A practical approach to interpretation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography for postoperative spine infection.

OBJECTIVE: 18F-fluorodeoxyglucose-PET/CT is the imaging modality of choice for the diagnosis of postoperative spine infection. Published interpretation criteria are variable and often incompletely described. The objective was to develop a practical and standardized approach. MATERIALS AND METHODS: Two-hundred-twenty-seven FDG-PET/CTs performed on 140 postoperative patients over a 7-year period were reviewed retrospectively. The presence or absence of infection was determined from clinical history, microbiology, other investigations, and clinical outcome during a minimum 6-month follow-up. RESULTS: No activity attributable to normal healing was seen in the post-discectomy space or at the bone-hardware interface in the absence of a complication at any stage. Within the incision, activity from normal healing persisted for months. Wound infections were diagnosed clinically, and most had already been treated before FDG-PET/CT was done to assess deep structures. With proven infection, 95% of cases had activity in bone or soft tissue outside the surgical field. The remaining 5% had activity confined to the post-discectomy space. Sterile hardware loosening may cause elevated activity which remains confined to the bone/hardware interface. Pathogens are introduced directly at the time of surgery and may be avirulent resulting in indolent infection with low-grade activity. At the same time, activity from non-infectious causes can be intense. A semi-quantitative method using SUVmax performed poorly compared with assessment of the distribution of activity. CONCLUSION: These observations have been incorporated into a checklist which is now being used at the time of interpretation. The potential sensitivity and specificity in the diagnosis of infection are close to 100%.

Azithromycin and the microbiota of cystic fibrosis sputum.

BACKGROUND: Azithromycin is commonly prescribed drug for individuals with cystic fibrosis (CF), with demonstrated benefits in reducing lung function decline, exacerbation occurrence and improving nutrition. As azithromycin has antimicrobial activity against components of the uncultured microbiome and increasingly the CF microbiome is implicated in disease pathogenesis - we postulated azithromycin may act through its manipulation. Herein we sought to determine if the CF microbiome changed following azithromycin use and if clinical benefit observed during azithromycin use associated with baseline community structure. RESULTS: Drawing from a prospectively collected biobank we identified patients with sputum samples prior to, during and after initiating azithromycin and determined the composition of the CF microbial community by sequencing the V3-V4 region of the 16S rRNA gene. We categorized patients as responders if their rate of lung function decline improved after azithromycin initiation. Thirty-eight adults comprised our cohort, nine who had not utilized azithromycin in at least 3 years, and 29 who were completely naïve. We did not observe a major impact in the microbial community structure of CF sputum in the 2 years following azithromycin usage in either alpha or beta-diversity metrics. Seventeen patients (45%) were classified as Responders - demonstrating reduced lung function decline after azithromycin. Responders who were naïve to azithromycin had a modest clustering effect distinguishing them from those who were non-Responders, and had communities enriched with several organisms including Stenotrophomonas, but not Pseudomonas. CONCLUSIONS: Azithromycin treatment did not associate with subsequent large changes in the CF microbiome structure. However, we found that baseline community structure associated with subsequent azithromycin response in CF adults.

Sputum microbiota is predictive of long-term clinical outcomes in young adults with cystic fibrosis.

