Pediatr Pulmonol. 2024 Jul 11. doi: 10.1002/ppul.27160. Online ahead of print.

ABSTRACT

BACKGROUND: New York (NY) State implemented a new cystic fibrosis (CF) newborn screen (NBS) algorithm in December 2017 with improvement in positive predictive value and unanticipated increased identification of infants with cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS). Repeat sweat testing is recommended in infants with CRMS. During the COVID-19 pandemic infants with CRMS were lost to follow up. With this quality improvement (QI) initiative, we aimed to perform repeat sweat testing in 25% of infants lost to follow up. We also describe consensus recommendations for CRMS from the NY CF NBS Consortium.

METHODS: Our QI team identified the primary drivers contributing to absent follow up, outreached to families, and created a questionnaire to evaluate parental understanding of CRMS using QI-based strategies.

RESULTS: Of 350 infants diagnosed with CRMS during the study period, 179 (51.1%) infants were lost to follow up. A total of 31 (17.3%) were scheduled for repeat sweat tests and followed up at CF Centers. Families reported high satisfaction with the CRMS knowledge questionnaire.

CONCLUSIONS: With this QI-based approach, we effectively recaptured infants with CRMS previously lost to follow up during the COVID-19 pandemic. Ongoing concerns about infection risk and lack of understanding on the part of families and pediatricians likely contributed to patients with CRMS lost to follow up. Consensus recommendations for CRMS include annual visits with repeat sweat testing until 2-6 years of age and education for adolescents about clinical and reproductive implications of CRMS.

PMID:38990093 | DOI:10.1002/ppul.27160

Antimicrob Agents Chemother. 2024 Jul 11:e0002924. doi: 10.1128/aac.00029-24. Online ahead of print.

ABSTRACT

Mycobacterium abscessus infections are emerging in cystic fibrosis patients, and treatment success rate in these patients is only 33% due to extreme antibiotic resistance. Thus, new treatment options are essential. An interesting target could be Lsr2, a nucleoid-associated protein involved in mycobacterial virulence. Zafirlukast is a Food and Drug Administration (FDA)-approved drug against asthma that was shown to bind Lsr2. In this study, zafirlukast treatment is shown to reduce M. abscessus growth, with a minimal inhibitory concentration of 16 µM and a bactericidal concentration of 64 µM in replicating bacteria only. As an initial response, DNA condensation, a known stress response of mycobacteria, occurs after 1 h of treatment with zafirlukast. During continued zafirlukast treatment, the morphology of the bacteria alters and the structural integrity of the bacteria is lost. After 4 days of treatment, reduced viability is measured in different culture media, and growth of M. abscessus is reduced in a dose-dependent manner. Using transmission electron microscopy, we demonstrated that the hydrophobic multilayered cell wall and periplasm are disorganized and ribosomes are reduced in size and relocalized. In summary, our data demonstrate that zafirlukast alters the morphology of M. abscessus and is bactericidal at 64 µM. The bactericidal concentration of zafirlukast is relatively high, and it is only effective on replicating bacteria but as zafirlukast is an FDA-approved drug, and currently used as an anti-asthma treatment, it could be an interesting drug to further study in in vivo experiments to determine whether it could be used as an antibiotic for M. abscessus infections.

PMID:38990015 | DOI:10.1128/aac.00029-24

mBio. 2024 Jul 11:e0035524. doi: 10.1128/mbio.00355-24. Online ahead of print.

