Presentation on theme: "C. difficile in the Age of Antimicrobial Stewardship"— Presentation transcript:
1 C. difficile in the Age of Antimicrobial Stewardship Darcy Whitlock, MSGI Disease Product Manager
2 Top 7 Threats to the Human Race Source adapted from Science, Vol 325, September 2009Available at
3 Infectious Disease & Antibiotics 1970: Surgeon General William Stewart said the US was “ready to close the book on infectious disease as a major health threat”Modern antibiotics, vaccination, and sanitation methods had done the job1995: Infectious disease is the 3rd leading cause of death behind heart disease & cancer2013: Infectious disease remains a critical concern as antimicrobial resistance increases
4 Inpatient SettingsOne in every three patients will receive two or more antibiotics in the course of their hospital stayOf the patients receiving antibiotics, three out of every four will receive unnecessary or redundant therapy, resulting in excessive use of antibioticsCDC – Get Smart Campaign
5 Outpatient SettingsEach year, tens of millions of antibiotics are prescribed unnecessarily for viral upper respiratory infectionsAntibiotic use in primary care is associated with antibiotic resistance at the individual patient levelThe presence of antibiotic-resistant bacteria is greatest during the month following a patient’s antibiotics use and may persist for up to 1 yearCDC – Get Smart Campaign
6 Improper Antimicrobial Use Longer duration than necessaryNoninfectious/nonbacterial syndromeTreatment of colonization/ contaminationUnnecessaryNecessaryAPUA slides / Levy presentation
7 Costs of Antibiotic Resistance Antibiotic resistance increases the economic burden on the entire US healthcare systemResistant infections cost more to treat and can prolong healthcare useMore than $1.1 billion is spent annually on unnecessary antibiotic prescriptions for respiratory infections in adultsIn total, antibiotic resistance is responsible for:$20 billion in excess healthcare costs$35 billion in societal costs8 million additional hospital daysCDC – Get Smart Campaign
8 “Every antibiotic expected by a patient, every unnecessary prescription written by a doctor, every uncompleted course of antibiotics is potentially signing a death warrant for a future patient.”Dryden, et al. 2009
9 Why Antimicrobial Stewardship? A balance of infection control and antibiotic managementAchieve optimal clinical outcomesDecrease adverse drug eventsC. difficileMinimize development of antimicrobial resistancePreserve antimicrobial resourcesReduce costs
10 Antimicrobial Stewardship Programs Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship – 2006Core members include:Infectious Disease PhysicianClinical PharmacistClinical MicrobiologistInfection Control ProfessionalInformation System Specialist
11 Simple Stewardship Solutions Treat only when necessaryUse narrow-spectrum agents whenever possibleUtilize rapid diagnosticsConsider higher doses or shorter duration
12 Rapid Diagnostics Test, Target, Treat Know the organism, know the appropriate treatmentReduce antibiotic overuse & unwanted side effectsShorten time to appropriate therapyTargeted therapy improves pharmacy savingsReduced infection transmission increases infection control savings
13 Ideal Diagnostic TestAffordable Sensitive (few false neg.) Specific (few false pos.) User friendly Rapid (30 min.) Equipment-free DeliverableMabey et al. Diagnostics for the Developing World.Nature Rev Microbiol 2004, 2:231-40
15 Risk Factors for C. difficile Previous antibiotic exposureSome cases unrelated to antibioticsDisruption to intestinal floraAdvanced ageHospitalizationCommunity acquisition becoming more commonPregnancy
16 C. difficile Economic Impact Several studies examine costs$3B$436MKyne, et al. Clin Infect Dis ; 34:O’Brien et al. Infect Control Hosp Epidemiol ; 46:Dubberke, et al. Clin Infect Dis ; 46:
17 Cycle of AntibioticsPrimary InfectionAntibiotic TreatmentC. difficile InfectionStart C. diff antibioticsD/C primary antibioticsPart of the difficulty in treating C. difficile is that it can impact treatments for other diseases.If someone is in the hospital being treated for a primary infection, let’s say pneumonia, the antibiotics prescribed will make the person susceptible to a C. difficile infectionPart of the treatment for C. difficile is discontinuing any other antibiotics and starting antibiotics specific for C. difficile.There’s a chance the original disease wasn’t fully cured when the primary antibiotics were discontinued, which means it could recur. Which puts us back at the start needing antibiotics to treat the primary infection.Of course, the antibiotics to treat the C. diff infection also put the patient at risk of contracting a C. diff infection. So we get not only a cycle of treating the primary infection, but possibly a C. diff infection relapse cycle.This creates huge issues for antibiotic stewardship and can lead to increasing antibiotic resistances.