BACKGROUND: Complex polymicrobial communities infect cystic fibrosis (CF) lower airways. Generally, communities with low diversity, dominated by classical CF pathogens, associate with worsened patient status at sample collection. However, it is not known if the microbiome can predict future outcomes. We sought to determine if the microbiome could be adapted as a biomarker for patient prognostication. METHODS: We retrospectively assessed prospectively collected sputum from a cohort of 104 individuals aged 18-22 to determine factors associated with progression to early end-stage lung disease (eESLD; death/transplantation <25 years) and rapid pulmonary function decline (>-3%/year FEV1 over the ensuing 5 years). Illumina MiSeq paired-end sequencing of the V3-V4 region of the 16S rRNA was used to define the airway microbiome. RESULTS: Based on the primary outcome analysed, 17 individuals (16%) subsequently progressed to eESLD. They were more likely to have sputum with low alpha diversity, dominated by specific pathogens including Pseudomonas. Communities with abundant Streptococcus were observed to be protective. Microbial communities clustered together by baseline lung disease stage and subsequent progression to eESLD. Multivariable analysis identified baseline lung function and alpha diversity as independent predictors of eESLD. For the secondary outcomes, 58 and 47 patients were classified as rapid progressors based on absolute and relative definitions of lung function decline, respectively. Patients with low alpha diversity were similarly more likely to be classified as experiencing rapid lung function decline over the ensuing 5 years when adjusted for baseline lung function. CONCLUSIONS: We observed that the diversity of microbial communities in CF airways is predictive of progression to eESLD and disproportionate lung function decline and may therefore represent a novel biomarker.

Diagnostic challenges in pyogenic spinal infection: an expanded role for FDG-PET/CT.

In a preliminary investigation of FDG-PET/CT for assessment of therapy response of pyogenic spine infection, it was concluded that activity confined to the margins of a destroyed or degenerated joint with bone-on-bone contact represents nonseptic inflammation, regardless of the intensity of uptake. Only activity in bone, soft tissue, or within the epidural space represents active infection. The purpose of this investigation was to assess the performance of these pattern-based interpretation criteria in a series of problem cases of proven or suspected spine infection. Eighty-two FDG-PET/CTs were done for initial diagnosis because other imaging failed to provide a definitive diagnosis and 147 FDG-PET/CTs were done to assess treatment responses. Pattern-based interpretations were compared with the clinical diagnosis based on bacterial cultures and outcomes after cessation or withholding of antibiotic therapy. Pattern-based interpretation criteria achieved a sensitivity and specificity of 98 and 100%, respectively, for initial diagnosis and a specificity of 100% for assessment of treatment response. The same data was analyzed using intensity of activity as the primary factor. Sensitivity and specificity using the intensity-based criteria were 93 and 68%, respectively, for initial diagnosis, and the specificity of a negative interpretation for therapy response was 55%. Differences from pattern-based criteria are highly significant. Pattern-based criteria perform well in problem cases with equivocal MR and for treatment response because they correctly eliminate activity from nonspecific inflammation associated with destroyed joints with bone-on-bone contact. Response occurs within a timeframe that is useful for managing antibiotic therapy.

Long-term clinical outcomes of 'Prairie Epidemic Strain' Pseudomonas aeruginosa infection in adults with cystic fibrosis.

RATIONALE: Epidemic Pseudomonas aeruginosa (PA) plays an important role in cystic fibrosis (CF) lung disease. A novel strain, the 'Prairie Epidemic Strain' (PES), has been identified in up to 30% of patients in Prairie-based Canadian CF centres. OBJECTIVE: To determine the incidence, prevalence and long-term clinical impact of PES infection. METHODS: A cohort of adults with CF was followed from 1980 to 2014 where bacteria isolated from clinical encounters were prospectively collected. Strain typing was performed using pulse-field gel electrophoresis and multilocus sequence typing. Patients were divided into one of four cohorts: no PA, transient PA, chronic PA with unique strains and chronic PES. Proportional Cox hazard and linear mixed models were used to assess for CF-associated respiratory death or transplantation, and rates of %FEV1 and body mass index (BMI) decline. RESULTS: 274 patients (51.7% male) were analysed: 44--no PA, 29--transient PA, 137--unique PA, 64--PES. A total of 92 patients (33.6%) died or underwent lung transplantation (2423.0 patient-years). PES infection was associated with greater risk of respiratory death or lung transplant compared with the no PA group (aHR, 3.94 (95% CI 1.18 to 13.1); p=0.03) and unique PA group (aHR, 1.75 (95% CI 1.05 to 2.92) p=0.03). Rate of lung function decline (%FEV1 predicted) was greatest in the PES group (1.73%/year (95% CI 1.63% to 1.82%); p<0.001). BMI improved over time but at an attenuated rate in the PES group (p=0.001). CONCLUSIONS: Infection with PES was associated with increased patient morbidity through three decades and manifested in an increased risk of respiratory death and/or lung transplantation.

