Tag Archive for: Robert J. Freishtat

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Therapeutic antibiotics associated with reductions in microbial diversity in CF

person pouring pills from bottle to hand

Researchers found that both insufficient beta-lactam pharmacokinetics (PK) and broad-spectrum antibiotics were associated with a greater decrease in species richness at the end of antibiotic therapy compared to pulmonary exacerbations onset.

There are more than 70,000 children and adults living with cystic fibrosis (CF) worldwide. Those with this progressive disease frequently suffer from recurrent episodes of lung infection and inflammation called pulmonary exacerbations.

In a new observational study led by Andrea Hahn, M.D., infectious diseases specialist at Children’s National Hospital, researchers found that both insufficient beta-lactam pharmacokinetics (PK) and broad-spectrum antibiotics were associated with a greater decrease in species richness at the end of antibiotic therapy compared to pulmonary exacerbations onset.

In prior studies evaluating the association between beta-lactam PK, insufficient beta-lactam PK was associated with reduced short-term decreases in microbial diversity compared to sufficient beta-lactam dosing. In this study researchers found that insufficient beta-lactam PK was associated with a greater short-term decrease in microbial diversity.

Dr. Hahn’s team also found that an increased presence of beta-lactam antibiotic resistance genes was associated with lower microbial diversity and lower lung function.

These studies suggest that community-level antibiotic resistance, rather than the resistance patterns of the most prevalent bacteria identified in cultures, may serve as a useful predictor of lung function recovery in individuals with cystic fibrosis (CF). This finding may aid clinicians in selecting the most effective antibiotics to treat pulmonary exacerbations in CF patients, thus enhancing their clinical outcomes.

Read the full study in Nature’s Scientific Reports.

Authors on the study from Children’s National Hospital include Andrea Hahn, M.D., M.S., Aszia Burrell, Hollis Chaney, M.D.Iman Sami-Zakhari, M.D.Anastassios Koumbourlis, M.D., M.P.H., and Robert J. Freishtat, M.D., M.P.H.

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Effect of antibiotics on microorganisms and lung function in children with CF

girl looking at medicine bottle

The study suggests that the use of antibiotics to treat PEx in children with CF may not be as harmful to the airway microbiome as previously believed.

Cystic fibrosis (CF) is a disease that affects many people, especially children. Pulmonary exacerbations (PEx) are common in people with CF and can cause a decline in lung function. These PEx are often treated with antibiotics, but little is known about how antibiotics affect the airway microbiome (the collection of microorganisms in the lungs) of people with CF over time.

Experts from Children’s National Hospital took part in a recent study which looked at how the airway microbiome and lung function of children with CF changed over the course of a year following an initial PEx. The study found that the diversity of the airway microbiome increased over the year despite a decrease in lung function associated with repeated PEx events requiring antibiotic therapy. This suggests that repeated treatment with antibiotics may not have a negative impact on the overall diversity of microorganisms in the lungs.

It is important for pediatricians to understand how antibiotics affect the airway microbiome in children with CF because it can help them make more informed decisions about treatment options. The findings of this study suggest that the use of antibiotics to treat PEx in children with CF may not be as detrimental to the airway microbiome as previously thought. This information can help pediatricians provide better care for children with CF and ultimately improve their overall health outcomes.

You can read the full study, Impact of Antibiotics on the Lung Microbiome and Lung Function in Children With Cystic Fibrosis 1 Year After Hospitalization for an Initial Pulmonary Exacerbation, in Open Forum Infectious Diseases.

Authors on the study from Children’s National Hospital include Zaina Inam, M.D., Aszia Burrell, Hollis Chaney, M.D., Iman Sami-Zakhari, M.D., Anastassios Koumbourlis, M.D., M.P.H., Robert J. Freishtat, M.D., M.P.H., and Andrea Hahn, M.D., M.S.

Staphylococcus

Airway microbial diversity in children with Cystic Fibrosis

Staphylococcus

Despite having less overall microbial richness, children with Cystic Fibrosis displayed a greater presence of Staphylococcus species.

Cystic Fibrosis (CF) is a disease that mainly affects the lungs and arises from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that encodes for the CFTR membrane protein located on certain secretory cells. CFTR dysfunction leads to complications such as the production of abnormally viscous mucus which causes chronic suppurative lung infections that require antibiotics to treat. New drugs called CFTR modulators can help improve CFTR protein function and some are even FDA-approved for use in children. In addition to CFTR protein function, the lung’s resident microbiota and its richness of diversity, plays an important role in both health and disease, including CF.

In a new study published in Heliyon, scientists from Children’s National Hospital examined the difference in the upper airway microbiome between children with CF and healthy controls. Age-related differences among children with CF and the impact of CFTR modulators on microbial diversity were also assessed. Seventy-five children between 0-6 years of age participated in the study, including 25 children with CF and 50 healthy controls. For CF participants, oropharyngeal swabs and clinical data were obtained from the biorepository, while data for controls were obtained during a single clinical visit.

