The Effect of Oral Azithromycin on the Response to Pulmonary Exacerbations Treated with Intravenous Tobramycin in Children with Cystic Fibrosis.

Ann Am Thorac Soc. 2019 Mar 15;:

Authors: Klingel M, Stanojevic S, Tullis E, Ratjen F, Waters V

Abstract
RATIONALE: Intravenous (IV) tobramycin is frequently used to treat pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF), but there is concern that azithromycin may interact with tobramycin making it less effective against Pseudomonas aeruginosa.
OBJECTIVE: The objective of this study was to determine whether oral azithromycin use was associated with worse lung function response to intravenous tobramycin treatment for PExs in a cohort of pediatric CF patients with chronic P. aeruginosa infection.
METHODS: Pediatric patients from the Toronto CF database were included if they had at least one PEx and had chronic P. aeruginosa infection. Response to treatment was defined as change in forced expiratory volume in 1 second (FEV1) from start to end of treatment, as well as recovery of FEV1 to > 90% of baseline (best FEV1 in the previous 6 months). Response to treatment was compared between patients who had received chronic azithromycin (azithromycin users) to those who had not (azithromycin non-users), using marginal structural modeling to account for baseline FEV1 as both a confounder and mediator.
RESULTS: There were 67 exacerbations (33 patients). Overall, 69% of azithromycin users and 61% of azithromycin non-users returned to >90% of baseline FEV1. However, after taking into account that azithromycin users had worse baseline FEV1 compared to azithromycin non-users , relative improvement in FEV1 was 9.5% (95% CI -18.7, -0.3)) lower in azithromycin users compared to azithromycin non-users.
CONCLUSIONS: Although a similar proportion of CF children with chronic P. aeruginosa infection on azithromycin recovered lung function compared to those not on azithromycin, when we consider these patients are sicker, azithromycin use was associated with less improvement in relative (but not absolute) FEV1 in patients treated with IV tobramycin for PExs.

PMID: 30874447 [PubMed - as supplied by publisher]

Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease.

Compr Physiol. 2019 Mar 15;9(2):839-872

Authors: Seidler U, Nikolovska K

Abstract
SLC26 family members are multifunctional transporters of small anions, including Cl- , HCO3 - , sulfate, oxalate, and formate. Most SLC26 isoforms act as secondary (coupled) anion transporters, while others mediate uncoupled electrogenic transport resembling Cl- channels. Of the 11 described SLC26 isoforms, the SLC26A1,2,3,6,7,9,11 are expressed in the gastrointestinal tract, where they participate in salt and water transport, surface pH-microclimate regulation, affect the microbiome composition, the absorption, and secretion of oxalate and sulfate, and other functions that require further study. Several intestinal or extra-intestinal diseases are related to SLC26A mutations. Patients with congenital chloride diarrhea (CLD) suffer from Cl- -rich acidic diarrhea and systemic alkalosis due to SLC26A3 mutations. Patients with osteochondrodysplastic syndromes experience skeletal defects due to SLC26A2 mutations, resulting in defective sulfate absorption in enterocytes and sulfate uptake in chondrocytes. Because of functional interactions between SLC26 and other proteins, such as the Cl- channel CFTR, some of the intestinal cystic fibrosis manifestations may be attributed to impaired SLC26 isoform localization and function. The altered expression of SLC26 members due to inflammation or operative procedures have important consequences on intestinal transport and barrier function in common diseases as inflammatory bowel disease or bariatric surgery. The present review gives an overview on the current state of knowledge of the intestinally expressed SLC26A isoforms (SLC26A1,2,3,6,7,9,11) from the history of their functional identification, cloning and expression, the insights into their function, interaction partners and regulation gained in heterologous expression systems and Slc26a-deficient mice, to information about their transcriptional regulation and roles in gastrointestinal disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:839-872, 2019.

PMID: 30873581 [PubMed - in process]

Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine.