Group B streptococcus (GBS) is an important pathogen in human disease- but what about in cystic fibrosis?

BACKGROUND: Group B Streptococcus (GBS) is a common commensal capable of causing severe invasive infections. Most GBS infections occur in neonates (often as pneumonia). GBS can also cause infection in adults with diabetes and other immunological impairments but rarely leads to pneumonia in adults. GBS has occasionally been found in the sputum of Cystic Fibrosis (CF) patients, an inherited condition known for progressive lung disease. However, the epidemiology and clinical significance of GBS in CF are not understood. METHODS: We retrospectively reviewed a large single-centre adult CF population with an associated comprehensive, prospectively collected bacterial biobank beginning in 1978. We identified all individuals with GBS isolated from their sputum on at least one occasion. The primary outcome was risk of pulmonary exacerbation (PEx) at the time of the first GBS isolate compared to the preceding visit. Secondary outcomes included determining: prevalence of GBS infection in a CF population, whether GBS infections where transient or persistent, whether GBS strains were shared among patients, change in % predicted FEV1 at the time of GBS isolate compared to the preceding visit, PEx frequency after the first GBS isolate, change in % predicted FEV1 after the first GBS isolate, and complications of GBS infection. RESULTS: GBS was uncommon, infecting 3.5% (11/318) adults within our cohort. Only three individuals developed persistent GBS infection, all lasting > 12 months. There were no shared GBS strains among patients. PEx risk was not increased at initial GBS isolation (RR 5.0, CI 0.69-36.1, p=0.10). In the two years preceding initial GBS isolation compared to the two following years, there was no difference in PEx frequency (median 2, range 0-4 vs 1, range 0 to 5, respectively, p=0.42) or lung function decline, as measured by % predicted FEV1, (median -1.0%, range -19 to 7% vs median -6.0%, range -18 to 22%, p=0.86). There were no invasive GBS infections. CONCLUSION: In adults with CF, GBS is uncommon and is generally a transient colonizer of the lower airways. Despite the presence of structural lung disease and impaired innate immunity in CF, incident GBS infection did not increase PEx risk, PEx frequency, rate of lung function decline, or other adverse clinical outcomes.

Virulence adaptations of Pseudomonas aeruginosa isolated from patients with non-cystic fibrosis bronchiectasis.

Pseudomonas aeruginosa is a major pathogen in chronic lung diseases such as cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis (nCFB). Much of our understanding regarding infections in nCFB patients is extrapolated from findings in CF with little direct investigation on the adaptation of P. aeruginosa in nCFB patients. As such, we investigated whether the adaptation of P. aeruginosa was indeed similar between nCFB and CF. From our prospectively collected biobank, we identified 40 nCFB patients who had repeated P. aeruginosa isolates separated by ≥6 months and compared these to a control population of 28 CF patients. A total of 84 nCFB isolates [40 early (defined as the earliest isolate in the biobank) and 41 late (defined as the last available isolate in the biobank)] were compared to 83 CF isolates (39 early and 44 late). We assessed the isolates for protease, lipase and elastase production; mucoid phenotype; swarm and swim motility; biofilm production; and the presence of the lasR mutant phenotype. Overall, we observed phenotypic heterogeneity in both nCFB and CF isolates and found that P. aeruginosa adapted to the nCFB lung environment similarly to the way observed in CF isolates in terms of protease and elastase expression, motility and biofilm formation. However, significant differences between nCFB and CF isolates were observed in lipase expression, which may allude to distinct characteristics found in the lung environment of nCFB patients. We also sought to determine virulence potential over time in nCFB P. aeruginosa isolates and found that virulence decreased over time, similar to CF.

