ridinilazole Efficacy and Safety Compared With Vancomycin For C. difficile Infection Treatment: Phase 2 Randomized,Double-Blind,Active-Controlled,Non-Inferiority Study

Article Summary:

Background

Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection.

Methods

We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935.

Findings

Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1–39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation.

Interpretation

Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted.

Funding

Wellcome Trust and Summit Therapeutics.

 

To read the article in its entirety, please click on the following link:

http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30235-9/fulltext

 

Dr Richard J Vickers, PhD'Correspondence information about the author Dr Richard J Vickers

 

Glenn S Tillotson, PhD

,

Richard Nathan, MD

,

Sabine Hazan, MD

,

John Pullman, MD

,

Christopher Lucasti, DO

,

Kenneth Deck, MD

,

Prof Bruce Yacyshyn, MD

,

Benedict Maliakkal, MD

,

Yves Pesant, MD

,

Bina Tejura, MD

,

Prof David Roblin, FRCP

,

Prof Dale N Gerding, MD

,

Prof Mark H Wilcox, MD

for the

 

See appendix for full details of the CoDIFy study group
Published: 28 April 2017
Open Access Article has an altmetric score of 76

Open access funded by Wellcome Trust

U.S. Food and Drug Administration (FDA) Has Approved Merck’s (MSD) ZINPLAVA ™ (bezlotoxumab) Injection 25mg/ml To Reduce Recurrence Of Clostridium difficile Infection In Patients 18 Years Of Age Or Older

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Merck  known as MSD outside the United States and Canada, on October 22, 2016 announced that the U.S. Food and Drug Administration (FDA) has approved ZINPLAVA™ (bezlotoxumab) Injection 25 mg/mL.

Merck anticipates making ZINPLAVA available in first quarter 2017.

ZINPLAVA is indicated to reduce recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and are at high risk for CDI recurrence.

ZINPLAVA is not indicated for the treatment of CDI.

ZINPLAVA is not an antibacterial drug. ZINPLAVA should only be used in conjunction with antibacterial drug treatment of CDI.

CDI is caused by bacteria that produce toxins, including toxin B. Symptoms of CDI include mild-to-severe diarrhea, abdominal pain and fever. The incidence of recurrent CDI is higher in certain patient populations, including people 65 years of age or older and those with compromised immune systems.

“For generations, Merck has been steadfast in its commitment to fighting infectious diseases – and that commitment continues today. ZINPLAVA is a human monoclonal antibody that binds to C. difficile toxin B and neutralizes its effects,” said Dr. Nicholas Kartsonis, vice president of clinical development, infectious diseases, Merck Research Laboratories.

Selected safety information about ZINPLAVA

Heart failure was reported more commonly in the two Phase 3 clinical trials in ZINPLAVA-treated patients compared to placebo-treated patients. These adverse reactions occurred primarily in patients with underlying congestive heart failure (CHF). In patients with a history of CHF, 12.7% (15/118) of ZINPLAVA-treated patients and 4.8% (5/104) of placebo-treated patients had the serious adverse reaction of heart failure during the 12-week study period. Additionally, in patients with a history of CHF, there were more deaths in ZINPLAVA-treated patients [19.5% (23/118)] than in placebo-treated patients [12.5% (13/104)] during the 12-week study period. The causes of death varied, and included cardiac failure, infections, and respiratory failure. In patients with a history of CHF, ZINPLAVA (bezlotoxumab) should be reserved for use when the benefit outweighs the risk.

The most common adverse reactions occurring within 4 weeks of infusion with a frequency greater than placebo and reported in ≥4% of patients treated with ZINPLAVA and Standard of Care (SoC) antibacterial drug therapy vs placebo and SoC antibacterial drug therapy included nausea (7% vs 5%), pyrexia (5% vs 3%) and headache (4% vs 3%).

Serious adverse reactions occurring within 12 weeks following infusion were reported in 29% of ZINPLAVA-treated patients and 33% of placebo-treated patients. Heart failure was reported as a serious adverse reaction in 2.3% of ZINPLAVA-treated patients and 1.0% of placebo-treated patients.

