Telavancin Promising Potential Treatment Option for MRSA in Cystic Fibrosis Patients

By Kristi Rosa

Responsible for several issues ranging from skin infections and sepsis to pneumonia and bloodstream infections, methicillin-resistant Staphylococcus aureus continues to plague patients in the health care and community setting, as well as the providers who treat them.

When acquired in patients with cystic fibrosis, clinical outcomes are known to be even worse, affecting several organs—primarily the lungs—and resulting in an increased rate of declined respiratory function as well as infections that can have severe, and sometimes deadly, consequences.

Now, however, for the first time, investigators have found that telavancin—a drug that is currently used to treat skin infections and hospital-acquired pneumonia—has potent in vitro activity and low resistance development potential when used against S aureus isolates in patients with cystic fibrosis, making it a promising potential treatment option for this population.

“Telavancin (TLV) is a lipoglycopeptide antibiotic approved by the US Food and Drug Administration in 2009 for the treatment of complicated skin and skin structure infections and in 2013 for the treatment of cases of nosocomial pneumonia, however its application for the treatment of CF-MRSA pneumonia infections was not known, so our studies are contributing to extending the application of TLV for CF treatment,” Adriana E. Rosato, PhD, associate professor in the department of Pathology and Genomic Medicine at Houston Methodist Research Institute told Contagion®. “We were also inspired by the fact that CF patients have a short life time—until 40 to 50 [years]—so our priority is to contribute to better treatment in this patient population.”

Dr. Rosato and her team hypothesized that TLV might be a promising treatment option for CF-patient-derived MRSA and MSSA infections, as in vitro studies have shown that TLV has activity against MRSA.

To prove this, the investigators screened a total of 333 strains of CF patient-derived S aureus of the wild-type or small-colony-variant phenotype, collected from both adults and children at 3 different cystic fibrosis centers: Houston Methodist Research Institute, UW Health and the Center for Global Infectious Disease Research. TLV was found to display activity against all 333 strains collected.

When testing the activity of the drug against 23 MRSA strains, the investigators observed intermediate resistance to ceftaroline (CPT)—a new beta-lactam antibiotic that targets PBP 2a in MRSA—in 20 of the strains, and high-level resistance to CPT in 3 of the strains. The authors note that although high levels of resistance to CPT is rare, intermediate resistance is more common in patients who have chronic infections.

“Among all strains, the TLV MIC90 was 0.06 mg/liter, i.e. 8-fold lower than the daptomycin (DAP) and CPT MIC90 and 25-fold lower than the linezolid (LZD) and vancomycin (VAN) MIC90,” the authors write.

Using time-kill experiments, the investigators assessed the in vitro effectiveness of TLV compared with DAP, VAN, and CPT. They found that TLV showed activity against all tested strains and displayed rapid bactericidal activity as well. The activity profile for the drug at a free serum concentration of 8 mg/liter showed that TLV performed better than VAN (16 mg/liter), LZD (10.4 mg/liter), and CPT (16 mg/liter).

The investigators also set out to determine the fate of mutation selection that could be projected by the potential prolonged use of TLV in patients with cystic fibrosis. To do this they looked at 3 specific strains: AMT 0114-48, WIS 664, and TMH 5007. They found that due to the ease of mutation selection which had been noted in control strains, TLV mutant resistance is independent of the CF patient background of the strains.

“We demonstrated that TLV has bactericidal activity against the S aureus strains tested, including those against which CPT and LZD displayed reduced activity, which might provide TLV a significant advantage over the drugs currently used to eradicate those strains and prevent future exacerbations,” the study authors write.

A clinical trial is currently underway to assess the pharmacokinetic profile of TLV in patients with cystic fibrosis, who usually need dose adjustment because of an increase in the volume of distribution and clearance.

“[The next step for our research is] to perform in-vivo analyses studies that could lead to translational application/clinical trial,” Dr. Rosato added. “However, we are limited in research funds to continue our investigations.”

Original article here.

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.