Front Pharmacol. 2019;10:121

Authors: Pranke I, Golec A, Hinzpeter A, Edelman A, Sermet-Gaudelus I

Abstract
An improved understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein structure and the consequences of CFTR gene mutations have allowed the development of novel therapies targeting specific defects underlying CF. Some strategies are mutation specific and have already reached clinical development; some strategies include a read-through of the specific premature termination codons (read-through therapies, nonsense mediated decay pathway inhibitors for Class I mutations); correction of CFTR folding and trafficking to the apical plasma membrane (correctors for Class II mutations); and an increase in the function of CFTR channel (potentiators therapy for Class III mutations and any mutant with a residual function located at the membrane). Other therapies that are in preclinical development are not mutation specific and include gene therapy to edit the genome and stem cell therapy to repair the airway tissue. These strategies that are directed at the basic CF defects are now revolutionizing the treatment for patients and should positively impact their survival rates.

PMID: 30873022 [PubMed]

Shifts in the relationship between mRNA and protein abundance of gill ion-transporters during smolt development and seawater acclimation in Atlantic salmon (Salmo salar).

Comp Biochem Physiol A Mol Integr Physiol. 2018 07;221:63-73

Authors: Christensen AK, Regish AM, McCormick SD

Abstract
Smolting Atlantic salmon exhibit a seasonal increase in seawater tolerance that is associated with changes in the abundance of major gill ion-transporter transcripts and proteins. In the present study, we investigate how the transcript and protein abundance of specific ion-transporter isoforms relate to each other during smolt development and seawater acclimation, and how each correlates to seawater tolerance. We show that during smolt development both mRNA and protein abundance of gill Na+/K+-ATPase α1a subunit (NKAα1a) decreased but the decrease in the mRNA was five-times greater than that of the protein. Gill NKAα1b mRNA levels increased only slightly (1.5-fold) throughout development whereas protein abundance increased 30-fold at its peak. Gill Na+/K+/2Cl- co-transporter 1 (NKCC1) increased at the mRNA and protein level (5- and 12-fold) in smolts. The abundance of a gill ion-transporter's mRNA and protein changed in the same direction through development and after seawater transfer, but the changes were not always strongly correlated: NKAα1a (r = 0.768), NKAα1b (r = 0.40), and NKCC1 (r = 0.898). The maintenance of plasma chloride concentration correlated most strongly with the abundance of NKAα1a mRNA, and the ratio of NKAα1b to NKAα1a mRNA and protein. Growth performance after seawater transfer correlated most strongly with the abundance of NKAα1b protein and the ratio of NKAα1b to NKAα1a protein. Our results indicate that the abundance of ion-transporter mRNA and protein do not always correlate well and a decrease in the abundance of gill NKAα1a mRNA and increase in NKAα1b protein are strong predictors of seawater tolerance and growth performance after seawater transfer.

PMID: 29627325 [PubMed - indexed for MEDLINE]

Cystic fibrosis transmembrane conductance regulator modulators: Present and future in cystic fibrosis treatment. A review.

Arch Argent Pediatr. 2019 Apr 01;117(2):e131-e136

Authors: De la Hoz D, Villamil Osorio M, Restrepo-Gualteros SM

Abstract
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are the present and future of drug management for patients with cystic fibrosis. The objective of this article is to review this therapeutic option. Scientific articles were reviewed by searching the MedLine database, which is available through the Cystic Fibrosis Foundation's official website, from 2009 to 2018, in English. Twelve articles about the current status of research in CFTR modulators were selected without restrictions regarding the type of study. To date, the United States Food and Drug Administration has approved three modulators: ivacaftor, lumacaftor + ivacaftor, and tezacaftor + ivacaftor, while other 11 drugs are being studied in different investigation phases. CFTR modulator therapy is a developing reality aimed at the highest goal of personalized medicine and promises to improve the quality of life of cystic fibrosis patients.

PMID: 30869491 [PubMed - in process]

Small-molecule ion channels increase host defences in cystic fibrosis airway epithelia.

