The thick, sticky mucous that characterizes Cystic Fibrosis is often what leads to serious bacterial infections in patients and can become life-threatening. Aggressive bacterial strains such as Staphylococcus aureus — more commonly known as MRSA — are threatening enough to hospital patients being treated for other diseases. For CF patients, however, the risk of developing a MRSA infection can prove fatal.
Fortunately, in spite of the difficulties in researching and treating MRSA in Cystic Fibrosis, there are a number of therapies and insights into fighting the infection on the horizon.
MRSA and Cystic Fibrosis: What you Need To Know
Methicillin Resistant Staphylococcus aureus (MRSA) has been a threat since the early 1960s. However, the infection has become more widespread in recent years.
MRSA is a mutated form of Staphylococcus aureus bacteria that is resistant to a number of common antibiotics. Early on, MRSA infections were common in hospitals and other healthcare facilities, however, the infection is no longer as much of a widespread threat as other bacteria, such as C. Diff. While most of the MRSA infections still occur in hospitals but it has now spread into our homes and other places beyond medical facilities.
In the non-medical setting, MRSA commonly generates skin infections but can infect the urinary tract, lungs, and blood. While S. aureus is commonly found on skin and in noses, and protects people from other bacterial pathogens, about 1 percent of these bacteria come in the form of MRSA. If left untreated, MRSA infections can cause severe tissue damage and in rare cases death. Even though MRSA is resistant to some antibiotics, it is not resistant to all.
CF patients are more susceptible to community acquired MRSA, but even more so in hospital acquired infections, which are referred to as nosocomial infections. The main reason for this is that CF patients often are admitted into hospitals, which increases their exposure to MRSA in the medical community. The thick mucus that is produced and trapped in the lungs of a CF patient increases the risk of a MRSA lung infection. Additionally, peripherally inserted central catheters (PICC) and other types of long-term intravenous (IV) access increases the risk of MRSA wounds or bloodstream infections. PICCs are a form of intravenous access that can be used as long-term chemotherapy, antibiotic or nutritional regimens. Placement of the catheter in a vein creates an access for bacteria and the catheter itself may be a harbinger of bacteria if not initially clean.
MRSA can be spread directly or indirectly, and what makes it so contagious is that it can live on inanimate objects for up to a number of months. As a result, patients can contract MRSA by touching someone who has it, an inanimate object that has it, or a caregiver or other person who has touched someone or something that was contaminated with it. To reduce the risk of getting MRSA when at home, CF patients are advised to avoid sharing equipment, razors, towels, and other personal items with family members.
Several Cystic Fibrosis studies have evaluated primary prophylaxis for methicillin sensitive Staph aureus using a number of agents and these studies demonstrated a decrease in acquisition of MRSA in children receiving antibiotics. Unfortunately, the studies were not randomized nor did they have high statistical significance. Furthermore, useful clinical outcomes like fewer hospitalizations or improved lung function were inconsistently observed.
Beyond that, the most serious concern with chronic use of anti-staphylococcal antibiotics is the increased risk of developing Pseudomonas aeruginosa. Researchers have reported increased P. aeruginosa acquisition in CF children followed from age 2 to 6 years of age treated with continuous cephalexin versus placebo. However, this was not observed with flucloxacillin prophylaxis. Many other agents have been used, but differences in findings occurred probably due to the duration of therapy and type used. In the U.K, flucloxacillin is administered from the time of diagnosis until 2 years of age to reduce cough, use of other antibiotics and inhibit Staph infections.
Nevertheless, anti-staphylococcal prophylaxis is not routinely practiced in North America. Some studies have demonstrated eradication of Staph from respiratory secretions with the use of anti-staphylococcal antibiotics, but failed to demonstrate concomitant improvement in pulmonary function or other clinical outcomes. Nevertheless, most clinical studies have used small sample size with variable follow up. Many more clinical trials are needed until CF and MRSA are cured.
Antipsychotic Drug Thioridazine and MRSA
Perhaps one way to deal with resistance is to stop it before it happens. Recent research done by a chemist at the University of Copenhagen may have solved this problem. Jørn B. Christensen, PhD, and colleagues from the University of Southern Denmark and King Christian X’s Hospital for Rheumatic Diseases in Gråsten, Denmark, have found that an isomer from an antipsychotic drug thioridazine (Mellaril, Novartis) can block a bacteria’s efflux pump, preventing their ability to shed antibiotics before the drugs can do their work. According to a recent press release, they have taken out a patent for this drug. While MRSA normally does not have an efflux pump, some rare cases with the gene has been reported.
Christensen and colleagues have indicated that they intend to use this new drug for the treatment of multi-drug resistant tuberculosis. They report that taken as a whole, the antipsychotic was demonstrated to kill bacteria without harming the patient, however the isomer they selected for patenting is the milder of the two associated with thioridazine, which makes it even more tolerable for the patient. Christensen notes, “We now have a substance that is able to block the bacteria’s efflux pump,” he said in the release. “At the very most, recipients of the medication may become slightly sluggish. This is also because very small doses are needed to affect the bacteria.”