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

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

Defining chronic Pseudomonas aeruginosa infection in cystic fibrosis

By Valerie Waters and Keith Grimwood

Cystic fibrosis (CF) is a genetic, multi-system disease due to mutations in the cystic fibrosis conductance regulator (CFTR) gene, leading to ineffective anion channel activity [1]. The resulting impaired mucociliary clearance permits initial acquisition of Pseudomonas aeruginosa and, if untreated, the establishment of persistent infection in the CF airways. It has long been recognized that chronic infection, often characterized by a mucoid P. aeruginosa phenotype, is associated with more rapid lung function decline and earlier death in individuals with CF [[2], [3], [4]]. Defining chronic P. aeruginosa infection is, therefore, an important step in identifying CF patients most at risk of lung disease progression. Traditionally, the Leed’s criteria has been used to define chronicity (as having >50% of sputum cultures being P. aeruginosa positive in the preceding 12 months), as it is the only clinically validated definition [5]. However, the Leed’s criteria are difficult to implement in young children unable to provide sputum and further limited by the required number of sputum samples and follow-up time [6].

In this issue of the Journal, studies by Heltshe et al. and Boutin et al. aim to re-define what chronic P. aeruginosa infection means in CF. In a retrospective cohort study using data from the US CF Foundation Patient Registry, Heltshe et al. followed close to 6000 early-diagnosed CF children for approximately 6 years [7]. Two-thirds acquired P. aeruginosa infection and of those, 6% had an initial mucoid phenotype. Furthermore, the majority (87%) of children who developed mucoid infection did so before meeting the definition of chronic infection (at least 3 yearly quarters P. aeruginosa positive in the preceding year). Initial P. aeruginosa infection with a mucoid phenotype has been previously described and is a recognized risk factor for failure of antimicrobial eradication therapy [[8], [9], [10]]. Whether this initial acquisition of a mucoid phenotype represents prior adaptation of P. aeruginosa in the CF host (either undetected or transmitted from a patient with chronic infection) or simply infection with an environmental strain particularly well-suited to the CF airways, is as of yet unknown [11]. It is clear, though, that mucoid P. aeruginosa does have an adaptive advantage in early CF infection as mucoidy was associated with an almost three-fold increased risk of transition to chronic infection in this current study. Despite the presence of this risk factor, however, only 13% of P. aeruginosa infected patients went on to develop chronic infection. Although Heltshe et al. did not provide details as to eradication strategies used in this cohort, this low incidence of persistent infection does speak to the overall effectiveness of current antimicrobial treatment for early P. aeruginosa infection.

Boutin et al. took their investigation a step further by using molecular methods, specifically quantitative polymerase chain reaction (qPCR), to define chronic P. aeruginosa infection [12]. In their study, patients with chronic infection had significantly higher levels of P. aeruginosa as measured by qPCR compared to those with intermittent infection. A single P. aeruginosa qPCR measurement in sputum had a sensitivity of 84% (with a specificity of 85%) in detecting chronic infection using a threshold of 103.4 colony forming units (CFU)/ml. A single sputum PCR measure had the advantage of not requiring 12 months of culture results as per the Leed’s criteria [5]. Furthermore, in their small study sample size, PCR was more discriminatory than mucoidy status in predicting chronicity, not surprisingly, given that alginate production (conferring mucoidy) is only one of several virulence factors contributing to the establishment of persistent P. aeruginosa infection in CF [13]. When used in throat swab samples, qPCR had a considerably lower sensitivity (82%) and specificity (56%) in detecting chronic infection, likely due in part to the lower bacterial burden observed in this specimen, compared to sputum. The low specificity of PCR in this setting (positive PCR, negative culture) may reflect the fact that a molecular signal may precede culture positivity. Early detection of P. aeruginosa infection, before culture conversion, in CF patients was originally suggested decades ago using serologic and, more recently, molecular methods [[14], [15], [16]]. Serology, however, has proven disappointing at identifying early P. aeruginosa infection [17]. Nevertheless, early detection may still be possible using highly-sensitive PCR techniques for identifying lower airway P. aeruginosa infection in a young, non-expectorating child. In the study by Boutin et al., P. aeruginosa detection in throat swabs by PCR alone was linked to a positive culture in sputum in three-quarters of cases. Previous studies comparing oropharyngeal cultures to bronchoalveolar lavage (BAL) cultures in children with CF demonstrated that oropharyngeal cultures had a positive predictive value of only 44%, but a negative predictive value of 95% in diagnosing lower airway P. aeruginosa infection [18]. Performing P. aeruginosa qPCR on culture negative throat swabs may further improve the diagnosis of lower airway infection in young children with CF who are unable to produce sputum, but this approach will still need to be validated by comparative studies employing BAL fluid samples. Unfortunately, using confirmatory induced sputum samples as suggested by Boutin et al., may produce unreliable results as these specimens are poor predictors of lower airway pathogens cultured from BAL specimens in young children with CF [19]. Finally, it is yet to be determined whether an earlier diagnosis of P. aeruginosa infection leads to improved eradication success rates and superior clinical outcomes.

