Adult Cystic Fibrosis Patients Research Articles

Cystic Fibrosis in Adults: A Paradigm of Frailty Syndrome? An Observational Study.

This study aimed to assess the main clinical and anamnestic characteristics of adult Cystic Fibrosis (CF) patients and to evaluate the association of frailty with the CF genotyping classification. In an observational cross-sectional study, all ambulatory CF patients over 18 years old who received a diagnosis at the Regional Cystic Fibrosis Center for adults were enrolled and assessed by spirometry for respiratory function, by ADL and IADL for functional status, and by the Study of Osteoporotic Fractures (SOF) Index for frailty. The study population consisted of 139 CF patients (mean age 32.89 ± 10.94 years old, 46% women). Most of the subjects were robust (60.4%). The pre-frail/frail group was more frequently females (p = 0.020), had a lower BMI (p = 0.001), worse respiratory function, a higher number of pulmonary exacerbations/years, cycles of antibiotic therapy, and hospitalization (all p < 0.001) with respect to robust patients. The pre-frail/frail subjects used more drugs and were affected by more CF-related diseases (all p < 0.001). In relation to logistic regression, the best predictor of the pre-frail/frail status was a low FEV1 level. The CF patients show similarities to older pre-frail/frail subjects, suggesting that CF might be considered an early expression of this geriatric syndrome. This finding could help to better define the possible progression of CF, but overall, it could also suggest the usefulness employing of some tools used in the management and therapy of frailty subjects to identify the more severe CF subjects.

Lung clearance index short-term variability in cystic fibrosis: a pre-post pulmonary exacerbation study

BackgroundMultiple Breath washout (MBW) represents an important tool to detect early a possible pulmonary exacerbation especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI) is the most commonly reported multiple breath washout (MBW) index and in the last years was used as management measure for evaluation. Our aim was to analyze clinical utility of LCI index variability in pulmonary exacerbation in CF after intravenous (IV) antibiotic therapy.MethodsA single-center study was conducted at CF Unit of Bambino Gesù Children’s Hospital among hospitalized > 3 years patients for pulmonary exacerbations and treated with antibiotic IV treatment for 14 days. MBW and spirometry were evaluated within 72 h of admission to hospital and at the end of hospitalization. Descriptive analysis was conducted and correlations between quantitative variables were investigated.ResultsFifty-seven patients (M22/F35) with an average age 18.56 (± 8.54) years were enrolled. LCI2.5 was significantly reduced at the end of antibiotic treatment in both pediatric and adult populations with an average reduction of -6,99%; 37/57 patients denoted an improvement, 20/57 are stable or worsened in LCI2.5 values and 4/57 (7.02%) had a significant deterioration (> 15%) at end of treatment. On the contrary a significative elevation of FEV1 and FVC were found, respectively of + 7,30% and of + 5,46%. A positive good correlection among LCI 2.5 and Scond (rho = + 0,615, p = 0.000) and LCI 2.5 and Sacin (rho = + 0,649, p = 0.000) and a negative strong correlation between FEV1 and LCI 2.5 were found in post treatment period. A similar modification of LCI 2.5 and FEV1 was noticed in both adult and pediatric population.ConclusionsLCI may have a role in the routine clinical care of both adult and pediatric CF patients as a good tool to assess response to IV antibiotic end-therapy in the same way as FEV1.

NorA efflux pump mediates Staphylococcus aureus response to Pseudomonas aeruginosa pyocyanin toxicity.

Endogenous transporters protect Staphylococcus aureus against antibiotics and also contribute to bacterial defense from environmental toxins. We evaluated the effect of overexpression of four efflux pumps, NorA, NorB, NorC, and Tet38, on S. aureus survival following exposure to pyocyanin (PYO) of Pseudomonas aeruginosa, using a well diffusion assay. We measured the PYO-created inhibition zone and found that only an overexpression of NorA reduced S. aureus susceptibility to pyocyanin killing. The MICPYO of the NorA overexpressor increased threefold compared to that of wild-type RN6390 and was reduced 2.5-fold with reserpine, suggesting that increased NorA efflux caused PYO resistance. The PYO-created inhibition zone of a ΔnorA mutant was consistently larger than that of a plasmid-borne NorA overexpressor. PYO also produced a modest increase in norA expression (1.8-fold at 0.25 µg/mL PYO) that gradually decreased with increasing PYO concentrations. Well diffusion assays carried out using P. aeruginosa showed that ΔnorA mutant was less susceptible to killing by PYO-deficient mutants PA14phzM and PA14phzS than to killing by PA14. NorA overexpression led to reduced killing by all tested P. aeruginosa. We evaluated the NorA-PYO interaction using a collection of 22 clinical isolates from adult and pediatric cystic fibrosis (CF) patients, which included both S. aureus (CF-SA) and P. aeruginosa (CF-PA). We found that when isolated alone, CF-PA and CF-SA expressed varying levels of PYO and norA transcripts, but all four CF-PA/CF-SA pairs isolated concurrently from CF patients produced a low level of PYO and low norA transcript levels, respectively, suggesting a partial adaptation of the two bacteria in circumstances of persistent co-colonization.

