Saturday, February 27, 2010

Smart Pseudomonas

Adapting To Clogged Airways Makes Common Pathogen Resist Powerful Antibiotics

People with cystic fibrosis frequently have lung infections that defy treatment. Cystic fibrosis is an inherited disease that clogs airways with thick mucous. While the life expectancy for children with cystic fibrosis has increased over the past few decades, many lives are still shortened in young adulthood by the ravages of lung infections.

These chronic infections are often caused by common, environmental microbes that mutate in ways that let them live and thrive in viscous lung secretions. The same adaptations also make the pathogens less likely to be killed off by powerful antibiotics, according to a recent study led by Dr. Lucas “Luke” Hoffman, University of Washington assistant professor of pediatrics.

Surprisingly, he added, the pathogens don’t need any previous exposure to the antibiotics to resist their effects. The results were published in the latest edition of PLoS Pathogen.

The researchers looked at Pseudomonas aeruginosa, a microbe that can infect a cystic fibrosis patient early in life and then undergo various changes as it establishes a chronic lung infection. Pseudomonas aeruginosa with specific alterations tend to give patients a poor outcome. Some of those alterations diminish the chances of eradicating the infection with antibiotics.

It’s believed that these adaptive alterations in Pseudomonas, all of which are caused by genetic changes, could be selected for by the environment inside a patient’s airways, the researchers noted. Characteristics that facilitate microbial survival begin to emerge.

The specific airway conditions that select for these genetic changes, Hoffman said, remain unclear. “But,” he added, “we have some clues from what is known about airway mucus.”

From the point of view of Pseudomonas, the physical properties of cystic fibrosis mucus, Hoffman said, “make it a great place for the stuff people routinely breathe in to set up shop.” Cystic fibrosis secretions contain a lot of nitrates and amino acids, which Pseudomonas can use to grow.

Inside mucus plugs oxygen levels are low. Some Pseudomonas strains can live in this oxygen-poor, nutrient-rich environment. Hoffman and his team found that a mutation that occurs commonly in Pseudomonas from cystic fibrosis patients allows the pathogen to grow better in the nutrient environment in cystic fibrosis secretions. This particular mutation inactivates a gene named lasR. Pseudomonas with this mutation apparently undergo a metabolic shift: consuming less oxygen while utilizing nitrate more efficiently. lasR mutant bacteria also can handle oxidative stress resulting from an imbalance of damaging substances called free radicals forming faster than they can be detoxified.

One source of oxidative stress encountered by Pseudomonas is the antibiotic treatment that is frequently given to people who have cystic fibrosis. Antibiotics like ciprofloxacin and tobramycin kill bacteria partly by inducing the overproduction of free radicals and causing oxidative stress. Hoffman and his team found that, because these mutant microbes are resistant to oxidative stress, they were relatively resistant to these antibiotics when grown in conditions that were like cystic fibrosis mucus.

“We learned that simply by adapting to the conditions inside the airways of cystic fibrosis patients, mutated Pseudomonas can withstand the effects of ciprofloxacin and tobramycin,” Hoffman said. They did not need any previous exposure to these antibiotics to reduce their susceptibility.

Hoffman and his team suspect that Pseudomonas is not the only microbe that can do this. Some of the characteristics conferred by the mutation in Pseudomonas are also exhibited in other microbes found in chronic lung infections, such as tuberculosis or the fungal pathogen, Cryptococcus neoformans, Hoffman noted. Metabolic shifts may be a way many microbes get the upper hand over their hosts — and over antibiotics.

This report, Hoffman said, may point to new ideas for treating chronic lung infections. Luckily, colonies of Pseudomonas with the lasR mutation are relatively easy to identify in hospital laboratories by their distinctive iridescent sheen. Because lasR mutant Pseudomonas has been associated with worse outcomes in cystic fibrosis patients, indentifying Pseudomonas with the lasR mutation may be of prognostic value and may indicate the need for treatment with specific antibiotics like monobactams, tetracyclines, or polymyxin, whose mode of action differs from ciprofloxacin and tobramycin. Other treatment methods may be targeted at preventing adaptive changes, such as the lasR mutation, in Pseudomonas, the researchers said.