Nature. 2019 Mar 13;:

Authors: Muraglia KA, Chorghade RS, Kim BR, Tang XX, Shah VS, Grillo AS, Daniels PN, Cioffi AG, Karp PH, Zhu L, Welsh MJ, Burke MD

Abstract
Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3- and Cl- secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1-3. Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3- secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+, K+-ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion. Amphotericin B also restored airway surface liquid pH, viscosity, and antibacterial activity in primary cultures of airway epithelia from people with cystic fibrosis caused by different mutations, including ones that do not yield CFTR, and increased airway surface liquid pH in CFTR-null pigs in vivo. Thus, unselective small-molecule ion channels can restore host defences in cystic fibrosis airway epithelia via a mechanism that is independent of CFTR and is therefore independent of genotype.

PMID: 30867598 [PubMed - as supplied by publisher]

A Practical Review of Proteasome Pharmacology.

Pharmacol Rev. 2019 Apr;71(2):170-197

Authors: Thibaudeau TA, Smith DM

Abstract
The ubiquitin proteasome system (UPS) degrades individual proteins in a highly regulated fashion and is responsible for the degradation of misfolded, damaged, or unneeded cellular proteins. During the past 20 years, investigators have established a critical role for the UPS in essentially every cellular process, including cell cycle progression, transcriptional regulation, genome integrity, apoptosis, immune responses, and neuronal plasticity. At the center of the UPS is the proteasome, a large and complex molecular machine containing a multicatalytic protease complex. When the efficiency of this proteostasis system is perturbed, misfolded and damaged protein aggregates can accumulate to toxic levels and cause neuronal dysfunction, which may underlie many neurodegenerative diseases. In addition, many cancers rely on robust proteasome activity for degrading tumor suppressors and cell cycle checkpoint inhibitors necessary for rapid cell division. Thus, proteasome inhibitors have proven clinically useful to treat some types of cancer, especially multiple myeloma. Numerous cellular processes rely on finely tuned proteasome function, making it a crucial target for future therapeutic intervention in many diseases, including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes, and cancer. In this review, we discuss the structure and function of the proteasome, the mechanisms of action of different proteasome inhibitors, various techniques to evaluate proteasome function in vitro and in vivo, proteasome inhibitors in preclinical and clinical development, and the feasibility for pharmacological activation of the proteasome to potentially treat neurodegenerative disease.

PMID: 30867233 [PubMed - in process]

Dismantling the bacterial virulence program.

Microb Biotechnol. 2019 Mar 12;:

Authors: Alford MA, Pletzer D, Hancock REW

Abstract
In the face of rising antimicrobial resistance, there is an urgent need for the development of efficient and effective anti-infective compounds. Adaptive resistance, a reversible bacterial phenotype characterized by the ability to surmount antibiotic challenge without mutation, is triggered to cope in situ with several stressors and is very common clinically. Thus, it is important to target stress-response effectors that contribute to in vivo adaptations and associated lifestyles such as biofilm formation. Interfering with these proteins should provide a means of dismantling bacterial virulence for treating infectious diseases, in combination with conventional antibiotics.

PMID: 30864265 [PubMed - as supplied by publisher]

Nasal Resistome Development in Infants With Cystic Fibrosis in the First Year of Life.

Front Microbiol. 2019;10:212

Authors: Allemann A, Kraemer JG, Korten I, Ramsey K, Casaulta C, SCILD Study Group, Wüthrich D, Ramette A, Endimiani A, Latzin P, Hilty M

Abstract
Polymicrobial infections of the respiratory tract due to antibiotic resistant bacteria are a great concern in patients with cystic fibrosis (CF). We therefore aimed at establishing a functional metagenomic method to analyze the nasal resistome in infants with CF within the first year of life. We included samples from patients before antibiotic treatment, which allowed obtaining information regarding natural status of the resistome. In total, we analyzed 130 nasal swabs from 26 infants with CF and screened for β-lactams (ampicillin, amoxicillin-clavulanic acid, and cefuroxime) and other classes of antibiotic resistances (tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole). For 69 swabs (53% of total), we found at least one non-susceptible phenotype. Analyses of the inserts recovered from non-susceptible clones by nanopore MinION sequencing revealed a large reservoir of resistance genes including mobile elements within the antibiotic naïve samples. Comparing the data of the resistome with the microbiota composition showed that the bacterial phyla and operational taxonomic units (OTUs) of the microbiota rather than the antibiotic treatment were associated with the majority of non-susceptible phenotypes in the resistome. Future studies will reveal if characterization of the resistome can help in clinical decision-making in patients with CF.