Vitamin D deficiency in patients with cystic fibrosis: a systematic review and meta-analysis

AimVitamin D is a prominent modulator of immunity and respiratory function. It plays a vital role in respiratory diseases such as cystic fibrosis (CF). S. However, there is a dearth of information on patients with CF. The purpose of the meta-analysis is to highlight the importance of following the existing guidelines regarding maintenance of Vitamin D serum levels in patients with CF.MethodsThe systematic search was conducted without utilizing any time or language limitations in original database from the beginning until March 2022. The meta-analysis was performed using a random-effects model. Heterogeneity was determined by I2 statistics and Cochrane Q test.ResultsPooled analysis using the random-effects model of the 8 case–control studies with 13 effect sizes revealed that the serum 25-OH-vitamin D in participants with cystic fibrosis was significantly lower than controls in pediatrics and adolescences (WMD: − 3.41 ng/ml, 95% CI − 5.02, − 1.80, p = < 0.001) and adults (WMD: − 2.60 ng/ml, 95% CI − 4.32, − 0.89, p = 0.003). Based on data from 12 studies (21 effect sizes) with a total of 1622 participants, the prevalence of vitamin D levels of 20–30 ng/ml in CF patients was 36% among pediatrics/adolescents and 63% among adults. In addition, 27% of pediatric/adolescent CF patients and 35% of adult CF patients had vitamin D levels of below 20 ng/ml.ConclusionsAs a result, according to the existing guidelines, our results proved the need to pay attention to the level of vitamin D in these patients.

Carriage of Neisseria meningitidis (meningococci) in the sputum of people with cystic fibrosis (CF): occupational health risks and mitigating interventions for physiotherapists

ObjectivesTo estimate the carriage of Neisseira meningitidis (meningococci) in expectorated sputum from people with cystic fibrosis (CF) and to evaluate potential ramifications of such carriage for the health and (NM) wellbeing of physiotherapists performing airway clearance techniques. DesignDescriptive observational study. Main outcome measuresMeningococcal carriage rate, CFTR mutation type and time to first meningococcal culture were determined. ResultsMicrobiological data was examined from 100 patients from birth to present (31/12/2021), equating to 2455 patient years. NM was isolated from 6/100 (6%) adult CF patients who had F508del/F508del (homozygous), F508del/other (heterozygous) and other mutations. The median and mean time to first isolation of NM was 213 months and 230 months (standard deviation = 27.6 months), respectively, shortest time was 209 months, longest time 278 months. ConclusionsPhysiotherapists should be aware of the risks to themselves of acquiring Neisseria meningtidis from CF patients’ respiratory aerosols, whilst performing airway clearance techniques. Physiotherapists with underlying medical conditions or with specific concerns about meningococcal disease should discuss their circumstances with their occupational health team, to ensure optimal protection.

The Impact of Pseudomonas aeruginosa Infection in Adult Cystic Fibrosis Patients-A Single Polish Centre Study.

Pseudomonas aeruginosa (PA) is one of the most predominant pathogens of lung infections, often causing exacerbations in adult patients with cystic fibrosis (CF). Microbiological characterization of 74 PA isolates and to evaluate the correlations between the bacterial features and 44 adult Polish CF cohort clinical parameters. The most common variant in the CF transmembrane conductance regulator (CFTR) gene was F508del (76.3%), followed by 3849+10kbC>T (26.3%). A total of 39.4% of the PA isolates showed multiple resistances. In patients with parameters pointing to a decline in lung function, there was a statistically significant moderate correlation with β-lactam resistance and a weak correlation between hospital frequency and colistin resistance. The mucoidity did not correlate with the biofilm formation ability, which showed 41.9% of the isolates. Proteolytic activity, observed in 60.8% of the clinical isolates, was weakly associated with motility detected in 78.4% of the strains. The genetic profiles of the PA were highly heterogeneous, and a weak positive correlation was established between cluster group and biofilm formation. The findings suggest that there is a high variety in P. aeruginosa populations in adult CF patients. There is a need to monitor PA strains in groups of patients with cystic fibrosis, in particular, in terms of the occurrence of antibiotic resistance related to a decline in lung function.

