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Publication: Multicenter Prevalence Study Comparing Molecular and Toxin Assays for Clostridioides difficile Surveillance, Switzerland

C. diff. RESEARCH

 

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Andreas F. Widmer, Reno Frei, Ed J. Kuijper, Mark H. Wilcox, Ruth Schindler, Violeta Spaniol, Daniel Goldenberger, Adrian Egli, Sarah Tschudin-Sutter , and Kuijper
Author affiliations: University Hospital Basel, Basel, Switzerland (A.F. Widmer, R. Frei, R. Schindler, V. Spaniol, D. Goldenberger, A. Egli, S. Tschudin-Sutter)Leiden University Medical Center, Leiden, the Netherlands (E.J. Kuijper)Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, and Leeds Teaching Hospitals, Leeds, UK (M.H. Wilcox)

Abstract

Public health authorities in the United States and Europe recommend surveillance for Clostridioides difficile infections among hospitalized patients, but differing diagnostic algorithms can hamper comparisons between institutions and countries. We compared surveillance based on the detection of C. difficile by PCR or enzyme immunoassay (EIA) in a nationwide C. difficile prevalence study in Switzerland. We included all routinely collected stool samples from hospitalized patients with diarrhea in 76 hospitals in Switzerland on 2 days, 1 in winter and 1 in summer, in 2015. EIA C. difficile detection rates were 6.4 cases/10,000 patient bed-days in winter and 5.7 cases/10,000 patient bed-days in summer. PCR detection rates were 11.4 cases/10,000 patient bed-days in winter and 7.1 cases/10,000 patient bed-days in summer. We found PCR used alone increased reported C. difficile prevalence rates by <80% compared with a 2-stage EIA-based algorithm.

 

Since its identification as a cause of antibiotic-associated pseudomembraneous colitis in 1978 (1), Clostridioides difficile has emerged as a major healthcare-associated pathogen worldwide. In the United States, C. difficile infection (CDI) rates doubled during 1996–2003 (2), and rates of CDI were reported to be 76.9 cases/10,000 discharges in 2005 (3). In a more recent national point-prevalence study including US healthcare facility in-patients, 13/1,000 patients were found to be either infected or colonized (4), a higher rate than had been previously estimated. In a national point-prevalence study of nosocomial infections in the United States, C. difficile was the most common causative pathogen overall (5). The increase largely has been attributed to the emergence of the hypervirulent strain, PCR ribotype 027 (RT027), which was identified as causative strain in 82% of cases during CDI outbreaks in Quebec, Canada, during 2001–2003 and accounted for 31% of all cases of healthcare-associated infections in the United States in 2011 (69). In Europe, CDI incidence varies across hospitals and countries with a weighted mean of 4.1 cases/10,000 patient-days per hospital in 2008 (10). The most recent study on CDI prevalence in Europe suggests an increase in the number of cases, reporting a mean of 7.0 cases/10,000 patient-bed days and ranging among countries from 0.7 to 28.7 cases/10,000 patient-bed days (11). The most common ribotype identified was RT027, which was detected in 4 countries: Germany, Hungary, Poland, and Romania (11).

To estimate and compare the burden of CDI across the United States, the US Centers for Disease Control and Prevention (CDC) began population-based CDI surveillance in 10 locations in 2011 (12). The European Centre for Disease Prevention and Control (ECDC) began coordinating CDI surveillance in acute care hospitals in Europe in 2016 (13). Both authorities provide case definitions based on different diagnostic approaches, including detection of C. difficile toxin A and B by enzyme immunoassay (EIA) or detection of toxin-producing C. difficile organisms by PCR. However, the use of different diagnostic algorithms to detect C. difficile might hamper comparisons between institutions and countries. Therefore, in a nationwide C. difficile multicenter prevalence study in Switzerland, we systematically compared surveillance measures based on detection of C. difficile in stool by either PCR as a stand-alone test or by a 2-stage algorithm consisting of an EIA to detect glutamate dehydrogenase (GDH) and toxins A and B.