ABSTRACT

The Type VI secretion system (T6SS) is a multicomponent apparatus, present in many Gram-negative bacteria, which can inhibit bacterial prey in various ecological niches. Pseudomonas aeruginosa assembles one of its three T6SS (H1-T6SS) to respond to attacks from adjacent competing bacteria. Surprisingly, repeated assemblies of the H1-T6SS, termed dueling, were described in a monoculture in the absence of an attacker strain; however, the underlying mechanism was unknown. Here, we explored the role of H2-T6SS of P. aeruginosa in triggering H1-T6SS assembly. We show that H2-T6SS inactivation in P. aeruginosa causes a significant reduction in H1-T6SS dueling and that H2-T6SS activity directly triggers retaliation by the H1-T6SS. Intraspecific competition experiments revealed that elimination of H2-T6SS in non-immune prey cells conferred protection from H1-T6SS. Moreover, we show that the H1-T6SS response is triggered independently of the characterized lipase effectors of the H2-T6SS, as well as those of Acinetobacter baylyi and Vibrio cholerae. Our results suggest that H1-T6SS response to H2-T6SS in P. aeruginosa can impact intraspecific competition, particularly when the H1-T6SS effector-immunity pairs differ between strains, and could determine the outcome of multistrain colonization.IMPORTANCEThe opportunistic pathogen Pseudomonas aeruginosa harbors three different Type VI secretion systems (H1, H2, and H3-T6SS), which can translocate toxins that can inhibit bacterial competitors or inflict damage to eukaryotic host cells. Unlike the unregulated T6SS assembly in other Gram-negative bacteria, the H1-T6SS in P. aeruginosa is precisely assembled as a response to various cell damaging attacks from neighboring bacterial cells. Surprisingly, it was observed that neighboring P. aeruginosa cells repeatedly assemble their H1-T6SS toward each other. Mechanisms triggering this "dueling" behavior between sister cells were unknown. In this report, we used a combination of microscopy, genetic and intraspecific competition experiments to show that H2-T6SS initiates H1-T6SS dueling. Our study highlights the interplay between different T6SS clusters in P. aeruginosa, which may influence the outcomes of multistrain competition in various ecological settings such as biofilm formation and colonization of cystic fibrosis lungs.

PMID:38990002 | DOI:10.1128/mbio.00355-24

Nat Biomed Eng. 2024 Jul 10. doi: 10.1038/s41551-024-01233-3. Online ahead of print.

ABSTRACT

Prime editing (PE) enables precise and versatile genome editing without requiring double-stranded DNA breaks. Here we describe the systematic optimization of PE systems to efficiently correct human cystic fibrosis (CF) transmembrane conductance regulator (CFTR) F508del, a three-nucleotide deletion that is the predominant cause of CF. By combining six efficiency optimizations for PE-engineered PE guide RNAs, the PEmax architecture, the transient expression of a dominant-negative mismatch repair protein, strategic silent edits, PE6 variants and proximal 'dead' single-guide RNAs-we increased correction efficiencies for CFTR F508del from less than 0.5% in HEK293T cells to 58% in immortalized bronchial epithelial cells (a 140-fold improvement) and to 25% in patient-derived airway epithelial cells. The optimizations also resulted in minimal off-target editing, in edit-to-indel ratios 3.5-fold greater than those achieved by nuclease-mediated homology-directed repair, and in the functional restoration of CFTR ion channels to over 50% of wild-type levels (similar to those achieved via combination treatment with elexacaftor, tezacaftor and ivacaftor) in primary airway cells. Our findings support the feasibility of a durable one-time treatment for CF.

PMID:38987629 | DOI:10.1038/s41551-024-01233-3

J Cyst Fibros. 2024 Jul 9:S1569-1993(24)00789-6. doi: 10.1016/j.jcf.2024.07.004. Online ahead of print.

ABSTRACT

BACKGROUND: Lung inflammation is associated with tissue damage in cystic fibrosis (CF). LAU-7b, a novel oral drug candidate, was shown to control inflammation and stabilize CFTR protein in the epithelial membrane during inflammatory stress in preclinical models of CF.

METHODS: A double-blind, randomized, placebo-controlled Phase 2 study was conducted to evaluate efficacy and safety of LAU-7b in adults with CF. LAU-7b or placebo was administered over 24 weeks as six 21-day treatment cycles each separated by 7 days. The primary efficacy endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at 24 weeks.

RESULTS: A total of 166 subjects received at least one dose of study drug (Intent-To-Treat population, ITT), of which 122 received ≥5 treatment cycles (Per-Protocol population, PP). Both treatment arms showed a mean lung function loss at 24 weeks of 1.18 ppFEV1 points with LAU-7b and 1.95 ppFEV1 with placebo, a 0.77 ppFEV1 (40 s) difference, p=0.345, and a 0.95 ppFEV1 (49 %) difference in the same direction in PP population, p=0.263. Primary analysis of mean ppFEV1 through 24 weeks showed differences of 1.01 and 1.23 ppFEV1, in the ITT (65 % less loss, p=0.067) and PP populations (78 % less loss, reaching statistical significance p=0.049), respectively. LAU-7b had an acceptable safety profile.