PMID: 30863369 [PubMed]

A pragmatic behavior-based habit index for adherence to nebulized treatments among adults with cystic fibrosis.

Patient Prefer Adherence. 2019;13:283-294

Authors: Hoo ZH, Wildman MJ, Campbell MJ, Walters SJ, Gardner B

Abstract
Background: Habit, a psychological process that automatically generates urges to perform a behavior in associated settings, is potentially an important determinant of medication adherence. Habit is challenging to measure because, as a psychological construct, it cannot be directly observed. We describe a method of using routinely available objective adherence data from electronic data capture (EDC) to generate a behavior-based index of adherence habit and demonstrate how this index can be applied.
Methods to generate the habit index: Our proposed habit index is a "frequency in context" measure. It estimates habit as a multiplicative product of behavior frequency (generated from weekly percentage adherence) and context stability (inferred from time of nebulizer use). Although different timescales can be used, we chose to generate weekly habit scores since we believe that this is the most granular level at which context stability can be reasonably calculated.
An application of the habit index: A hallmark of habit is to predict future behavior, hence we used time series method to cross-correlate the habit index with nebulizer adherence in the subsequent week among 123 adults with cystic fibrosis (52, 42.3% female; median age 25 years) over a median duration of 153 weeks (IQR 74-198 weeks). The mean cross-correlation coefficient (R) between the habit index and subsequent adherence was 0.40 (95% CI 0.36-0.44). Adjusting for current adherence, the unstandardized regression coefficient (B) for the habit index was 0.30 (95% CI -1.04 to 1.65).
Conclusion: We have described a pragmatic method to infer "habit" from adherence data routinely captured with EDC and provided proof-of-principle evidence regarding the feasibility of this concept. The continuous stream of data from EDC allows the habit index to unobtrusively assess "habit" at various time points over prolonged periods, and hence the habit index may be applicable in habit formation studies.

PMID: 30863018 [PubMed]

Characterisation and anti-biofilm activity of glycerol monolaurate nanocapsules against Pseudomonas aeruginosa.

Microb Pathog. 2019 Mar 09;:

Authors: Lopes LQS, de Almeida Vaucher R, Giongo JL, Santos RCV

Abstract
Pseudomonas aeruginosa is a ubiquitous microorganism that commonly causes hospital-acquired infections, including pneumonia, bloodstream and urinary tract infections and it is well known for chronically colonising the respiratory tract of patients with cystic fibrosis, causing severe intermittent exacerbation of the condition. P. aeruginosa may appear in the free form cell but also grows in biofilm communities adhered to a surface. An alternative to conventional antimicrobial agents are nanoparticles that can act as carriers for antibiotics and other drugs. In this context, the study aimed to characterise and verify the anti-biofilm potential of GML Nanocapsules against P. aeruginosa. The nanocapsules showed a mean diameter of 190.7 nm, polydispersion index of 0.069, the zeta potential of -23.3 mV. The microdilution test showed a MIC of 62.5 μg/mL to GML and 15.62 μg/mL to GML Nanocapsules. The anti-biofilm experiments demonstrated the significant reduction of biomass, proteins, polysaccharide and viable P. aeruginosa in biofilm treated with GML Nanocapsules while the free GML did not cause an effect. The AFM images showed a decrease in a biofilm which received GML. The positive results suggest an alternative for the public health trouble related to infections associated with biofilm.

PMID: 30862561 [PubMed - as supplied by publisher]

The Relative Contribution of Food Groups to Macronutrient Intake in Children with Cystic Fibrosis: A European Multicenter Assessment.

