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 in adults with CF associates with response to inhaled tobramycin.

BACKGROUND: Inhaled tobramycin powder/solution (TIP/S) use has resulted in improved clinical outcomes in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa. However, TIP/S effect on the CF sputum microbiome has not been explored. We hypothesised that TIP/S has additional 'off-target' effects beyond merely P. aeruginosa and that baseline microbiome prior to initiation of therapy is associated with subsequent patient response. METHODS: We drew sputum samples from a prospectively collected biobank. Patients were included if they had one sputum sample in the 18 months before and after TIP/S. Bacterial 16S rRNA gene profiling was used to characterise the sputum microbiome. RESULTS: Forty-one patients met our inclusion criteria and 151 sputum samples were assessed. At baseline, median age was 30.4 years (IQR 24.2-35.2) and forced expiratory volume in 1 (FEV1) second was 57% predicted (IQR 44-74). Nineteen patients were defined a priori as responders having no net decrease in FEV1 in the year following TIP/S. No significant changes were observed in key microbiome metrics of alpha (within-sample) or beta (between-sample) diversity for samples collected before and after TIP/S. However, significant beta-diversity (Bray-Curtis) differences were noted at baseline between patients based on response status. Notably, responders were observed to have a higher abundance of Staphylococcus in pretherapy baseline samples. CONCLUSIONS: Our longitudinal study demonstrates that the sputum microbiome of patients with CF is relatively stable following inhaled tobramycin over many months. Intriguingly, our findings suggest that baseline microbiome may associate with patient response to TIP/S-suggesting the sputum microbiome could be used to personalise therapy.

Cystic fibrosis gene modifier SLC26A9 modulates airway response to CFTR-directed therapeutics.

Cystic fibrosis is realizing the promise of personalized medicine. Recent advances in drug development that target the causal CFTR directly result in lung function improvement, but variability in response is demanding better prediction of outcomes to improve management decisions. The genetic modifier SLC26A9 contributes to disease severity in the CF pancreas and intestine at birth and here we assess its relationship with disease severity and therapeutic response in the airways. SLC26A9 association with lung disease was assessed in individuals from the Canadian and French CF Gene Modifier consortia with CFTR-gating mutations and in those homozygous for the common Phe508del mutation. Variability in response to a CFTR-directed therapy attributed to SLC26A9 genotype was assessed in Canadian patients with gating mutations. A primary airway model system determined if SLC26A9 shows modification of Phe508del CFTR function upon treatment with a CFTR corrector. In those with gating mutations that retain cell surface-localized CFTR we show that SLC26A9 modifies lung function while this is not the case in individuals homozygous for Phe508del where cell surface expression is lacking. Treatment response to ivacaftor, which aims to improve CFTR-channel opening probability in patients with gating mutations, shows substantial variability in response, 28% of which can be explained by rs7512462 in SLC26A9 (P = 0.0006). When homozygous Phe508del primary bronchial cells are treated to restore surface CFTR, SLC26A9 likewise modifies treatment response (P = 0.02). Our findings indicate that SLC26A9 airway modification requires CFTR at the cell surface, and that a common variant in SLC26A9 may predict response to CFTR-directed therapeutics.

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.

Community-associated methicillin-resistant Staphylococcus aureus necrotizing pneumonia without evidence of antecedent viral upper respiratory infection.

BACKGROUND: USA300 community-associated (CA) methicillin-resistant Staphylococcus aureus (MRSA) strains causing necrotizing pneumonia have been reported in association with antecedent viral upper respiratory tract infections (URI). METHODS: A case series of necrotizing pneumonia presenting as a primary or coprimary infection, secondary to CA-MRSA without evidence of antecedent viral URI, is presented. Cases were identified through the infectious diseases consultation service records. Clinical and radiographic data were collected by chart review and electronic records. MRSA strains were isolated from sputum, bronchoalveolar lavage, pleural fluid or blood cultures and confirmed using standard laboratory procedures. MRSA strains were characterized by susceptibility testing, pulsed-field gel electrophoresis, spa typing, agr typing and multilocus sequence typing. Testing for respiratory viruses was performed by appropriate serological testing of banked sera, or nucleic acid testing of nasopharyngeal or bronchoalveloar lavage specimens. RESULTS: Ten patients who presented or copresented with CA necrotizing pneumonia secondary to CA-MRSA from April 2004 to October 2011 were identified. The median length of stay was 22.5 days. Mortality was 20.0%. Classical risk factors for CA-MRSA were identified in seven of 10 (70.0%) cases. Chest tube placement occurred in seven of 10 patients with empyema. None of the patients had historical evidence of antecedent URI. In eight of 10 patients, serological or nucleic acid testing testing revealed no evidence of acute viral coinfection. Eight strains were CMRSA-10 (USA300). The remaining two strains were a USA300 genetically related strain and a USA1100 strain. CONCLUSION: Pneumonia secondary to CA-MRSA can occur in the absence of an antecedent URI. Infections due to CA-MRSA are associated with significant morbidity and mortality. Clinicians need to have an awareness of this clinical entity, particularly in patients who are in risk groups that predispose to exposure to this bacterium.

HISTORIQUE: Des souches USA300 de Staphylococcus aureus résistant à la méthicilline (SARM) d'origine non nosocomiale (ONN) responsables d'une pneumonie nécrosante ont été signalées après des infections des voies respiratoires supérieures. MÉTHODOLOGIE: Les chercheurs présentent une série de cas de pneumonie nécrosante se manifestant sous forme d'infection ou de co-infection primaire découlant du SARM-ONN, sans manifestation d'IVRS virale antérieure. Ils ont dépisté les cas en dépouillant les dossiers des services de consultation en infectiologie. Ils ont colligé les données cliniques et radiographiques en analysant les dossiers papier et électroniques. Les souches de SARM avaient été isolées dans les expectorations, le lavage broncho-alvéolaire, le liquide pleural ou les hémo-cultures et confirmées au moyen d'analyses de laboratoire standards. Les souches de SARM étaient caractérisées par les tests de susceptibilité, l'électrophorèse sur gel en champ pulsé, le typage du gène spa ou du gène agr ou le typage génomique multilocus. Les tests de dépistage des virus respiratoires ont été faits au moyen du test sérologique pertinent du sérum en réserve ou du test d'amplification des acides nucléiques des échantillons de lavage nasopharyngé ou broncho-alvéolaire. RÉSULTATS: Entre avril 2004 et octobre 2011, les chercheurs ont dépisté dix patients qui présentaient, seule ou conjointement, une pneumonie nécrosante d'ONN secondaire à une infection par le SARM-ONN. Ils ont été hospitalisés pendant une période médiane de 22,5 jours. Le taux de mortalité s'élevait à 20,0 %. Les chercheurs ont constaté des facteurs de risque classiques de SARM-ONN dans sept des dix cas (70,0 %). Sept des dix patients faisant de l'empyème avaient eu un drain thoracique. Aucun des patients n'avait d'antécédents démontrés d'IVRS. Chez huit des dix patients, le test sérologique et le test d'amplification des acides nucléiques n'ont révélé aucune manifestation de co-infection virale aiguë. Huit souches étaient des SARMC-10 (USA300). Les deux autres étaient une souche liée génétiquement au USA300 et une souche USA1100. CONCLUSION: La pneumonie secondaire au SARM-ONN peut se manifester en l'absence d'IVRS antérieure. Les infections causées par le SARM-ONN s'associent à une morbidité et une mortalité importantes. Les cliniciens doivent connaître cette entité clinique, notamment chez les patients qui font partie de groupes vulnérables qui les prédisposent à être exposés à cette bactérie.

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.