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Median cystic fibrosis (CF) survival has increased dramatically over time due to several factors, including greater availability and use of antimicrobial therapies. During the progression of CF lung disease, however, the emergence of multidrug antimicrobial resistance can limit treatment effectiveness, threatening patient longevity. Current planktonic-based antimicrobial susceptibility testing lacks the ability to predict clinical response to antimicrobial treatment of chronic CF lung infections. There are numerous reasons for these limitations including bacterial phenotypic and genotypic diversity, polymicrobial interactions, and impaired antibiotic efficacy within the CF lung environment. The parallels to other chronic diseases such as non-CF bronchiectasis are discussed as well as research priorities for moving forward., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Antimicrobial resistance (AMR) can present significant challenges in the treatment of cystic fibrosis (CF) lung infections. In CF and other chronic diseases, AMR has a different profile and clinical consequences compared to acute infections and this requires different diagnostic and treatment approaches. This review defines AMR, explains how it occurs, describes the methods used to measure AMR as well as their limitations, and concludes with future directions for research and development in the area of AMR in CF., (Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Infection is a common complication of cystic fibrosis (CF) airway disease. Current treatment approaches include early intervention with the intent to eradicate pathogens in the hope of delaying the development of chronic infection and the chronic use of aerosolized antibiotics to suppress infection. The use of molecules that help restore CFTR (cystic fibrosis transmembrane conductance regulator) function, modulate pulmonary inflammation, or improve pulmonary clearance may also influence the microbial communities in the airways. As the pipeline of these new entities continues to expand, it is important to define when key pathogens are eradicated from the lungs of CF patients and, equally important, when new pathogens might emerge as a result of these novel therapies., (Copyright © 2018 American Society for Microbiology.)

Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects aged 1-69 years who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). 18 anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16 out of 57 genera had a ≥5% prevalence across centres.Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria, whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher total anaerobe/total aerobe CFU ratio was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared with a Pseudomonas -dominated group with similar proportions of subjects that were homozygous for F508del.In summary, anaerobic bacteria occurred at an early age. In sputum-producing subjects anaerobic bacteria were associated with milder disease, suggesting that targeted eradication of anaerobes may not be warranted in sputum-producing CF subjects., Competing Interests: Conflict of interest: G.G. Einarsson's work is supported by a grant from IMI (iABC; Inhaled Antibiotics in Bronchiectasis and Cystic Fibrosis). N. Gotman reports grants from AECF, during the conduct of the study. S. Davis Thomas reports grants from the National Institutes of Health (NIH), during the conduct of the study. P.H. Gilligan reports grants from the NIH, during the conduct of the study. M.C. Wolfgang reports grants from the NIH, during the conduct of the study. J.S. Elborn reports grants from Northern Ireland Research and Development, during the conduct of the study. R.C. Boucher is Chairman of the Board of Parion Sciences, a privately held UNC spin-out company focused on developing therapies for CF, and has received monetary compensation for this role. M.M. Tunney reports grants from Health and Social Care Research and Development Division, Public Health Agency, Northern Ireland, during the conduct of the study; and grants from Alaxia, outside the submitted work., (Copyright ©ERS 2018.)

Background: Mycobacterium abscessus infection is associated with declining lung function in cystic fibrosis (CF), but there is little evidence on clinical efficacy to guide treatment., Methods: Retrospective review of 37 CF patients treated for M. abscessus respiratory infection at a single center from 2006 to 2014. Outcomes included change in FEV 1 at 30, 60, 90, 180, and 365days after treatment and clearance of M. abscessus from sputum cultures., Results: Lung function was significantly improved after 30 and 60days of treatment, but not at later time points. Gains were inversely related to starting lung function. Antibiotic choices did not influence outcomes except for greater clearance with clarithromycin., Conclusions: Treatment of M. abscessus resulted in short term improvement in lung function that is inversely related to pre-treatment FEV 1 ., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