Methods

Study Design

We performed a nationwide multicenter prevalence study of toxigenic C. difficile detected in stool samples routinely collected from hospitalized patients with diarrhea. Our study followed the design of a previous point-prevalence study for maximal comparability between our results and data from Europe (11). University Hospital Basel, a tertiary care center in Switzerland, coordinated the study. All hospitals participating in Swissnoso (https://www.swissnoso.chExternal Link), a national infection prevention network, were asked to participate. The Swissnoso network consists of 85 acute care hospitals that account for a total of 26,341 beds.

The Ethics Committee Northwest and Central Switzerland (Ethikkommission Nordwest-und Zentralschweiz) issued a declaration of no objection for this study. We adhered to STROBE guidelines for reporting on observational studies (14).

Sample Collection

All stool samples collected from inpatients >1 year of age with diarrhea that were submitted to the microbiology laboratory on 2 specified sampling days, 1 in winter and 1 in summer, in 2015 were eligble for inclusion. Only 1 sample per patient was included. In addition, stool samples that tested positive for toxigenic C. difficile <1 week prior to each study day also were collected from all institutions to obtain a more detailed estimate of ribotype distribution in Switzerland.

We collected the following institutional data for all hospitals and their affiliated microbiology laboratories: contact information; detailed information regarding laboratory diagnostics in place; and detailed information on the total number of admissions, number of beds, and number of patients hospitalized on the 2 days of the study. We also collected information on the total number of diagnosed CDI cases at each institution during the study year. For each eligible stool sample, we collected the following data: date of sample collection, age and gender of patient, ward location and clinical specialty, institution, whether a C. difficile test was ordered by the treating physician, and result of the C. difficile test if testing was performed at the local laboratory.

Procedures

We tested all stool samples at the Division of Clinical Microbiology of the University Hospital Basel by using a 2-stage algorithm consisting of EIA and PCR. We performed EIA to detect GDH and toxins A and B by using C. DIFF QUIK CHEK COMPLETE (Techlab, https://www.techlab.comExternal Link), following the manufacturer’s instructions. We then performed PCR to detect the toxin B gene by using the RealStar PCR Kit (Altona Diagnostics, https://www.altona-diagnostics.comExternal Link). For detected C. difficile, we performed strain typing by using high-resolution capillary gel-based PCR ribotyping according to the method previously described by Stubbs et al. (15).

Outcomes

We calculated reported and measured rates of detected toxigenic C. difficile per 10,000 patient bed-days across participating institutions. We compared differences in testing algorithms for detection of toxigenic C. difficile across institutions in Switzerland and performance characteristics of diagnostic algorithms. We considered the proportion of missed toxigenic C. difficile cases and ribotype distributions as additional outcomes. We further assessed the proportion of laboratories using optimized C. difficile diagnostic tests, which we defined as using an algorithm recommended by the European Society of Clinical Microbiology and Infectious Diseases (16).

Statistical Analyses

We separately calculated rates for each diagnostic algorithm performed in the coordinating center laboratory. In addition, we separately calculated rates for dedicated children’s hospitals. We defined missed C. difficile cases as those in which tests were negative at the participating hospital’s laboratory but positive at our institution. We used descriptive statistics to report ribotypes and differences in diagnostic algorithms across all participating institutions. All analyses were performed in Stata version 15.1 (StataCorp, https://www.stata.comExternal Link).

Results

Figure 1. Distribution of centers participating in a prevalence study comparing molecular and toxin assays for nationwide surveillance of Clostridioides difficile, Switzerland. Red circles represent the location of participating centers.

Participating institutions included 76/85 (89.4%) institutions belonging to the Swissnoso network. Among participating institutions, 5 were academic teaching hospitals, 3 were dedicated children’s hospitals, and 36 were affiliated microbiology laboratories. Participating institutions were distributed across all geographic regions of Switzerland (Figure 1).