2226. Trough- Versus AUC-Based Vancomycin Monitoring for Treatment of Acute Pulmonary Exacerbations of Adult Cystic Fibrosis Patients

Abstract Background Therapeutic drug monitoring (TDM) for IV vancomycin (VAN) in adults with cystic fibrosis (CF) historically has utilized trough concentrations. Recent VAN TDM guidelines recommend area under the curve (AUC)-monitoring to reduce the risk of vancomycin-induced kidney injury. However, limited data is available in adult CF patients to support this practice. The aim of the study was to determine the safety and efficacy of VAN AUC-monitoring in adult CF patients. Methods This single-center, retrospective, observational cohort study included adult CF patients admitted from July 1, 2017 to July 1, 2022 with an acute pulmonary exacerbation that received VAN for at least 72 hours with available VAN plasma concentrations for TDM. Eligible patients with multiple hospital admissions during the study period were incorporated as separate encounters. The primary outcome was incidence of acute kidney injury (AKI). A subgroup efficacy analysis was performed in patients with methicillin-resistant S. aureus (MRSA) in the sputum 3 months prior to or 3 weeks after hospitalization. Results One hundred forty-three patients were included in the study [AUC cohort (n=39) and trough cohort (n=104)]. Concurrent nephrotoxins was more common in the AUC cohort than in the trough cohort (97% vs 81%; p = 0.01), but rate of AKI was similar (7.7% vs 10.6%, respectively; p = 0.76). No significant differences were seen in achievement of TDM goal, incidence of supratherapeutic exposure or vancomycin accumulation, duration of vancomycin, length of stay, or number of vancomycin concentrations. AUC monitoring was associated with earlier achievement of TDM goal [median 0 days (0-2) vs 2 days (0-4); p &amp;lt; 0.01], lower total daily doses to achieve TDM goal [38.6 ±13 mg/kg/day vs 58.4 ±18.7mg/kg/day; p &amp;lt; 0.01], and fewer regimen changes [median 1 change (0-2) vs 2 changes (1-3); p &amp;lt; 0.01] compared to trough monitoring. In patients with MRSA, pulmonary function recovery, readmission, and mortality was similar. Conclusion In adult CF patients, the rates of AKI were similar between VAN TDM methods, but VAN AUC monitoring resulted in a therapeutic regimen sooner at lower total daily VAN doses and fewer number of regimen changes without significantly increasing the number of concentrations compared to trough monitoring. Disclosures James Sanders, PhD, PharmD, Merck &amp; Co., Inc.: Grant/Research Support|Shionogi Inc.: Grant/Research Support

Current cough and sputum assessed by the cough and sputum assessment-questionnaire (CASA-Q) is associated with quality of life impairment in cystic fibrosis

BackgroundCough and sputum are major symptoms in cystic fibrosis (CF) that contribute to the impairment of quality of life.MethodsThis prospective single centre cross-sectional pilot study aimed to evaluate the results of a self-administered questionnaire assessing cough and sputum symptoms (2 domains), and their impact (2 domains) on daily activities in the previous week, named the Cough and Sputum Assessment Questionnaire (CASA-Q) in CF adult patients at stable state, and to analyse associations with clinical, functional, microbiological, radiological data, and two quality of life scales: the Cystic Fibrosis Questionnaire Revised (CFQ-R) and the Saint George Respiratory Questionnaire (SGRQ).ResultsForty-eight patients were included in this analysis (69% men; median age of 27.8 ± 8.1 years; median body mass index of 21.8 + 3.3 kg/m²; mean FEV1 of 64 ± 30% of the predicted value). The mean values of the CASA-Q domains were 58 ± 23 for cough symptoms, 77 ± 24 for cough impact, 62 ± 25 for sputum symptoms and 84 ± 21 for sputum impact. Impairment in CASA-Q cough and sputum domains was associated with dyspnea mMRC scale (p < 0.005 for all 4 domains of CASA-Q) and exacerbations in the previous year (p < 0.05 for CASA-Q symptoms domains). We also found correlations between all domains of the CASA-Q and quality of life questionnaires including SGRQ (p < 0.001) and to a lesser extend CFQ-R. We identified a clinical phenotype (female gender, ΔF508 heterozygous mutation, dyspnea mMRC scale) associated with an impairment of CASA-Q score and quality of life using a 2-step cluster analysis.ConclusionsCASA-Q allows the assessment of cough and sputum in CF adult patients and is associated with quality of life impairment. This simple easy-to-use tool could be used in routine clinical practice and in clinical studies to assess cough and sputum in CF patients.Trial RegistrationThe study was registered on ClinicalTrials.gov (NCT02924818, first posted on 5th October 2016).

