Window of opportunity for treatment of early cystic fibrosis lung infections

Technical University of Denmark

CF-patients have a genetic defect which results in dehydrated sticky mucous in the lungs, leading to severe and persistent lung infections often caused by Pseudomonas aeruginosa.

The research shows that within the first two to three years after infection with P. aeruginosa, the bacteria are already adapting rapidly to the environment, growing slower and optimizing their fitness to survive.

“Across all of our patients within the first three years, the bacteria on average slow their growth rates significantly and they reduce their susceptibility to ciprofloxacin, a first line drug in treatment of CF-patients. This means that one should pay extra close attention in this period of time to avoid the infection becoming persistent,” says Jennifer Bartell, Postdoc at The Novo Nordisk Foundation Center for Biosustainability (DTU Biosustain) and co-first author.

Looking beyond antibiotic resistance

Clinicians usually focus on detecting antibiotic resistance during infections, and this appears to be an effective way to follow the development of short-term acute infections.

Antibiotic resistant bacteria are identified by their ability to survive above a specific concentration of an antibiotic. The researchers saw a rapid increase in the concentration of antibiotics that the bacteria could tolerate. But at the same time, few bacteria achieved detectable antibiotic resistance in the early infection period of CF. The researchers suspect this pre-resistance adaptation to be an underused marker of progression in the infection. This pre-resistance adaptation likely occurs in other persistent infections, such as chronic obstructive pulmonary disease (COPD).

Besides looking for antibiotic resistance, clinicians also monitor bacterial mucoidity — a trait where bacteria produce a protective, slimy coating, as a marker of a chronic infection.

But according to the new study, bacteria can become persistent and resilient to treatment regardless of the appearance of mucoidity. Other bacterial traits such as the ability to attach to surfaces and aggregate in biofilms — hefty structured layers of adherent cells — evolve more consistently in these persisting infections than mucoidity and may serve as a better sign of early chronic infection.

“We can see which traits might actually be valuable for the clinicians to monitor in addition to antibiotic resistance,” says Lea Sommer, Postdoc at Rigshospitalet and co-first author.

Potential for new diagnostic tools

The researchers identified these important evolving traits of P. aeruginosa by screening 443 isolates from 39 young cystic fibrosis (CF) patients over a ten-year period and mapping traits adapting in tandem using statistical modeling approaches. Usually, studies focus on bacterial isolates collected from older CF-patients with chronic infections, who have become multi-drug resistant and already have adapted to the human lungs.

These results emphasize that trait evolution measurements are important and should not be neglected, even though genomic tests are advancing.

“In this early phase, the bacteria change a lot and become much more robust, but the doctors do not necessarily see this with current clinical measurements,” says Lea Sommer.

Going forward, the researchers wish to find out how the adapting bacteria respond to a larger panel of antibiotics that are used to treat patients. Armed with this comprehensive map of evolutionary pathways, clinicians would have a much better chance of categorizing the infection and, hence, take the necessary precautionary steps.

“In the clinic, doctors would potentially be able to take a single patient’s bacterial screening data and analyze how this patient responds to the current treatment. As we gain experience with more patients, it will be easier to assess what can be done to stop the transition to chronic infection, “says Jennifer Bartell.

Thus, this could pave the way for developing more fine-tuned personalized treatments for all patients suffering from continuous persisting infections, such as CF, COPD, and perhaps diabetics with chronically infected wounds.

Original article: https://www.sciencedaily.com/releases/2019/03/190304121505.htm

UC Berkeley professor collaborates on study to improve cystic fibrosis treatment

By  Stanley Von Ehrenstein-Smith of The Daily Californian

UC Berkeley professor Terry Machen is collaborating with researchers from Canada to discover new treatments for cystic fibrosis, an incurable genetic disease that cuts decades off the lives of patients.

The research, a collaboration between UC Berkeley and the University of Saskatchewan, or USask, in Canada that began in 2016, is based on a unique method developed by the Canadian researchers to measure fluid secretion in the lungs. Cystic fibrosis is characterized by thick, viscous mucus that clogs the airways and causes bacteria to accumulate, leading to frequent infections that damage the airways.

“This treatment predicates an idea that if you inhale a solution that is more concentrated at the blood, the patient will get this salty solution in the lungs,” said Juan Ianowski, a study co-director and USask assistant professor of physiology. “The salt will cause osmosis or water movement through a concentration gradient and water movement from the blood side into the airways.”

The effects of this treatment change the properties of the mucus to become “normal,” allowing the patient to cough it out or have it moved through cilia, tiny hairlike structures, in the lung. This hypersaline treatment originated in Australia and has been used for decades to alleviate the symptoms of cystic fibrosis.

The research team — co-directed by Ianowski and Julian Tam, a respirologist at USask — found a way to develop this treatment by observing the way in which the hypersaline solution stimulated neuron cells that are present in the lungs rather than solely crediting the solution for its established osmotic effects.

“Neurons that are present in the airway are constantly monitoring the conditions of the airway, (becoming) deactivated in cystic fibrosis,” Ianowski said. “These neuron cells would also contribute to the production of water in the lumen of the airway.”

The research group determined that 50 percent of the liquid produced in the airway when the hypertonic saline is administered comes from the nervous system stimulating the production of fluids.

The impacts of these potential treatments enable cystic fibrosis patients to modulate the amount of the hypertonic saline solution as well as potentially disengage or engage certain aspects of their nervous system to manage a more desirable response.

“The main goal is to come up with new formulations that will allow us to make this treatment last longer and reduce negative reactions in the patient,” Ianowski said. “We want to make the treatment stronger, last longer, or cause it to inhibit some components such as a coughing reaction.”

The research team is funded by Cystic Fibrosis Canada and will be continuing to study developed treatments for cystic fibrosis.

Machen, campus professor emeritus of molecular and cell biology and study contributor, said “amazingly effective” drugs for cystic fibrosis have been made available for patients by pharmaceutical companies including Vertex. The disadvantage, however, is that these drugs cost $300,000 a patient per year.

“It would be a big addition to the field if we could develop something that made things better and is also cheaper,” Machen said.

Stanley von Ehrenstein-Smith covers research and ideas. Contact him at svonehrensteinsmith@dailycal.org and follow him on Twitter at @von_ehrenstein.

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

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.

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.