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Wednesday, April 14, 2010

Antimicrobial properties protect cystic fibrosis patients from infection

Antimicrobial properties protect cystic fibrosis patients from infection

Published Date: 14 April 2010 I

TS antimicrobial properties have been known for centuries - the Egyptians, Greeks, and Romans all used copper to clean wounds and promote good hygiene.But now the substance is enjoying a rebirth - and a new Sheffield healthcare development is leading the way.

The Cystic Fibrosis Unit at the Northern General Hospital will be the first NHS facility to embrace copper's unique properties by using it on door handles, locks and push and and kick door plates. it is just one of the pioneering elements of the unit which is being brought to the city as part of a £1 million Star-backed campaign to make it 'world class'.

The Copper Development Agency has also got on board, commissioning metal worker Adaesi Ukairo to produce a piece of copper artwork for the unit.

Bryony Samuel, from the agency, said: "The science behind the use of copper in infection control is not new, but what is more recent is the laboratory work which proves that it does kill germs and viruses. A study found that there was 90 to 100 per cent less contamination on copper surfaces, compared to non-copper surfaces."

The news is particularly relevant to cystic fibrosis patients who are very vulnerable to infection.
Rebecca Haverty, lead designer from the unit's architects Race Cottam, said: "Common materials such as plastics may look clean but they have no inherent antimicrobial efficacy.
Copper alloys can help to fight infection so we were very keen to use them."

Consultant Dr Frank Edenborough added: "Once CF patients get infections they can be difficult to get rid of and they tend to suffer recurrent bouts. The more they have an infection, the more their lungs are damaged." Visit www.shctonline.org.uk or call 0114 271 1351


Pharmaxis Completes Phase 3 Trial Of Bronchitol

Pharmaxis Completes Phase 3 Trial Of Bronchitol

Published: 14-Apr-2010

Pharmaxis, a specialist pharmaceutical company, has completed second six month, Phase 3 international trial assessing the effectiveness of Bronchitol in people with cystic fibrosis.

The double blind, placebo controlled, randomised study comparing 400mg of Bronchitol twice a day to control included 305 participants, and was conducted across 53 sites in 7 countries. Pharmaxis said that the last participant has completed the final clinical visit and the trial has run on time and on budget.

Pharmaxis has now completed blinded efficacy and safety period, an optional 26 week open-label uncontrolled Bronchitol extension is still running.

The trial is the second of two trials in cystic fibrosis, required by the FDA, before a marketing application can be submitted in the US. A total of 600 cystic fibrosis patients have now been recruited into the two Bronchitol Phase 3 clinical trials.

The primary efficacy end-point is change in lung function from baseline as determined by FEV1 (forced expiratory volume in one second) over 26 weeks. The results of the trial is expected to be available shortly after data review and statistical analysis of the various endpoints have been completed.

Pharmaxis said that the trial has been designed under the FDA’s Special Protocol Assessment (SPA) scheme. Pharmaxis has received Orphan Drug Designation and fast track status from the FDA for Bronchitol in cystic fibrosis.

Based on the results of the first Phase III trial reported in May 2009, Pharmaxis had filed a marketing authorisation application with the European Medicines Agency in October 2009. The regulatory review is expected to conclude during the second half of 2010.

Alan Robertson, CEO of Pharmaxis, said: “We are very pleased to announce this important milestone. The support of the US Cystic Fibrosis Foundation has been important in conducting this trial efficiently and there has been considerable enthusiasm from patients and the clinical centres involved. It is hoped this trial will confirm that Bronchitol has the opportunity to impact the way people with cystic fibrosis live their lives.”


Monday, April 12, 2010

Positive Results from Optimer Pharmaceuticals' Second Phase 3 Study of Fidaxomicin for the Treatment of Clostridium difficile

Press Release Source: Optimer Pharmaceuticals, Inc. On Saturday April 10, 2010, 9:30 am EDT
SAN DIEGO, April 10 /PRNewswire-FirstCall/ -- Optimer Pharmaceuticals, Inc.

(Nasdaq:OPTR - News) announced that the top-line results from its second fidaxomicin Phase 3 clinical study in patients with Clostridium difficile infection (CDI) were presented today at the 20th Annual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Vienna, Austria.

