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Ribotypes and Prevalence of Clostridium difficile (C. diff) Hypervirulent Strain: NAP1/B1/027

The Hypervirulent Strain of Clostridium Difficile: NAP1/B1/027

– A Brief Overview



Abstract

Clostridium difficile is a gram-positive bacterium notorious for causing epidemic diarrhea globally with a significant health burden. The pathogen is clinically challenging with increasing antibiotic resistance and recurrence rate. We provide here an in-depth review of one particular strain/ribotype 027, commonly known as NAP1/B1/027 or North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis type B1, polymerase chain reaction ribotype 027, which has shown a much higher recurrence rate than other strains.

Introduction & Background

Clostridium difficile (C. diff) is a gram-positive, anaerobic, motile, spore-forming, rod-shaped bacteria [1-2]. It has been isolated from almost all mammals, including pigs, cows, horses, elephants, and Kodiak bears, as well as in poultry and ostriches. It has also been found in the soil and feces of humans and animals. It is transmitted from person to person by the fecal-oral route. The C. diff isolates found in animals are similar to the ones found in humans, but according to Hensgens et al., this similarity does not mean that interspecies transmission occurs. However, immunocompromised people are still at risk for interspecies transmission [1]. Its pathogenicity is dependent on the two toxins that it produces: enterotoxin A (Toxin A or TcdA) and cytotoxin B (Toxin B or TcdB). Enterotoxin damages the actin in target cells which leads to neutrophil infiltration, inflammation, and necrosis of epithelial cells. Cytotoxin B has been shown to damage tight junctions of epithelial cells, which increases vascular permeability and causes hemorrhage [2-3]. These toxins form the basis of stool analysis when diagnosing people with the suspected infection. Despite all the virulence characters described, C. diff is a poor competitor against other gut flora in the human colon. In a healthy colon, this pathogen is not in sufficient quantity to produce a clinically significant disease. Risk factors that disrupt this balance include antibiotics exposure, health care environment, acid suppressants, and elemental diet. The bacterium can cause severe watery diarrhea that can progress to pseudomembranous colitis [3-8]. It has been named as one of the three microorganisms with an ‘urgent’ threat level by the Centers for Disease Control and Prevention (CDC) based on its public health impact in the United States (US) with an estimated $1.5 billion US in annual health care expenditures [8]. Patients who have more than three episodes of unexplained and new onset unformed stools in 24 hours should be referred for testing for a Clostridium difficile infection (CDI). Also, patients with risk factors described previously should undergo testing for this pathogen [9]. The ribotype 027 strain of C. diff is particularly noteworthy as contradicting evidence in the literature is present regarding the disease severity it causes. We provide here a brief overview of the epidemiology, pathophysiology, and treatment of this particular strain.

Review

Ribotypes and prevalence of Clostridium difficile (C. diff)

Clostridium difficile can be characterized according to its ribotyping which is performed using the polymerase chain reaction. Several different ribotypes have been associated with CDI. The ribotypes 001, 002, 014, 046, 078, 126, and 140 have been found to be prevalent in the Middle East [10-12]. In Asia, ribotypes 001, 002, 014, 017, and 018 are more prevalent [13-15]. The predominant strains in Europe and North America include ribotypes 001, 014, 020, 027, and 078 [6]. The ribotype 027 (also referred to as NAP1/B1/027) has emerged in the last decade. Studies have underlined antimicrobial resistance as one of the causes of its epidemic outbreaks. Capillary electrophoresis (CE) ribotyping is used as the standard for characterization of C. diff isolates. This method relies on the intergeneric region variability between 16S and 23S ribosomal deoxyribonucleic acid (DNA) [16]. Ribotype 027 was found to have reduced susceptibility to metronidazole, rifampicin, moxifloxacin, clindamycin, imipenem, and chloramphenicol [17-18]. It is clinically and financially concerning as it leads to severe disease presentation, as well as antimicrobial resistance with high morbidity and mortality rates as compared to other strains [19]. Strains, such as ribotype 027 (especially its spores), spread more easily within the hospital because they can resist the hospital environment, cleaning, and disinfectants [1]. An observational study conducted on patients admitted with diarrhea in a Veteran Affairs Medical Center showed that around 22% of the patients were positive for the NAP1/B1/027 strain out of all the people who tested positive for CDI. Further, a reduction in the rate of diarrhea caused by the NAP1/B1/027 strain was observed with a prevalence of 16.9% in 2016, down from 26.2% in 2013. An increase in the level of awareness and education was thought to be the reason for this decline [20]. The prevalence of this strain in North America is reportedly around 22% – 36%. Ribotype 027 was identified as the most prevalent strain causing CDI with recent outbreaks in North America [20-22]. The prevalence of this strain was shown to be 48% in hospitals in Poland with an outbreak of CDI during September 2011 to August 2013 [21].