Radiological and clinical evaluation of triple combination modulating therapy effectiveness in adult patients with cystic fibrosis

ObjectivesPrevious studies showed the clinical effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in cystic fibrosis (CF) patients and a recently published study evaluated twelve CF patients that performed chest and sinus computed tomography (CT) examinations and showed that ETI decreased pulmonary and sinus morphological abnormalities after one year of treatment. The aim of the present study was to evaluate the role of CFTR modulator therapy in improving radiological and clinical scores one year after ETI therapy initiation in a wider CF patient population. Materials and methodsBetween January 2020 and December 2022, 44 CF adult patients received elexacaftor-tezacaftor-ivacaftor (ETI) therapy for at least one year and underwent a chest CT examination at our hospital before and one year after ETI therapy initiation. Experienced radiologists who were blinded to the treatment assessed the images in consensus. The Brody-II score (BSII), the Lund-Mackay score (LM score) and the Sheikh-Lind CT sinus disease severity scoring system (SL score) were evaluated. Clinical scores such as cystic fibrosis clinical score (CFCS), Cystic Fibrosis Questionnaire-Revised (CFQ-R) score, the 22-item SinoNasal Outcome Test (SNOT-22) questionnaire and the CF-specific 28-modal abdominal symptom score (CFAbd-Score) were evaluated. Forced expiratory volume in 1 ​s (FEV1) and forced vital capacity (FVC) were also assessed. Paired samples t-tests were used to compare differences before and after one year of ETI therapy initiation, and Pearson's correlation coefficient was used to evaluate changes in FEV1 and total BSII and in FVC and total BSII. ResultsTotal BIIS one year after ETI initiation showed statistically significant lower scores (−6.0 p, p ​< ​0.0001). In particular, mucous plugging (−15.8 p, p ​< ​0.0001), peribronchial thickening (−16.2 p, p ​< ​0.0001) and parenchyma (−0.3 p, p ​= ​0.0397) showed statistically significant lower scores. LM score, SL score, FEV1, FVC, CFCS, CFQ-R, SNOT-22 and CFAbd-Score showed statistically significant lower scores one year after ETI initiation (p ​< ​0.0001). The correlation between ΔFEV1 and Δtotal BSII was statistically significant and moderate (r ​= ​−0.5188, p ​= ​0.0003), and the correlation between ΔFVC and Δtotal BSII was statistically significant and weak (r ​= ​−0.3160, p ​= ​0.0367). ConclusionEvolution of imaging findings on CT during follow-up closely correlate with improved clinical scores and functional data one year after ETI therapy initiation, indicating that CT may be a useful adjunct during follow-up of CF patients under this treatment as an objective measure of disease improvement.

THU294 Glucagon Like Peptide-1 Analogue Therapy In Obese Patients With Cystic Fibrosis Related Diabetes