A novel selective agar (RGM medium) has been advocated for the isolation of rapidly growing mycobacteria from the sputa of cystic fibrosis (CF) patients. The aim of this study was to compare RGM medium to Burkholderia cepacia selective agar (BCSA) and a standard acid-fast bacillus (AFB) culture method for the isolation of nontuberculous mycobacteria (NTM) from patients with CF. The applicability of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the identification of NTM isolated on RGM medium was also assessed. Respiratory samples ( n = 869) were collected from 487 CF patients and inoculated directly onto RGM medium and BCSA. Cultures were incubated at 30°C and examined for up to 28 days. A subset of 212 samples (from 172 patients) was also cultured by using a mycobacterial growth indicator tube (MGIT) and on Lowenstein-Jensen medium following dual decontamination. By using a combination of all methods, 98 mycobacteria were isolated from 869 samples (11.3%). The sensitivity of RGM medium (96.9%) was significantly higher than that of BCSA (35.7%) for the isolation of mycobacteria ( P < 0.0001). The sensitivity of RGM medium was also superior to that of standard AFB culture for the isolation of mycobacteria (92.2% versus 47.1%; P < 0.0001). MALDI-TOF MS was effective for the identification of mycobacteria in RGM medium. RGM medium offers a simple and highly effective tool for the isolation of NTM from patients with CF. Extended incubation of RGM medium for 28 days facilitates the isolation of slow-growing species, including members of the Mycobacterium avium complex (MAVC)., (Copyright © 2017 American Society for Microbiology.)

Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality. Previously, M. abscessus was thought to be independently acquired by susceptible individuals from the environment. However, using whole-genome analysis of a global collection of clinical isolates, we show that the majority of M. abscessus infections are acquired through transmission, potentially via fomites and aerosols, of recently emerged dominant circulating clones that have spread globally. We demonstrate that these clones are associated with worse clinical outcomes, show increased virulence in cell-based and mouse infection models, and thus represent an urgent international infection challenge., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Relationships between clinical outcomes and novel respiratory pathogens such as Trichosporon are not well understood., Methods: Respiratory cultures from CF patients were screened for novel pathogens Trichosporon and Chryseobacterium as well as other pathogens over 28months. Relationships between microbiologic and clinical data were assessed using univariate and multivariate methods., Results: Of 4934 respiratory cultures from 474 CF patients, 37 cultures from 10 patients were Trichosporon positive. Patients with positive Trichosproron cultures had a greater decline in FEV1 over time (-3.9%/year vs. -1.3%/year, p<0.05), whereas Chryseobacterium did not influence lung function. These findings were confirmed in multivariate analyses that included age, gender, and other common pathogens as confounders. Treatment of Trichosporon infected patients was associated with improved lung function., Conclusions: Trichosporon can be recovered from a small but clinically meaningful fraction of CF patients. The presence of Trichosporon, but not Chryseobacterium, is associated with greater declines in lung function., (Copyright © 2016 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The localization of Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) lungs, alone or during coinfection with Pseudomonas aeruginosa, is poorly understood. We performed immunohistochemistry for Bcc and P. aeruginosa bacteria on 21 coinfected or singly infected CF lungs obtained at transplantation or autopsy. Parallel in vitro experiments examined the growth of two Bcc species, Burkholderia cenocepacia and Burkholderia multivorans, in environments similar to those occupied by P. aeruginosa in the CF lung. Bcc bacteria were predominantly identified in the CF lung as single cells or small clusters within phagocytes and mucus but not as "biofilm-like structures." In contrast, P. aeruginosa was identified in biofilm-like masses, but densities appeared to be reduced during coinfection with Bcc bacteria. Based on chemical analyses of CF and non-CF respiratory secretions, a test medium was defined to study Bcc growth and interactions with P. aeruginosa in an environment mimicking the CF lung. When test medium was supplemented with alternative electron acceptors under anaerobic conditions, B. cenocepacia and B. multivorans used fermentation rather than anaerobic respiration to gain energy, consistent with the identification of fermentation products by high-performance liquid chromatography (HPLC). Both Bcc species also expressed mucinases that produced carbon sources from mucins for growth. In the presence of P. aeruginosa in vitro, both Bcc species grew anaerobically but not aerobically. We propose that Bcc bacteria (i) invade a P. aeruginosa-infected CF lung when the airway lumen is anaerobic, (ii) inhibit P. aeruginosa biofilm-like growth, and (iii) expand the host bacterial niche from mucus to also include macrophages., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objectives: Test the hypothesis that the link between respiratory viruses and pulmonary exacerbation in cystic fibrosis (CF) reflects increased frequency or severity of lower airways infection., Study Design: Molecular respiratory viral panels (RVPs), cell counts, and quantitative bacterial cultures were assessed in 235 bronchoalveolar lavage fluid (BALF) samples from 138 children with CF. Relationships among the data were analyzed using multivariate methods., Results: RVPs were positive in 67 (28.5%) BALF samples from 52 (37.7%) patients, with rhinovirus/enterovirus most common (82.4% of RVP+). RVP+ patients were younger (5.4 years, IQR 3.0-9.7 vs. 8.0 years, IQR 3.5-12.9; P < 0.01), more likely to have respiratory symptoms (74.6% vs. 55.2%, P < 0.01), and had higher BALF percent neutrophils (70.5%, IQR 46-85% vs. 59.3%, IQR 34-77%; P < 0.05). Percent predicted FEV1 at bronchoscopy was diminished from baseline in both groups, but recovered in the RVP- (90.2 ± 22.2% vs. 89.6 ± 19.7%, P = 0.62) but not the RVP+ subjects (95.7 ± 21.1% vs. 89.1 ± 18.0%, P < 0.05). RVP status did not alter recovery rates of typical CF respiratory pathogens including Staphylococcus aureus (44.8% vs. 42.9%) and Pseudomonas aeruginosa (25.4% vs. 25.6%). However, common respiratory pathogens (Haemophilus species, Moraxella species, and Streptococcus pneumoniae) were recovered more frequently from RVP+ samples independent of age (OR 3.6, 95% CI 1.8-7.5, P < 0.001)., Conclusions: Respiratory viruses were frequently detected in BALF from CF patients and associated with markers of disease severity. Respiratory viruses did not impact frequency or severity of infection with typical CF pathogens, but rates of infection with common respiratory pathogens were increased. This finding may have treatment implications., (© 2013 Wiley Periodicals, Inc.)