NAP1/B1/027 strain

Toxigenicity and Pathogenesis

The North American pulsed-field gel electrophoresis type 1, restriction endonuclease analysis type B1, polymerase chain reaction ribotype 027 (NAP1/B1/027) strain has been shown to contain a gene locus, CdtLoc, that encodes for CD196 ADP-ribosyltransferase (CDT) or binary toxin. The bacterium also produces Toxin A and Toxin B, similar to non-027 ribotypes, through the PaLoc gene locus [23-24]. CDT was first isolated by Popoff et al. [25]. The toxin comprises two separate toxin components: CDTa and CDTb. CDTa, which is an ADP-ribosyltransferase enzyme, modifies actin which results in depolymerization and destruction of the actin cytoskeleton in the gut. CDTb binds to gut cells and increases uptake of CDTa. The destruction caused by CDT favors adherence of bacteria and increased uptake of Toxin A and Toxin B [26].

In addition to the toxins, this strain (along with few others) carries a base pair frameshift deletion at nucleotide 117 of the TcdC gene, which is a negative regulator of Toxins A and B. A mutation in this gene thus causes hyperexpression of toxins by this particular strain. Warny et al. showed that NAP1/B1/027 produces Toxin A approximately 16 times and Toxin B approximately 23 times more than the control strains [27]. One study also proposed that increased sporulation by this strain may also be associated with the increased spread of CDI [28]. The virulent factors associated with NAP1/B1/027 strain have been summarized in Table 1.

Virulent factor Mechanism
1. Toxin A (Enterotoxin A or TcdA) Damages the actin in target cells which leads to neutrophil infiltration, inflammation, and necrosis of epithelial cells [24].
2. Toxin B (Cytotoxin B or TcdB) Damages tight junctions of epithelial cells, which increases vascular permeability and causes hemorrhage [24].
3. CDTa toxin Modification of actin with ADP-ribosylation that results in actin depolymerization and destruction of the cytoskeleton that assists in adherence of bacteria to gut epithelial cells [25-26].
4. CDTb toxin Facilitates uptake of CDTa toxin into the gut epithelial lining [25-26].
5. Hypersporulation Increases reproduction and spread of bacteria [28].
6. TcdC gene mutation (18-bp deletion) Increases the production of Toxin A and Toxin B by down-regulation of feedback inhibitor involved in suppressing toxin production [27].

Previous studies have shown contradicting evidence regarding the severity of disease caused by this particular strain. A recent retrospective analysis by Bauer et al. concluded that NAP1/B1/027 was associated with a decreased odds of severe disease (odds ratio (OR): 0.35, 95% confidence interval (CI) 0.13 – 0.93) and did not increase in-hospital mortality (OR: 1.02, 95% CI 0.53 – 1.96) or recurrence rate (OR: 1.16, 95% CI 0.36 – 3.77) [23]. Several other studies conducted (including cross-sectional, case-control, and cohort studies) did not show any worse outcomes compared to other strains [29-31]. Sirad et al. demonstrated that although NAP1/B1/027 strain may produce more toxins compared to other strains, they produced fewer spores and were not always associated with severe disease [32]. On the contrary, Rao et al. conducted a cohort study and concluded that ribotype 027 was associated with severe CDI (OR: 1.73, 95% CI 1.03 – 2.89; p = 0.037) and increased mortality (OR: 2.02, 95% CI 1.19 – 3.43; p = 0.009) compared to other ribotypes [24]. Another study showed similar results with the North American pulsed-field gel electrophoresis type 1 (NAP1) strain. Multivariate regression analysis exhibited an increase in the severity of CDI with the NAP1 strain (OR: 1.66, 95% CI: 1.90 – 2.54) and increased mortality (OR: 2.12, 95% CI: 1.22 – 3.68) [33]. One study from Quebec labeled this strain to be responsible for severe diseases twice as frequently as compared to other strains [34].