Clinical investigator Derrick Crook, M.D. presented the positive top-line results that the Company had previously announced in February 2010. In the trial, fidaxomicin met the primary endpoint of non-inferiority in clinical cure compared to Vancocin®. Importantly, fidaxomicin also had significantly lower recurrence rates compared to Vancocin (p = 0.002), and significantly higher global cure rates (defined as cure with no recurrence within four weeks of completing therapy) compared to Vancocin (p < 0.001). The robust results from this second fidaxomicin Phase 3 trial confirm the results from the first fidaxomicin Phase 3 trial. Together these trials enrolled more than 1,100 subjects thus making them the two largest comparative studies ever conducted against Vancocin in CDI.

"Fidaxomicin offers potential advantages over existing therapies as a single agent that can provide a high cure rate and fewer recurrences for Clostridium difficile infection," said Dr. Crook, M.D., Consultant Microbiologist/Infectious Diseases and Professor of Infectious Diseases and Microbiology, Experimental Medicine Division, Nuffield Department of Clinical Medicine (NDM), University of Oxford. "Moreover, we found that even in patients with the hypervirulent BI/NAP1/027 subtype, fidaxomicin provided an improvement in recurrence rates compared to the currently approved treatment."

Additional data presented for the first time by Dr. Crook included a subgroup analysis of the BI/NAP1/027 strain and the non-BI/NAP1/027 strain showing clinical cure, recurrence and global cure rates for fidaxomicin compared to Vancocin®. Most notably, Fidaxomicin showed a clinically meaningful reduction in recurrence rates and higher global cure rates compared to Vancocin in both strain type subgroups. Clinical cure rates for fidaxomicin and Vancocin were similar in these two strain type subgroups.

Dr. Crook also presented baseline demographic and disease characteristics of study participants which were similar between the fidaxomicin and Vancocin arms. The BI/NAP1/027 strain was identified in 32% of subjects in the second Phase 3 study. 54% of the study participants were over the age of 65, 68% were in-patients, and 15% had a prior episode of CDI. An average of 7.5 bowel movements per day was observed among all subjects. The incidence of adverse events and serious adverse events was similar in the fidaxomicin and Vancocin arms.

In a separate poster presentation, Mark A. Miller, M.D., head of the Division of Infectious Diseases, Chair of the Infection Prevention and Control Unit at the Jewish General Hospital in Montreal, Quebec, Canada, presented analyses from the first fidaxomicin Phase 3 clinical study in patients with CDI regarding three of the 14 severity criteria specified in the CDI treatment guidelines recently published by The European Society of Clinical Microbiology and Infectious Diseases (ESCMID). Three of ESCMID's 14 severity criteria (temperature, leukocyte count and serum creatinine) had been routinely collected from all subjects in this study and were examined in relationship to clinical cure, recurrence, global cure, and time to resolution of diarrhea (TTROD). According to the ESCMID guidelines, patients with one or more of the criteria could be classified as a severe CDI patient. Out of 596 subjects from this study, 155, or 26%, had one or more of the three ESCMID severity criteria monitored in the study. A validated severity index, score, or categorization system does not exist at the present time for predicting CDI outcomes based on risk factors. The analyses indicated that the three ESCMID criteria monitored in the study were useful in predicting CDI treatment outcomes.

Fidaxomicin Clinical Study Design

The second Phase 3 trial was a multi-center, randomized, double-blind clinical trial, which enrolled 535 adult subjects. Subjects with confirmed CDI received either fidaxomicin (200 mg q12h) or Vancocin (125 mg q6h). This study was conducted in approximately 100 clinical sites throughout North America and Europe. The study was designed to evaluate safety and compare the response to treatment in subjects during and after a 10-day course of therapy. Non-inferiority in clinical cure (defined as patients requiring no further CDI therapy two days after completion of study medication, as determined by the investigator) compared to Vancocin was the primary endpoint. If cured, subjects were monitored for a subsequent four-week period to evaluate recurrence, which was a secondary endpoint. Global cure, also a secondary endpoint, was defined as patients who were cured and did not have a recurrence during this subsequent four-week period.

About Clostridium difficile Infection

CDI has become a significant medical problem in hospitals, long-term care facilities, and in the community. It is a serious illness caused by infection of the inner lining of the colon by C. difficile bacteria, which produces toxins that cause inflammation of the colon, severe diarrhea and, in the most serious cases, death. Patients typically develop CDI from the use of broad-spectrum antibiotics that disrupt normal gastrointestinal (gut) flora, and thus allowing C. difficile bacteria to flourish.