Abstract Disclosure: A.R. Ankireddypalli: None. A. Moheet: None. Introduction: Cystic fibrosis (CF) has classically been associated with malnutrition and being underweight. Intense emphasis on nutritional augmentation and advancement in medical therapies including recent introduction of CFTR modulators have significantly reduced the prevalence of malnutrition in CF. However, this success has been accompanied by a significant rise in overweight/obesity in CF. Recent studies have reported that one-third of all adult CF patients are overweight or obese. Glucagon like peptide receptor-1 agonists (GLP-1RA) therapy is an effective treatment for type 2 diabetes mellitus (T2DM) and obesity. Current guidelines for CF related diabetes (CFRD), recommend insulin as the mainstay of treatment. However, with increase in prevalence of obesity, there is increased interest in examining the role of incretin-based therapies in CFRD. Gastrointestinal (GI) symptoms like abdominal pain, steatorrhea, gastroparesis are common in CF. Concerns about the potential GI side effects had previously dampened the enthusiasm for these drugs in CF.The objective of this case series is to demonstrate impact on glycemic control and weight, and tolerability of GLP1-RA treatment in obese patients with CFRD and pancreatic insufficiency (PI) after 1 year of therapy. Case 1: A 21-year-old female with CF (delta F508 homozygote) and PI, was diagnosed with CRFD at 15 years. She was initially on lantus 14 units daily with HbA1c of 6.7%. She was started on CFTR modulator therapy and with increase in BMI from 37 to 45 in 1 year with HbA1c of 8.9%. She was started on semaglutide and tolerated the medication well with no GI side effects. 1 year later her BMI reduced to 42 and HbA1c was 8.2%. Case 2: A 62-year-old male with CF (delta F508 heterozygote) and PI, diagnosed with CFRD at age 44 years. He was on lantus 66 units and aspart 1 unit per 5 grams carbohydrate coverage. He was started on CFTR modulator and in 1 year BMI increased from 53 to 57. He was started on semalglutide, which he tolerated well with no GI symptoms. 1 year later his Hba1c improved to 7% with a BMI of 54. Discussion: In this era of CFTR modulator therapy, CF patients are faced with changing metabolic parameters, including weight gain and developing T2DM phenotype with insulin resistance. There is one previous case report of short duration of GLP-1RA use in CFRD. We report &amp;gt; 1 year of clinical experience of GLP-1RA use in 2 patients. GLP-1RA was well tolerated in these patients with improvement in glycemic control and weight loss. GLP-1 RA should be considered in obese, PI patients with CFRD as an add-on therapy to insulin. However, larger studies with long-term follow up are required to study the full impact of GLP-1RA to establish it as a treatment option in CFRD. Presentation: Thursday, June 15, 2023

Decreased plasma levels of sphingolipids and total cholesterol in adult cystic fibrosis patients

BackgroundSphingolipid species in the lung epithelium have a critical role for continuity of membrane structure, vesicular transport, and cell survival. Sphingolipid species were reported to have a role in the inflammatory etiology of cystic fibrosis by previous work. The aim of the study was to investigate the levels of plasma sphingomyelin and ceramide in adult cystic fibrosis (CF) patients and compared with healthy controls. Materials and methodsBlood samples were obtained from CF patients at exacerbation (n = 15), discharge (n = 13) and stable periods (n = 11). Healthy individuals (n = 15) of similar age served as control. Levels of C16–C24 sphingomyelin and C16–C24 ceramide were measured in the plasma by LC-MS/MS. Also, cholesterol and triglyceride levels were determined in plasma samples of the patients at stable period. ResultsAll measured sphingomyelin and ceramide levels in all periods of CF patients were significantly lower than healthy controls except C16 sphingomyelin level in the stable period. However, plasma Cer and SM levels among exacerbation, discharge, and stable periods of CF were not different. CF patients had significantly lower cholesterol levels compared to healthy individuals. We found significant correlation of cholesterol with C16 sphingomyelin. ConclusionWe observed lower plasma Cer and SM levels in adult CF patients at exacerbation, discharge, and stable periods compared to healthy controls. We didn't find any significant difference between patient Cer and SM levels among these three periods. Our limited number of patients might have resulted with this statistical insignificance. However, percentage of SM16 levels were increased at discharge compared to exacerbation levels, while percentage of Cer16 and Cer 20 decreased at stable compared to exacerbation. Inclusion of a larger number of CF patients in such a follow up study may better demonstrate any possible difference between exacerbation, discharge, and stable periods.

Effect of 18 months elexacaftor-tezacaftor-ivacaftor on body mass index and glycemic control in adults with cystic fibrosis

Malnutrition and cystic fibrosis related diabetes (CFRD) are common comorbidities in cystic fibrosis (CF). Cystic fibrosis transmembrane regulator (CFTR) modulators have shown beneficial effects on respiratory status. This study aims to determine the effect of elexacaftor-tezacaftor-ivacaftor (ETI) on body mass index (BMI) and glycemic control. A retrospective, observational study of a cohort of 17 adult CF patients was conducted at the CF reference center of Ghent University Hospital. BMI evolution was analyzed 18 months before and 0, 3, 6, 12 and 18 months after the start of ETI. The evolution of insulin dependence and the 2h oral glucose tolerance test (OGTT) results were described until 36 months after start of ETI, in a small subgroup of ten patients with CFRD or impaired glucose tolerance (IGT). A significant increase in mean BMI of 1.2kg/m2 (±1.3 SD) was observed. Most weight gain was observed in the first 3 months after starting treatment. This effect was sustained during the observed period of 18 months. Six patients had insulin dependent CFRD, of which three were able to stop insulin after starting ETI. Two patients with CFRD treated with dietary measures showed an initial normalization of the 2h OGTT, but deterioration at 36 month follow-up. After initiation of ETI an increase in BMI was observed in adults with CF. ETI can have a beneficial impact on glucose metabolism in patients with CFRD, leading to a possible need for reduction or cessation of insulin therapy.