J Acad Nutr Diet. 2019 Mar 09;:

Authors: Calvo-Lerma J, Hulst J, Boon M, Martins T, Ruperto M, Colombo C, Fornés-Ferrer V, Woodcock S, Claes I, Asseiceira I, Garriga M, Bulfamante A, Masip E, Walet S, Crespo P, Valmarana L, Martínez-Barona S, Pereira L, de Boeck K, Ribes-Koninckx C

Abstract
BACKGROUND: Optimal nutrition for children with cystic fibrosis (CF) improves prognosis and survival, but an increased caloric intake recommendation for this population raises concerns about the nutrient profile of their diets.
OBJECTIVE: Our aim was to assess the relative contribution of food groups to the total macronutrient intake of European pediatric patients with CF.
DESIGN: We conducted a cross-sectional study in which the participants recorded dietary intake from 2016 to 2017. Specifically developed nutritional composition databases were used to obtain nutritional data, including macronutrients and food groups, according to previously standardized criteria.
PARTICIPANTS/SETTING: Two hundred and seven pediatric patients with CF from six European centers were involved in the My App for Cystic Fibrosis self-management project.
MAIN OUTCOME MEASURES: Participants reported dietary intake with a detailed 4-day food record.
STATISTICAL ANALYSIS PERFORMED: Descriptive analyses of nutrient intake, food group consumption, and dietary origin of macronutrients were conducted with R software.
RESULTS: Similar patterns were found in nutrient and food group intake; both sugar and saturated fatty acids contributed >10% each to the total daily energy intake in all the centers. Large mean and median percent differences were observed in the intake of other nutrient and food groups, because sweets and snacks were consumed once or twice a day, and fruit and vegetables were consumed two or three times a day. Milk, meat, sweets and snacks, and oils were the main sources of fat in all centers.
CONCLUSIONS: Study findings indicated less than optimal nutrient profiles, especially for sugars and saturated fatty acids, resulting from the high consumption of meat, dairy, and processed products and low consumption of fish, nuts, and legumes. These results can serve as a basis for future tailored interventions that target improved adherence to nutritional recommendations for patients with CF.

PMID: 30862484 [PubMed - as supplied by publisher]

Factors associated with opioid use after endoscopic sinus surgery.

Laryngoscope. 2019 Mar 12;:

Authors: Raikundalia MD, Cheng TZ, Truong T, Kuchibhatla M, Ryu J, Abi Hachem R, Jang DW

Abstract
OBJECTIVES/HYPOTHESIS: Responsible prescribing of postoperative pain medications is necessary in combatting the current opioid epidemic in the United States. The goal of this study was to determine which clinical factors affect opioid usage following functional endoscopic sinus surgery (FESS).
STUDY DESIGN: Retrospective medical records study.
METHODS: This is a single-institution retrospective study of subjects undergoing FESS by the senior author between September 2016 and December 2017. Opioid usage was assessed for each patient at the first postoperative visit. Univariate and multivariable analyses were performed to investigate factors associated with pain medication usage. Patients using opioids prior to surgery were excluded.
RESULTS: A total of 136 patients were stratified into three groups based on number of opioid tablets taken during the first week after surgery: 31 patients (23%) took no opioids, 61 patients (45%) took one to five tablets, and 44 patients (32%) took more than five tablets. Gender, extent of surgery, revision surgery, polyp status, and cystic fibrosis did not significantly vary between the three groups. Multinomial logistic regression analysis with backward stepwise variable selection method revealed that those who had septoplasty (odds ratio [OR]: 4.84, 95% confidence interval [CI]: 1.68-13.98; P < .01) or were of younger age (OR 0.96, 95% CI: 0.93-0.99; P = .01) had significantly higher odds of taking >5 tablets.
CONCLUSIONS: The majority of patients undergoing FESS did not take more than 5 opioid tablets after surgery. Concurrent septoplasty and younger age were associated with increased opioid usage. Knowledge of such factors can help surgeons to assess opioid prescribing patterns and to counsel their patients on postoperative pain. Laryngoscope, 2019.

PMID: 30861579 [PubMed - as supplied by publisher]

Severe ileocecal inflammatory syndrome in adult patients with cystic fibrosis.

