepacia complex bacteremia at a medical center in Taiwan.

Burkholderia cepacia complex (BCC) represents a group of multidrug-resistant gram-negative bacteria that cause infections among immunocompromised hosts. Bacteremia occurs in patients who are chronically ill and is associated with substantial morbidity and mortality. The aim of this study was to investigate the clinical characteristics and outcomes of BCC bacteremic patients without cystic fibrosis. We conducted a retrospective study at the National Taiwan University Hospital. Adults with BCC bacteremia from January 2015 to May 2019 were enrolled. The primary outcome was 14-day mortality. Multivariable logistic regression was performed for outcome analysis. One-hundred and ninety-five patients were analyzed and their mean age was 67 years. Over 95% of the BCC isolates were susceptible to trimethoprim/sulfomethoxazole (TMP/SXT). Levofloxacin resistance rates were high, with only 25.1% of isolates being susceptible. Pairwise comparisons were made between different definitive regimens including meropenem-monotherapy, ceftazidime-monotherapy, levofloxacin-monotherapy, TMP/SXT-monotherapy, tigecycline-monotherapy as well as combination versus monotherapy. No regimen was significantly associated with survival in our study. Multivariable logistic regression showed that the Pitt bacteremia score (adjust odds ratio [aOR],1.46; 95% confidence interval [CI],1.19-1.79; p<0.001), underlying metastatic cancer (aOR, 2.73; 95% CI, 1.01-7.39; p=0.047), inappropriate definitive treatment independently predicted greater 14-day mortality (aOR, 8.21; 95% CI, 2.49-27.08; p<0.001). No single regimen is associated with improved mortality. After adjusting for other potential confounders, our data suggest selection of an appropriate antibiotic provide better clinical outcomes among patients with BCC bacteremia.

Burkholderia vietnamiensis causing infections in noncystic fibrosis patients in a tertiary care hospital in Mexico

Burkholderia cepacia complex (Bcc) species are opportunistic pathogens widely distributed in the environment and often infect people with cystic fibrosis (CF). This study aims to determine which genomovars of the Bcc can cause infections in non-CF patients from a tertiary care hospital in Mexico and if they carry virulence factors that could increase their pathogenicity. We identified 23 clinical isolates that carry the recA gene. Twenty-two of them belongs to the genomovar V (B. vietnamiensis) and one to the genomovar II (B. multivorans). Thirteen pulsotypes were identified among 22 B. vietnamiensis isolates. All clinical isolates produced biofilm were motile and cytotoxic on murine macrophage-like RAW264.7 and in A549 human lung epithelial cells. In conclusion, B. vietnamiensis causes infections in non-CF patients in a tertiary care hospital in Mexico, rapid identification of this pathogen can help physicians to establish a better antimicrobial treatment.

The Genetic relatedness of Burkholderia contaminans clinical isolates from cystic fibrosis and non-cystic fibrosis patients in Argentina.

The Burkholderia cepacia complex (BCC) bacteria are opportunistic pathogens that cause nosocomial infections and are especially dangerous for cystic fibrosis (CF) patients. Burkholderia contaminans is an emerging BCC species isolated from CF patients that also occurs as a contaminant in pharmaceutical and personal care products, sometimes linking it with outbreaks. A total of 55 B. contaminans isolates from CF and non-CF patients in Argentina were identified by recA sequencing and MALDI TOF MS. A standardized Pulsed Field Gel Electrophoresis (PFGE) protocol was set up in order to assess genetic diversity, outbreak investigations, and possible clone persistence. All isolates were identified as B. contaminans by both MALDI-TOF MS and recA sequence analysis. PFGE has enabled us to compare and determine the genetic relationship between B. contaminans isolates. Isolates were distributed in different PFGE clusters with evidence of the presence and persistence of a clone, over a period of 3 years, in the same hospital. This large hospital outbreak involved CF and non-CF patients. Moreover, PFGE results showed a good correlation between sporadic or outbreak-related isolates and the available epidemiological information. These findings highlight the importance of B. contaminans in Argentina and provide evidence for encouraging the surveillance of highly transmissible clones. The study also contributes to global knowledge about B. contaminans infections.

Potential Cross-Transmission of Mycobacterium abscessus among Non-Cystic Fibrosis Patients at a Tertiary Hospital in Japan.