Survival has improved in patients with cystic fibrosis (CF), in part because of aggressive antimicrobial management. Two multidrug-resistant environmental bacteria, the Burkholderia cepacia group and nontuberculous mycobacteria, have emerged. Improving genomic and proteomic technologies are allowing better identification of bacteria and fungi found in the CF lung and detection of viral agents that may be associated with pulmonary exacerbations. Anaerobic bacteria and Streptococcus angionsus group organisms may play a role in chronic CF lung infections. The diversity of organisms declines perhaps as a result of aggressive antimicrobial therapy, and an apex predator, Pseudomonas aeruginosa, may emerge in many patients with CF., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We evaluated the performance of the Bruker Biotyper and the bioMérieux Vitek MS with both the SARAMIS v4.09 and Knowledge Base v2.0 databases for the identification of 203 non-glucose-fermenting Gram-negative rods that had previously been identified by 16S rRNA gene sequencing. Including those that underwent repeat testing, 96.6%, 90.1%, and 93.6% of isolates, respectively, had identifications that agreed with the previous identification.

Background: Mycobacterium abscessus in cystic fibrosis (CF) patients is considered a contraindication to lung transplantation. We examine the post-transplant outcomes of CF patients with M. abscessus pre-transplant., Methods: CF patients transplanted at the University of North Carolina from 1992 to 2012 were retrospectively examined. Patients with at least one respiratory sample positive for M. abscessus prior to transplantation were included. Data collected included age, FEV1, body mass index (BMI), systemic steroid use, diabetes mellitus, ventilatory assistance, co-existent CF pathogens, imaging, post-transplant complications, and survival. RESULTS (N = 13): At transplant, mean age was 24.6 yr, mean BMI was 18.1 kg/m(2), six had 3+ positive smears for M. abscessus, and three were ventilator dependent. All met American Thoracic Society microbiological criteria for disease pre-transplant. Three patients developed M. abscessus-related complications, with clearance of the organism following treatment. Survival post-transplant shows 77% alive at one yr, 64% at three yr, and 50% at five yr; none died of M. abscessus. The survival data showed no statistically significant difference (p = 0.8) compared with a contemporaneously transplanted population of CF patients without M. abscessus (n = 154)., Conclusion: Lung transplantation, with favorable survival, is possible in CF patients with M. abscessus. Even if M. abscessus recurs, local control and clearance is possible., (© 2013 John Wiley & Sons A/S.)