Current therapeutic options for CDI include the off-label use of metronidazole and oral vancomycin, the only FDA-approved treatment. However, approximately 20% to 30% of CDI patients who initially respond to these treatments experience a clinical recurrence following cessation of antibiotic administration.

Primary risk factors for CDI include broad-spectrum antibiotic use (such as cephalosporins and fluoroquinolones), advanced age (over 65) and emerging hyper-virulent strains (BI/NAP1/027, 078, 001) of C. difficile. Increasing incidence, higher treatment failures and recurrence with current therapies have resulted in greater awareness and concern of CDI among medical professionals and public health officials.

About Fidaxomicin

Fidaxomicin is the first in a new class of antibiotics called macrocycles, which inhibit the bacterial enzyme RNA polymerase, resulting in the death of C. difficile. The narrow-spectrum profile of fidaxomicin may eradicate C. difficile selectively with minimal disruption to the normal intestinal flora, while most broad-spectrum antibiotics, including metronidazole and vancomycin, disrupt these flora. Fidaxomicin may facilitate the return of the normal physiological conditions in the colon and reduce the probability of CDI recurrence.

About Optimer Pharmaceuticals

Optimer Pharmaceuticals, Inc. is a biopharmaceutical company focused on discovering, developing and commercializing innovative anti-infectives to treat serious infections and address unmet medical needs. Optimer has two late-stage anti-infective product candidates under development. Fidaxomicin is a narrow spectrum antibiotic being developed for the treatment of Clostridium difficile infection. Optimer has reported positive top-line results from two Phase 3 trials of fidaxomicin. Pruvel™ is a prodrug in the fluoroquinolone class of antibiotics being developed as a treatment for infectious diarrhea. Optimer has also successfully completed two Phase 3 trials with Pruvel. Additional information can be found at http://www.optimerpharma.com.

Friday, April 9, 2010

Co-spray dried mannitol-ciprofloxacin dry powder inhaler for cystic fibrosis

Eur J Pharm Sci. 2010 Apr 2.

Co-spray dried mannitol-ciprofloxacin dry powder inhaler for cystic fibrosis and chronic obstructive pulmonary disease.

Adi H, Young PM, Chan HK, Agus H, Traini D.

Advanced Drug Delivery Group, Faculty of Pharmacy (A15), University of Sydney, Sydney, NSW 2006, Australia.

The aim of this study was to assess the potential of delivering a combination therapy, containing mannitol (a sugar alcohol with osmotic characteristics), and ciprofloxacin hydrochloride, (an antibacterial fluoroquinolone), as a dry powder inhaler (DPI) formulation for inhalation.

Single and combination powders were produced by spray drying ciprofloxacin and mannitol, from aqueous solution, at different ratios and under controlled conditions, as to obtain similar particle size distributions. Each formulation was characterised using laser diffraction, scanning electron microscopy, differential scanning calorimetry, dynamic vapour sorption, X-ray powder diffraction, and colloidal force microscopy.

The in vitro aerosol performance of each formulation was studied using an Aerolizer(R) DPI device and a multistage liquid impinger (analysed using high performance liquid chromatography). In addition, a disk diffusion test was performed to assess the in vitro antimicrobial activity of each formulation and starting materials.

All formulations had similar particle size distributions, however, the morphology, thermal properties and moisture sorption was dependent on the relative percentages of each component. In general, the combination formulation containing 50% w/w mannitol appeared to have the best aerosol performance, good stability and lowest particle cohesion (as measured by colloid probe microscopy. Furthermore, of the formulations tested, mannitol did not appear to alter the effectiveness of the ciprofloxacin antimicrobial activity to Staphylococcus aureus, Pseudomonas aeruginosa and Streptococcus pyrogenes.

The combination of co-spray dried mannitol and ciprofloxacin from a DPI is an attractive approach to promote mucous clearance in the respiratory tract while simultaneously treating local chronic infection, such as chronic obstructive pulmonary disease and cystic fibrosis.

Friday, April 2, 2010

Licorice May Block Effectiveness Of Drug Widely Used By Transplant Patients

Licorice May Block Effectiveness Of Drug Widely Used By Transplant Patients
ScienceDaily (Mar. 31, 2009) —

Chemists in Taiwan are reporting that an ingredient in licorice — widely used in various foods and herbal medicines — appears to block the absorption of cyclosporine, a drug used by transplant patients to prevent organ rejection. This drug interaction could potentially result in transplant rejection, causing illness and even death among patients worldwide who take cyclosporine and licorice together, the researchers caution.