Z Gastroenterol. 2019 Mar;57(3):312-316

Authors: Henker R, Oltmanns A, Wald A, Tuennemann J, Opitz S, Hoffmeister A, Wirtz H, Mössner J, Jansen-Winkeln B, Karlas T

Abstract
The relevance of gastrointestinal manifestations of cystic fibrosis (CF) is increasing due to an improved life expectancy. We report on 2 adult patients with prior lung transplantation who presented with a severe inflammatory disorder of the ileocecal region. One patient underwent ileocecal resection; the second patient died after emergency surgery for intestinal perforation. Both cases did not show typical signs of CF-related distal intestinal obstruction syndrome or extensive fibrosing colonopathy. However, the clinical and histopathological findings revealed CF-induced inflammatory alterations of the intestinal mucosa. Thus, these cases illustrate a further CF-related bowel disorder, which can be especially relevant in long-term CF survivors.

PMID: 30861555 [PubMed - in process]

Clinical validation of an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy through a prospective interventional study in paediatric patients with Cystic Fibrosis.

PLoS One. 2019;14(3):e0213216

Authors: Calvo-Lerma J, Hulst J, Boon M, Colombo C, Masip E, Ruperto M, Fornés-Ferrer V, van der Wiel E, Claes I, Garriga M, Roca M, Crespo-Escobar P, Bulfamante A, Woodcock S, Martínez-Barona S, Andrés A, de Boeck K, Ribes-Koninckx C, MyCyFAPP project

Abstract
BACKGROUND: A method to adjust Pancreatic Enzyme Replacement Therapy in Cystic Fibrosis is not currently available.
OBJECTIVES: To assess the in vivo efficacy of a method to adjust the dose of enzymatic supplement in CF extrapolated from previous in vitro digestion studies (theoretical optimal dose, TOD). Secondly, to assess how individual patient characteristics influence the expected coefficient of fat absorption (CFA) and thus to identify an individual correction factor to improve TOD.
METHODS: A prospective interventional study in 43 paediatric patients with CF from 5 European centres. They followed a 24h fixed diet with the theoretical optimal dose for each meal. Faecal collection was carried out between colorimetric markers in order to include all the faeces corresponding to the fixed diet. Beta regression models were applied to assess the associations of individual patient characteristics with the CFA.
RESULTS: Median CFA was 90% (84, 94% 1st, 3rd Q.) with no significant differences among centres. Intestinal transit time was positively associated with CFA (p = 0.007), but no statistical associations were found with and age, gender, phenotype or BMI. Regression model showed no improvement of the in vitro predicted theoretical optimal dose when taking individual patient characteristics into account.
CONCLUSION: Strict adherence to the theoretical optimal dose of enzymatic supplement for a prescribed meal, led to median CFA levels at the clinical target of 90% with a low variability between patients. The proposed method can be considered as a first approach for an evidence-based method in PERT dosing based on food characteristics. Results have to be confirmed in free dietary settings.

PMID: 30861039 [PubMed - in process]

Antimicrobial properties of basidiomycota macrofungi to Mycobacterium abscessus isolated from patients with cystic fibrosis.