In ZINPLAVA-treated patients, 10% experienced one or more infusion specific adverse reactions compared to 8% of placebo-treated patients, on the day of or the day after, the infusion. Infusion specific adverse reactions reported in ≥0.5% of patients receiving ZINPLAVA and at a frequency greater than placebo were nausea (3%), fatigue (1%), pyrexia (1%), dizziness (1%), headache (2%), dyspnea (1%) and hypertension (1%). Of these patients, 78% experienced mild adverse reactions, and 20% of patients experienced moderate adverse reactions. These reactions resolved within 24 hours following onset.

As with all therapeutic proteins, there is a potential for immunogenicity following administration of ZINPLAVA. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to bezlotoxumab in two Phase 3 studies with the incidence of antibodies in other studies or to other products may be misleading. Following treatment with ZINPLAVA in these two studies, none of the 710 evaluable patients tested positive for treatment-emergent anti-bezlotoxumab antibodies.

About bezlotoxumab

Bezlotoxumab was developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb), and was licensed to Merck in 2009.

About Merck

For 125 years, Merck has been a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships.

For more information, visit www.merck.com

To read this article in its entirety please click on the following link

http://www.pharmiweb.com/PressReleases/pressrel.asp?ROW_ID=187373#.WAsjR8li9kk

C. difficile and Healthcare-Associated Infections Discussed Live on C. diff. Radio

CdiffRadioPost

#CdiffRadio

C Diff Foundation, Sponsor, with Founder Nancy C. Caralla, Executive Director and                                 Dr. Chandrabali Ghose, Chairperson of the Research and Development Community will be broadcasting live on Tuesdays delivering the most up-to-date information pertaining to a leading super-bug/ Healthcare Associated Infection (HAI),  C. difficile, with additional HAI’s, and a variety of related healthcare topics.

Topic experts, C. diff. Survivors, Physicians, and Healthcare Providers will be joining your hosts to discuss HAI prevention, treatments, clinical trials,  mental health, grief and illness, nutrition, antibiotic resistance, environmental safety products and much more – on a global level.

Tune in Tuesdays beginning March 3rd at 11 AM Pacific Time (2 PM Eastern Time, 7 PM UK) on the VoiceAmerica network  http://www.voiceamerica.com/show/2441/c-diff-spores-and-more

C. diff. CDC Reports That Progress Is Being Made in Infection Control in U.S. Hospitals

C. diff. CDC Reports On Major Healthcare-Associated Infections – Progress Being Made In Infection Control In U.S. Hospitals

Progress Being Made in Infection Control in U.S. Hospitals; Continued Improvements Needed

Progress has been made in the effort to eliminate infections that commonly threaten hospital patients, including a 46 percent decrease in central line-associated bloodstream infections (CLABSI) between 2008 and 2013, according to a report released today by the Centers for Disease Control and Prevention.  However, additional work is needed to continue to improve patient safety.

CDC’s Healthcare-Associated Infections (HAI) progress report is a snapshot of how each state and the country are doing in eliminating six infection types that hospitals are required to report to CDC. For the first time, this year’s HAI progress report includes state-specific data about hospital lab-identified methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections and Clostridium difficile (C. difficile) infections (deadly diarrhea).

Preventing infections in the first place means that patients will not need antibiotics to treat those infections.  This can help to slow the rise of antibiotic resistance and avoid patient harm from unnecessary side-effects and C. difficile infections, which are associated with antibiotic use. Continued progress and expanded efforts to prevent HAIs will support the response to the threat of antibiotic resistance

The annual National and State Healthcare-associated infection Infection Progress Report expands upon and provides an update to previous reports detailing progress toward the goal of eliminating HAIs. The report summarizes data submitted to CDC’s National Healthcare Safety Network (NHSN), the nation’s healthcare-associated infection tracking system, which is used by more than 14,500 health care facilities across all 50 states, Washington, D.C., and Puerto Rico. Healthcare-associated infections are a major, yet often preventable, threat to patient safety. On any given day, approximately one in 25 U.S. patients has at least one infection contracted during the course of their hospital care, demonstrating the need for improved infection control in U.S. healthcare facilities.

“Hospitals have made real progress to reduce some types of healthcare-associated infections – it can be done,” said CDC Director Tom Frieden, M.D., M.P.H. “The key is for every hospital to have rigorous infection control programs to protect patients and healthcare workers, and for health care facilities and others to work together to reduce the many types of infections that haven’t decreased enough.”