The basis for these contradictory findings can be explained by several reasons, including study design, study population, sample size, the method of detection for C. diff, study setting, and unmeasured confounders. Given these contradictory results, healthcare providers should focus on treating this infection based on their clinical judgment and markers of severe infection, including the number of diarrheal episodes, signs of dehydration, creatinine level, albumin level, white blood cell count, associated co-morbidities, immunocompromised state, etc.

Prevention

Preventive strategies employed for NAP1/B1/027 strain are similar to strategies taken for other strains. These include barrier methods (gloves and gown while examining patient), use of disposable equipment, handwashing with soap and water, disinfecting the environment, and antimicrobial stewardship [35]. Further vaccines are being developed targeting the toxins, including TcdA and TcdB, for simultaneous prevention and treatment of CDI. Actoxumab and bezlotoxumab, which are monoclonal antibodies against TcdA and TcdB, are being investigated for this purpose. A combined Phase III trial (MODIFY I (NCT01241552) and MODIFY II (NCT01513239)) showed benefit from bezlotoxumab, but the combination of actoxumab and bezlotoxumab did not yield any further benefit [36]. Bezlotoxumab has received Food and Drug Administration (FDA) approval in October 2016 and is to be used in patients more than 18 years of age, who are at high risk of recurrence from CDI, and are receiving antibiotics [37]. A novel tetravalent vaccine against TcdA, TcdB, CDTa, and CDTb has been proposed by Secore et al. using a hamster model which has shown promising results [38].

A novel drug, SYN-004 (ribaxamase), is under investigation that has shown promising results for preventing CDI. This drug, which is a β-lactamase, is excreted into the gut and degrades the excess antibiotic that prevents disruption of normal gut flora, ultimately preventing CDI [39]. The Phase IIa clinical trial of this drug showed that ribaxamase at a dose of 150 mg every six hours results in an undetectable concentration of ceftriaxone in the intestine which can potentially decrease the likelihood of a C. diff infection, given the less probability of disruption of the gut bacteria.

Resistance to Antibiotics and Treatment

Cases of NAP1/B1/027 reported in Panama were found to be highly resistant to clindamycin, moxifloxacin, levofloxacin, ciprofloxacin, and rifampin but were susceptible to metronidazole and vancomycin [40]. Susceptibility of ribotype 027 and non-027 ribotypes to different antibiotics was tested in a study in Canada. Ribotype 027 showed a resistance of 92.2% to moxifloxacin compared to 11.2% for other strains. Similarly, 78.2% of ribotype 027 strains were resistant to ceftriaxone compared to 15.7% of other strains. Ribotype 027 demonstrated a greater than four-fold higher minimum inhibitory concentration (MIC) to metronidazole (4 vs. 1 μg/ml) and two-fold higher MIC for fidaxomicin (1 vs. 2 μg/ml). For clindamycin and vancomycin, the resistance was similar in both groups [41].

Resistance to erythromycin is linked to mutations in the ribosomal methylase genes, whereas resistance to fluoroquinolones is due to a mutation in DNA gyrase. Resistance to rifamycin and fidaxomicin is attributed to ribonucleic acid (RNA) polymerase methylation. The presence of phenicol and lincosamide genes has been shown to cause resistance to linezolid. A study conducted in hospitals of Mexico showed some isolates of ribotype 027 to have reduced susceptibility to fidaxomicin despite the unavailability of this drug in Mexico and the patients being unexposed to it [42]. Antibiotics form the basis of treatment for the NAP1/B1/027 strain. Currently, no specific Infectious Diseases Society of America (IDSA) guidelines are available to guide treatment for this particular strain, and hence, the treatment is similar to a non-NAP1/B1/027 strain [9]. Based on the current guidelines for treating CDI overall, we propose the following table for treating infection caused by the NAP1/B1/027 strain (Table 2).