CONCLUSION: Although the study did not meet its primary efficacy endpoint in the ITT population, LAU-7b was generally well tolerated and showed evidence of preservation of lung function to support further development.

PMID:38987119 | DOI:10.1016/j.jcf.2024.07.004

J Asthma. 2024 Jul 10:1-12. doi: 10.1080/02770903.2024.2376919. Online ahead of print.

ABSTRACT

In the field of severe asthma, the concept of disease control has recently been integrated by the one of clinical remission. With this new concept, we move on to analyze the efficacy of therapy on multiple parameters simultaneously, starting with the mandatory discontinuation of the systemic glucocorticoids, to which is added the effect on exacerbations, respiratory function, and symptoms control. The Italian severe asthma registry SANI (Severe Asthma Network Italy) drafted criteria for the definition of disease remission, allowing patients to be classified into two groups, partial and complete remission. The greater dynamism of the definition, provided by SANI, allows us to hypothesize its practical use, concerning therapy management of severe asthma patients, starting from the level of remission, with the aim to facilitate the clinical decision on replacement, continuation or modulation of patients' therapy.

PMID:38984764 | DOI:10.1080/02770903.2024.2376919

J Sci Food Agric. 2024 Jul 10. doi: 10.1002/jsfa.13732. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) patients frequently experience gut microbiota dysbiosis. Probiotic supplementation is a potential therapeutic approach to modify gut microbiota and improve CF management through the gut-lung axis. The aim of this study was to investigate the effect of Lactobacillus reuteri supplementation on pulmonary function test, respiratory symptoms and growth in CF patients.

METHODS: A randomized, placebo-controlled clinical trial was carried out on 40 children with CF aged from 6 to 20 years. Participants were designated to receive either L. reuteri or placebo daily for 4 months. Pulmonary function tests, weight, height and body mass index (BMI) z-scores were measured pre and post treatment.

RESULTS: The median baseline BMI of the patients was 16.28 kg m-2. A significant change in the probiotic group's BMI z-score after the study period was observed (P = 0.034) but not for weight and height z-scores (P > 0.05). After treatment, Pseudomonas aeruginosa grew in sputum cultures of seven in the placebo and one patient in the intervention group (P = 0.03) while at baseline it grew in the sputum of four patients in each group. There was no significant difference in forced expiratory volume in the first second, forced expiratory flow at 25-75% or forced vital capacity change between the two groups after the treatment period (P > 0.05). Additionally, no significant differences were found in pulmonary exacerbations, hospitalization frequencies or COVID-19 infection between the two groups during the study (P > 0.05).

CONCLUSION: The results suggest that L. reuteri supplementation may impact the growth of severely malnourished CF patients. Furthermore, it may be concluded that this strain might reduce P. aeruginosa in the sputum culture of CF patients. © 2024 Society of Chemical Industry.

PMID:38982876 | DOI:10.1002/jsfa.13732

Heart Lung. 2024 Jul 8;68:145-153. doi: 10.1016/j.hrtlng.2024.06.016. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with cystic fibrosis (CF) experience increased oxidative stress. Tele-exercise can be a new method to improve exercise in CF.

OBJECTIVE: This study aimed to investigate the effect of telehealth-based exercise training using different modalities (combined exercise training group, CombG, core stabilization exercise group, SG), in comparison with control group (CG), on exercise capacity, oxidative stress, and irisin in children with CF.

METHODS: Thirty-nine children with CF (mean age=11.41±2.18 years, mean FEV1(z-score)=-0.66±1.96) were included in the study. The children were randomly allocated to groups. The CombG and SG performed core stabilization exercises (CS) 3 days per week for 8 weeks. The CombG also performed aerobic exercises 3 days per week in addition to CS. Physical activity (PA) recommendations were provided to the CG. Exercise capacity was evaluated using the Modified Shuttle Test (MST). Oxidative stress was assessed using total antioxidant status (TAS), total oxidant status (TOS), Oxidative Stress Index (OSI), malondialdehyde (MDA), and superoxide dismutase (SOD). The irisin level was also measured.