Reduction in Pseudomonas aeruginosa sputum density during a cystic fibrosis pulmonary exacerbation does not predict clinical response.

BACKGROUND: Pulmonary exacerbations (PEx) are critical events in cystic fibrosis (CF), responsible for reduced quality of life and permanent loss of lung function. Approximately 1/4 of PEx are associated with failure to recover lung function and/or resolve symptoms. Developing tools to optimize PEx treatment is of paramount importance. METHODS: We retrospectively audited all adults infected with Pseudomonas aeruginosa, experiencing PEx necessitating parenteral antibiotic therapy from 2006-2012 from our center. Quantitative analysis of sputum at admission, twice-weekly during hospitalization, and end of therapy were compared to baseline (most recent healthy) and follow-up (after PEx) samples. Change in P. aeruginosa burden from baseline was assessed for any and all morphotypes (ALL), as well as mucoid (MUC) and non-mucoid (NON) isolates specifically. PEx were identified as failures if >90% of baseline pulmonary function was not recovered. RESULTS: Forty-six patients meeting the above inclusion and exclusion criteria experienced 144 PEx during this time (median 3, IQR 2-6). Patients were treated for a median 14 days (IQR 13-16). No increase in ALL, MUC or NON were detected at PEx, nor was there an association between change in sputum density and magnitude of lung function decline. PEx failures were observed in 30% of events. Reductions of at least 1-log and 2 log P. aeruginosa sputum density was observed in 57% and 46% (ALL), 73% and 55% (MUC) and 58% and 46% (NON) of PEx, respectively. Factors associated with greater reduction of P. aeruginosa sputum density included choice of ß-lactam antibiotic, antibiotics with in vitro predicted activity and treatment duration. PEx associated with reductions in P. aeruginosa sputum density were not associated with a reduced risk of PEx failure. CONCLUSIONS: Enhanced killing of P. aeruginosa during PEx does not predict improved clinical outcomes. Studies accounting for the polymicrobial nature of CF respiratory disease and the heterogeneity of P. aeruginosa causing chronic infection may enable the identification of a more appropriate pathogen(s) based biomarker of PEx outcomes.

Prevalence and impact of Streptococcus pneumoniae in adult cystic fibrosis patients: a retrospective chart review and capsular serotyping study.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease characterized by complex polymicrobial communities within the lower respiratory tract. S. pneumoniae, while a well-defined pathogen in the general population, has rarely been identified in CF. Furthermore, prevalence studies on Pneumococcus in CF have predominantly focused on the infant and pediatric populations, and outcome data is lacking. METHODS: Through a review of our comprehensive clinical and microbiologic database from a single adult CF center in Canada from 1978-2013 we sought to determine the incidence, prevalence, serotype and clinical impact of Pneumococcus in adults with CF. RESULTS: Only fifteen of 318 adult CF patients (5%) were ever found to have transient Pneumococcus colonization, and none developed persistent infection although length of carriage varied. As all isolates were stored, capsular serotyping could be performed using a multiplex PCR panel. Capsular serotyping revealed a varied distribution of several serotypes within these isolates. Lung function testing at time of incident Pneumococcus isolation was compared with values before and after isolation and showed no significant reduction in spirometry values, nor was there an increased need for rescue antibacterial therapy. CONCLUSION: Within our center, incident Pneumococcus infection is neither common, associated with a disproportionate clinical deterioration nor results in chronic infection.

Clinical implications and characterization of Group A Streptoccoccus infections in adults with cystic fibrosis.