First line treatment Alternative treatment
Initial non-severe infection Oral vancomycin, 125 mg four times daily for 10 days Fidaxomicin, 200 mg twice daily for 10 days; If neither is available, then use metronidazole, 500 mg three times daily for 10 days
First non-severe recurrence Repeat oral vancomycin, 125 mg four times daily for 10 days Fidaxomicin, 200 mg twice daily for 10 days
Second non-severe recurrence Oral vancomycin taper as follow: 125 mg four times daily for seven to 14 days, 125 mg twice daily for seven days, 125 mg twice once daily for seven days, 125 mg once every other day for seven days, 125 mg once every three days for 14 days Fidaxomicin, 200 mg orally twice daily for 10 days, or a fecal microbiota transplant
Subsequent non-severe recurrence Fecal microbiota transplant Tapering oral vancomycin with probiotics, IVIG, fidaxomicin
Severe disease Oral vancomycin, 125 mg four times daily, increase to 500 mg four times daily if no improvement noted in 24-48 hours or associated complications, including renal failure, ileus, etc. Fidaxomicin if the patient cannot tolerate oral vancomycin for any reason
Ileus Add IV metronidazole, 500 mg every eight hours, to oral vancomycin or fidaxomicin therapy; consider general surgery consult as needed Intracolonic vancomycin, IVIG

This strain has not shown any resistance to fidaxomicin, but there has been some contradicting evidence to this. A case report was published in 2017 in which the NAP1 C. diff infection, resistant to treatment with fidaxomicin and fecal transplants, was effectively treated with intravenous immunoglobulin (IVIG) [43]. Given the emerging threat of antibiotic resistance, increasing awareness, controlling infections, and antimicrobial stewardship can be effective measures to reduce this threat [17].

Currently, several novel antibiotics are under investigation which have gone through various randomized controlled trials for CDI treatment. Ridinilazole and cadazolid have completed Phase II trials, while surotomycin has completed two Phase III trials which have shown promising results [44-47].

Conclusions

The data regarding the NAP1/B1/027 strain is inconclusive with ongoing debates whether this particular strain is associated with severe disease. Further research, including meta-analyses, are needed to solve this enigma. Clinicians should guide treatment based on their judgment and objective evidence of disease severity.


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Recurrent Clostridium difficile associated diarrhea (rCDAD) Research Study Begins Enrollment

A research consortium across multiple institutions has begun enrolling patients in a clinical trial examining whether fecal microbiota transplantation by enema is safe and effective in preventing recurrent Clostridium difficile-associated disease, according to a press release.

The researchers hope to enroll 162 volunteers aged 18 years or older who have had two or more episodes of C. difficile-associated disease (CDAD) within the past 6 months, according to the release.

Trial sites include Emory University, Duke University Medical Center and Vanderbilt University Medical Center.

Each site is a member of the Vaccine and Treatment Evaluation Unit, which is a network funded by the National Institute of Allergy and Infectious Diseases (NIAID).

The researchers hope to enroll 162 volunteers aged 18 years or older who have had two or more episodes of C. difficile-associated disease (CDAD) within the past 6 months, according to the release.

Clostridium difficile-associated disease, a significant problem in health care facilities, causes an estimated 15,000 deaths in the United States each year,” Anthony S. Fauci, MD, NIAID director, said in the release. “This randomized, controlled trial aims to provide critical data on the efficacy and long-term safety of using fecal microbiota transplants by enema to cure C. diff infections.”

Volunteers will be enrolled in the trial after completing a standard course of antibiotics for a recurrent CDAD episode, presuming their diarrhea symptoms cease on treatment.

Participants will then be randomly assigned to either a group (n = 108) that will take an anti-diarrheal medication and receive a stool transplant (FMT) delivered by retention enema, or a group (n = 54) that will take an anti-diarrheal medication and receive a placebo solution delivered by retention enema.

The placebo is a saline solution that has been colored to mimic an active stool transplant product, to ensure that the study is partially blinded.

Researchers will collect stool and blood samples from participating at designated intervals for a year from the date of effective treatment for CDAD, or from the date of their last treatment if it was unsuccessful, according to the release.

Investigators will evaluate the stool samples for gut microbial diversity and infectious pathogens changes and will examine the blood samples for metabolic syndrome markers.

