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pill bottles and pills

Impact of anaerobic antibacterial spectrum on cystic fibrosis

Researchers from Children’s National Hospital found that broad spectrum antianaerobic therapy had greater and longer lasting effects on the lung microbiome of persons with cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the chloride ion channel encoding CF transmembrane conductance regulator gene, leading to multiple morbidities and early mortality. In a new clinical study, researchers from Children’s National Hospital found that broad spectrum antianaerobic therapy had greater and longer lasting effects on the lung microbiome of persons with CF.

They found this difference when comparing the microbiology and clinical outcomes in children with CF who were treated with “broad” or “narrow” antianaerobic antibiotics for exacerbations of their disease. While there are many factors that determine whether “narrow” or “broad” spectrum antibiotics are used, the data showed that the recovery of pulmonary function was similar between those groups.

“The findings prove that most providers are following best practices when treating patients with cystic fibrosis using the narrowest spectrum of antibiotics possible, and reserving broad spectrum agents for more advanced disease when culture data shows more resistant bacteria,” says  Michael Bozzella, the study’s lead author.

The study, published in the Pediatric Infectious Disease Journal, analyzed how the spectrum of antibiotics prescribed to patients with cystic fibrosis impacts the population of bacteria in their lungs how it ties back to lung function.

“Research like this improves antibiotic and antimicrobial stewardship,” said Bozzella. “When speaking with families and patients with cystic fibrosis, providers can be more aware of the relationship between lung microbiome, disease state, and antibiotics and create more holistic treatment plans.”

Dr. Bozzella did this research as a fellow at Children’s National and he’s now an Infectious Disease Attending Physician at Children’s Hospital Colorado. Additional authors from Children’s National include: Andrea Hahn, M.D., M.S., Hollis Chaney, M.D.Iman Sami Zakhari, M.D.Anastassios Koumbourlis, M.D., M.P.H. and Robert Freishtat, M.D., M.P.H.

mother helping child with inhaler

Beta-lactam and microbial diversity in cystic fibrosis

mother helping child with inhaler

The study, published in the Journal of Investigative Medicine, examined the hypotheses that beta-lactam antibiotic PK and PD is associated with changes in richness and alpha diversity following treatment of a pulmonary exacerbations and determined associations between antibiotic PK, PD, antibiotic resistance and lung function.

Cystic fibrosis (CF) is a chronic lung disease that affects more than 30,000 people in the United States and 70,000 people worldwide. While this chronic disease is characterized by acute pulmonary exacerbations that are frequently treated with antibiotics, the impact of antibiotics on airway microbial diversity remains a critical knowledge gap.

A new study led by researchers at Children’s National Hospital found that beta-lactam antibiotic pharmacokinetic (PK) and pharmacodynamic (PD) target attainment during treatment is associated with suppressed recovery of microbial diversity, following a pulmonary exacerbation in children and adolescents with CF.

“By laying the groundwork for understanding how antibiotic PK may influence microbial diversity following pulmonary exacerbation, we hope to identify improved ways to guide antibiotic therapy in persons with CF,” says Andrea Hahn, M.D., M.S., an infectious diseases specialist at Children’s National and lead author of the study.

The study, published in the Journal of Investigative Medicine, examined the hypotheses that beta-lactam antibiotic PK and PD is associated with changes in richness and alpha diversity following treatment of a pulmonary exacerbations and determined associations between antibiotic PK, PD, antibiotic resistance and lung function.

“Beta-lactam antibiotics are frequently used to treat pulmonary exacerbations in persons with CF, yet are not routinely optimized,” says Dr. Hahn. “This study demonstrates the importance of beta-lactam PK’s on changes within the airway microbiome and provides context for care providers regarding the potential long-term impacts of antibiotic use in persons with CF, to ensure that we are optimizing therapy with each pulmonary exacerbation.”

Additional authors from Children’s National include: Aszia Burrell, Hollis Chaney, M.D.Iman Sami Zakhari, M.D.Anastassios Koumbourlis, M.D., M.P.H. and Robert Freishtat, M.D., M.P.H.

schistosome

Parasite-derived molecule could accelerate recovery from UTI

schistosome

Eggs from S. haematobium may produce the molecule IPSE to reduce the immune response against them, which happens to dampen UTI-induced bladder inflammation.