BACKGROUND: Persistent airway infection is a hallmark feature of cystic fibrosis (CF). However, increasingly it has been observed that non-classical pathogens may transiently infect CF lower airways. Streptococcus pyogenes (Group A Streptococcus; (GAS)) is an uncommon but potentially dangerous cause of community-acquired pneumonia. Our aim was to determine the incidence, natural history, and clinical impact of GAS infections in CF and phenotypically and genotypically characterize the isolates. METHODS: We retrospectively evaluated the Calgary Adult CF Clinic biobank to identify adults with at least one GAS isolate. Patient demographics, medical and pulmonary exacerbation (PEx) histories were evaluated. The primary outcome was PEx occurrence at incident GAS culture. Secondary outcomes evaluated were changes in lung function and PEx frequency following GAS isolation. Isolates were assessed for extra-cellular virulence factor production capacity and ability to produce quorum sensing (AI-2). Isolates were genotyped using pulse-field gel electrophoresis (PFGE). RESULTS: Fifteen individuals who cultured GAS twenty times were identified. At the time of GAS isolation, 47% (7/15) of subjects experienced a PEx and half of these (4/7) were severe. Individuals were more likely to have a PEx at the time of the index GAS isolate compared to the preceding visit (RR = 6.0, 95% CI 0.82-43.0, p = 0.08), particularly if GAS was the numerically dominant sputum pathogen (RR = 6.5, 95% CI 1.00-43.0, p = 0.009). There were no changes in PEx frequency or rate of lung function decline following GAS. None of the patients developed chronic airways infection, bacteremia, necrotizing pneumonia or empyema. Susceptibility was universal to common anti-Streptococcal antibiotics and anti-Pseudomonal antibiotics commonly used in CF, with the exception of azithromycin. GAS isolates varied in their production of protease, DNase, and AI-2 but these did not correlate with PEx, and none produced elastase, chrondrotin sulfatase or H202. One patient had prolonged carriage with the same isolate and two patients had isolates with similar PFGE patterns. CONCLUSIONS: GAS was an uncommon lower respiratory pathogen of adults with CF. Identification of GAS in sputum was frequently associated with PEx, particularly when numerically dominant. However, transient GAS infection did not result in chronic infection nor appreciably change long-term disease trajectory.

Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Interpretation Criteria for Assessment of Antibiotic Treatment Response in Pyogenic Spine Infection.

PURPOSE: The objective of the study was to determine if fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) can assess the response of patients with pyogenic spine infection to antibiotic treatment in a clinically useful time frame. METHODS: Twenty-eight patients with suspected pyogenic spine infection had baseline (18)F-FDG PET/CT. Patients with proven or probable infection were divided into good and poor responders to antibiotic therapy based on clinical criteria. These patients had a follow-up (18)F-FDG PET/CT 6-8 weeks later. RESULTS: Six of 28 patients were deemed negative for infection based on (18)F-FDG PET/CT. Two patients were excluded because of discrepancies in interpretation. Of the 20 patients deemed positive for infection, 13 had a pathogen isolated and all showed (18)F-FDG uptake in bone and/or soft tissue at baseline. Patients with a poor clinical response to treatment had persistent (18)F-FDG uptake in bone and/or soft tissue on follow-up. Patients with good clinical response had uptake confined to the margins of the destroyed disc. None of these patients had recurrent infection, even if antibiotics had already been discontinued at the time of the follow-up scan. CONCLUSIONS: (18)F-FDG uptake confined to the margins of a destroyed disc after antibiotic therapy of pyogenic spine infection must not be considered indicative of persistent infection and likely represents mechanically induced inflammation. (18)F-FDG uptake in bone or soft tissue does indicate active infection. Quantification of activity could not reliably differentiate patients with active infection from those without active infection and those who had had a successful response to therapy. The pattern of activity is critical to accurate interpretation.

Twenty-five-year outbreak of Pseudomonas aeruginosa infecting individuals with cystic fibrosis: identification of the prairie epidemic strain.