Participating institutions reported collecting a fecal sample for microbiological workup in »65% (SD +25%) of all patients with hospital-onset diarrhea. Among participating institutions, 15/76 (19.7%) did not begin CDI treatment before fecal sample collection. Among institutions that initiated treatment before collecting fecal samples, 23/76 (30.3%) began treatment in <2% of patients, 12/76 (15.8%) began treatment in 3%–5% of patients, 8/76 (10.5%) began treatment in 6%–10% of patients, and 1 (1.3%) began treatment in 11%–20% of patients. The other 17 (22%) institutions were not able to provide an estimate of these data.

Overall, 354 stool samples were submitted to the coordinating center, of which 338 were eligible for study inclusion; 16 samples were excluded because they were not liquid, their submitted data were incomplete, or they were duplicate samples from 1 patient. Among 338 samples included, 250 were collected as part of the point-prevalence study. We excluded 8 of these because the samples were collected from patients <1 year of age. In all, we included 242 samples in the point-prevalence study.

Diagnostic Algorithms

Figure 2. Testing algorithms at the 36 laboratories participating in a prevalence study comparing molecular and toxin assays for nationwide surveillance of Clostridioides difficile, Switzerland. EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NAAT, nucleic…

Among the 36 participating laboratories, 1 routinely tested all diarrheal stool samples for toxigenic C. difficile and 35 tested only if a specific test was requested. Optimized diagnostic tests for detection of toxigenic C. difficile were used by 58% (21/36) of laboratories in the winter sampling period and by 61% (22/36) in the summer sampling period. Among laboratories not following the recommendations of the European Society of Clinical Microbiology and Infectious Diseases (16), 9 in the winter sampling period and 10 in the summer sampling period used a nucleic acid amplification test (NAAT) alone, and 5 in the winter sampling period and 3 in the summer sampling period used EIAs for A and B toxins either as a standalone test or as an initial screening test. Only 1 laboratory reported having established PCR ribotyping methodologies (Figure 2).

Point-Prevalence Analyses

We collected demographic characteristics of patients whose stool samples tested positive by our testing algorithms (Table 1). C. difficile tests were required and performed for 68% (165/242) of stool samples; 6% (27/165) were reported as positive by the affiliated microbiology laboratory.

At the coordinating center, we detected C. difficile in 9% (21/242) of samples by EIA for GDH and A and B toxins and in 12% (30/242) of samples by PCR alone. Among all 27 samples reported as positive by the participating centers, we confirmed 18 (67%) by EIA and 24 (89%) by PCR. Among 138 samples reported as negative by the participating centers, 1 (1%) sample tested positive by EIA and 3 (2%) tested positive by PCR at the coordinating center. Among 77 samples not tested for C. difficile at the participating centers, we detected C. difficile in 2 (3%) by EIA and in 3 (4%) by PCR. Among 21 stool samples that tested positive by EIA at the coordinating center, a C. difficile test was not requested in 2 (10%) cases. Among 30 samples that tested positive by PCR at the coordinating center, a C. difficile test was not requested in 3 cases (10%; Table 2).

Measured detection and testing rates of toxigenic C. difficile were higher than the reported rates across all participating institutions (Table 3). Depending on the diagnostic algorithm applied, the largest difference in prevalence across all institutions was measured during the winter sampling period, which had a prevalence of 6.4 cases/10,000 patient bed-days by EIA and 11.4 cases/10,000 patient bed-days by PCR alone. Thus, across all institutions, rates of toxigenic C. difficile detection by PCR alone were <80% higher than detection rates by EIA for GDH and A and B toxins. In addition, detection rates by PCR alone were <100% higher in dedicated children’s hospitals (Table 3).

Ribotype Distribution

Figure 3. Distribution of PCR ribotypes among 107 samples collected in a prevalence study comparing molecular and toxin assays for nationwide surveillance of Clostridioides difficile, Switzerland. *Unknown ribotype.

We cultured and ribotyped 107 toxigenic C. difficile strains, 29 from the 2 point-prevalence days and 78 collected <1 week before each prevalence day. We identified a large diversity of C. difficile ribotypes, 23 (22%) had not been referenced before. The ribotypes most commonly identified included RT014 (12/107; 11%), presumably hypervirulent RT078 (9/107; 8%), RT001 (7/107; 7%), and RT002 (7/107; 7%) (Figure 3).