IPSE, a urogenital parasite-derived immunomodulatory molecule, can suppress bladder pathogenesis and anti-microbial peptide gene expression in bacterial urinary tract infection (UTI) according to a new study led by Michael Hsieh, Ph.D., director of Transitional Urology at Children’s National Hospital.

Half of all girls and women, and about 5% of boys and men, will have at least one urinary tract infection (UTI) in their lifetimes.

“Although antibiotics are very helpful for these infections, there are concerns that overuse of antibiotics may contribute to antibiotic-resistant infections,” Dr. Hsieh said. “There are also concerns that antibiotic therapy for UTI does not uniformly resolve infection-induced or inflammation-associated symptoms quickly.”

Parasitic infections are often associated with bacterial co-infections for unclear reasons. This may be true for urogenital schistosomiasis (caused by Schistosoma haematobium infection) and bacterial urinary tract co-infection (UTI), the study noted. Dr. Hsieh and other leading experts previously reported that this co-infection is facilitated by S. haematobium eggs triggering interleukin-4 (IL-4) production and sought to dissect the underlying mechanisms.

“Despite S. haematobium’s ability to make hosts more susceptible to UTI, we have identified IPSE, a bladder parasite protein, as a potential anti-inflammatory agent to accelerate recovery from UTI,” Dr. Hsieh explained. “S. haematobium eggs may produce IPSE to reduce the immune response against them, which happens to dampen UTI-induced bladder inflammation. It may be possible to develop IPSE as novel therapeutic to accelerate recovery from UTI.”

The study’s data showed that IPSE may play a major role in S. haematobium-associated urinary tract co-infection, although in an unexpected way. The study’s findings also indicated that IPSE either works in concert with other IL-4 -inducing factors to increase susceptibility of S. haematobium-infected hosts to bacterial co-infection or does not contribute to enchaining vulnerability to this co-infection.

You can find the full study published in Parasites and Vectors. Learn more about the Children’s National Department of Urology.

Baby in the NICU

Quality improvement initiative reduces vancomycin use in NICU

Baby in the NICU

A quality improvement initiative in the Neonatal Intensive Care Unit (NICU) at Children’s National Hospital led to a significant reduction in treatment with intravenous vancomycin, an antibiotic used for resistant gram positive infections, which is often associated with acute kidney injury.

A quality improvement initiative in the Neonatal Intensive Care Unit (NICU) at Children’s National Hospital led to a significant reduction in treatment with intravenous vancomycin, an antibiotic used for resistant gram positive infections, which is often associated with acute kidney injury. The findings, published in the journal Pediatrics, show the initiative reduced vancomycin use in patients by 66%, and the NICU has sustained the reduction for more than a year.

Vancomycin is a broad-spectrum antibiotic often used to treat methicillin-resistant Staphylococcus aureus (MRSA) infection. It’s one of the most commonly prescribed antibiotics in NICUs, but its overuse poses an increased risk of morbidity. Benchmarking data showed that in 2017, vancomycin use at Children’s National Hospital was significantly higher than use at peer institutions, suggesting there was likely an opportunity to optimize use of this drug.

The intervention program was led by Rana Hamdy, M.D., M.S.C.E., M.P.H., an infectious diseases specialist at Children’s National, Lamia Soghier, M.D., medical unit director of the Children’s National NICU, and other team members from neonatologyinfectious diseases, pharmacy, nursing and quality improvement. The team accomplished the prescribing reduction by sequentially implementing a four-step approach involving interdisciplinary team building and provider education, pharmacist-initiated 48-hour time-outs, clinical pathway development and prospective audit with feedback.

“Our interdisciplinary quality improvement team was devoted to this project and implemented interventions that, early on, led not only to reduction in vancomycin use, but to better outcomes in our patients with fewer episodes of vancomycin-associated acute kidney injury,” said Dr. Hamdy. “This led to early buy-in from the prescribers, ultimately changing the culture of antibiotic prescribing in the NICU.”

Following the NICU’s intervention program to improve patient safety, vancomycin use in patients decreased from 112 days of therapy per 1,000 patient-days to 38 days of therapy per 1,000 patient-days. During the intervention program, the researchers noted that this was “the first work to show a significant change in vancomycin-associated acute kidney injury in neonates.”