Transmissible strains of Pseudomonas aeruginosa have been described for cystic fibrosis (CF) and may be associated with a worse prognosis. Using a comprehensive strain biobank spanning 3 decades, we sought to determine the prevalence and stability of chronic P. aeruginosa infection in an adult population. P. aeruginosa isolates from sputum samples collected at initial enrollment in our adult clinic and at the most recent clinic visit were examined by a combination of pulsed-field gel electrophoresis and multilocus sequence typing and compared against a collection of established transmissible and local non-CF bronchiectasis (nCFB) isolates. A total of 372 isolates from 107 patients, spanning 674 patient-years, including 66 patients with matched isolates from initial and final encounters, were screened. A novel clone with increased antibacterial resistance, termed the prairie epidemic strain (PES), was found in 29% (31/107 patients) of chronically infected patients referred from multiple prairie-based CF centers. This isolate was not found in those diagnosed with CF as adults or in a control population with nCFB. While 90% (60/66 patients) of patients had stable infection over a mean of 10.8 years, five patients experienced strain displacement of unique isolates, with PES occurring within 2 years of transitioning to adult care. PES has been present in our cohort since at least 1987, is unique to CF, generally establishes chronic infection during childhood, and has been found in patients at the time of transition of patients from multiple prairie-based CF clinics, suggesting broad endemicity. Studies are under way to evaluate the clinical implications of PES infection.

The airway microbiome of persons with cystic fibrosis correlates with acquisition and microbiological outcomes of incident Stenotrophomonas maltophilia infection.

Rationale: Chronic infection with Stenotrophomonas maltophilia in persons with cystic fibrosis (pwCF) has been linked to an increased risk of pulmonary exacerbations and lung function decline. We sought to establish whether baseline sputum microbiome associates with risk of S. maltophilia incident infection and persistence in pwCF. Methods: pwCF experiencing incident S. maltophilia infections attending the Calgary Adult CF Clinic from 2010-2018 were compared with S. maltophilia-negative sex, age (+/-2 years), and birth-cohort-matched controls. Infection outcomes were classified as persistent (when the pathogen was recovered in ≥50% of cultures in the subsequent year) or transient. We assessed microbial communities from prospectively biobanked sputum using V3-V4 16S ribosomal RNA (rRNA) gene sequencing, in the year preceding (Pre) (n = 57), at (At) (n = 22), and after (Post) (n = 31) incident infection. We verified relative abundance data using S. maltophilia-specific qPCR and 16S rRNA-targeted qPCR to assess bioburden. Strains were typed using pulse-field gel electrophoresis. Results: Twenty-five pwCF with incident S. maltophilia (56% female, median 29 years, median FEV1 61%) with 33 total episodes were compared with 56 uninfected pwCF controls. Demographics and clinical characteristics were similar between cohorts. Among those with incident S. maltophilia infection, sputum communities did not cluster based on infection timeline (Pre, At, Post). Communities differed between the infection cohort and controls (n = 56) based on Shannon Diversity Index (SDI, p = 0.04) and clustered based on Aitchison distance (PERMANOVA, p = 0.01) prior to infection. At the time of incident S. maltophilia isolation, communities did not differ in SDI but clustered based on Aitchison distance (PERMANOVA, p = 0.03) in those that ultimately developed persistent infection versus those that were transient. S. maltophilia abundance within sputum was increased in samples from patients (Pre) relative to controls, measuring both relative (p = 0.004) and absolute (p = 0.001). Furthermore, S. maltophilia abundance was increased in sputum at incident infection in those who ultimately developed persistent infection relative to those with transient infection, measured relatively (p = 0.04) or absolute (p = 0.04), respectively. Conclusion: Microbial community composition of CF sputum associates with S. maltophilia infection acquisition as well as infection outcome. Our study suggests sputum microbiome may serve as a surrogate for identifying infection risk and persistence risk.

Stenotrophomonas maltophilia natural history and evolution in the airways of adults with cystic fibrosis.