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Discussion

In this nationwide multicenter study, we found that PCR as a stand-alone test increased reported C. difficile prevalence rates <80% compared with a 2-stage EIA-based algorithm. At first glance, this finding was not surprising given the higher sensitivity of EIA (16). However, the fact that our results and conclusions are based on a nationwide cohort representing all geographic regions of Switzerland adds to the study’s credibility. In addition, our results strengthen the advice of the European Society of Clinical Microbiology and Infectious Diseases study group for C. difficile against use of a single commercial test for diagnosing CDI because of the low positive predictive values when CDI prevalence is low, 46% at a CDI prevalence of 5% (16). However, CDC and ECDC protocols for CDI surveillance define a case of CDI as the combination of diarrheal stool and a positive PCR (12,13). In addition, the clinical practice guidelines for CDI in adults and children published by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America recommend testing by different approaches, such as multistep algorithms or NAAT, depending on the degree of clinical suspicion (17). Based on a systematic review and meta-analysis, the American Society of Microbiology also recommends different approaches, including NAAT-only testing, and algorithms that include GDH and NAAT or GDH, toxins, and NAAT (18). Although these recommendations stand to reason for detection of CDI in individual patients, our results challenge their utility for meaningful comparisons in surveillance studies and suggest that uniform definitions should be provided.

On both point-prevalence days, we noted a higher nationwide rate of toxigenic C. difficile than previously reported in incidence studies performed at different institutions in Switzerland (1921). Our findings suggest that CDI rates have increased during the last decade in Switzerland, a finding that is in line with reports from other countries in Europe (11). Using the same diagnostic algorithm, diagnostic test, and a similar study design to the multicenter point-prevalence study of CDI in hospitalized patients with diarrhea in Europe, the nationwide mean prevalence rates are comparable in Switzerland (mean 6.1 cases/10,000 patient bed-days) and Europe (7.0 cases/10,000 patient bed-days) (11). Because we only included liquid stools in our study, our mean prevalence rate of 9.3 cases/10,000 patient bed-days measured by PCR fulfills the ECDC case definition and further shows that CDI is increasing substantially nationwide.

We found a lower proportion of missed detection of toxigenic C. difficile in Switzerland (9.5%), driven by the absence of clinical suspicion, compared with Europe (23%), which equates to 1 missed case of C. difficile per day among the included institutions in Switzerland. False-negative testing accounted for 1 additional missed diagnosis during both point-prevalence days, which extrapolates to »550 missed cases of C. difficile per year among hospitals across the nation.

We detected a variety of different RTs during our study period, 21% of which had not been referenced before. Of note, we did not recover hypervirulent RT027, but RT078 was the third most common strain circulating in Switzerland during our study. In contrast, a point-prevalence study in Europe identified RT027 as the most commonly circulating strain during its study period but did not detect RT078. RT078 has been associated with similarly severe disease manifestations as RT027, but RT078 has been reported to affect younger patients and to be linked more commonly with community-associated disease in the Netherlands (22). RT078 has been isolated from piglets with diarrhea, possibly suggesting ongoing transmission by introduction to the food chain because isolates from humans and pigs were found to be highly genetically related (22). A component of RT078 infections also was reported in Northern Ireland, which has a large pig population and »1:1 ratio of cattle to humans (23). In Switzerland, RT078 has been isolated previously from 6 wastewater treatment plants, suggesting its dissemination in the community (24). Except for both hypervirulent RT027 and RT078, we identified other similarities in RT distribution between Switzerland and the rest of Europe; RT014, RT001, RT002, and RT020 were among the 10 most commonly identified ribotypes in both settings.