The study is the first report of this potential drug interaction, the scientists say. Their findings will be presented at the American Chemical Society's 237th National Meeting.

"I would suggest that transplant patients avoid taking licorice," warns Pei-Dawn Lee Chao, Ph.D., a chemist at China Medical University in Taichung, Taiwan.

The researchers say they do not know exactly how much licorice it takes to have a toxic effect in humans. Since licorice-based products vary widely in their content of its main active ingredient, a substance called glycyrrhizin, Chao suggests that patients taking cyclosporine avoid licorice altogether. Thousands of patients also take cyclosporine for rheumatoid arthritis, certain skin conditions, and other diseases.

Researchers have known for years that certain medications, foods, and herbs can reduce levels of cyclosporine in the body and should be avoided when taking that immunosuppressant drug. These include St. John's wort, quercetin (an ingredient found in onions and other plants that's also a dietary supplement), onions, ginger, and ginkgo. Other studies show that some substances, such as grapefruit juice, can actually boost cyclosporine levels. Now, it appears that licorice will join the growing list of substances that reduce the absorption of cyclosporine, the researchers say.

In the new study, Chao and colleagues fed cyclosporine to laboratory rats with and without various doses of pure glycyrrhizin and natural licorice extract. Much to the scientists' surprise, levels of cyclosporine dropped in the animals fed licorice or glycyrrhizin.

The researchers are trying to find out why licorice interferes with cyclosporine. Chao says there are no known scientific reports linking consumption of licorice to ill effects in transplant patients. Doctors, however, have not been looking for such a link, she added. The government of Taiwan funded the research through the Committee of Chinese Medicine and Pharmacy, Ministry of Health, R.O.C.

Licorice is a popular herb that has been used in food and medicines for thousands of years. Its active ingredient, glycyrrhizin, is 50 times sweeter than sugar, leading to herb's popular use in candy, herbal teas, and other foods. Some alternative health care providers use licorice root to treat a wide range of illnesses, including the common cold, stomach ulcers, and liver disease.
The new study adds to a growing number of reports indicating that licorice can trigger potentially dangerous drug interactions. Other studies have shown that licorice can interfere with the effectiveness of high blood pressure medications, aspirin, anti-inflammatory drugs, insulin and oral contraceptives. Chao and colleagues say patients should check with their doctor before consuming licorice with any critical drugs that might trigger unhealthy interactions.

Trip to the Candy Store Might Help Ward Off Rare, but Deadly Infections

Licorice Root: Trip to the Candy Store Might Help Ward Off Rare, but Deadly Infections
ScienceDaily (Jan. 4, 2010) —

As it turns out, children were not the only ones with visions of sugar plums dancing in their heads over this past holiday season. In a new research report published in the January 2010 issue of the Journal of Leukocyte Biology, a team of scientists from the University of Texas Medical Branch and Shriners Hospitals for Children shows how a compound from licorice root (glycyrrhizin from Glycyrrhiza glabra) might be an effective tool in battling life-threatening, antibiotic-resistant infections resulting from severe burns.

Specifically, they found that in burned mice, glycyrrhizin improved the ability of damaged skin to create small proteins that serve as the first line of defense against infection. These proteins, called antimicrobial peptides, work by puncturing the cell membranes of bacteria similar to how pins pop balloons.

"It is our hope that the medicinal uses of glycyrrhizin will lead to lower death rates associated with infection in burn patients," said Fujio Suzuki, Ph.D., one of the researchers involved in the work. Suzuki also said that more research is necessary to determine if this finding would have any implications for people with cystic fibrosis, who can develop Pseudomonas aeruginosa infections in their lungs.

To make this discovery, Suzuki and colleagues used three groups of mice. The first group was normal, the second group was burned and untreated, and the third group was burned and treated with glycyrrhizin. The skin of the untreated burned mice did not have any detectable antimicrobial peptides that prevent bacteria from growing and spreading, but the normal mice did. The skin of the untreated burned mice also had immature myeloid cells, which indicate an inability of the skin to produce antimicrobial peptides needed to prevent infection. The mice treated with glycyrrhizin, however, were more like the normal mice as they had the antimicrobial peptides and no immature myeloid cells.