The next step for Christensen is to recruit investors to put the drug on the market. Thioridazine is already approved by the FDA, so the drug developers hope that the formula will be approved more quickly. Christensen notes that if that fails, he has an alternative plan: “I would rather donate this discovery to a [non-governmental organization] able to use this substance in poor countries that suffer from drug-resistance problems than watch it collect dust in the industrialized world.”
The ‘Buttery’ molecule and CF flare-ups
In a report published in early 2014, a molecule that had been linked to lung injuries in factory workers producing microwave popcorn was thought to play an important role in microbial functions in individuals with CF. According to Katrine Whiteson, San Diego State postdoctoral researcher and lead investigator, the molecule is known as 2,3-butanedione or diacetyl and it can be detected in higher concentrations in CF patients versus healthy individuals.
It is well known that CF individuals experience day-to-day persistent coughing with increased mucus production and periodic flare-ups of these symptoms, referred to as exacerbations. It is believed that most of the permanent scarring in lung tissue occurs during these exacerbations. If patients knew of oncoming flare-ups, they could respond earlier and ward off some of the damage. Whiteson notes, “Unfortunately, right now there’s really no good way to detect when someone’s about to have an exacerbation.”
Currently, the problem is that when cultures are taken from CF patients, labs don’t usually observe a major difference between microbes that grow when a CF patient is feeling healthy and when they are feeling sick. This creates a problem for healthcare professionals when deciding what antibiotic to administer — it is simply a trial and error situation. This dilemma begs the question: What is different about the CF lung during these exacerbations?
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To determine what the difference was during lung exacerbations, Whiteson and colleagues studied the molecules produced by microbes in the airway. Researchers measured breath gases from CF patients and healthy volunteers and found elevated levels of diacetyl in CF patients’ lungs. This molecule is the main ingredient in microwave popcorn flavoring and has a buttery flavor. The molecule is toxic and known to damage the lungs of popcorn factory workers.
Whiteson and her colleagues think that various species of oral streptococcus also produce diacetyl via a fermentation process. The molecule can also activate harmful effects on other bacteria that are common in the lungs of CF individuals. It is known that when P. aeruginosa comes in contact with diacetyl, it causes the production of toxic compounds which may be at least in part responsible for CF’s lung damage. Since the research used small sample size, the next step will be to validate their results with a larger pool.
Whiteson and her teammates believe a new technology that works like a breathalyzer could be designed to test for the presence of diacetyl. Patients could monitor themselves on regular basis and get an early warning signal that an exacerbation is coming and then take antibiotics to prevent it from occurring. So, Whiteson is currently working with a Silicon Valley biotech company (Metabolomx) to develop a microchip that can detect diacetyl as well as other indicators.
Nanotechnologies Meet MRSA
Researchers at IBM and the Institute of Bioengineering and Nanotechnology have found a nanomedicine in which new types of polymers have been demonstrated to physically detect and destroy antibiotic-resistant bacteria such as MRSA as well as other bacteria.
The nano structures are physically attracted to infected cells like a magnet, allowing them to selectively eradicate resistant microbes without damaging healthy cells. The polymers prevent bacteria from developing resistance by breaking through the bacterial cell wall and membrane.
Some bacteria are challenging to destroy due to their ability to evolve resistance, since current therapies leave their cell wall and membrane intact. Furthermore, high doses of antibiotics that are required to kill bacteria also destroy healthy red blood cells in addition to contaminated ones.
According to Dr. James Hedrick, Advanced Organic Materials Scientist, IBM Research – Almaden, “The number of bacteria in the palm of a hand outnumbers the entire human population. With this discovery we’ve been able to leverage decades of materials development traditionally used for semiconductor technologies to create an entirely new drug delivery mechanism that could make them more specific and effective.” The biodegradable nanostructures can be injected directly into the body or applied topically. The nanostructures can be applied to deodorants, soaps, hand sanitizers, table wipes, preservatives as well as be applied to a lung infection.
Clinical trials and CF patients with MRSA
Clinical trials are a very important part of clinical research looking for new ways to prevent, detect and treat disease. Trials are truly at the heart of medical advances. These trials determine whether a new test or therapy will work and work safely. Clinical trials go far beyond how well a new therapy will work and work safely but they also evaluate quality of care and improving quality of life for individuals who have chronic diseases. Clinical trials provide hope for many individuals and offer and opportunity to help researchers find better therapies for others in the future.
Clinical trials are currently available for individuals who have CF with MRSA and the trials need more participants. Cystic fibrosis patients who are battling MRSA should consult with their doctor about participating in clinical trials where CF patients with MRSA are needed.
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