RESULTS: Children's baseline sex, age, BMI, and FEV1 z-scores were similar (p > 0.05). The MST distance (p = 0.047,np2=0.157) and%MST distance (p = 0.045, np2=0.159) significantly improved in the CombG compared with the SG and CG. Although TAS and SOD decreased over time (p < 0.05), no significant changes were observed for TAS, TOS, OSI, MDA, SOD, and irisin parameters between the groups after training (p > 0.05).

CONCLUSIONS: Combining aerobic exercise training with core stabilization applied using telehealth improved exercise capacity more than core stabilitation training only or PA recommendations in children with CF.

PMID:38981171 | DOI:10.1016/j.hrtlng.2024.06.016

Genome Med. 2024 Jul 9;16(1):86. doi: 10.1186/s13073-024-01359-8.

ABSTRACT

BACKGROUND: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated.

METHODS: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort.

RESULTS: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%).

CONCLUSIONS: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

PMID:38982539 | DOI:10.1186/s13073-024-01359-8

Respir Res. 2024 Jul 10;25(1):269. doi: 10.1186/s12931-024-02889-w.

ABSTRACT

BACKGROUND: Cystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis.

METHODS: Small molecule potentiators, previously identified in CFTR binding studies, were tested for activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement.

RESULTS: We showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures.

CONCLUSION: Together, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

PMID:38982492 | DOI:10.1186/s12931-024-02889-w

Acta Diabetol. 2024 Jul 9. doi: 10.1007/s00592-024-02329-7. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF)-related diabetes (CFRD), characterized by partial to complete impaired insulin secretion, is the most common extra-pulmonary complication of CF. Actually, insulin is the only approved therapy for its management. Advanced hybrid closed loop (AHCL) systems are the gold standard therapy for type 1 diabetes and have been proposed for other insulin-dependent forms of diabetes, including CFRD. With AHCL systems, people with CFRD can better manage several typical disease-related issues, such as minimal insulin requirements, its variability due to exacerbations or concomitant steroid therapies, nutritional behaviors, the co-existence of CF complications as intestinal malabsorption or liver disease. SmartGuard, the AHCL system for Medtronic Minimed 780G, requires a minimum of 8 units per day to operate. In this paper, we expose a case of two young women with CFRD with total daily insulin requirements < 8 UI, using off-label SmartGuard system over a 3 years of follow-up period, suggesting an evaluation of its use also in people with minimal insulin needs, considering its beneficial impact in glucose control and quality of life.

PMID:38981873 | DOI:10.1007/s00592-024-02329-7

Cas Lek Cesk. 2024;163(3):87-93.

ABSTRACT

Gene therapy is gradually becoming a mainstream treatment modality and is no longer the preserve of large university departments whose laboratories master nucleic acid analytical procedures and whose clinical teams manage its administration. It was originally designed for genetic diseases that, because of their prevalence, were a group known as rare diseases. Gene therapy has so far been applied in children to act before the disease development. These new treatments have also begun to be applied for common diseases such as metabolic disorders (e. g. diabetes) and even for those that are increasingly affecting us, such as various malignancies and diseases of the central nervous system (e. g. Alzheimer's disease). The targets targeted by GT are genes, where pathogenic alterations in the form of pathogenic variants (formerly mutations) induce phenotypic disorders, and our aim is either to knock them out of function (e. g. haemoglobinopathies) or to replace them with genes with normal function, which we introduce into the genome using one of the appropriate vectors, such as viruses or liposomes. The process of GT can take place directly inside the patient's body (in vivo) or outside the body on isolated cells (ex vivo), which are usually stem cells (iPSCs, induced pluripotent stem cell). After treatment, these cells are returned to the patient's body to fulfil their "destiny". In a broader sense, GT can target the product of gene transcription, which is the messenger RNA, or the end product of gene function, such as functional proteins (eg. cystic fibrosis). Any of these approaches have been used successfully in various diseases, depending on their availability, which is determined, among other things, by the costs associated with GT or the accessibility of the target tissue. Ultimately, it is not only the validation of the efficacy and safety of GT, but also economic reasons that determine why GT has been slow to develop and is mostly undertaken only by large and wealthy institutions. Another decisive factor is that from initial experimental work through clinical trials, the whole process of its development normally takes up to a decade.