Four key interventions were sequentially implemented to successfully achieve and sustain the reduction in vancomycin use. Intervention 1 was the development of an interdisciplinary and provider education team that addressed institutional antibiotic prescribing practices. Intervention 2, a pharmacist-initiated 48-hour time-out, involved clinical pharmacists identifying patients who have been on antibiotics for ≥ 48 hours and encouraged their providers to either discontinue vancomycin or to switch to a narrow-spectrum antibiotic. Intervention 3 consisted of the development of new clinical pathways including discontinuing vancomycin in infants at low risk for MRSA. Lastly, intervention 4, antimicrobial stewardship program (ASP) prospective audit and feedback, involved an ASP member reviewing all NICU vancomycin orders and issuing appropriate recommendations for NICU providers and pharmacists to be carried out within 24 hours.

This project was taken on as part of Children’s National Quality Improvement and Leadership Training (QuILT) course sponsored by the Quality & Safety Department. This notable work was highlighted in the 2019 annual Quality and Safety report and by the Magnet® program as an exemplary example of nursing-physician partnership working to improve patient care.

The associated article, “Reducing Vancomycin Use in a Level IV Neonatal Intensive Care Unit,” will be published July 1 in Pediatrics. The lead author is Dr. Rana Hamdy, an infectious diseases specialist and director of the Antimicrobial Stewardship Program. Twenty notable co-authors are also from Children’s National.

bacterial extracellular vesicle

Once overlooked cellular messengers could combat antibiotic resistance

bacterial extracellular vesicle

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors. The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

Children’s National Hospital researchers for the first time have isolated bacterial extracellular vesicles from the blood of healthy donors, a critical step to better understanding the way gut bacteria communicate with the rest of the body via the bloodstream.

For decades, researchers considered circulating bacterial extracellular vesicles as bothersome flotsam to be jettisoned as they sought to tease out how bacteria that reside in the gut whisper messages to the brain.

There is a growing appreciation that extracellular vesicles – particles that cells naturally release – actually facilitate intracellular communication.

“In the past, we thought they were garbage or noise,” says Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute. “It turns out what we throw away is not trash.”

Kylie Krohmaly, a graduate student in Dr. Freishtat’s laboratory, has isolated from blood, extracellular vesicles from Escherichia coli and Haemophilus influenzae, common bacteria that colonize the gut, and validated the results via electron microscopy.

“The images are interesting because they look like they have a bit of a halo around them or penumbra,” Krohmaly says.

The team theorizes that the solar eclipse lookalikes contain important signaling proteins and chromatin, DNA from the human host.

“It’s the first time anyone has pulled them out of blood. Detecting them is one thing. Pulling them out is a critical step to understanding the language the microbiome uses as it speaks with its human host,” Dr. Freishtat adds.

Krohmaly’s technique is so promising that the Children’s National team filed a provisional patent.

The Children’s research team has devised a way to gum up the cellular works so that bacteria no longer become antibiotic resistant. Targeted bacteria retain the ability to make antibiotic-resistance RNA, but like a relay runner dropping rather than passing a baton, the bacteria are thwarted from advancing beyond that step. And, because that gene is turned off, the bacteria are newly sensitive to antibiotics – instead of resistant bacteria multiplying like clockwork these bacteria get killed.

“Our plan is to hijack this process in order to turn off antibiotic-resistance genes in bacteria,” Dr. Freishtat says. “Ultimately, if a child who has an ear infection can no longer take amoxicillin, the antibiotic would be given in tandem with the bacteria-derived booster to turn off bacteria’s ability to become antibiotic resistant. This one-two punch could become a novel way of addressing the antibiotic resistance process.”