View the full article here: http://www.bmedreport.com/archives/10015

Friday, February 26, 2010

First Time Finding the Baby in a Cake

As some of you know a couple of weeks ago a super sweet cyster out in the community decided to send me a King Cake so I could be a part of their Mardi Gras celebration. You can find the post about it here. Well, video has finally surfaced of us finding the famous baby in that cake. Let me just tell you, a bit creepy!!!

Thursday, February 25, 2010

Thankful for New Drugs!!!

This Thankful Thursday is a pretty easy one! I'm so thankful for the new drug just approved by our FDA :) I've heard nothing but great things about this drug from fellow cysters and fibros and I really can't wait to try it out myself. Make sure to call your clinic ASAP to see if this is a drug that can help you and one that you can get on sooner rather than later.

The drug by the way is Cayston, also known as AZLI. Think of it as another TOBI type of drug that can be done during your off month of TOBI or can be done instead of TOBI all together. It has to be taken three times a day, but the great part is, the treatment takes 2 to 3 minutes!!!

Bring it on!

Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted marketing approval for Cayston(R) (aztreonam for inhalation solution) as a treatment to improve respiratory symptoms in cystic fibrosis (CF) patients with Pseudomonas aeruginosa (P. aeruginosa). Cayston's safety and efficacy have not been established in pediatric patients below the age of 7, patients with forced expiratory volume in one second (FEV1) of less than 25 percent or greater than 75 percent predicted, or patients colonized with Burkholderia cepacia.

Cayston is administered at a dose of 75 mg three times daily over a 28-day period and is delivered via the Altera(R) Nebulizer System, a portable, drug-specific delivery device using the eFlow(R) Technology Platform, developed by PARI Pharma GmbH. PARI Pharma also contributed to the development of Cayston's drug formulation for delivery with the Altera Nebulizer System. Cayston will be available in the United States by the end of next week through certain specialty pharmacies.

"All of us at Gilead extend our thanks to the investigators and to the people with cystic fibrosis who took part in the Cayston clinical trials," said Norbert Bischofberger, PhD, Gilead's Executive Vice President, Research and Development and Chief Scientific Officer. "We look forward to making Cayston available to the cystic fibrosis community as soon as possible."

CF is a chronic, debilitating genetic condition that affects the respiratory and digestive systems of approximately 70,000 people worldwide, including 30,000 people in the United States. Chronic respiratory tract infection with P. aeruginosa contributes to the decline in pulmonary function, which is often associated with morbidity and mortality among CF patients.

"Since its founding in the 1950s, the Cystic Fibrosis Foundation has worked to advance the care and treatment of cystic fibrosis and we are pleased with the progress to date," said Robert J. Beall, PhD, President and Chief Executive Officer, Cystic Fibrosis Foundation. "However, a significant need for new treatments remains for people with cystic fibrosis, particularly for those with chronic pseudomonal infection. As the first new inhaled antibiotic approved for use in cystic fibrosis in more than a decade, Cayston therefore represents an important therapeutic option in the care of patients with cystic fibrosis."

Cayston received conditional marketing authorizations in the European Union and Canada in September 2009 and was approved in Australia in January 2010. Applications for marketing approval of Cayston are currently pending in Switzerland and Turkey.

Reimbursement and Access to Care

Gilead also announced today the establishment of a program designed to minimize barriers to access for Cayston for uninsured, privately insured and government-insured people with cystic fibrosis.

Additionally, Gilead is launching the Cayston(R) Access Program, a call center developed with Cystic Fibrosis Foundation Pharmacy, LLC, a wholly owned subsidiary of the Cystic Fibrosis Foundation. The program will assist people with cystic fibrosis and members of their care team with insurance verification, referral to participating specialty pharmacies, claims support and co-pay assistance. For information about the Cayston Access Program, call 1-877-7CAYSTON (877-722-9786) or visit www.cayston.com.

About Cayston

Cayston (aztreonam for inhalation solution) 75 mg is an inhaled antibiotic for patients with cystic fibrosis who have P. aeruginosa. Aztreonam has potent in vitro activity against gram-negative aerobic pathogens including P. aeruginosa. Cayston contains aztreonam formulated with lysine, a proprietary formulation of aztreonam developed specifically for inhalation. Aztreonam formulated with arginine has previously been approved by FDA for intravenous administration.

Cayston is administered three times a day for a 28-day course, followed by 28 days off of Cayston therapy. Cayston is administered by inhalation and should only be used with an Altera Nebulizer System. Patients should use a bronchodilator before administration of Cayston.