PMID:38981729

J Clin Psychol Med Settings. 2024 Jul 9. doi: 10.1007/s10880-024-10023-7. Online ahead of print.

ABSTRACT

Cystic Fibrosis (CF) is a progressive condition resulting in reduced lung function and strongly associated with elevated anxiety and depression symptoms. Self-concept refers to an individual's overarching sense of identity, a positive level of which is widely associated with reduced anxiety and depression. There is a significant lack of self-concept research within CF. This study explores the association between self-concept and anxiety and depression in adults with CF. 64 adults living with CF in Western Australia completed validated online questionnaires (Generalised Anxiety Disorder-7, Patient Health Questionnaire-9, Tennessee Self-Concept Questionnaire 2: Short-Form) and consented to the collection of medical data. Descriptive, t-test, correlation and multiple regression analysis were undertaken. Higher levels of self-concept were associated with lower levels of anxiety and depression symptoms. Lower self-concept levels were a significant predictor of increased anxiety and depression symptoms after accounting for physical health status. Mean self-concept scores for those who required mental health intervention were significantly lower compared to those that did not. This study identifies a significant relationship between self-concept and anxiety and depression in adults with CF. Further research is required to establish causation and test the feasibility of self-concept interventions in reducing anxiety and depression symptoms.

PMID:38980550 | DOI:10.1007/s10880-024-10023-7

Pediatr Pulmonol. 2024 Jul 9. doi: 10.1002/ppul.27165. Online ahead of print.

ABSTRACT

BACKGROUND: The decline in pulmonary function is a predictor of disease progression in patients with cystic fibrosis (CF). This study aimed to determine the decline rate of percent predicted forced expiratory volume in 1 s (ppFEV1) based on the data of the CF Registry of Turkey. The secondary aim was to investigate the risk factors related to the decline in ppFEV1.

METHODS: A retrospective cohort study of CF patients over 6 years old, with pulmonary function data over at least 2 years of follow-up was extracted from the national CF registry for years 2017-2019. Patients were classified according to disease severity and age groups. Multivariate analysis was used to predict the decline in ppFEV1 and to investigate the associated risk factors.

RESULTS: A total of 1722 pulmonary function test results were available from 574 patients over the study period. Mean diagnostic age was older and weight for age, height for age, and body mass index z scores were significantly lower in the group of ppFEV1 < 40, while chronic Pseudomonas aeruginosa (p < .001) and mucoid P. aeruginosa colonization (p < .001) were significantly higher in this group (p < .001). Overall mean annual ppFEV1 decline was -0.97% (95% confidence interval [CI] = -0.02 to -1.92%). The mean change of ppFEV1 was significantly higher in the group with ppFEV1 ≥ 70 compared with the other (ppFEV1 < 40 and ppFEV1: 40-69) two groups (p = .004). Chronic P. aeruginosa colonization (odds ratio [OR] = 1.79 95% CI = 1.26-2.54; p = .01) and initial ppFEV1 ≥ 70 (OR = 2.98 95% CI = 1.06-8.36), p = .038) were associated with significant ppFEV1 decline in the whole cohort.

CONCLUSIONS: This data analysis recommends close follow-up of patients with normal initial ppFEV1 levels at baseline; advocates for early interventions for P. aeruginosa; and underlines the importance of nutritional interventions to slow down lung disease progression.

PMID:38980199 | DOI:10.1002/ppul.27165

mSphere. 2024 Jul 9:e0033524. doi: 10.1128/msphere.00335-24. Online ahead of print.