Rapidly growing mycobacteria (RGM) are respiratory pathogens in patients with cystic fibrosis (CF), but detection generally requires specialized cultures for acid-fast bacilli (AFB; AFB cultures). We determined that RGM could be recovered from routine cultures of samples from patients with CF by extending incubation of the Burkholderia cepacia selective agar (BCSA) from 5 to 14 days. To explore the impact of this modification, we compared results from routine and AFB cultures of samples from CF patients for 2 years before (4,212 samples by routine culture, 1,810 samples by AFB culture, 670 patients) and 2 years after (4,720 samples by routine culture, 2,179 samples by AFB culture, 695 patients) the change. Clinical relevance was assessed with samples from a subgroup of 340 patients followed regularly throughout both periods. Extending incubation of BCSA enhanced RGM recovery from routine cultures (0.7% before, 2.8% after; P < 0.001); recovery from AFB cultures was unchanged (5.5% before, 5.7% after). Estimates of RGM detection sensitivity by culture or patient-based methods ranged from ∼65 to 75% for routine cultures (nonsignificantly lower than the ∼80 to 85% for AFB cultures) and were adversely affected by coculture with mold or nonpseudomonal, nonfermenting Gram-negative rods. In the after period, 16 CF patients met the criteria for RGM infection by routine culture, including 4 who did not meet the criteria for RGM infection by AFB culture. We conclude that a simple methodological change enhanced recovery of RGM from routine cultures. The modified culture method could be utilized to improve screening for RGM in CF patients or as a simpler method to follow patients with known RGM infection. However, this method should be used cautiously in patients with certain coinfections.

Background: Although nontuberculous mycobacteria (NTM) are recognized pathogens in cystic fibrosis (CF), associations with clinical outcomes remain unclear., Methods: Microbiological data was obtained from 1216 CF patients over 8years (481+/-55patients/year). Relationships to clinical outcomes were examined in the subset (n=271, 203+/-23 patients/year) with longitudinal data., Results: Five hundred thirty-six of 4862 (11%) acid-fast bacilli (AFB) cultures grew NTM, with Mycobacterium abscessus (n=298, 55.6%) and Mycobacterium avium complex (n=190, 35.4%) most common. Associated bacterial cultures grew Stenotrophomonas or Aspergillus species more often when NTM were isolated (18.2% vs. 8.4% and 13.9% vs. 7.2%, respectively, p<0.01). After controlling for confounders, patients with chronic M. abscessus infection had greater rates of lung function decline than those with no NTM infection (-2.52 vs. -1.64% predicted FEV(1)/year, p<0.05)., Conclusions: NTM infection is common in CF and associated with particular pathogens. Chronic M. abscessus infection is associated with increased lung function decline., (Copyright (c) 2009 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

We prospectively determined the prevalence of community-associated Staphylococcus aureus in a large cystic fibrosis (CF) center between October 2005 and October 2007. We found that 2.7% (19/707) of the CF patients who had cultures during the study period were infected with this organism, representing 14% of the total methicillin-resistant Staphylococcus aureus strains (n = 140) recovered from the patient population during the study period.

Background: The impact of infection with Burkholderia gladioli in cystic fibrosis, other chronic airway diseases and immunosuppressed patients is unknown., Methods: A six-year retrospective review of all patients with B. gladioli infection was performed in a tertiary referral center with cystic fibrosis and lung transplantation programs. In addition, a targeted survey of all 251 lung transplant recipients was performed. Available B. gladioli isolates were analyzed via pulsed field gel electrophoresis., Results: Thirty-five patients were culture positive for B. gladioli, including 33 CF patients. No bacteremia was identified. Isolates were available in 18 patients and all were genetically distinct. Two-thirds of these isolates were susceptible to usual anti-pseudomonal antibiotics. After acquisition, only 40% of CF patients were chronically infected (> or =2 positive cultures separated by at least 6 months). Chronic infection was associated with resistance to > or =2 antibiotic groups on initial culture and failure of eradication after antibiotic therapy. The impact of acquisition of B. gladioli infection in chronic infection was variable. Three CF patients with chronic infection underwent lung transplantation. One post-transplant patient developed a B. gladioli mediastinal abscess, which was treated successfully., Conclusions: The majority of patients' culture positive for B. gladioli at our center have CF. B. gladioli infection is often transient and is compatible with satisfactory post-lung transplantation outcomes.

Pseudomonas aeruginosa is an opportunistic pathogen that is a major cause of mortality in cystic fibrosis (CF) patients. This bacterium has numerous genes controlled by cell to cell signaling, which occurs through a complex circuitry of interconnected regulatory systems. One of the signals is the Pseudomonas Quinolone Signal (PQS), which was identified as 2-heptyl-3-hydroxy-4-quinolone. This intercellular signal controls the expression of multiple virulence factors and is required for virulence in an insect model of P. aeruginosa infection. Previous studies have implied that the intercellular signals of P. aeruginosa are important for human disease, and our goal was to determine whether PQS was produced during human infections. In this report, three types of samples from CF patients infected with P. aeruginosa were analyzed for the presence of PQS. Sputum, bronchoalveolar lavage fluid, and mucopurulent fluid from distal airways of end-stage lungs removed at transplant, all contained PQS, indicating that this cell to cell signal is produced in vivo by P. aeruginosa infecting the lungs of CF patients.