ABSTRACTMycobacterium abscessus (M. abscessus) is a highly antimicrobial-resistant pathogen that causes refractory pulmonary disease. Recently, the possibility of M. abscessus cross-transmission among cystic fibrosis (CF) patients has been reported. CF is rare in Asia, but M. abscessus pulmonary disease is common. Therefore, we investigated the possibility of M. abscessus cross-transmission in a Japanese hospital setting. Of 104 M. abscessus isolates, 25 isolates from 24 patients were classified into four clusters based on their variable number of tandem repeat profiles and were subjected to whole-genome sequencing (WGS). The epidemiological linkages among our patients were investigated by integrating the WGS data of previously reported nosocomial outbreak-related M. abscessus clinical isolates in the United Kingdom and the United States. Eight transmissible clusters (TCs) were identified. The United Kingdom and United States isolates were assigned to four clusters (TC1, TC2, TC5, and TC8) and one cluster (TC3), respectively. A total of 12 isolates from our hospital belonged to 4 clusters (TC4, TC5, TC6, and TC7). Epidemiological linkage analysis inferred direct or indirect transmission between patients in our hospital in TC4 and TC5 but not in TC6 and TC7. In TC5, the single nucleotide polymorphism distance between isolates from Japanese and United Kingdom patients was less than 21; however, there was no contact. This study revealed that genetically closely related isolates exist, even in non-CF patients. However, the transmission route remains unclear, and further research is warranted to clarify whether cross-transmission is involved.IMPORTANCE Although the possibility of Mycobacterium abscessus (M. abscessus) cross-transmission in cystic fibrosis (CF) patients has often been reported, it is not clear whether similar events have occurred in Asian non-CF patients. Whole-genome sequencing analysis of M. abscessus isolates from Fukujuji Hospital in Japan indicated that genetically closely related M. abscessus isolates exist. In addition, according to epidemiological linkage analysis, some clusters were suspected of direct or indirect transmission between patients within our hospital. However, the transmission route of M. abscessus remains unclear, because interestingly, one cluster showed a single nucleotide polymorphism distance of less than 21 from the United Kingdom isolates, but no epidemiological linkage was identified.

Molecular Epidemiological Characteristics of Mycobacterium abscessus Complex Derived from Non-Cystic Fibrosis Patients in Japan and Taiwan.

ABSTRACTMycobacterium abscessus complex (MABC) is a group of emerging, highly antimicrobial-resistant non-tuberculous mycobacteria. Specific MABC clones are spreading globally in patients with cystic fibrosis (CF); however, associated genomic epidemiology is lacking in East Asia, with very few patients with CF. Here, we investigated MABC populations derived from non-CF patients in Japan and Taiwan. Analysis of whole-genome sequencing data of 220 MABC isolates revealed that 112, 105, and 3 were M. abscessus subsp. abscessus (ABS), M. abscessus subsp. massiliense (MAS), and M. abscessus subsp. bolletii (BOL), respectively. Moreover, >50% of ABS and >70% of MAS were related to four predominant clones in the region. Known mutations conferring macrolide resistance were rare (1.4%) and were not enriched in the predominant clones. Conversely, the macrolide-susceptible erm(41) T28C mutation was significantly enriched in one predominant ABS clone. The most predominant ABS clone was genetically related to the previously described dominant circulating clone (DCC)1 in patients with CF, whereas no isolates were related to DCC2; isolates related to DCC3 were not necessarily predominant in our sample set. We found that the erm(41) T28C mutants spread globally, and some of them reacquired the functional erm(41) gene through both point mutation and recombination. This study revealed predominant MABC clones in Japan and Taiwan and their relationship with the globally superadding clones in the patient community with CF. Our study provides insights into the genetic characteristics of globally dominant and area-specific strains isolated from patients with or without CF and differences between globally spread and regionally specific strains.IMPORTANCE Members of Mycobacterium abscessus complex (MABC) are frequently isolated from patients. Studies have reported that predominant clones of MABC (known as dominant circulating clones; DCCs) are distributed worldwide and transmitted from humans to humans in patients with cystic fibrosis (CF). However, associated genomic epidemiology has not yet been conducted in East Asia, including Japan and Taiwan, where there are only a few patients with CF. Using whole-genome sequencing data derived from non-CF patients in Japan and Taiwan, we revealed prevalent clones and the incidence of macrolide resistance-associated mutations in the MABC population in this region. We also clarified the associations between these predominant clones and DCCs in the global CF patient community. Our results would assist further studies in elucidating the genetic characteristics of strains isolated from patients with or without CF, the differences between globally spread and regionally specific strains, and the adaptive evolution of MABC within the host.

Influence of Comorbidities and Airway Clearance on Mortality and Outcomes of Patients With Severe Bronchiectasis Exacerbations in Taiwan.