All participants will be monitored for adverse side effects for 3 years following the completion of recurrent CDAD treatment.

Source:  https://www.healio.com/gastroenterology/infection/news/online/%7B1402ede4-5de1-40a3-b23f-a0070e01ad7a%7D/trial-testing-fmt-for-recurrent-diarrheal-disease-begins

CutisPharma Announces FDA Approval Of FIRVANQ™ (vancomycin hydrochloride) for Oral Solution for Treatment of Clostridium difficile Associated Diarrhea (CDAD) and Staphylococcus aureus Colitis

CutisPharma Announces FDA Approval Of FIRVANQ™ For Treatment Of  Clostridium Difficile Associated Diarrhea (CDAD) And Staphylococcus Aureus Colitis

 

FDA-approved vancomycin oral liquid therapy expected to improve patient access and reduce pharmacist  burden by no longer having to compound liquid formulations

CutisPharma announced today, January 29, 2018,  that the US Food and Drug Administration (FDA) has approved FIRVANQ™ (vancomycin hydrochloride) for oral solution, for the treatment of Clostridium difficile associated diarrhea and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains.

“We are pleased to announce the FDA approval of FIRVANQ,” said Neal I. Muni, MD, MSPH, Chief Executive Officer of CutisPharma. “FIRVANQ’s approval is an important step forward to providing patients the only FDA-approved vancomycin oral liquid treatment option for Clostridium difficile associated diarrhea, a life-threatening condition that affects over a half-million patients in the United States annually.”

Upon its launch, which is targeted to be April 2, 2018, FIRVANQ™ will replace CutisPharma’s FIRST®-Vancomycin Unit-of-Use Compounding Kit, which has been available to pharmacists that need a convenient, accurate, and compliant way to compound vancomycin oral liquid therapy. FIRVANQ™ will be commercially available in 25 mg/mL and 50 mg/mL strengths in convenient 150 mL and 300 mL sizes.  FIRVANQ™ is designed to be easy to use and has the potential to be a cost-effective alternative to existing vancomycin therapies.

“As a practicing infectious disease physician treating many patients with CDAD, having an FDA-approved vancomycin oral liquid formulation that is affordable and accessible to my patients is very beneficial,” said Stuart Johnson, MD, Loyola University Medical Center. “Patient access is currently limited by the fact that only a select few pharmacies perform compounding in the outpatient setting these days, given the many new regulations in place.  Availability of an FDA-approved vancomycin oral liquid treatment will effectively allow any pharmacy to stock this therapy, and hopefully encourage third-party payer reimbursement, significantly improving accessibility and convenience for patients.”

About CutisPharma

CutisPharma, Inc., based in Wilmington, Mass., is a privately held, specialty pharmaceutical company that has been the industry leader for 20 years in providing innovative solutions to pharmacists.  CutisPharma’s FIRST® Unit-of-Use Compounding Kits have benefited millions of patients who are unable to swallow conventional oral dosage forms such as tablets and capsules and whose needs are not served by commercially available therapies. The Company’s first FDA-approved Kit will allow significantly broader patient access, convenience to pharmacists and patients alike by reducing the need for compounding, and serve as a potential cost-saving option to existing treatments.  For more information, visit www.cutispharma.com

Zinplava has been launched by MSD in the UK

MSD has launched Zinplava in the UK, offering patients a novel therapeutic option for the prevention of Clostridium difficile recurrence.

Zinplava (bezlotoxumab) is not an antibacterial and is not indicated to actually treat the infection, but is a monoclonal antibody designed to neutralise C. difficile toxin B, which can damage the gut wall and cause inflammation, leading to diarrhoea.

It is the first and only EC licensed non-antibiotic option indicated to prevent recurrence of Clostridium difficile infection (CDI) in high-risk adults.

Around one-in-four patients experience a recurrence after the initial episode, and more than 40 percent of these have further recurrence, highlighting the need for new options able to break the infection cycle.

Pivotal Phase III clinical studies showed the rate of infection recurrence through week 12 to be significantly lower in patients given Zinplava (17.4 percent and 15.7 percent) or Zinplava and actoxumab (15.9 percent and 14.9 percent) than those taking a placebo (27.6 percent) and (25.7 percent), respectively.