Our study has some limitations, most of which are intrinsic to point-prevalence studies. First, our study only reflects frequency of toxigenic C. difficile detected on 2 days in 2015; therefore, we cannot draw solid conclusions regarding incidence. We expanded the timeframe for assessing the distribution of ribotypes circulating in Switzerland by an additional week for each prevalence day, but this still represents a limited collection of the true incidence. Second, we cannot rule out introduction of bias to testing policies at the participating hospitals, which might have increased testing on the 2 point-prevalence days. However, we did not provide any promotional information regarding our study, so alterations in daily clinical practice among treating physicians is unlikely on these 2 days. Third, we only included liquid stool samples for analyses, but we did not consider any other preanalytical factors, such as the use of laxatives, for testing eligibility. Finally, we applied surveillance definitions recommended by CDC and ECDC rather than defintions used for the clinical diagnosis of CDI in individual patients, such as detection of C. difficile in the context of symptoms related to CDI. Therefore, we cannot rule out detection of toxigenic C. difficile from colonization rather than infection in some cases.

In conclusion, this nationwide multicenter study reveals that PCR as a stand-alone test results in an increase of C. difficile prevalence rates of <80% compared with a 2-stage EIA-based algorithm. Our findings underscore the need for consistent testing algorithms for meaningful interinstitutional and nationwide comparisons. Our results also challenge the utility of the current CDC and ECDC case definitions and highlight the need for uniform recommendations on diagnostic approaches.

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Dr. Widmer is head of the infection control program at University Hospital Basel, University of Basel, Switzerland. His research interests include all aspects of Clostridioides difficile and the epidemiology and prevention of hospital-acquired infections.

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Acknowledgments

We acknowledge and thank the ESCMID (European Society of Clinical Microbiology and Infectious Diseases) Study group for C. difficile (ESGCD) for professional support. We also thank all participating centers and laboratories (Appendix).

Astellas Pharmaceuticals Europe provided financial support for this study. The funder did not influence the study design and did not contribute to data collection, data analysis, data interpretation, or writing of the report. Astellas Pharma Europe reviewed the report for factual accuracy before submission, in line with the terms of the funding agreement. The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Alere provided C. DIFF QUIK CHEK COMPLETE test kits for conducting EIAs to detect GDH and toxins A and B.

The authors declare the following possible conflicts of interest: A.W. is a member of the Astellas and Merck Sharp & Dohme Corp. advisory boards for C. difficile and reports grants from the Swiss National Science Foundation. S.T.-S. is a member of the Astellas and Merck Sharp & Dohme Corp. advisory boards for C. difficile and reports grants from the Swiss National Science Foundation (grant nos. NRP72 and 407240_167060), the Gottfried und Julia Bangerter-Rhyner Stiftung, and the Fund for the Promotion of Teaching and Research of the Voluntary Academic Society, Base

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DOI: 10.3201/eid2610.190804

Original Publication Date: September 09, 2020

 

Resource:  https://wwwnc.cdc.gov/eid/article/26/10/19-0804_article

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Severe Cases of C.diff. Infection (CDI)Study Suggests the Most Routinely Prescribed Antibiotic Is Not the Best Treatment

Over the past two decades there has been a sharp rise in the number and severity of infections caused by the bacteria Clostridium difficile  (C. diff ) now the most common healthcare-acquired infection in the United States.

 

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But a new study suggests that the most routinely prescribed antibiotic is not the best treatment for severe cases. Scientists at the VA Salt Lake City Health Care System and University of Utah report that patients with a severe C. diff infection (CDI) were less likely to die when treated with the antibiotic vancomycin compared to the standard treatment of metronidazole.

The findings will be published online on Feb. 6, 2017 on the Journal of the American Medical Association (JAMA) Internal Medicine website.

C. diff does not cause illness outright. The bacterium produces two chemicals that are toxic to the human body. These toxins work in concert to irritate the cells of the Large intestinal lining producing the symptoms associated with the illness. Symptoms of CDI include watery diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness. Severe cases are associated with inflammation of the colon.

Current guidelines primarily recommend two antibiotics metronidazole or vancomycin to treat CDI. While vancomycin was the original treatment, the medical community has favored metronidazole for the past few decades, because it is less expensive and will limit vancomycin resistance in other hospital-acquired infections. The guidelines are based on small clinical trials carried out about 30 years ago.