Bronchiectasis is characterized by systemic inflammation and multiple comorbidities. This study aimed to investigate the clinical outcomes based on the bronchiectasis etiology comorbidity index (BACI) score in patients hospitalized for severe bronchiectasis exacerbations. We included non-cystic fibrosis patients hospitalized for severe bronchiectasis exacerbations between January 2008 and December 2016 from the Chang Gung Research Database (CGRD) cohort. The main outcome was the 1-year mortality rate after severe exacerbations. We used the Cox regression model to assess the risk factors of 1-year mortality. Of 1,235 patients who were hospitalized for severe bronchiectasis exacerbations, 641 were in the BACI < 6 group and 594 in the BACI ≥ 6 group. The BACI ≥ 6 group had more previous exacerbations and a lower FEV1. Pseudomonas aeruginosa (19.1%) was the most common bacterium, followed by Klebsiella pneumoniae (7.5%). Overall, 11.8% of patients had respiratory failure and the hospital mortality was 3.0%. After discharge, compared to the BACI < 6 group, the BACI ≥ 6 group had a significantly higher cumulative incidence of respiratory failure and mortality in a 1-year follow-up. The risk factors for 1-year mortality in a multivariate analysis include age [hazard ratio (HR) 4.38, p = 0.01], being male (HR 4.38, p = 0.01), and systemic corticosteroid usage (HR 6.35, p = 0.001), while airway clearance therapy (ACT) (HR 0.50, p = 0.010) was associated with a lower mortality risk. An increased risk of respiratory failure and mortality in a 1-year follow-up after severe exacerbations was observed in bronchiectasis patients with multimorbidities, particularly older age patients, male patients, and patients with a history of systemic corticosteroid use. ACT could effectively improve the risk for 1-year mortality.

A Potential High-Risk Clone of Pseudomonas aeruginosa ST463.

Pseudomonas aeruginosa is one of the most common opportunistic pathogens, which causes severe nosocomial infections because of its well-known multidrug-resistance and hypervirulence. It is critical to curate routinely the epidemic P. aeruginosa clones encountered in the clinic. The aim of the present study was to investigate the connection between virulence factors and antimicrobial resistance profiles in epidemic clones. Herein, we found that ST463 (O4), ST1212 (O11), and ST244 (O5) were prevalent in 30 isolates derived from non-cystic fibrosis patients, based on multilocus sequence type (MLST) and serotype analysis. All isolates were multidrug-resistant (MDR) and each was resistance to at least three classes of antibiotics in antimicrobial susceptibility tests, which was consistent with the presence of the abundant resistance genes, such as blaOXA–50, blaPAO, aph(3′), catB7, fosA, crpP, and blaKPC–2. Notably, all blaKPC–2 genes were located between ISKpn6-like and ISKpn8-like mobile genetic elements. In addition, classical exotoxins encoded by exoU, exoS, and pldA were present in 43.44% (13/40), 83.33% (25/30), and 70% (21/30) of the isolates, respectively. The expression of phz operons encoding the typical toxin, pyocyanin, was observed in 60% of isolates (18/30) and was quantified using triple quadrupole liquid chromatograph mass (LC/MS) assays. Interestingly, compared with other MLST types, all ST463 isolates harbored exoU, exoS and pldA, and produced pyocyanin ranging from 0.2 to 3.2 μg/mL. Finally, we evaluated the potential toxicity of these isolates using hemolysis tests and Galleria mellonella larvae infection models. The results showed that ST463 isolates were more virulent than other isolates. In conclusion, pyocyanin-producing ST463 P. aeruginosa, carrying diverse virulence genes, is a potential high-risk clone.

The respiratory microbiome after lung transplantation: Reflection or driver of respiratory disease?

With the introduction of high-throughput sequencing methods, our understanding of the human lower respiratory tract's inhabitants has expanded significantly in recent years. What is now termed the "lung microbiome" has been described for healthy patients, as well as people with chronic lung diseases and lung transplants. The lung microbiome of lung transplant recipients (LTRs) has proven to be unique compared with nontransplant patients, with characteristic findings associated with disease states, such as pneumonia, acute rejection, and graft failure. In this review, we summarize the current understanding of the lung microbiome in LTRs, not only focusing on bacteria but also highlighting key findings of the viral and the fungal community. Based on our knowledge of the lung microbiome in LTRs, we propose multiple opportunities for clinical use of the microbiome to improve outcomes in this population.

Burkholderia cepacia complex bacteremia outbreaks among non-cystic fibrosis patients in the pediatric unit of a university hospital.