This report focuses on national and state progress in reducing infections occurring within acute care hospitals.

Although not covered by the report released today, the majority of C. difficile infections and MRSA infections develop in the community or are diagnosed in healthcare settings other than hospitals.

Other recent reports on infections caused by germs such as MRSA and C. difficile suggest that infections in hospitalized patients only account for about one-third of all the healthcare-associated infections.

Tracking National Progress On the national level, the report found a:

  • 46 percent decrease in central line-associated bloodstream infections (CLABSI) between 2008 and 2013. A central line-associated bloodstream infection occurs when a tube is placed in a large vein and either not put in correctly or not kept clean, becoming a highway for germs to enter the body and cause deadly infections in the blood.
  • 19 percent decrease in surgical site infections (SSI) related to the 10 select procedures tracked in the report between 2008 and 2013. When germs get into the surgical wound, patients can get a surgical site infection involving the skin, organs, or implanted material.
  • 6 percent increase in catheter-associated urinary tract infections (CAUTI) since 2009; although initial data from 2014 seem to indicate that these infections have started to decrease. When a urinary catheter is either not put in correctly, not kept clean, or left in a patient for too long, germs can travel through the catheter and infect the bladder and kidneys.
  • 8 percent decrease in MRSA bloodstream infections between 2011 and 2013.
  • 10 percent decrease in C. difficile infections between 2011 and 2013. 

Research shows that when healthcare facilities, care teams, and individual doctors and nurses, are aware of infection control problems and take specific steps to prevent them, rates of targeted HAIs can decrease dramatically.

Data for Local Action The report provides data that can be used by hospitals to target improvements in patient safety in their facilities. For example, together with professional partners, CDC, the Centers for Medicare & Medicaid Services (CMS) Quality Improvement Organizations and Partnership for Patients initiative, and the Agency for Healthcare Research and Quality’s (AHRQ) Comprehensive Unit-based Safety Program (CUSP) increased attention to the prevention of catheter-associated urinary tract infections, resulting in a reversal of the recent increase seen in these infections. CAUTI data for early 2014 demonstrating these improvements will be publicly available on the CMS Hospital Compare website in 2015. CDC is also working to use HAI data to help identify specific hospitals and wards that can benefit from additional infection control expertise.

“Healthcare-associated infection data give healthcare facilities and public health agencies knowledge to design, implement and evaluate HAI prevention efforts,” said Patrick Conway, Deputy Administrator for Innovation and Quality and Chief Medical Officer of the Center for Medicare & Medicaid Services. “Medicare’s quality measurement reporting requires hospitals to share this information with the CDC, demonstrating that, together, we can dramatically improve the safety and quality of care for patients.”

“Successful programs such as CUSP demonstrate that combining sound HAI data with effective interventions to prevent these infections can have enormous impact,” said AHRQ Director Richard Kronick, Ph.D.

State Data  Not all states reported or had enough data to calculate valid infection information on every infection in this report. The number of infections reported was compared to a national baseline.

In the report, among 50 states, Washington, D.C., and Puerto Rico, 26 states performed better than the nation on at least two of the six infection types tracked by state (CLABSI, CAUTI, MRSA, C. difficile, and SSI after colon surgery and abdominal hysterectomy). Sixteen states performed better than the nation on three or more infections, including six states performing better on four infections. In addition, 19 states performed worse than the nation on two infections, with eight states performing worse on at least three infections.

The national baseline will be reset at the end of 2015. Starting in 2016, HAI prevention progress from 2016-2020 will be measured in comparison to infection data from 2015.

The federal government considers elimination of healthcare-associated infections a top priority and has a number of ongoing efforts to protect patients and improve healthcare quality.

CDC provides expertise and leadership in publishing evidence-based infection prevention guidelines, housing the nation’s healthcare-associated infection laboratories, responding to health care facility outbreaks, and tracking infections in these facilities.

Other federal and non-federal partners are actively working to accelerate the ongoing prevention progress across the country. In collaboration with CDC, these agencies use data and expertise to mount effective prevention programs and guide their work.

Source:  CDC

January 14, 2015