“Notably, bezlotoxumab reduces the risk of the recurrence of CDI for at least 3 months, compared with standard of care antibiotic therapy. This is welcome addition to our limited options to reduce the considerable morbidity and mortality associated with CDI,” commented Mark Wilcox, Professor of Medical Microbiology at the University of Leeds.

“Antimicrobial resistance is a key national issue and we hope with bezlotoxumab to not only help achieve a reduction in the number of recurrent episodes of CDI but also a reduction in the amount of antibiotic prescriptions that would otherwise be needed to treat these recurrent episodes,” added Dr Mike England, MSD’s Interim Medical Director.

Zinplava is administered as a single, one-off, one-hour intravenous infusion alongside standard-of-care antibiotic therapy for the treatment of CDI.

 

C Diff Foundation and C diff Survivors Alliance Network Share a Winter 2017 Bulletin

Greetings from the main office of the C Diff Foundation and the C diff Survivors Alliance Network located in New Port Richey, Florida.  As we close 2017 we mark the 5th anniversary of the two organizations. We want to share with you a summary and reflection on this year’s events and campaigns moving our mission forward and message delivered worldwide. The mission and promoting C.diff. Awareness has been shared this year with  listeners in over 25 Counties during Season III on C. diff. Spores and More Global Broadcasting Network (www.cdiffradio.com),  5,000+ visitors during global events, 9,600+ residents and business owners throughout villages and communities by our dedicated volunteer patient advocates, to over 1,000 clinicians who received up-to-date data expanding their knowledge during workshops and local symposiums offered worldwide, 3,000+ incoming calls received through the Nationwide Hot-Line 1-844-FOR-CDIF with the thousands of e-mails received seeking assistance.

After each event, workshop, meeting, introduction we thank the individuals for sharing  in five years of opportunity to provide life-saving data educating and advocating for C. difficile infection prevention, treatments, environmental safety and support worldwide.  The mission of the C Diff Foundation is the momentum of charity that has proven effective and grown over the past five years.  A single act of charity grows into more and greater charity worldwide.  The work each member of the C Diff Foundation, with hundreds of Volunteer Patient Advocates, promote the Foundation’s mission which never stops with a single act.  Instead, it builds, it grows, and it expands into an exponential impact of good in the world helping to save lives.  We thank you for your continued support and encourage you to continue your journey, proposing three verbs important to the C Diff Foundation and the C diff Survivors Alliance Network in general.

The first of these verbs is “to promote” C.diff. Awareness. It is the first step that opens doors in educating individuals, clinicians, communities in learning more about this life-threatening infection which causes a great amount of pain and suffering around the globe.  It is essential and it is the compass in reaching shared goals.

The second verb is “to heighten awareness” across the nation to continue proclaiming November Clostridium difficile infection awareness month. The Governors proclaimed November C. difficile (C.diff) infection awareness month in 2017 and we encourage them “to welcome” this proclamation in 2018 with more than a yearly executive order of greeting or inviting their residents to take notice.  We look forward to working with delegates, with your support, to make this proclamation statement nationwide and welcome the importance of the time, education, programs, and agenda in place addressing this life-threatening infection.  The C Diff Foundation advocates and supports the individuals and families suffering during and after being treated for a C. diff. infection.

Finally, the third verb that the C Diff Foundation and C diff Survivors Alliance Network propose is “to go.”  Here we are all challenged to do something big or small — with what we are able to do.  With the unity of members with volunteers with patients, families, and clinicians we can make a difference with enthusiasm and simplicity to get up and go.  We can do for others  today what we could not do for ourselves during our time of illnesses, during the long periods of isolation, during the losses, and during the pain and suffering.

As members of the C Diff Foundation we know that our enthusiasm  for our mission is the desire to bring awareness and promote C. difficile infection prevention, treatments, environmental safety and support worldwide.  We witness changes by the data and information being delivered within villages,  through major cities and in small communities — it is only by taking this path that we gain satisfaction knowing that the news delivered with enthusiasm “to promote, to heighten awareness and to go” with the members and volunteers in the C Diff Foundation and C diff Survivors Alliance Network creates positive results.