"Burns are the most painful of all injuries," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology, "and the deadly Pseudomonas infections that can result from severe burns do more than add insult to those injuries. This research should serve as an important stepping stone toward helping develop new drugs that help prevent or treat Pseudomonas."

Patient segregation and aggressive antibiotic eradication therapy can control methicillin-resistant Staphylococcus aureus at large cystic fibrosis cen

J Cyst Fibros. 2010 Mar;9(2):104-9. Epub 2010 Jan 3.

Patient segregation and aggressive antibiotic eradication therapy can control methicillin-resistant Staphylococcus aureus at large cystic fibrosis centres.

Doe SJ, McSorley A, Isalska B, Kearns AM, Bright-Thomas R, Brennan AL, Webb AK, Jones AM.
Manchester Adult CF Centre, University Hospitals of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK. simondoe@doctors.org.uk

BACKGROUND: The prevalence of MRSA in patients with CF has risen in recent years. We adhere to a policy of segregation and barrier nursing to manage patients with MRSA, and we actively pursue eradication of MRSA. We have evaluated our experiences of MRSA infection in our large adult CF centre.

METHOD: A retrospective review of all MRSA-positive patients from 1998 to 2008 was undertaken. Isolates were subjected to molecular identification to elucidate possible patient-to-patient transmission events. Eradication attempts were scrutinised.

RESULTS: We have maintained a low incidence and prevalence (below 3%) of MRSA within this large cohort. A total of 15 pulsotypes of MRSA were identified among the 24 isolates examined, epidemiological data suggested no patient-patient transmission. Based on 6 month follow-up data, successful eradication was achieved in 81% patients. This includes those who had harboured infection for some time. Twenty-one (80.8%) required only one course of treatment, 3 (11.6%) patients required two different regimes and 2 (7.5%) required three courses to fully eradicate the organism.

CONCLUSION: Strict infection control procedures can control MRSA infection and keep the prevalence low in CF clinics. Eradication is achievable in the majority of patients even when significant time has lapsed from initial isolation. In some instances, up to 3 courses of antibiotics were required to achieve eradication.

Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis--a pilot randomized controlled trial.

Pediatr Pulmonol. 2010 Apr;45(4):356-62.

Garlic as an inhibitor of Pseudomonas aeruginosa quorum sensing in cystic fibrosis--a pilot randomized controlled trial.

Smyth AR, Cifelli PM, Ortori CA, Righetti K, Lewis S, Erskine P, Holland ED, Givskov M, Williams P, Cámara M, Barrett DA, Knox A.

Division of Child Health, University of Nottingham, Nottingham, UK. alan.smyth@nottingham.ac.uk

Pseudomonas aeruginosa forms biofilms in the cystic fibrosis lung. Quorum sensing (QS) controls biofilm maturation, immune evasion, antibiotic tolerance and virulence factor production. Garlic shows QS inhibitory activity in vitro and in animal models. We report the first clinical trial in man of a QS inhibitor.

We randomized 34 patients to garlic or olive oil capsules (both 656 mg daily). Clinical outcomes and safety bloods were measured at baseline and after 8 weeks treatment. In this exploratory study, analysis was per protocol. Eight patients withdrew, leaving 26 for analysis (13 garlic).

With placebo, there was a greater decline in mean (SD) percentage change from baseline FEV(1) [-3.6% (11.3)] than with garlic [-2.0% (12.3)]. This was not significant (mean difference = 1.6, 95% CI -12.7 to 15.9, P = 0.8). The mean (SD) increase in weight was greater with garlic [1.0% (2.0)] than with placebo [0.6% (2.0)]--non-significant (mean difference = 0.4%, 95% CI -1.3 to 2.0, P = 0.6).

The median (range) change in clinical score with garlic was -1 (-3 to 5) and 1 (-1 to 4) with placebo (negative score means improvement). This was non-significant [median difference = -1 (-3 to 0), P = 0.16]. In the garlic group, seven patients had IV antibiotics versus five placebo. There was a highly significant correlation between plasma and sputum measurements of the QS molecule 3-oxo-C12-HSL (Pearson correlation coefficient = 0.914, P = 0.004). At the end of treatment five patients in each group had abnormal liver function or triglycerides and five garlic patients (one placebo) reported minor adverse effects.

Garlic capsules were well tolerated. Although there was no significant effect of garlic compared to placebo in this pilot study, there was a suggestion of improvement with garlic which should be investigated in a larger trial.

PMID: 20306535 [PubMed - in process]