Machine learning to help cystic fibrosis decision-making

By James Hayes

New research claims to have demonstrated that machine learning techniques can predict with a 35% improvement in accuracy – in comparison to existing statistical methods – whether a cystic fibrosis patient should be referred for a lung transplant.

The research, led by Professor Mihaela van der Schaar of the Alan Turing Institute at the University of Oxford, has been generated through a partnership between The Alan Turing Institute and charity the Cystic Fibrosis Trust. Continue reading Machine learning to help cystic fibrosis decision-making

AIT’s Inhaled Nitric Oxide Shows Potential in Fighting Bacterial Infection Prevalent in CF Patients

By Alice Melao

Inhaled nitric oxide (NO) was shown to be an effective antibacterial agent against Mycobacterium abscessus infection in preclinical studies, as well as in a pilot clinical trial, according to AIT Therapeutics.

The company discussed the latest data on its NO product in two poster presentations during the 3rd Annual World Bronchiectasis Conference held recently at Georgetown University in Washington, D.C.

NO is a small molecule that is an important mediator of immune defense mechanisms against infections. The compound has been shown to have broad-spectrum antibacterial activity against several strains of bacteria that often infect patients with underlying lung diseases, including cystic fibrosis (CF).

Continue reading AIT’s Inhaled Nitric Oxide Shows Potential in Fighting Bacterial Infection Prevalent in CF Patients

Cinnamon Oil Compound Might Block Bacteria Like P. aeruginosa from Forming Biofilms

By: Alice Melao

A natural component found in cinnamon oil, known as cinnamaldehyde or CAD, may be able to prevent Pseudomonas aeruginosa bacteria from spreading in an organism and inhibit their ability to form antibiotic-resistant biofilms, researchers show.

These findings may support further study into anti-microbial medications that can help control the behavior of these so-called superbugs, or treatment-resistant bacteria, which represent a serious healthcare problem for people with cystic fibrosis and other diseases.

The discovery was reported in “Cinnamaldehyde disrupts biofilm formation and swarming motility of Pseudomonas aeruginosa,” published in the journal Microbiology.

“Humans have a long history of using natural products to treat infections, and there is a renewed focus on such antimicrobial compounds,” Sanjida Halim Topa, PhD, a researcher at Swinburne University of Technology in Australia, and lead study author, said in a university news release. “Natural products may offer a promising solution to this problem.”

Cinnamaldehyde, one of the major components of cinnamon oil, is responsible for its characteristic flavor. This compound is known to have antimicrobial activity against many bacteria, including P. aeruginosa; a stomach ulcer-causing bacteria called Helicobacter pylori; and Listeria monocytogenes, which is responsible for the food-borne infection listeriosis.

“We hypothesized that using natural antimicrobials, such as essential oils, might interfere in [drug-resistant] biofilm formation,” Topa said. “Though many previous studies have reported antimicrobial activity of cinnamon essential oil, it is not widely used in the pharmaceutical industry.”

Working with researchers at Nanyang Technological University in Singapore, the team conducted several experiments to evaluate the impact of different concentrations of cinnamaldehyde on P. aeruginosa biofilms.

They found that non-lethal amounts of the essential oil compound could disrupt by 75.6 % antibiotic-resistant, preformed P. aeruginosa biofilms. Cinnamaldehyde was found to prevent the production of a bacterial-signaling protein essential for bacteria communication and biofilm formation. [Biofilms, or microbe communities whose growth is facilitated by the thick and sticky mucus that marks CF, are known to promote antibiotic resistance in P. aeruginosa lung infections.]

In a concentration-dependent manner, cinnamaldehyde also could reduce the motility of the bacteria, preventing them from spreading elsewhere, the scientists reported.

These findings, the researchers wrote, show “CAD can disrupt biofilms and other surface colonization phenotypes through the modulation of intracellular signaling processes.”

They are now investigating the use of cinnamaldehyde embedded-wound dressings as a way to treat skin infections.

Original article here.

Importance of Early Diagnosis, Treatment of NTM Infections

By Ashraf Malhas, PhD.

An earlier diagnosis and treatment of nontuberculous mycobacteria (NTM) infection in patients with cystic fibrosis (CF) may positively affect the patient’s lung function, a study suggests.