“For many years the two antibiotics were considered to be equivalent in their ability to cure C. diff and prevent recurrent disease,” says Stevens. “Our work and several other studies show that this isn’t always the case.” In the current issue of JAMA Internal Medicine, the research team looked at the effectiveness of the two drugs by comparing the risk of mortality after treatment with these two antibiotics.

The investigators conducted the largest study to date by examining the data from more than 10,000 patients treated for CDI through the US Department of Veterans Affairs healthcare system from 2005 to 2012. A severe case of CDI was defined as a patient with an elevated white blood cell count or serum creatinine within four days of the CDI diagnosis. A mild to moderate case of CDI was defined as a patient with normal white blood cell counts and creatinine levels. About 35 percent of cases in this study were considered severe.

Patients with a severe case of CDI had lower mortality rates when treated with vancomycin compared to metronidazole (15.3 percent versus 19.8 percent). The scientists calculated that only 25 patients with severe CDI would need to be treated with vancomycin to prevent one death. “That is a powerful, positive outcome for our patient’s well-being,” explains Stevens. She cautions that the researchers still do not understand how the choice of antibiotic affects mortality rates.

“Although antibiotics are one of the greatest miracles of modern medicine, there are still tremendous gaps in our knowledge about when and how to use them to give our patients the best health outcomes,” explains Michael Rubin, M.D., Ph.D., an associate professor in internal medicine and an investigator at the VA Salt Lake City Health Care System.

“This research shows that if providers choose vancomycin over metronidazole to treat patients with severe CDI, it should result in a lower risk of death for those critically ill patients,” said Rubin. This study showed that less than 15 percent of CDI patients, including severe cases, received vancomycin.

The study results did not show a difference in the rate of the illness returning following either antibiotic treatment whether the initial illness was mild to moderate or severe. Nor did it show a difference for the rate of death following either antibiotic treatment for mild to moderate CDI cases.

Stevens cautions that the study was observational in nature and does not prove cause and effect of the drug. In addition, the study focused on patients that were primarily men; however, past studies show that the C. diff treatment outcomes for men and women were similar.

According to Stevens, future work should balance the targeted application of vancomycin treatment, especially for severe CDI cases, with economic considerations and the consequences of antibiotic resistance. “The optimal way to move forward is to do decision analysis that allows us to weigh the pros and cons of the various treatment strategies,” she says.

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The research was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development.

In addition to Stevens and Rubin, co-authors include Richard Nelson, Karim Khader, Makoto Jones, Lindsay Croft and Matthew Samore (University of Utah and the VA Salt Lake City Health Care System), Elyse Schwab-Daugherty and Kevin A. Brown (Public Health Ontario and University of Toronto), Tom Greene (University of Utah), Melinda Neuhauser (VA Pharmacy Benefits Management Services) and Peter Glassman and Matthew Bidwell Goetz (VA Greater Los Angeles Healthcare System).

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Listen and View Panelists:  Peter L. Salgo, MD; Erik Dubberke, MD; Lawrence J. Brandt, MD; Dale N. Gerding, MD; and Daniel E. Freedberg, MD, MS,

Topic of discussion:  Understanding Why Clostridium difficile Infections (CDI) Occur In the Community

The second video the panelists discuss:

The Pathophysiology of Clostridium difficile Infection (CDI)  and Its Impact On the Gastrointestinal System.

See more at: http://www.mdmag.com/peer-exchange/clostridium-difficile-infections/understanding-why-clostridium-difficile-infections-occur-in-the-community#sthash.r4Z6jNwk.dpuf

 

 

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

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.

Please see Prescribing Information for ZINPLAVA (bezlotoxumab) at http://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_pi.pdf 

 

Patient Information for ZINPLAVA at http://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_ppi.pdf

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.

Please see Prescribing Information for ZINPLAVA (bezlotoxumab) at http://www.merck.com/product/usa/pi_circulars/z/zinplava/zinplava_pi.pdf 

 

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

 

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