Int J Mycobacteriol. 2019 Jan-Mar;8(1):93-97

Authors: Millar BC, Nelson D, Moore RE, Rao JR, Moore JE

Abstract
Background: Antimicrobial resistance (AMR) has now emerged as a global public health crisis. Of particular concern is AMR associated with the genus Mycobacterium, including Mycobacterium tuberculosis and the nontuberculous mycobacteria (NTM). Emergence of the NTM, in particular Mycobacterium abscessus, in patients with cystic fibrosis (CF) represents both a diagnostic and a treatment dilemma. Such resistance drives the need to investigate novel sources of antimicrobials. Medicinal fungi have a well-documented history of use in traditional oriental therapies. Not only is this an ancient practice, but also still today, medical practice in Japan, China, Korea, and other Asian countries continue to rely on fungal-derived antibiotics. A study was, therefore, undertaken to examine the antimicrobial activity of 23 native macrofungal (mushrooms/toadstools) taxa, collected from woodlands in Northern Ireland against six clinical (CF) isolates of M. abscessus, as well as M. abscessus National Collection of Type Cultures (NCTC) Reference strain (NCTC 13031).
Methods: Free-growing saprophytic and mycorrhizal macrofungi (n = 23) belonging to the phylum Basidiomycota were collected and were definitively identified employing Polymerase Chain reaction/ITS DNA sequencing. Macrofungal tissues were freeze-dried and reconstituted before employment in antibiotic susceptibility studies.
Results: All macrofungi examined showed varying inhibition of the M. abscessus isolates examined with the exception Russula nigricans. The macrofungi displaying maximum antimycobacterial activity against the clinical isolates were (in descending order) M. giganteus (33.6 mg/ml), Hygrocybe nigrescens (38.5 mg/ml) and Hypholoma fasciculare (25.3 mg/ml).
Conclusion: Macrofungi may represent a source of novel antimicrobials against M. abscessus, which have not yet been fully explored nor exploited clinically. This is the first report describing the antimycobacterial properties of extracts of M. giganteus against M. abscessus. Further work is now required to identify the constituents and mode of the inhibitory action of these macrofungi against the M. abscessus. Given the gravity of AMR in the NTMs, particularly M. abscessus and the clinical treatment dilemmas that such AMR present, antibiotic drug discovery efforts should now focus on investigating and developing antibacterial compounds from macrofungi, particularly M. giganteus, where there are no or limited current treatment options.

PMID: 30860186 [PubMed - in process]

Common alternative diagnoses among a pediatric hospital-based cohort evaluated for tuberculosis in Karachi, Pakistan: The need for facilitated referral in tuberculosis clinics.

Int J Mycobacteriol. 2019 Jan-Mar;8(1):42-47

Authors: Shakoor S, Mir F, Hasan R

Abstract
Background: Children evaluated for tuberculosis (TB) are often diagnosed with miscellaneous conditions that mimic TB. Knowledge of differentials informs policy on service provision through liaison with referral centers offering definitive diagnosis and treatment for common alternative disorders.
Methods: We reviewed medical records of children who were offered diagnostic testing for TB (culture or Xpert MTB/RIF) at a tertiary care hospital in Karachi, Pakistan to identify common alternative diagnoses among children who are evaluated for TB.
Results: From January 2014 to December 2015, of 126 culture or Xpert MTB/RIF negative children presenting with chronic symptoms, 31 were diagnosed and treated for TB based on clinical criteria (5 of 48 children with pulmonary and 26 of 78 with extrapulmonary presentations; 10.4% and 33.3%, respectively). Among remaining 95 patients, common alternative diagnoses to pulmonary TB (n = 43) were bacterial pneumonia or empyema (60.5%, n = 25) and underlying bronchiectasis (20.9%, n = 9). Among 52 extrapulmonary presentations, the most common alternative diagnoses were lymphoproliferative disorders (n = 11, 21.1%), bacterial infections (n = 11, 21.1%), and autoimmune disorders (n = 9, 17.3%). Of note, five children were diagnosed with underlying primary immunodeficiencies (9.6%). Children with alternative disorders were treated for TB in 25 of 95 cases (26.3%). Although 77.8% (n = 98) children were followed up at the facility, 15.9% (n = 20) were lost to follow-up.
Conclusions: Pediatric TB mimics many disorders that primary level centers are not equipped to diagnose or manage, leading to suboptimal outcomes. Knowledge of common alternative diagnoses is essential to inform facilitated referral for common mimicking disorders in children.

PMID: 30860178 [PubMed - in process]

Antimycobacterial strategies to evade antimicrobial resistance in the nontuberculous mycobacteria.

Int J Mycobacteriol. 2019 Jan-Mar;8(1):7-21

Authors: Millar BC, Moore JE

Abstract
The nontuberculous mycobacteria (NTM) have recently emerged as important bacterial pathogens of both animals and humans. Of particular, concern is the high level of antimicrobial resistance (AMR) displayed by these organisms, which complicates treatment and potential successful outcomes. This review, therefore, wishes to examine novel compounds and approaches to combatting AMR in the NTMs, specifically examining antimycobacterial (NTM) compounds from plants and venoms, as well as examining synergistic and combination effects with other antimicrobials. Novel and modified drugs including new inhaled drugs are examined, as well as the repurposing of existing drugs for antimycobacterial activity. Many of these novel interventions are at various stages of development, from initial concept through to licensed intervention. The challenge remains to translate these interventions from in vitro laboratory models to effective in vivo interactions. When these are realized, then we will have the opportunity of overcoming NTM AMR, to the benefit of medicine, society, and humanity.