Introduction: Stenotrophomonas maltophilia is an opportunistic pathogen infecting persons with cystic fibrosis (pwCF) and portends a worse prognosis. Studies of S. maltophilia infection dynamics have been limited by cohort size and follow-up. We investigated the natural history, transmission potential, and evolution of S. maltophilia in a large Canadian cohort of 321 pwCF over a 37-year period. Methods: One-hundred sixty-two isolates from 74 pwCF (23%) were typed by pulsed-field gel electrophoresis, and shared pulsotypes underwent whole-genome sequencing. Results: S. maltophilia was recovered at least once in 82 pwCF (25.5%). Sixty-four pwCF were infected by unique pulsotypes, but shared pulsotypes were observed between 10 pwCF. In chronic carriage, longer time periods between positive sputum cultures increased the likelihood that subsequent isolates were unrelated. Isolates from individual pwCF were largely clonal, with differences in gene content being the primary source of genetic diversity objectified by gene content differences. Disproportionate progression of CF lung disease was not observed amongst those infected with multiple strains over time (versus a single) or amongst those with shared clones (versus strains only infecting one patient). We did not observe evidence of patient-to-patient transmission despite relatedness between isolates. Twenty-four genes with ≥ 2 mutations accumulated over time were identified across 42 sequenced isolates from all 11 pwCF with ≥ 2 sequenced isolates, suggesting a potential role for these genes in adaptation of S. maltophilia to the CF lung. Discussion: Genomic analyses suggested common, indirect sources as the origins of S. maltophilia infections in the clinic population. The information derived from a genomics-based understanding of the natural history of S. maltophilia infection within CF provides unique insight into its potential for in-host evolution.

Measuring the burden of cystic fibrosis: A scoping review.

BACKGROUND: Cystic fibrosis (CF) contributes a significant economic burden on individuals, healthcare systems, and society. Understanding the economic impact of CF is crucial for planning resource allocation. METHODS: We conducted a scoping review of literature published between 1990 and 2022 that reported the cost of illness, and/or economic burden of CF. Costs were adjusted for inflation and reported as United States dollars. RESULTS: A total of 39 studies were included. Direct healthcare costs (e.g., medications, inpatient and outpatient care) were the most frequently reported. Most studies estimated the cost of CF using a prevalence-based (n = 18, 46.2 %), bottom-up approach (n = 23, 59 %). Direct non-healthcare costs and indirect costs were seldom included. The most frequently reported direct cost components were medications (n = 34, 87.2 %), inpatient care (n = 33, 84.6 %), and outpatient care (n = 31, 79.5 %). Twenty-eight percent (n = 11) of studies reported the burden of CF from all three perspectives (healthcare system (payer), individual, and society). Indirect costs of CF were reported in approximately 20 % of studies (n = 8). The reported total cost of CF varied widely, ranging from $451 to $160,000 per person per year (2022 US$). The total cost depended on the number of domains and perspectives included in each study. CONCLUSIONS: Most studies only reported costs to the healthcare system (i.e., hospitalizations and healthcare encounters) which likely underestimates the total costs of CF. The wide range of costs reported highlights the importance of standardizing perspectives, domains and costs when estimating the economic burden of CF.

The cystic fibrosis airway microbiome.

PURPOSE OF REVIEW: Culture and molecular approaches have established that lower airway infections are polymicrobial. We consider how this new perspective in cystic fibrosis (CF) may affect treatment choices. RECENT FINDINGS: Standard clinical microbiology of CF infection exacerbations often fails to provide indications of microbial causes that may drive the onset of exacerbation and the anticipated bacteriologic responses to the usual parenteral antibiotics prescribed as treatment. Antimicrobial responses by nonclassical members of the CF airway microbiome may explain why most patients clinically improve. These other organisms contribute to disease either directly as pathogens missed by conventional microbiology or through synergy with conventional pathogens. With these considerations, therapy may best be guided by directed antibiotic therapy to numerically significant isolates. An example is the Streptococcus milleri group, which we now believe to represent new pathogens that profile the exacerbations of infection in the CF lung and that necessitate specific antibiotic therapy to prevent loss of lung function and reduce frequency of exacerbations. SUMMARY: A comprehensive understanding of airway infections offers the potential for improved disease management in CF patients. Accurate quantitative microbiology will be a prerequisite for routine intervention based on the polymicrobial perspective of CF infection exacerbations.