ABSTRACT

Over 160,000 people worldwide suffer from cystic fibrosis (CF), a genetic condition that causes mucus to accumulate in internal organs. Lung decline is a significant health burden for people with CF (pwCF), and chronic bacterial pulmonary infections are a major cause of death. Stenotrophomonas maltophilia complex (Smc) is an emerging, multidrug-resistant CF pathogen that can cause pulmonary exacerbations and result in higher mortality. However, little is known about the antagonistic interactions that occur between Smc isolates from pwCF and competitor bacteria. We obtained 13 Smc isolates from adult and pediatric pwCF located in the United States or Australia. We co-cultured these isolates with Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli. We also performed whole-genome sequencing of these Smc isolates and compared their genomes using average nucleotide identity analyses. We observed that some Smc CF isolates can engage in antagonistic interactions with P. aeruginosa and S. aureus but recovered a substantial number of P. aeruginosa and S. aureus cells following co-cultures with all tested Smc isolates. By contrast, we discovered that most Smc CF isolates display strong antibacterial properties against E. coli cells and reduce recovery below detectable limits. Finally, we demonstrate that Smc CF strains from this study belong to diverse phylogenetic lineages.

IMPORTANCE: Antagonism toward competitor bacteria may be important for the survival of Stenotrophomonas maltophilia complex (Smc) in external environments, for the elimination of commensal species and colonization of upper respiratory tracts to enable early infections, and for competition against other pathogens after establishing chronic infections. These intermicrobial interactions could facilitate the acquisition of Smc by people with cystic fibrosis from environmental or nosocomial sources. Elucidating the mechanisms used by Smc to eliminate other bacteria could lead to new insights into the development of novel treatments.

PMID:38980073 | DOI:10.1128/msphere.00335-24

mSphere. 2024 Jul 9:e0038124. doi: 10.1128/msphere.00381-24. Online ahead of print.

ABSTRACT

Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen's effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.

PMID:38980071 | DOI:10.1128/msphere.00381-24

bioRxiv [Preprint]. 2024 Jun 28:2024.06.27.601069. doi: 10.1101/2024.06.27.601069.

ABSTRACT

The opportunistic pathogen Pseudomonas aeruginosa causes debilitating lung infections in people with cystic fibrosis, as well as eye, burn, and wound infections in otherwise immunocompetent individuals. Many of P. aeruginosa 's virulence factors are regulated by environmental changes associated with human infection, such as a change in temperature from ambient to human body temperature. One such virulence factor is protease IV (PIV). Interestingly, piv expression is higher at ambient temperatures (22-28°C) compared to human body temperature (37°C). We found that piv expression was thermoregulated at stationary phase, but not exponential phase, and that piv is thermoregulated at the level of transcription. Protein levels of known transcriptional regulators of piv , the quorum sensing regulator LasR and the gene-silencing histone nucleoid silencing proteins MvaT/MvaU, were not thermoregulated. Using a transcriptional reporter for piv , we show that LasR activates piv expression at stationary phase at 25°C but not 37°C, while MvaT/MvaU are not required for piv thermoregulation. We also identified a las box in the piv promoter, which is important for piv thermoregulation. We propose that LasR directly regulates piv at stationary phase at 25°C but has a negligible impact at 37°C. Here, we show that piv is uniquely regulated by LasR in a temperature-dependent manner. Our findings suggest that the LasRI quorum sensing regulon of P. aeruginosa may not be fully characterized and that growth at non-standard laboratory conditions such as lower temperatures could reveal previously unrecognized quorum sensing regulated genes.

IMPORTANCE: Pseudomonas aeruginosa is a versatile opportunistic pathogen capable of causing many different types of infections that are often difficult to treat, such as lung infections in people with cystic fibrosis. Temperature regulates the expression of many virulence factors that contribute to P. aeruginosa 's ability to cause infection, yet our mechanistic understanding of virulence factor thermoregulation is poor. In this study, we show that the virulence factor protease IV is thermoregulated at the level of transcription via temperature-dependent upregulation by the quorum sensing regulator, LasR. Mechanistic studies of virulence factor thermoregulation will expand our understanding of how P. aeruginosa experiences different environments, including the mammalian host. Our work also highlights the importance of growth conditions in studying gene regulation, as it elucidates the regulation of protease IV by LasR, which was previously not well understood.

PMID:38979315 | PMC:PMC11230357 | DOI:10.1101/2024.06.27.601069

Infect Drug Resist. 2024 Jul 4;17:2773-2783. doi: 10.2147/IDR.S455515. eCollection 2024.