Analysis revealed that CF patients had less microbial diversity and different composition of the upper airway microbiome compared to age similar controls, a finding that is consistent with research on the lower airways. Despite having less overall microbial richness, children with CF displayed a greater presence of Staphylococcus species, (a main driver of the pulmonary exacerbations characteristic of CF), three Rothia operational taxonomic units (OTUs) and two Streptococcus OTUs. CF patients received a significantly higher number of antibiotics courses within the previous year compared to healthy controls, and further investigation will be necessary to understand the impact of antibiotics on the upper airway microbiome of infants and children with CF.

Longitudinal comparisons to study effects of age and CFTR modulation on the microbiome of children with CF were also undertaken. Younger CF patients (those 0 to <3 years of age at study enrollment), were more likely to have culturally-normal respiratory flora and more stable microbial composition over time than older CF patients (those ≥ 3–6 years of age at study enrollment), with no significant differences in alpha or beta diversity. Older CF patients were significantly more likely to be receiving a CFTR modulator than younger patients. CF patients receiving CFTR modulators had higher microbial diversity measures than those not receiving CFTR modulators and were closer (but still significantly lower) in microbial richness to healthy controls. No significant differences in beta diversity were found between the three groups.

This study adds to the growing body of evidentiary support for the use of CFTR modulators in improving airway microbial diversity in CF patients. Future studies with a larger cohort and greater focus on the impact on early initiation of CFTR modulators on microbial diversity and clinical outcomes is necessary.

The study, “Airway microbial diversity is decreased in young children with cystic fibrosis compared to healthy controls but improved with CFTR modulation,” was recently published in Heliyon. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Aszia Burrell; Emily Ansusinha; Hollis Chaney, M.D.; Iman Sami, M.D.; Geovanny F. Perez, M.D.; Anastassios C. Koumbourlis, M.D., M.P.H.; Robert McCarter, Sc.D.; and Robert J. Freishtat, M.D., M.P.H..

child using inhaler

The search for new Cystic Fibrosis clinical biomarkers

child using inhaler

Physician-scientists from Children’s National Hospital are unlocking new insights into Cystic Fibrosis by studying the type and number of bacteria in the lungs.

Cystic Fibrosis (CF) is a genetic disorder that chiefly affects the lungs and results in the production of abnormally dehydrated, viscous mucus. The inability to adequately clear this mucus leads to bacterial retention and both intermittent and chronic lung infections which require antibiotic therapy to treat. Researchers have used 16S rDNA amplicon sequencing for years in the attempts to characterize the airway microbiomes of CF patients, and more recently have used shotgun whole genome sequencing (WGS) techniques to obtain further details regarding bacterial species and strains. Previous studies on the airway microbiomes of CF patients have revealed that inter-person variability is high and can sometimes exceed intra-person variability. This can preclude generalizations regarding the CF population as a whole, which includes more than 30,000 Americans.

A recently published case study examined a young child with advanced and severely aggressive CF over a 12-month period, during which five pulmonary exacerbations occurred. A total of 14 sputum samples were collected across three clinical periods- baseline, exacerbation, and treatment. Samples were subsequently genetically sequenced (via 16s rDNA sequencing and, in three instances, WGS) and volatile metabolites were analyzed. The researchers hypothesized that if signature microbiome and metabolome characteristics correlated with one other and could be identified for each disease state, this data could serve as conglomerate biomarkers for the continuum of CF clinical states within an individual. In turn, this could inform future study design in a larger cohort.

Across all sputum samples, 109 individual operational taxonomic units (OTUs) and 466 distinct volatile metabolites were identified. 16s rDNA sequencing and WGS revealed that Escherichia coli and Staphylococcus aureus were the predominant bacteria during most baseline and exacerbation samples, despite some significant fluctuations in relative abundances. After the patient’s fifth antibacterial course, however, Achromobacter xylosoxidans became the new dominant bacterium.

Analysis revealed that the phylum Bacteroidetes and the genus Stenotrophomonas were significantly more abundant in treatment periods compared to baseline and exacerbation periods. WGS revealed the presence of bacteriophages as well as antibiotic resistance genes (mostly due to multi-drug resistance mechanisms), which can have important clinical ramifications and adds some dimensionality to the genetic analysis.

Volatile metabolite analysis found that observable fluctuations in metabolome composition coincided with fluctuations in the sputum microbiome. In this case, the microbiome and volatile metabolites produced by these bacteria provided an accurate assessment of the child’s clinical state. More specifically, the authors saw a distinct shift in both the microbiome and volatile metabolites with antibiotic treatment across the five independent pulmonary exacerbations. These additional assessments of the bacteria within the CF airway could provide an additional technique beyond standard bacterial cultures to better understand how the patient is responding to antibiotic treatment. Future studies in a larger group of children with CF may provide further insights into bacteria and volatile metabolite combinations that predict pulmonary exacerbation.

The article, “Longitudinal Associations of the Cystic Fibrosis Airway Microbiome and Volatile Metabolites: A Case Study,” was published in Frontiers in Cellular and Infection Microbiology. The lead author is Andrea Hahn, M.D., M.S., an investigator at the Children’s National Research Institute. Notable authors include Iman Sami, M.D., pulmonologist at Children’s National; Anastassios C. Koumbourlis, M.D., M.P.H, director of the Cystic Fibrosis Center; and Robert J. Freishtat, M.D., M.P.H, senior investigator at the Center for Genetic Medicine Research.