Elexacaftor/Tezacaftor/Ivacaftor Improves Bronchial Artery Dilatation Detected by Magnetic Resonance Imaging in Patients with Cystic Fibrosis.

Rationale: Magnetic resonance imaging (MRI) detects improvements in mucus plugging and bronchial wall thickening, but not in lung perfusion in patients with cystic fibrosis (CF) treated with elexacaftor/tezacaftor/ivacaftor (ETI). Objectives: To determine whether bronchial artery dilatation (BAD), a key feature of advanced lung disease, indicates irreversibility of perfusion abnormalities and whether BAD could be reversed in CF patients treated with ETI. Methods: A total of 59 adults with CF underwent longitudinal chest MRI, including magnetic resonance angiography twice, comprising 35 patients with CF (mean age, 31 ± 7 yr) before (MRI1) and after (MRI2) at least 1 month (mean duration, 8 ± 4 mo) on ETI therapy and 24 control patients with CF (mean age, 31 ± 7 yr) without ETI. MRI was assessed using the validated chest MRI score, and the presence and total lumen area of BAD were assessed with commercial software. Results: The MRI global score was stable in the control group from MRI1 to MRI2 (mean difference, 1.1 [-0.3, 2.4]; P = 0.054), but it was reduced in the ETI group (-10.1 [-0.3, 2.4]; P < 0.001). In the control and ETI groups, BAD was present in almost all patients at baseline (95% and 94%, respectively), which did not change at MRI2. The BAD total lumen area did not change in the control group from MRI1 to MRI2 (1.0 mm2 [-0.2, 2.2]; P = 0.099) but decreased in the ETI group (-7.0 mm2 [-8.9, -5.0]; P < 0.001). This decrease correlated with improvements in the MRI global score (r = 0.540; P < 0.001). Conclusions: Our data show that BAD may be partially reversible under ETI therapy in adult patients with CF who have established disease.

Phenotypic and genotypic characteristics of Pseudomonas aeruginosa isolated from cystic fibrosis patients with chronic infections

Patients with cystic fibrosis are predisposed to chronic respiratory tract infections caused by Pseudomonas aeruginosa. As the disease progresses, the microorganism diversifies into genotypically and phenotypically different strains which may coexist in the patient's airways for years. Adaptation of the microorganism to the airways of patients with cystic fibrosis probably occurs in response to the host's airway environment, the elements of the immune system and antibiotic therapy. Due to the chronic persistence of the microorganism in the airways, a comprehensive molecular analysis was conducted. The analysis included 120 strains isolated from 10 adult cystic fibrosis patients with chronic P. aeruginosa infection. The aim of the study was to analyze the molecular patterns of P. aeruginosa strains and to trace their transmission in the population of cystic fibrosis patients, as well as to study a relationship of the disease with specific phenotypic features. In the research, a genotypic analysis of P. aeruginosa was performed using pulsed-field gel electrophoresis. The results of a number of phenotypic features of the strains were added to the outcomes of the molecular studies. As a result, 28 different genotypes were distinguished. The study also showed cross-transmission of strains between patients. 3 transmissible clusters were identified, including IG1 and IG2 clusters with 9 strains of P. aeruginosa each, obtained from 2 patients and IG3 cluster with 6 strains of P. aeruginosa isolated from 3 patients. Moreover, it was found that in some patients, several unrelated strains of P. aeruginosa may transiently or permanently infect the respiratory tract. A comprehensive understanding of the P. aeruginosa adaptation may help to develop more effective antimicrobial therapies and to identify new targets for future drugs in order to prevent progression of the infection to chronic stages.

Ceftolozane/tazobactam heteroresistance in cystic fibrosis-related Pseudomonas aeruginosa infections.