Burkholderia cepacia complex (Bcc) comprises multi-drug resistant, Gram-negative, motile, and aerobic bacteria. Bcc causes severe nosocomial infections particularly in patients with intravascular catheters and in those with cystic fibrosis. We studied a Bcc outbreak in non-cystic fibrosis patients. We analyzed data from six patients hospitalized at our center. Blood cultures identified as infectious were incubated onto 5% blood sheep agar, chocolate agar, and eosin methylene blue (EMB) agar. We examined possible sites that could be sources of infection at the clinic. We confirmed isolations with pulsed-field gel electrophoresis (PFGE) tests. The first patient was hospitalized due to left renal agenesis, urinary tract infection, and renal failure. Bcc was isolated in blood cultures obtained due to high fever on the third day of hospitalization. We stopped new patient hospitalizations after detecting Bcc in blood cultures of other five patients. We did not detect further positive specimens obtained from other clinic and the patient rooms. PFGE patterns were similar in all clinical isolates of Bcc indicating that the outbreak had originated from the source. Bcc infection should be considered in cases of nosocomial outbreaks of multi-drug resistant organisms that require hospitalization at intensive care units. Control measures should be taken for prevention of nosocomial infections and required investigations should be done to detect the source of infection.

P099 Evaluation by plethismography of cystic fibrosis and non-cystic fibrosis patients

P099 Evaluation by plethismography of cystic fibrosis and non-cystic fibrosis patients

833. Characteristics and Utilization Patterns of Colistin Compared with Newer Agents in Gram-Negative Infections

BackgroundColistin has resurfaced in light of Gram-negative (GN) resistance. New antibiotics to treat antibiotic resistant GN infections (eg, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam [new agents]), have recently been approved but their use vs colistin is unclear. We compared the overall use of colistin and new agents from 2014 to 2018 in patient days on therapy (PDOT).MethodsData on non-cystic fibrosis patients from the Premier Healthcare Database was used. PDOT was tabulated quarterly for Premier hospitals and projected to the US population. A subset of data from 2016 to 2018 with microbiologically confirmed GN (MCGN) infections was selected for adult inpatients receiving ≥3 days of therapy with colistin, new agents, carbapenems, or extended-spectrum cephalosporins. The index infection was defined either as the first carbapenem-resistant (CR) or -sensitive infection if no CR infection occurred. Patients could be treated with ≥1 antibiotic per infection. Utilization was examined by pathogen and patient characteristics.ResultsPDOT with colistin decreased from 2015 to 2018, while new agents have increased (Figure). During 2015–2018, colistin and any of 3 new agents were used by 3,320 and 5,781 inpatients, respectively, of whom, 649 (20%) and 1,284 (22%) had MCGN pathogens. Colistin-treated patients were sicker than patients treated with new agents (Table), underlying renal disease was present in 34.5% vs 36.3 %, and median length of stay of 17 vs 15 days, respectively. Mean total hospital cost was $93,815 vs $84,013 for colistin and new agents, respectively. Mortality was greater in colistin patients (18% vs 12%; p< 0.0001). CR infections constituted similar proportions of colistin and new agent use (79% vs 75%). Colistin accounted for 15.2% of CR Acinetobacter treatments and 9.7% of CR Enterobacterales (CRE) treatments compared with 4.5% and 12.8%, respectively, for new agents.Figure. Projected Inpatient PDOT Table. ConclusionColistin use has decreased simultaneously with the introduction and increased use of new agents in the USA. Colistin was used more frequently in sicker patients and for Acinetobacter spp. infections than for CRE infections. Patients on colistin have worse outcomes, probably due to baseline differences in their health status.DisclosuresStephen Marcella, MD, Shionogi Inc. (Employee) Casey Doremus, MS, Shionogi Inc. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

Immune defects in patients with pulmonary Mycobacterium abscessus disease without cystic fibrosis.

The prevalence of Mycobacterium abscessus infections in non-cystic fibrosis (CF) patients has increased in recent years. In this study, we investigate whether immune defects explain the apparent susceptibility to this opportunistic infection in non-CF patients.We performed stimulations of peripheral blood mononuclear cells and whole blood from 13 patients with M. abscessus pulmonary disease and 13 healthy controls to investigate their cytokine production after 24 h and 7 days.Patients were predominantly women (54%) with a mean age of 59 years; 62% had nodular bronchiectatic disease. Many patients had predisposing pulmonary diseases, such as COPD (46%), and asthma (23%). Patients with COPD showed an impaired interleukin (IL)-6 response to M. abscessus and a reduced IL-17 response to Candida, together with a M. abscessus-specific enhanced IL-22 production. Patients without COPD showed higher levels of interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory molecule. Within the non-COPD patients, those with bronchiectasis showed defective interferon (IFN)-γ production in response to Candida albicans.In conclusion, susceptibility to M. abscessus is likely determined by a combination of immunological defects and predisposing pulmonary disease. The main defect in the innate immune response was a shift of the ratio of IL-1β to IL-1Ra, which decreased the bioactivity of this pathway in the adaptive immune response. In the adaptive immune response there was defective IL-17 and IFN-γ production. Patients with COPD and bronchiectasis showed different cytokine defects. It is therefore crucial to interpret the immunological results within the clinical background of the patients tested.