NTM are a group of bacterial species, found in soil and water, which are not usually associated with human disease, except if they infect susceptible individuals, such as CF patients.

An increasing incidence of NTM infections in CF patients has been observed, with recent studies reporting a prevalence of 32.7%. The exact reasons behind this, the risk factors, the species involved, and effective treatments for NTM infections in CF patients remain largely unknown.

In the study “Clinical course and significance of nontuberculous mycobacteria and its subtypes in cystic fibrosis,” published in the journal BMC Infectious Diseases, researchers analyzed the prevalence of NTM infections in CF patients to identify factors associated with these infections, as well as monitor current treatments.

The study initially involved 360 CF patients, of whom 30 (8%) were identified as being positive for NTM infection. Of these, 28 patients were further analyzed, and their results compared with 26 matched CF patients not infected with NTM (the control group).

Within the NTM group, 17 patients were infected with a class of NTM known as slow-growing, eight patients were infected with rapidly growing NTM, while three were positive for both types.

Those infected with slow-growing NTM were generally older (range of 6.4 to 41.6 years) than those infected with the rapid-growing types (3.1 to 21.5 years), but that difference did not reach statistical significance. However, the age at CF diagnosis was significantly lower in the slow-growing NTM group compared to the rapid-growing NTM group.

When lung function was assessed in the two groups, researchers found that lung function as measured by predicted expiratory flow was significantly higher before NTM infection, regardless of the type of NTM.

Regarding treatment patterns, the team found that significantly more patients infected with slow-growing NTM had received penicillin/beta-lactamase and rifampin following infection compared to before infection.

“An earlier CF diagnosis was associated with a higher isolation of slow-growing NTM and greater antimicrobial use after infection,” the researchers wrote, adding that “NTM acquisition is associated with a worsening of [lung function]. Thus, both the early diagnosis and treatment of an NTM infection in patients with CF may positively impact lung function.”

The team believes that “increased awareness by clinicians on different NTM subtypes and more universal treatment plan for NTM infection in the CF population may positively impact patient management and outcomes.”

Original article here.

Triclosan, often maligned, may have a good side — treating cystic fibrosis infections

By Chris Waters

Maybe you’ve had the experience of wading in a stream and struggling to keep your balance on the slick rocks, or forgetting to brush your teeth in the morning and feeling a slimy coating in your mouth. These are examples of bacterial biofilms that are found anywhere a surface is exposed to bacteria in a moist environment.

Besides leading to falls in streams or creating unhealthy teeth, biofilms can cause large problems when they infect people. Biofilms, multicellular communities of bacteria that can grow on a surface encased in their own self-produced matrix of slime, can block immune cells from engulfing and killing the bacteria or prevent antibodies from binding to their surface.

On top of this, bacteria in a biofilm resist being killed by antibiotics due to the sticky nature of the matrix and activation of inherent resistant mechanisms, such as slow-growing cells or the ability to pump antibiotics out of the cell.

Biofilms are one of the primary growth modes of bacteria, but all antibiotics currently used clinically were developed against free-swimming planktonic bacteria. This is why they do not work well against biofilms.

My laboratory studies how and why bacteria make biofilms, and we develop new therapeutics to target them. Because antibiotic resistance is the most problematic aspect of biofilms during infections, we set out to identify novel molecules that could enhance antibiotic activity against these communities.

We discovered that an antimicrobial that has recently obtained a bad reputation for overuse in many household products could be the secret sauce to kill biofilms.

The hunt for antibiotic superchargers

To find such compounds, we developed an assay to grow plates of 384 tiny biofilms of the bacterium Pseudomonas aeruginosa. We did this to screen for molecules that enhance killing by the antibiotic tobramycin. We chose this bacterium and this antibiotic as our test subjects because they are commonly associated with cystic fibrosis lung infections and treatment.

People with cystic fibrosis (CF) are at particular risk from biofilm-based infections. These infections often become chronic in the lungs of cystic fibrosis patients and are often never cleared, even with aggressive antibiotic therapy.