Cystic fibrosis (CF) patients are often colonized with Pseudomonas aeruginosa. During treatment, P. aeruginosa can develop subpopulations exhibiting variable in vitro antimicrobial (ABX) susceptibility patterns. Heteroresistance (HR) may underlie reported discrepancies between in vitro susceptibility results and clinical responses to various ABXs. Here, we sought to examine the presence and nature of P. aeruginosa polyclonal HR (PHR) and monoclonal HR (MHR) to ceftolozane/tazobactam in isolates originating from CF pulmonary exacerbations. This was a single-centre, non-controlled study. Two hundred and forty-six P. aeruginosa isolates from 26 adult CF patients were included. PHR was defined as the presence of different ceftolozane/tazobactam minimum inhibitory concentration (MIC) values among P. aeruginosa isolates originating from a single patient specimen. Population analysis profiles (PAPs) were performed to assess the presence of MHR, defined as ≥4-fold change in the ceftolozane/tazobactam MIC from a single P. aeruginosa colony. Sixteen of 26 patient specimens (62%) contained PHR P. aeruginosa populations. Of these 16 patients, 6 (23%) had specimens in which PHR P. aeruginosa isolates exhibited ceftolozane/tazobactam MICs with categorical differences (i.e. susceptible versus resistant) compared to results reported as part of routine care. One isolate, PSA 1311, demonstrated MHR. Canonical ceftolozane/tazobactam resistance genes were not found in the MHR isolates (MHR PSA 1311 or PHR PSA 6130). Ceftolozane/tazobactam PHR exists among P. aeruginosa isolates in this work, and approximately a quarter of these populations contained isolates with ceftolozane/tazobactam susceptibiilty interpretations different from what was reported clinically, supporting concerns surrounding the utility of traditional susceptibility testing methodology in the setting of CF specimens. Genome sequencing of isolates with acquired MHR to ceftolozane/tazobactam revealed variants of unknown significance. Future work will be centred on determining the significance of these mutations to better understand these data in clinical context.

Moraxella catarrhalis in People with Cystic Fibrosis

BACKGROUND: The gammaproteobacteria, Moraxella catarrhalis (MC) is commonly isolated from respiratory specimens from people with cystic fibrosis (PwCF), although its prevalence and clinical significance in cystic fibrosis (CF) remains largely unreported in international patient registries and the wider scientific literature. AIM AND OBJECTIVE: The aim of this study was to examine the time-to-first-isolation of MC and to correlate this with patient gender and CF transmembrane conductance regulator (CFTR) mutation type. MATERIALS AND METHODS: The microbiology of respiratory specimens from 100 adult (≥18 years) PwCF was examined (50 females; 50 males; mean age 24.6 years ± 6.25 (Standard deviation [SD]) from birth to present, equating to 2455 patient-years. Time-to-first-isolation was determined and correlated with (i) CFTR mutation type and (ii) PwCF gender. RESULTS: MC was isolated from 27 (27/100 [27%] adult CF patients [18 female/9 males]); (i) F508del/F508del homozygous (55.6%; 15/27) and (ii) F508del/other heterozygous (37.0%; 10/27) and (iii) Other (7.4%; 2/27). The median and mean time to the first isolation of MC was 60 months and 71.8 months (SD = 66.2 months; standard error of the mean = 12.7 months), respectively; shortest time was 1 month, the longest time was 254 months. The highest rate of MC isolation was from 2 years until 10 years and by the age of 18 years, approximately 96.3% of positive patients had recorded their first MC isolate. By 21.2 years, all positive patients had recorded their first MC isolation. There was no statistical significance in the time-to-first-isolation of MC in relation to the CFTR mutation group or with patient gender. CONCLUSIONS: MC is commonly isolated from respiratory specimens of PwCF. This work represents an advance in biomedical science as it identifies time points in the person with CF’s disease staging, which may allow mitigating infection prevention interventions to be established, as well as vigilance to help prevent MC acquisition.

Staphylococcus aureus Small-Colony Variants from Airways of Adult Cystic Fibrosis Patients as Precursors of Adaptive Antibiotic-Resistant Mutations.