We are truly grateful for your continued dedication, efforts and support and thank you again for making this year’s November anniversary such a special occasion through the growth and advances made worldwide.   Let’s carry the mission into the New Year, carving new paths to witness the decline of newly diagnosed cases of Clostridium difficile (C.diff., C. difficile) infections and saving lives worldwide.

“None of us can do this alone ~ All of us can do this together.”

 

 

Medicare Penalties Include Antibiotic-Resistant Bacteria In Hospital Patient Injury Reporting

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The federal government has cut payments to 769 hospitals with high rates of patient injuries, for the first time counting the spread of antibiotic-resistant germs in assessing penalties.

The punishments come in the third year of Medicare penalties for hospitals with patients most frequently suffering from potentially avoidable complications, including various types of infections, blood clots, bed sores and falls.

This year – 2016 –  the government also examined the prevalence of two types of bacteria resistant to drugs.

Based on rates of all these complications, the hospitals identified by federal officials this week will lose 1 percent of all Medicare payments for a year — with that time frame beginning this past October. While the government did not release the dollar amount of the penalties, they will exceed a million dollars for many larger hospitals. In total, hospitals will lose about $430 million, 18 percent more than they lost last year, according to an estimate from the Association of American Medical Colleges.

The reductions apply not only to patient stays but also will reduce the amount of money hospitals get to teach medical residents and care for low-income people.

Forty percent of the hospitals penalized this year – 2016 – escaped punishment in the first two years of the program, a Kaiser Health News analysis shows. Those 306 hospitals include the University of Miami Hospital in Florida, Cambridge Health Alliance in Massachusetts, the University of Michigan Health System in Ann Arbor and Mount Sinai Hospital in New York City.

Nationally, hospital-acquired conditions declined by 21 percent between 2010 and 2015, according to the federal Agency for Healthcare Research and Quality, or AHRQ. The biggest reductions were for bad reactions to medicines, catheter infections and post-surgical blood clots.

Still, hospital harm remains a threat. AHRQ estimates there were 3.8 million hospital injuries last year, which translates to 115 injuries during every 1,000 patient hospital stays during that period.

Each year, at least 2 million people become infected with bacteria that are resistant to antibiotics, including nearly a quarter million cases in hospitals. The Centers for Disease Control and Prevention estimates 23,000 people die from them.

Infection experts fear that soon patients may face new strains of germs that are resistant to all existing antibiotics. Between 20 and 50 percent of all antibiotics prescribed in hospitals are either not needed or inappropriate, studies have found. Their proliferation — inside the hospital, in doctor’s prescriptions and in farm animals sold for food — have hastened new strains of bacteria that are resistant to many drugs.

One resistant bacteria that Medicare included into its formula for determining financial penalties for hospitals is methicillin-resistant Staphylococcus aureus, or MRSA, which can cause pneumonia and bloodstream and skin infections. MRSA is prevalent outside of hospitals and sometimes people with it show no signs of disease. But these people can bring the germ into a hospital, where it can be spread by health care providers and be especially dangerous for older or sick patients whose immune system cannot fight the infection.

Hospitals have had some success in reducing MRSA infections, which dropped by 13 percent between 2011 and 2014, according to the CDC. AHRQ estimates there were 6,300 cases in hospitals last year.

The second bacteria measured for the penalties is Clostridium difficile, known as C. diff, It can be spread through contaminated surfaces or hands. ………,

C. diff has challenged infection control efforts. While hospital infections dropped 8 percent from 2008 to 2014, there was a “significant increase” in C. diff that final year, the CDC says. AHRQ estimated there were 100,000 hospital cases last year.

“The reality is we don’t know how to prevent all these infections,” said Dr. Louise Dembry, a professor at the Yale School of Medicine and president of the Society for Healthcare Epidemiology of America.

The Hospital-Acquired Condition Reduction Program also factors in rates of infections from hysterectomies, colon surgeries, urinary tract catheters and central line tubes. Those infections carry the most weight in determining penalties, but the formula also takes into account the frequency of bed sores, hip fractures, blood clots and four other complications.