After we screened 6,080 small molecules in the presence of tobramycin, we found multiple compounds that showed the antibiotic enhancement activity we were searching for. Of particular interest was the antimicrobial triclosan because it has been widely used in household products like toothpaste, soaps and hand sanitizers for decades, indicating that it had potential to be safely used in CF patients. Triclosan has also garnered a bad reputation due to its overuse, and states like Minnesota have banned it from these products. The Food and Drug Administration banned its use from hand soaps in September 2016. This ruling was not based on safety concerns, but rather because the companies that made these products did not demonstrate higher microbial killing when triclosan was added, compared to the base products alone.

Another fact that piqued our interest is that P. aeruginosa is resistant to triclosan. Indeed, treatment with either tobramycin or triclosan alone had very little activity against P. aeruginosa biofilms, but we found that the combination was 100 times more active, killing over 99 percent of the bacteria.

We further studied this combination and found that it worked against P. aeruginosa and other bacterial species that had been isolated from the lungs of CF patients. The combination also significantly enhanced the speed of killing so that at two hours of treatment, virtually all of the biofilm is eradicated.

Our efforts are now focused on pre-clinical development of the tobramycin-triclosan combination. For CF, we envision patients will inhale these antimicrobials as a combination therapy, but it could also be used for other applications such as diabetic non-healing wounds.

Although questions about the safety of triclosan have emerged in the mainstream media, there are actually dozens of studies, including in humans, concluding that it is well tolerated, summarized in this extensive EU report from 2009. My laboratory completely agrees that triclosan has been significantly overused, and it should be reserved to combat life-threatening infections.

The next steps for development are to initiate safety, efficacy and pharmacological studies. And thus far, our own studies indicate that triclosan is well tolerated when directly administered to the lungs. We hope that in the near future we will have enough data to initiate clinical trials with the FDA to test the activity of this combination in people afflicted with biofilm-based infections.

We think our approach of enhancing biofilm activity with the addition of novel compounds will increase the usefulness of currently used antibiotics. Learning about how these compounds work will also shed light on how bacterial biofilms resist antibiotic therapy.

Original article here.

Anaerobic bacteria cultured from CF airways correlate to milder disease-a multisite study

Anaerobic and aerobic bacteria were quantitated in respiratory samples across three cystic fibrosis (CF) centres using extended culture methods. Subjects, ages 1–69 years, who were clinically stable provided sputum (n=200) or bronchoalveolar lavage (n=55). Eighteen anaerobic and 39 aerobic genera were cultured from 59% and 95% of samples, respectively; 16/57 genera had a ≥5% prevalence across centres. Analyses of microbial communities using co-occurrence networks in sputum samples showed groupings of oral, including anaerobic, bacteria whereas typical CF pathogens formed distinct entities. Pseudomonas was associated with worse nutrition and F508del genotype, whereas anaerobe prevalence was positively associated with pancreatic sufficiency, better nutrition and better lung function. A higher ratio of total anaerobe/total aerobe colony forming units was associated with pancreatic sufficiency and better nutrition. Subjects grouped by factor analysis who had relative dominance of anaerobes over aerobes had milder disease compared to a Pseudomonas-dominated group with similar proportions of subjects being homozygous for F508del. In summary, anaerobic bacteria occurred at an early age. In sputum producing subjects anaerobic bacteria were associated with milder disease suggesting that targeted eradication of anaerobes may not be warranted in sputum producing CF subjects.

Full article here.

Positive Data from the CARE CF 1 Clinical Study of Oral Lynovex in Cystic Fibrosis Exacerbations

NovaBiotics Ltd (“NovaBiotics”) announces that its oral therapy for cystic fibrosis (CF), Lynovex®, has met the study objectives of the CARE CF 1 clinical trial.