Prototypic Staphylococcus aureus and their small-colony variants (SCVs) are predominant in cystic fibrosis (CF), but the interdependence of these phenotypes is poorly understood. We characterized S. aureus isolates from adult CF patients over several years. Of 18 S. aureus-positive patients (58%), 13 (72%) were positive for SCVs. Characterization included genotyping, SCCmec types, auxotrophy, biofilm production, antibiotic susceptibilities and tolerance, and resistance acquisition rates. Whole-genome sequencing revealed that several patients were colonized with prototypical and SCV-related clones. Some clonal pairs showed acquisition of aminoglycoside resistance that was not explained by aminoglycoside-modifying enzymes, suggesting a mutation-based process. The characteristics of SCVs that could play a role in resistance acquisition were thus investigated further. For instance, SCV isolates produced more biofilm (p < 0.05) and showed a higher survival rate upon exposure to ciprofloxacin and vancomycin compared to their prototypic associated clones. SCVs also developed spontaneous rifampicin resistance mutations at a higher frequency. Accordingly, a laboratory-derived SCV (ΔhemB) acquired resistance to ciprofloxacin and gentamicin faster than its parent counterpart after serial passages in the presence of sub-inhibitory concentrations of antibiotics. These results suggest a role for SCVs in the establishment of persistent antibiotic-resistant clones in adult CF patients.

The influence of the genotype and respiratory tract microflora on lung function and nutritional status in adult cystic fibrosis patients in long-term follow-up

In recent years, an increase in the number of patients with chronic infection with nonfermenting gram-negative bacteria (NFGNB) in adult patients with cystic fibrosis (CF) has increased. The genotype and phenotype characteristics, NFGNB structure, changes in sensitivity and the development of antibiotic resistance in adult patients have not been adequately studied.Aim. To determine the impact of genotype severity and Achromobacter xylosoxidans sensitivity to carbapenems on the functional and nutritional status of adult cystic fibrosis patients over a period 2016 – 2021.Materials. Retrospective analysis of genotypic and microbiological data from 54 adult CF patients and their effects on FEV1 and BMI over a period 2016 – 2021. Sputum cultures were confirmed by MALDI-TOF mass spectrometer. Depending on the severity of the mutation, the patients were divided into 2 groups: group 1 (“severe” genotype) – patients who had 2 mutations of class I – III; group 2 (“soft” genotype) – at least 1 class IV – VI mutation.Results. The group of patients with “mild” mutations had a higher BMI (kg / m2) than the group with severe mutations for a longer period of follow-up from 2018 – 2021 than in the group with severe mutations: BMI (2016) – 21.14 ± 3.55 / 19.28 ± 3.13 (p = 0.163); BMI (2017) – 21.27 ± 3.43 / 18.31 ± 2.05 (p = 0.123); BMI (2018) – 21.17 ± 4.00 / 18.80 ± 2.12 (p = 0.025); BMI (2019) – 21.01 ± 4.20 / 18.55 ± 2.53 (p = 0.049); BMI (2020) – 20.94 ± 4.12 / 18.41 ± 2.15 (p = 0.050). Age at diagnosis was 20.36 ± 2.18 years for “mild” genotypes and was higher (p = 0.042) than for “severe” genotypes (6.27 ± 1.53 years). All 7 patients who died (100%) were in the “severe” genotype group (23.3%). Functional status assessment showed no differences in FEV1 over 6 years between the “severe” and “mild” genotype groups: FEV1 (2016) – p = 0.51; FEV1 (2017) – p = 0.39; FEV1 (2018) – p = 0.51; FEV1 (2019) – p = 0.35; FEV1 (2020) – p = 0.48. Nonfermenting Gram-negative bacteria accounted for 49.9% of the isolated microorganisms. The group of carbapenem-resistant Achromobacter xylosoxidans lost the FEV1 level faster every year for 6 years (p &lt; 0.05) compared to the group of the sensitive variant.Conclusion. In general, patients with the “mild” genotype have higher nutritional status and do not differ from patients with the “severe” genotype in terms of FEV1. The survival rate of patients with the “mild” genotype patients survival rate is higher, despite the later diagnosis and start of treatment. Development of carbаpenem resistance in Achromobacter xylosoxidans is associated with an unfavorable prognosis of the functional status decline.

P043 Changes in body composition in adult cystic fibrosis patients within six months of initiation elexacaftor/tezacaftor/ivacaftor therapy in Argentina

Background: Nutritional status is intimately linked with pulmonary function and survival in cystic fibrosis (CF). The impact of elexacaftor-tezacaftor-ivacaftor (ETI) in weight gain remains incompletely described.

P055 No impact of elexacaftor/tezacaftor/ivacaftor (ETI) CFTRm therapy on male infertility due to CBAVD in two adult cystic fibrosis patients: case report

P055 No impact of elexacaftor/tezacaftor/ivacaftor (ETI) CFTRm therapy on male infertility due to CBAVD in two adult cystic fibrosis patients: case report