ABSTRACT

BACKGROUND: Ceftaroline fosamil is approved for the treatment of complicated skin and soft tissue infections (cSSTI) and community-acquired pneumonia (CAP); however, data on its real-world use and effectiveness in Europe and Latin America are currently limited. This retrospective observational study assessed ceftaroline fosamil use and treatment outcomes in adults hospitalized with cSSTI or CAP treated with ceftaroline fosamil in a usual care setting in Europe and Latin America. Results for patients with cSSTI are reported.

METHODS: Data from patients with cSSTI who received ≥4 consecutive intravenous ceftaroline fosamil doses up to May 31, 2019, were collected from sites in Brazil, Colombia, France, Greece, Italy, and Spain. Patient characteristics, clinical management, hospitalization information, microbiological diagnosis, and clinical responses were summarized descriptively. Healthcare resource use variables were evaluated by clinical response to ceftaroline fosamil.

RESULTS: Data for 132 patients were included (58.3% male; mean age 58.5 years). Most common lesions were cellulitis/fasciitis (62.1%), abscess (34.1%), and post-surgical wounds (19.7%). Pathogens most frequently identified were methicillin-resistant (18.2%) and methicillin-susceptible Staphylococcus aureus (17.4%). Median (range) ceftaroline fosamil treatment duration was 8 (2-60) days (daily doses of 1200 [400-2400] mg); 78 patients (59.1%) received monotherapy. In total, 75 (56.8%) patients had additional antibiotics after ceftaroline fosamil. Clinical response occurred in 118 (89.4%) patients. All-cause 30-day readmission occurred in 13 (9.8%) patients, and all-cause 30-day mortality in 7 (5.3%). Clinical response to ceftaroline was associated with >25% shorter length of hospital and intensive care stay, and with ~40% lower hospital costs, versus non-responders.

CONCLUSION: Ceftaroline fosamil was effective in treating adults with cSSTI and clinical response to ceftaroline fosamil was associated with reductions in healthcare resource use compared with non-responders, in Europe and Latin America.

CLINICALTRIALSGOV IDENTIFIER: NCT04198571.

PMID:38979062 | PMC:PMC11230118 | DOI:10.2147/IDR.S455515

Front Mol Biosci. 2024 Jun 24;11:1446875. doi: 10.3389/fmolb.2024.1446875. eCollection 2024.

NO ABSTRACT

PMID:38978977 | PMC:PMC11228291 | DOI:10.3389/fmolb.2024.1446875

ERJ Open Res. 2024 Jul 8;10(4):00165-2024. doi: 10.1183/23120541.00165-2024. eCollection 2024 Jul.

ABSTRACT

RATIONALE: Nontuberculous mycobacteria (NTM) has been reported to be transmitted between people with cystic fibrosis (CF) attending CF centres. A suspected Mycobacterium abscessus outbreak was investigated at the University of Texas Southwestern (UTSW) Adult CF Program using a combination of pathogen genomic sequencing and epidemiologic methods. The objectives of the present study were to apply the Healthcare-Associated Links in Transmission of NTM (HALT NTM) study to investigate the occurrence of potential healthcare-associated transmission and/or acquisition of NTM among people with CF infected with genetically similar NTM isolates.

METHODS: Whole-genome sequencing of respiratory M. abscessus isolates from 50 people with CF receiving care at UTSW was performed to identify genetically similar isolates. Epidemiologic investigation, comparison of respiratory and environmental isolates, and home residence watershed mapping were studied.

MEASUREMENTS AND MAIN RESULTS: Whole-genome sequencing analysis demonstrated seven clusters of genetically similar M. abscessus (four ssp. abscessus and three ssp. massiliense). Epidemiologic investigation revealed potential opportunities for healthcare-associated transmission within three of these clusters. Healthcare environmental sampling did not recover M. abscessus, but did recover four human disease-causing species of NTM. No subjects having clustered infections lived in the same home residence watershed. Some subjects were infected with more than one M. abscessus genotype, both within and outside of the dominant circulating clones.

CONCLUSIONS: Healthcare-associated person-to-person transmission of M. abscessus appears to be rare at this centre. However, polyclonal infections of M. abscessus species and subspecies, not originating from the endemic hospital environment, suggest multiple shared modes of acquisition outside the healthcare setting.

PMID:38978544 | PMC:PMC11228611 | DOI:10.1183/23120541.00165-2024