CARE CF 1 assessed the effects of two weeks of Lynovex treatment as an adjunct to standard of care therapy (SOCT) in CF, compared to placebo plus SOCT. This trial was designed to determine whether the inclusion of Lynovex capsules alongside SOCT lessened the clinical impact of exacerbations in adults with CF, as measured by symptom severity and levels of bacteria and inflammatory mediators in sputum and blood.  CARE CF 1 was a 6-arm study with the primary objectives of determining the optimal dose and regimen of Lynovex in patients with exacerbations of CF-associated lung disease and to further evaluate the safety and tolerability of Lynovex in exacerbating CF patients.  Continue reading Positive Data from the CARE CF 1 Clinical Study of Oral Lynovex in Cystic Fibrosis Exacerbations

Cystic Fibrosis Disease Severity Linked to Immune Overreaction to Fungus, Study Reports

By Ana Pena

Disease severity in cystic fibrosis (CF) may be associated with an overreaction of the immune system to the fungus Aspergillus fumigatus, particularly due to a type of white blood cell called a phagocyte — which ingests and kills invading organisms — a study suggests.

U.K. researchers found that phagocytes from CF patients release higher amounts of harmful reactive oxygen species in response to Aspergillus fumigatus, a common cause of lung infection in these patients.

The study, “Aspergillus-induced superoxide production by cystic fibrosis phagocytes is associated with disease severity,” was published in the journal ERC Open Research.

Recent studies have supported the idea that the widespread environmental fungus Aspergillus fumigatus may play a critical role in CF lung disease.

Up to 58% of CF patients are colonized with this fungus, and an estimated 47.7% of adult patients are affected by either allergic reactions or infection caused by the fungus.

Persistent infections with A. fumigatus are also known to be adversely correlated with lung function and hospitalization in CF patients.

Researchers hypothesized that the anti-fungal defense mechanism in CF patients might be altered and have an impact on the progression of lung disease.

To investigate this hypothesis, the team compared the immune response of phagocytes from CF patients with those of healthy individuals used as controls, and tried to correlate them to clinical metrics of disease severity.

For original article please visit CF News Today.

Toothpaste ingredient may bust up cystic fibrosis biofilms

By Chris Waters and Sarina Gleason

A common antibacterial substance in toothpaste may combat life-threatening diseases such as cystic fibrosis when combined with an with an FDA-approved drug, researchers report.

Researchers have found that when triclosan, a substance that reduces or prevents bacteria from growing, combines with an antibiotic called tobramycin, it kills the cells that protect the CF bacteria, known as Pseudomonas aeruginosa, by up to 99.9 percent.

CF is a common genetic disease with one in every 2,500 to 3,500 people diagnosed with it at an early age. It results in a thick mucus in the lungs, which becomes a magnet for bacteria.

These bacteria are notoriously difficult to kill because a slimy barrier known as a biofilm, which allows the disease to thrive even when treated with antibiotics, protects them.

“The problem that we’re really tackling is finding ways to kill these biofilms,” says Chris Waters, lead author of the study and a microbiology professor at Michigan State University.

According to Waters, there are many common biofilm-related infections that people get, including ear infections and swollen, painful gums caused by gingivitis. But more serious, potentially fatal diseases join the ranks of CF including endocarditis, or inflammation of the heart, as well as infections from artificial hip and pacemaker implants.

Waters and his coauthors grew 6,000 biofilms in petri dishes, added in tobramycin along with many different compounds, to see what worked better at killing the bacteria. Twenty-five potential compounds were effective, but one stood out.

“It’s well known that triclosan, when used by itself, isn’t effective at killing Pseudomonas aeruginosa,” says coauthor Alessandra Hunt, a postdoctoral associate of microbiology and molecular genetics. “But when I saw it listed as a possible compound to use with tobramycin, I was intrigued. We found triclosan was the one that worked every time.”

Triclosan has been used for more than 40 years in soaps, makeup, and other commercial products because of its antibacterial properties. Recently, the FDA ruled to limit its use in soaps and hand sanitizers due to insufficient data on its increased effectiveness and concern about overuse. Clear evidence has shown, though, that its use in toothpaste is safe and highly effective in fighting gingivitis, and it is still approved for use.

“Limiting its use is the right thing to do,” says coauthor Michael Maiden, a graduate student in medicine. “The key is to avoid creating resistance to a substance so when it’s found in numerous products, the chances of that happening increase.”

Tobramycin is currently the most widely used treatment for CF, but it typically doesn’t clear the lungs of infection, Waters says. Patients typically inhale the drug, yet still find themselves chronically infected their whole lives, eventually needing a lung transplant.