The natural history and genetic diversity of Haemophilus influenzae infecting the airways of adults with cystic fibrosis.

Haemophilus influenzae is a Gram-negative pathobiont, frequently recovered from the airways of persons with cystic fibrosis (pwCF). Previous studies of H. influenzae infection dynamics and transmission in CF predominantly used molecular methods, lacking resolution. In this retrospective cohort study, representative yearly H. influenzae isolates from all pwCF attending the Calgary Adult CF Clinic with H. influenzae positive sputum cultures between 2002 and 2016 were typed by pulsed-field gel electrophoresis. Isolates with shared pulsotypes common to ≥ 2 pwCF were sequenced by Illumina MiSeq. Phylogenetic and pangenomic analyses were used to assess genetic relatedness within shared pulsotypes, and epidemiological investigations were performed to assess potential for healthcare associated transmission. H. influenzae infection was observed to be common (33% of patients followed) and dynamic in pwCF. Most infected pwCF exhibited serial infections with new pulsotypes (75% of pwCF with ≥ 2 positive cultures), with up to four distinct pulsotypes identified from individual patients. Prolonged infection by a single pulsotype was only rarely observed. Intra-patient genetic diversity was observed at the single-nucleotide polymorphism and gene content levels. Seven shared pulsotypes encompassing 39% of pwCF with H. influenzae infection were identified, but there was no evidence, within our sampling scheme, of direct patient-to-patient infection transmission.

A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients.

Lung disease is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. A modest number of bacterial pathogens have been correlated with pulmonary function decline; however, microbiological and molecular evidence suggests that CF airway infection is polymicrobial. To obtain a more complete assessment of the microbial community composition and dynamics, we undertook a longitudinal study by using culture-independent and microbiological approaches. In the process, we demonstrated that within complex and dynamic communities, the Streptococcus milleri group (SMG) can establish chronic pulmonary infections and at the onset of 39% of acute pulmonary exacerbations, SMG is the numerically dominant pathogen. We report the comprehensive polymicrobial community dynamics of a CF lung infection in a clinically relevant context. If a given organism, such as Pseudomonas aeruginosa, becomes resistant to antibiotic therapy, an alternative treatment avenue may mediate the desired clinical response by effectively managing the composition of the microbial community.

Macrolide and clindamycin resistance in Streptococcus milleri group isolates from the airways of cystic fibrosis patients.

Organisms belonging to the Streptococcus milleri group (SMG) are known for their role in pyogenic infections but have recently been implicated as etiological agents of pulmonary exacerbation in adult patients with cystic fibrosis (CF). The prolonged exposure of CF patients to antibiotics prompted us to investigate the susceptibility profiles of 118 SMG isolates from the airways of CF patients to 12 antibiotics compared to 43 SMG isolates from patients with invasive infections. We found that approximately 60% of all isolates failed to grow using the standard medium for disc diffusion, Mueller-Hinton blood agar (MHBA), so we explored the usefulness of brain heart infusion (BHI) agar for susceptibility testing. Zone-of-inhibition comparisons between BHI and MHBA showed strong correlations for six antibiotics, and interpretations were similar for both medium types. For ceftriaxone and cefepime, both groups of isolates were highly susceptible. Tetracycline resistance levels were comparable between the two groups (22% in CF isolates and 17.4% in invasive isolates). However, more than half of the CF isolates were not susceptible to azithromycin, erythromycin, and clindamycin, compared to 11%, 13%, and 6.5% of invasive isolates, respectively. There were 5-fold and 8-fold increased risks of azithromycin and clindamycin resistance, respectively, for the isolates from the airways of CF patients relative to the invasive isolates. Macrolide resistance was strongly linked to chronic azithromycin therapy in CF patients. This study shows that BHI agar is a suitable alternative for antimicrobial susceptibility testing for the SMG and that SMG isolates from the airways of CF patients are more resistant to macrolides and clindamycin than strains isolated from patients with invasive infections.