Over a 6-year period, Burkholderia cepacia complex species were isolated from cystic fibrosis (CF) patients receiving care at The University of North Carolina Hospitals (clinic CF patients) and from those referred from other treatment centers. Fifty-six isolates collected from 30 referred patients and 26 clinic CF patients were characterized by pulsed-field gel electrophoresis (PFGE) and were assayed by PCR to detect the cable pilin gene, cblA. PFGE results indicated that six separate clusters (clusters A to F) were present among the 56 isolates and that three clusters (clusters A, B, and E) consisted only of isolates from referred patients infected with B. cepacia complex isolates prior to referral. However, one cluster (cluster C) consisted of isolates from four CF patients, and hospital records indicate that this cluster began with an isolate that came from a referred patient and that spread to three clinic CF patients. Cluster D consisted of two isolates from clinic CF patients, and hospitalization records are consistent with nosocomial, patient-to-patient spread. cblA was present in only 4 of the 56 isolates and included isolates in cluster E from the referred patients. Our results indicate a lack of spread of a previously characterized, transmissible clone from referred patients to our clinic CF population. Only two instances of nosocomial, patient-to-patient spread could be documented over the 6-year period. An additional spread of an isolate (cluster F) from a referred patient to a clinic patient could not be documented as nosocomial and may have been the result of spread in a nonhospitalized setting. The majority (36 of 56) of our B. cepacia complex-infected CF patients harbor isolates with unique genotypes, indicating that a diversity of sources account for infection. These data suggest that CF patients infected with B. cepacia complex and referred for lung transplantation evaluation were not a major source of B. cepacia complex strains that infected our resident CF clinic population.

Non-tuberculous mycobacteria (NTM) are environmental microbes that can cause pulmonary infection and are especially problematic in bronchiectasis patients with or without cystic fibrosis (CF). Microbiological identification of NTM in these patients is difficult given the high microbial burden in the lungs and the need to differentiate between colonization and transient and true infection. Determining if and when to initiate antimicrobial treatment against this multi-drug-resistant group of organisms is also challenging. To address the changing landscape of care for these patients, the U.S. Cystic Fibrosis Foundation and the European Cystic Fibrosis Society convened an expert committee in 2016 and drafted new guidelines for the management of NTM in CF patients. These recommendations update the 2007 American Thoracic Society and Infectious Disease Society of America guidelines on the diagnosis and treatment of NTM pulmonary infections. Here, we provide data to support the new recommendations and discuss the advancements and ongoing challenges associated with NTM infections. [ABSTRACT FROM AUTHOR]

Background: In patients with cystic fibrosis, infection with Pseudomonas cepacia is associated with poor outcomes. However, the extent of person-to-person transmission and the source of P. cepacia infection after lung transplantation are not well defined. Using DNA-based typing systems, we sought to determine the genetic relatedness of P. cepacia infection at one cystic fibrosis center.Methods: We analyzed 65 P. cepacia isolates gathered over a period of eight years at a single cystic fibrosis center from 17 clinic patients and from 5 patients who underwent double-lung transplantation. The isolates were analyzed by ribotyping and chromosomal fingerprinting based on pulsed-field gel electrophoresis.Results: Analyses of serial isolates revealed that each clinic patient and transplant recipient harbored a different P. cepacia clone that was persistent. In the transplant recipients, the preoperative and postoperative isolates were identical. In the two patients with disseminated infection after lung transplantation, isolates from multiple sites were identical and indicated clonal expansion of the previous respiratory P. cepacia strain. Pulsed-field gel electrophoresis proved both more discriminative and more practical than ribotyping as a means of defining the genetic relatedness of the P. cepacia isolates.Conclusions: Our serial analyses in patients with cystic fibrosis at one center found distinct strains of P. cepacia persistently infecting each patient and no evidence of person-to-person transmission of this organism. P. cepacia infection after lung transplantation was due to the persistence of the strain present before transplantation. [ABSTRACT FROM AUTHOR]