In summary, the recent studies by Heltshe et al. and Boutin et al. further our understanding of how chronic P. aeruginosa infection develops in CF and how to better recognize it [7,12]. Ultimately, prevention of chronic P. aeruginosa infection and its deleterious effects on lung function and survival is the goal.

Original article in Journal of Cystic Fibrosis 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.

6 ways to get back into shape after a CF-setback

For people with cystic fibrosis, getting “back” into shape is a common occurrence. Because of the nature of the disease, patients often experience setbacks in both their health and fitness routines. But, exercise is an important and essential part of remaining compliant with treatments and medications in order to live a longer, healthier life with CF.

Continue reading 6 ways to get back into shape after a CF-setback

Low Level of Zinc Ions in Lungs Contribute to Buildup of Mucus in CF

When two channels that are supposed to move chloride and sodium ions out of cells in the lungs fail to function properly, it leads to the mucus buildup seen in cystic fibrosis.

Japanese researchers have discovered that the channel dysfunctions also reduce the amount of zinc ions going into the lungs, further contributing to the thick mucus accumulation.

Their study, published in the journal EBioMedicine, is titled “Zinc Deficiency via a Splice Switch in Zinc Importer ZIP2/SLC39A2 Causes Cystic Fibrosis-Associated MUC5AC Hypersecretion in Airway Epithelial Cells.Continue reading Low Level of Zinc Ions in Lungs Contribute to Buildup of Mucus in CF

Therapy for Reducing P. Aeruginosa Lung Infections Planned Phase 1 Trial

Arch Biopartners recently completed a good manufacturing practice (GMP) production campaign for AB569, a potential inhalation treatment for antibiotic-resistant bacterial lung infections in people with cystic fibrosis (CF) chronic obstructive pulmonary disease (COPD) and other conditions. The campaign, intended to ensure the quality of the investigative therapy, was directed by Dalton Pharma Services.

AB569 is composed of ethylenediaminetetraacetic acid (EDTA) and sodium nitrite, two compounds approved by the U.S. Food and Drug Administration (FDA) for use in people. AB569 can be administered alone or in combination with other compounds to treat multi-drug resistant bacterial infections that can cause reduced lung function.

Pseudomonas aeruginosa is one of the most common bacterial infections in patients with respiratory diseases, including CF, COPD, and pneumonia.

In preclinical studies, AB569 was shown to be capable of killing drug-resistant bacteria like P. aeruginosa and other common pathogens associated with chronic lung infections.

The company also announced that a Phase 1 clinical trial to investigate the safety and pharmacokinetic profile of AB569, planned to start in January, will be conducted at the Cincinnati Veterans Affairs Medical Center (CVAMC). According to an Arch Biopartners press release, Ralph Panos, chief of medicine at CVAMC, will lead the trial.

Three escalating doses of nebulized AB569 will be used to evaluate tolerance to the treatment in about 25 healthy volunteers. Each will be given a single administration of nebulized AB569  to characterize the pharmacokinetic profile of plasma nitrite and nitrate metabolites, exhaled nitric oxide, and circulating hemoglobin.

Pharmacokinetics studies how a drug is absorbed, distributed and metabolized in, and expelled by, the body.

Should the Phase 1 trial in volunteers be successful, Arch Biopartners plans to move its AB569 program into a Phase 2 trial to test its effectiveness in treating chronic P.aeruginosa infections in COPD patients.

AB569 received orphan drug status by the FDA in November 2015 as a potential treatment of P. aeruginosa lung infections in CF patients. Orphan drug status is given to investigative medicines intended for people with rare diseases to speed their development and testing.

Original article: https://cysticfibrosisnewstoday.com/2017/12/12/arch-biopartners-readies-ab569-potential-treatment-for-cf-copd-lung-infections-for-phase-1-trial/