PMID: 30860173 [PubMed - in process]

Squaramide-based synthetic chloride transporters activate TFEB but block autophagic flux.

Cell Death Dis. 2019 Mar 11;10(3):242

Authors: Zhang S, Wang Y, Xie W, Howe ENW, Busschaert N, Sauvat A, Leduc M, Gomes-da-Silva LC, Chen G, Martins I, Deng X, Maiuri L, Kepp O, Soussi T, Gale PA, Zamzami N, Kroemer G

Abstract
Cystic fibrosis is a disease caused by defective function of a chloride channel coupled to a blockade of autophagic flux. It has been proposed to use synthetic chloride transporters as pharmacological agents to compensate insufficient chloride fluxes. Here, we report that such chloride anionophores block autophagic flux in spite of the fact that they activate the pro-autophagic transcription factor EB (TFEB) coupled to the inhibition of the autophagy-suppressive mTORC1 kinase activity. Two synthetic chloride transporters (SQ1 and SQ2) caused a partially TFEB-dependent relocation of the autophagic marker LC3 to the Golgi apparatus. Inhibition of TFEB activation using a calcium chelator or calcineurin inhibitors reduced the formation of LC3 puncta in cells, yet did not affect the cytotoxic action of SQ1 and SQ2 that could be observed after prolonged incubation. In conclusion, the squaramide-based synthetic chloride transporters studied in this work (which can also dissipate pH gradients) are probably not appropriate for the treatment of cystic fibrosis yet might be used for other indications such as cancer.

PMID: 30858361 [PubMed - in process]

The effects of cycled inhaled aztreonam on the cystic fibrosis (CF) lung microbiome.

J Cyst Fibros. 2019 Mar 08;:

Authors: Heirali AA, Acosta N, Storey DG, Workentine ML, Somayaji R, Laforest-Lapointe I, Leung W, Quon BS, Berthiaume Y, Rabin HR, Waddell BJ, Rossi L, Surette MG, Parkins MD

Abstract
BACKGROUND: To improve clinical outcomes, cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infections are prescribed inhaled anti-pseudomonal antibiotics. Although, a diverse microbial community exists within CF airways, little is known about how the CF microbiota influences patient outcomes. We hypothesized that organisms within the CF microbiota are affected by inhaled-antibiotics and baseline microbiome may be used to predict therapeutic response.
METHODS: Adults with chronic P. aeruginosa infection from four clinics were observed during a single 28-day on/off inhaled-aztreonam cycle. Patients performed serial sputum collection, CF-respiratory infection symptom scores (CRISS), and spirometry. Patients achieving a decrease of ≥2 CRISS by day 28 were categorized as subjective responders (SR). The airway microbiome was defined by Illumina MiSeq analysis of the 16S rRNA gene.
RESULTS: Thirty-seven patients (median 37.4 years and FEV1 44% predicted) were enrolled. No significant cohort-wide changes in the microbiome were observed between on/off AZLI cycles in either alpha- or beta-diversity metrics. However, at an individual level shifts were apparent. Twenty-one patients (57%) were SR and fourteen patients did not subjectively respond. While alpha-diversity metrics did not associate with response, patients who did not subjectively respond had a higher abundance of Staphylococcus and Streptococcus, and lower abundance of Haemophilus.
CONCLUSIONS: The CF microbiome is relatively resilient to AZLI perturbations. However, associated changes were observed at the individual patient level. The relative abundance of key "off-target" organisms associated with subjective improvements suggesting that the microbiome may be used as a tool to predict patient response - potentially improving outcomes.

PMID: 30857926 [PubMed - as supplied by publisher]