ISEV2020 Annual Meeting presentation
(Timing may be subject to change due to COVID-19 safety precautions)
Oral with poster session 3: Neurological & ID
Saturday May 23, 2020, 5 p.m. to 5:05 p.m. (ET)
“Detection of bacterial extracellular vesicles in blood from healthy volunteers”
Kylie Krohmaly, lead author; Claire Hoptay, co-author; Andrea Hahn, M.D., MS, infectious disease specialist and co-author; Robert J. Freishtat, M.D., MPH, associate director, Center for Genetic Medicine Research at Children’s National Research Institute and senior author.

gut bacteria

Understanding gut bacteria: forces for good (and sometimes evil)

gut bacteria

In a paper published Sept. 11, 2019, in PLOS ONE, a multi-institutional research team led by George Washington University (GW) faculty found 157 different types of organisms (eight phyla, 18 classes, 23 orders, 38 families, 59 genera and 109 species) living inside the guts of healthy volunteers.

Back in 2015, an interdisciplinary group of research scientists made their case during a business pitch competition: They want to create a subscription-based service, much like 23andMe, through which people could send in samples for detailed analyses. The researchers would crunch that big data fast, using a speedy algorithm, and would send the consumer a detailed report.

But rather than ancestry testing via cheek swab, the team sought to determine the plethora of diverse bacterial species that reside inside an individual’s gut in their ultimate aim to improve public health.

Hiroki Morizono, Ph.D., a member of that team, contributed detailed knowledge of Bacteroides, a key organism amid the diverse array of bacterial species that co-exist with humans, living inside our guts. These symbiotic bacteria convert the food we eat into elements that ensure their well-being as well as ours.

“Trillions of bacteria live in the gut. Bacteroides is one of the major bacterial species,” says Morizono, a principal investigator in the Center for Genetic Medicine Research at Children’s National in Washington, D.C. “In our guts they are usually good citizens. But if they enter our bloodstream, they turn evil; they’re in the wrong place. If you have a bacteroides infection, the mortality rate is 19%, and they resist most antibiotic treatments.”

The starting point for their project – as well as step one for better characterizing the relationship between gut bacteria and human disease – is taking an accurate census count of bacteria residing there.

In a paper published Sept. 11, 2019, in PLOS ONE, a multi-institutional research team led by George Washington University (GW) faculty did just that, finding 157 different types of organisms (eight phyla, 18 classes, 23 orders, 38 families, 59 genera and 109 species) living inside the guts of healthy volunteers.

The study participants were recruited through flyers on the GW Foggy Bottom campus and via emails.  They jotted down what they ate and drank daily, including the brand, type and portion size. They complemented that food journal by providing fecal samples from which DNA was extracted. Fifty fecal metagenomics samples randomly selected from the Human Microbiome Project Phase I research were used for comparison purposes.

“The gut microbiome inherently is really, really cool. In the process of gathering this data, we are building a knowledge base. In this paper, we’re saying that by looking at healthy people, we should be able to establish a baseline about what a normal, healthy gut microbiome should look like and how things may change under different conditions,” Morizono adds.

And they picked a really, really cool name for their bacteria abundance profile: GutFeelingKB.

“KB is knowledge base. Our idea, it’s a gut feeling. It’s a bad joke,” he admits. “Drosophila researchers have the best names for their genes. No other biology group can compete. We, at least, tried.”

Next, the team will continue to collect samples to build out their bacteria baseline, associate it with clinical data, and then will start looking at the health implications for patients.

“One thing we could use this for is to understand how the bacterial population in the gut changes after antibiotic treatment. It’s like watching a forest regrow after a massive fire,” he says. “With probiotics, can we do things to encourage the right bacteria to grow?”

In addition to Morizono, study co-authors include Lead Author Charles H. King, and co-authors Hiral Desai, Allison C. Sylvetsky, Jonathan LoTempio, Shant Ayanyan, Jill Carrie, Keith A. Crandall, Brian C. Fochtman, Lusine Gasparyan, Naila Gulzar, Najy Issa, Lopa Mishra, Shuyun Rao, Yao Ren, Vahan Simonyan, Krista Smith and Senior Author, Raja Mazumder, all of George Washington University; Paul Howell and Sharanjit VedBrat, of KamTek Inc.; Konstantinos Krampis, of City University of New York; Joseph R. Pisegna, of VA Greater Los Angeles Healthcare System; and Michael D. Yao, of Washington DC VA Medical Center.

Financial support for research described in this post was provided by the National Science Foundation under award number 1546491 and the National Institutes of Health National Center for Advancing Translational Sciences under award number UL1TR000075.