“Most transplants aren’t a viable option though for these patients and those who do have a transplant see a 50 percent failure rate within five years,” he says. “The other issue is that tobramycin can be toxic itself.” Known side effects from the drug include kidney toxicity and hearing loss.

“Our triclosan finding gives doctors another potential option and allows them to use significantly less of the tobramycin in treatment, potentially reducing its use by 100 times,” Hunt says.

Within the next year, Waters and his colleagues will begin testing the effectiveness of the combination therapy on mice with hopes of it heading to a human trial soon after since both drugs are already FDA approved.

Just brushing your teeth with toothpaste that has triclosan won’t help to treat lung infections though, Maiden says.

“We’re working to get this potential therapy approved so we can provide a new treatment option for CF patients, as well as treat other biofilm infections that are now untreatable. We think this can save lives,” he says.

The research appears in the journal Antimicrobial Agents and Chemotherapy.

The National Institutes of Health, Cystic Fibrosis Foundation, and Hunt for a Cure in Grand Rapids, Michigan funded the research.

Source: Michigan State University

Potential Therapy for Infections in CF Gets Patent

AB569Arch Biopartners’ treatment candidate for bacterial infections in patients with cystic fibrosis, chronic obstructive pulmonary disease (COPD), and other respiratory conditions, has received a U.S. patent.

The U.S. Patent and Trademark Office issued patent 9,925,206 to the University of Cincinnati, which granted Arch Biopartners an exclusive commercial license on all patents related to AB569. The inventor is Daniel Hassett, PhD, a principal scientist at Arch and professor at the University of Cincinnati College Of Medicine.

“This patent issuance, which protects the composition of AB569, gives Arch a stronger commercial position to pursue treating not just CF patients, but also the millions of other patients that have chronic antibiotic resistant lung infections including those with COPD,” Richard Muruve, CEO of Arch, said in a press release. “It also opens the door for Arch to develop treatments for many other indications where antibiotic resistance is a problem, such as urinary tract infections and wound care.”

Bacterial infections in the lungs are a serious problem in patients with CF, COPD, or ventilator-associated pneumonia. Cystic fibrosis patients are susceptible to bacterial respiratory infections as a result of abnormal mucus production in the lungs and airways.

In particular, the bacterium Pseudomonas aeruginosa (P. aeruginosa) affects most adult CF patients and 40 percent of CF children ages 6 to 10. The mucoid form of P. aeruginosa is highly resistant to conventional antibiotics and immune-mediated killing. It causes a rapid decline in lung function and a poor overall clinical prognosis.

Antibiotic use in the treatment of CF and COPD patients with chronic bacterial respiratory infections is increasing, which correlates with a higher prevalence of antibiotic-resistant strains.

AB569 is a non-antibiotic therapy made of sodium nitrite and ethylenediaminetetraacetic acid (EDTA), two compounds approved by the U.S. Food and Drug Administration (FDA) for human use. The treatment has a different mechanism of action from antibiotics that may increase effectiveness, Arch believes.

“AB569 has two active ingredients that produce a dramatic and synergistic effect at killing many antibiotic resistant bacteria including Pseudomonas aeruginosa (P. aeruginosa), which commonly causes severe chronic infections in the lungs of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) patients,” Hassett said. “AB569 has the potential to make a significant medical impact on treating infection where traditional antibiotics fail.”

In preclinical experiments, the therapy showed significant ability to kill several types of Gram-negative and Gram-positive bacteria.

The safety and pharmacokinetics of a single administration of nebulized AB569 are now being evaluated in a Phase 1 clinical trial with up to 25 healthy volunteers at the Cincinnati Veterans Affairs Medical Center (CVAMC). Pharmacokinetics refers to how a drug is absorbed, distributed, metabolized, and expelled by the body. Enrollment of volunteers started in February.

If the Phase 1 study provides positive results, the company plans to start a Phase 2 trial to test the effectiveness of AB569 in the treatment of chronic lung infections caused by P. aeruginosa and other bacterial pathogens in CF and/or COPD patients.

AB569 previously received orphan drug status from the FDA for the treatment of CF patients infected with P. aeruginosa, and orphan medicinal product designation from the European Medicines Agency.

For original article, click here.