Article from Business Wire. February 22, 2010. To read the full article please click here.

Tuesday, February 23, 2010

Top Ten Toys I Never Grew Out Of


(**Written by Mandi)
Sunday night Ronnie and I went to listen to live music with friends of ours to celebrate one of our good friend's birthdays. As a little birthday gift, Ronnie and I bought her a Giant Googly Ball (see the picture to the left) that lights up when you push a button inside. It was a huge hit. Even people that weren't there with us took their turn playing with it. That got us talking on the car ride home about classic toys we still loved as adults. Here's our list in no particular order:

10. Etch a Sketch - You all know this one well. Two knobs on the lower left and right hand sides under the screen. The toy that takes massive amounts of concentration to make good images on even at an old age.
9. Pin Art - What other toy can you spent hours with making your hand and face into metal art? I used to love seeing that I could create, and would find myself fascinated with just the mere feel of it.
8. Slinky - Who walks the stair without a care. It shoots so high in the sky. Bounce up and down just like a clown. Everyone knows its Slinky. The best present yet to give or get. The kids will all want to try. The hit of the day when you're ready to play. Everyone knows it's Slinky. It's Slinky, It’s Slinky for fun it's the best of the toys It's Slinky, It’s Slinky the favorite of girls and boys.

7. Yo Yo - Now, I never was good enough to compete in any competitions, and never attended any conventions. But I did enjoy them and mastered the art of walking the dog and around the world.
6. Lite Bright - Ah there's nothing like making images out of little neon light bulbs. There's no wonder this is a toy that's been around since the 60s!

5. Slap Bracelet - It's metal covered in fabric, it's a bracelet, it's dangerous and removed from the market, it's CLASSIC!
4. Magnadoodle - I think my love for this toy stems from a fascination that it actually works!

3. View Master - Like your own personal slide show, no electricity needed.

2. Rubiks Cube - I've never once been able to actually make all the sides the same color, so I've never actually been GOOD at this toy. But I can waste hours playing with it.

1. Magic 8 ball - Will I marry him? Will my hair look good blonde? Will I get an A on my math test? The answer to all life's questions can be found in the infinite wisdom of the Magic 8 ball.



What are your favorite toys that you just never grew out of. We all have them!

Monday, February 22, 2010

Pre-marriage Counseling by Rondi

Sunday, February 21, 2010

Drug Improved Survival in Mice With Cystic Fibrosis

It may only be mice, but it's a start....

In the search for new treatments for cystic fibrosis, U.S. researchers have identified a defective signaling pathway that contributes to the severity of the inherited lung disease.

Cystic fibrosis causes thick, sticky mucus to build up in the lungs and digestive tract, and is one of the most common potentially lethal genetic diseases in children and young adults.

In the new study, the researchers found that correcting the defective signaling pathway for a protein called peroxisome proliferator-activated receptor-y (PPAR-y) reduced cystic fibrosis symptoms in mice.

"Cystic fibrosis results from a genetic mutation in a channel, or membrane pore, that facilitates the transport of chloride and bicarbonate electrolytes from inside the cell to the spaces outside the cell," lead investigator Dr. Gregory Harmon, of the University of California, San Diego School of Medicine, said in a news release from the school.

"Loss of the cystic fibrosis pore channel results in inflammation and mucus accumulation. It also results in dehydration of the cell surfaces that make up the lining spaces inside the lungs and other affected organs, such as the intestinal tract," he explained.

Working with cells from mice and human cell lines from cystic fibrosis patients, Harmon and his colleagues determined that multiple genes affected by PPAR-y were reduced in cystic fibrosis.

The researchers then treated mice with cystic fibrosis with the drug rosiglitazone (a drug that binds and activates PPAR-y) and found that gene expression was largely normalized and survival improved. Among the other findings:

  • Drug treatment also corrected part of the inflammatory process associated with cystic fibrosis.
  • Deleting PPAR-y in the intestine of mice worsened cystic fibrosis.
  • Activating PPAR-y can increase bicarbonate production in intestinal tissue by increasing the activity of bicarbonate-producing enzymes called carbonic anhydrases.

"For the first time, we are able to use a drug that activates bicarbonate transport without affecting chloride transport, and see improvement in the disease," Harmon said.

The findings, published in the Feb. 14 issue of Nature Medicine, may lead to new treatments for cystic fibrosis.