Specialized hospitals, such as those that treat psychiatric patients, veterans and children, are exempted from the penalties, as are hospitals with the “critical access” designation for being the only provider in an area. Of the remaining hospitals, the Affordable Care Act requires that Medicare penalize the 25 percent that perform the worst on these measures, even if they have reduced infection rates from previous years.

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To read the article in its entirety click on the following link to be redirected:

http://triblive.com/news/healthnow/11702788-74/hospitals-hospital-penalties

FDA Grants Qualified Infectious Disease Product and Fast Track Designation To Morphochem’s IV Antibacterial Product Candidate MCB3837 To Treat C.diff. Infections

Morphochem is a clinical-stage pharmaceutical company, announced July 25, 2016 that the U.S. Food and Drug Administration (FDA) has designated Morphochem’s intravenous (IV) antibacterial product candidate MCB3837 as a Qualified Infectious Disease Product (QIDP) for the treatment of Clostridium difficile infection (CDI).

At the same time, the FDA has granted Fast Track designation to the compound’s development program for the treatment of CDI. MCB3837 is the IV prodrug of MCB3681, an antibacterial targeted at the treatment of CDI, which is a serious and potentially fatal disease regarded as an urgent healthcare threat.

Under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act, the QIDP designation provides certain incentives for the development of new antibacterial drug products, such as priority review and additional five years of marketing exclusivity granted at the time of marketing approval. The Fast Track designation enables more frequent interactions with the FDA, often leading to earlier drug approval and access for patients.

“After the U.S. FDA’s acceptance of Morphochem’s IND in June, we are glad to have now received both QIDP and Fast Track designation for MCB3837” says Thomas Kapsner, M.D., Morphochem’s Chief Executive Officer. “These designations will help us to expedite the development of this promising IV compound for the many severely ill CDI patients who cannot be treated orally. By providing an effective IV therapy, we aim to improve the prospects and quality of life of these patients.”

Morphochem is planning to initiate a proof-of-concept Phase 2 clinical trial of MCB3837/3681 in severe CDI patients in H2 2016.

About MCB3837/MCB3681 MCB3837 is a water-soluble injectable small-molecule prodrug of the active substance MCB3681, which is being developed for the IV treatment of CDI. Three Phase 1 clinical studies have proved MCB3837/MCB3681 to be safe and tolerable. In pre-clinical studies, MCB3681 demonstrated remarkable Gram-positive antimicrobial activity against C. difficile pathogens including the highly virulent BI/NAP1/027 strain, with no cross-resistance to any established class of antibacterial.

In a multiple-dose Phase 1b study with healthy volunteers, high fecal concentrations of MCB3681 were observed resulting in a pronounced effect on clostridia and other Gram-positive species while sparing Gram-negative species, including the bacteroides that protect the intestine against colonization with harmful pathogens potentially causing gastrointestinal infections. Due to this strong pharmacodynamic effect in humans, its narrow Gram-positive spectrum, and its favorable impact on the commensal flora, MCB3681 has the potential to target C. difficile pathogens selectively and effectively.

 

Key risk factors for developing CDI include the use of antibiotics (as they suppress the normal bowel flora) and advanced age. Up to 40 percent of patients develop severe / severe and complicated CDI, associated with significantly higher morbidity and mortality rates. Treatment is currently dominated by oral therapies which, however, tend to prove ineffective for severely ill patients as they often have difficulties swallowing or digesting tablets, or problems retaining the oral medication in or moving it along the gastrointestinal tract. Alternatives are limited, as there is no approved IV therapy available at present.

About Morphochem Morphochem Aktiengesellschaft für kombinatorische Chemie is a private clinical-stage pharmaceutical company located in Munich, Germany. Morphochem is a 100-percent subsidiary of Biovertis AG, headquartered in Vienna, Austria.  Biovertis’s major shareholder is TVM Capital Life Science.  Morphochem is fully dedicated to the development and commercialization of MCB3837/MCB3681, which the company hopes to introduce as the first approved intravenous therapy for severe Clostridium difficile infections.

To read the article in its entirety click on the link below:

http://www.einnews.com/pr_news/336679603/fda-grants-qidp-and-fast-track-designations-to-mcb3837-morphochem-s-novel-intravenous-antibacterial-to-treat-c-difficile-infections