18 Gastrointestinal Disease: Impossible but True Impossible to diagnose on clinical symptoms alone, but frequently doneWhat’s the primary symptom of any GI disease?100s of causes, often treated empirically with antibioticsPrimary causes: bacterial infection, viral infection, functional disorders, autoimmune disease, food allergiesAntibiotics may cure infection, may not affect disease but it runs its course and they appear to work. But can hurt the patient by increasing risk of C. diff, or worseTest patients so we can target the cause…Cure InfectionHurt Patient
19 Treat the Right Patients Lab tests are essential for proper diagnosis and to avoid empiric antibiotic treatmentWhat if a test:Doesn’t actually tell if someone is sickTakes so long for results the doctor has already treated the patient empirically
20 DNA = Cookbook; Gene = Recipe Think about a cookbook for a minute. If you want to cook something, you can go to the cookbook and find a recipe, follow the instructions, and end up with the finished item.That’s the same way C. diff makes something like toxin. It has a cookbook too, it’s DNA. The DNA holds all the information it needs for everything it has to make.Just like a cookbook is broken up into recipes, so is the DNA, but we call the recipes Genes. A gene is the instructions how to make one specific thing. For instance there’s a gene for Toxin B. If C. diff needs to make toxin it will find the gene recipe and follow the instructions encoded there to make the toxin.Now, just because we have a cookbook doesn’t mean we’re making every dish one after the other all day long. It means we have the information there if we need it.And that’s exactly the same thing C. diff is doing. Just because it has the gene for Toxin doesn’t mean it’s turned on making toxin all the time. It means it has the information there if it needs it.And that’s an important point to remember as we continue to talk about DNA molecular testing.GeneProduct
21 C. difficile Toxins A&B Toxins cause the disease symptoms Toxin results most closely correlate to disease state and clinical outcomeNot all toxin assays perform equallyToxins produced only when needed by the bacteriaTypically in response to nutritional or environmental stress
22 Molecular Testing Nucleic Acid Amplification Tests (NAAT) DNA test, PCR, LAMP, isothermal NATDetects the gene (DNA) that encodes for toxinGreat for sensitive identification,but doesn’t always tell us what’shappeningDoesn’t indicate if gene is turned onproducing toxin in the patientWe commonly call DNA tests a molecular test. More technically it’s called a Nucleic Acid Amplification Test.1 – PCR is the most well known, but there are other methods like LAMP and isothermal tests available now3 – How many of you have seen an episode of CSI where they find a drop of blood at a crime scene and rush it back to the lab for a DNA test? They identify whose blood it is – Great! Very sensitive identification. But we don’t know why the blood was there. Was that person a victim, where they the perpetrator of a crime, or an innocent bystander who tripped and fell and scraped their knee earlier in the day?This is the same problem with DNA testing for C. diff – is the C. diff the perpetrator of disease, or an innocent bystander in a patient whose symptoms are caused by something else?
23 C. difficile GDH Antigen Glutamate dehydrogenase (GDH) produced in large amounts by all C. difficile bacteriaGDH shows C. difficile is present & growingVery sensitive detection of bacteriaDoes not indicate if they produce toxin, need follow-up test for toxin
24 What Test is Best? There is no optimal test for C. difficile Each method has advantages & drawbacksMethodAdvantageDrawbackGDHSensitive detection, shows bacteria are presentDoesn’t say if C. difficile strain can produce toxinToxin A/BIndicates active disease,Most clinically relevantWill not identify carriers, may not detect all positive patientsMolecularSensitive detection of toxigenic bacteriaDoesn’t say if toxin is present, does not differentiate active disease[Read chart across, Advantage and disadvantage for each method]
25 Guidelines: Points All in Agreement Toxin A/B testing should not be used as a stand-alone testGDH screening prior to toxin testing is recommended for improved sensitivityRepeat testing (C. diff x 3) not helpful and should be discouraged when using more sensitive testing methods (GDH or molecular)Since there’s no easy answer for C. diff testing, several societies have set out guidelines with recommendations for testing. These include:IDSA – Infectious Diseases Society of AmericaSHEA – Society for Healthcare Epidemiology of AmericaASM – American Society for MicrobiologyDH – UK Dept. of HealthFor the most part the guidelines are all in agreement:1 – This isn’t saying not to use a Tox A/B test, only that they shouldn’t be used stand-alone
26 Molecular Testing Disagreement ASM: Molecular can be used stand-alone or as confirmation of rapid resultsSHEA/IDSA: PCR has high sensitivity & specificity, looks promising, but not enough data yet to recommendUK: PCR is a good screening test, but not specific for active diseaseFollow up with sensitive toxin test for clinical activity
27 UK Guidelines - 2012 Largest most comprehensive study ever done 12,441 samples compared to patient clinical features & outcomesGDH, Toxin, NAAT, Cytotoxicity, Toxigenic CultureTesting for active toxin production is critical for determining disease state & clinical outcome1 – This study compared to patient disease, not just other lab tests like a lot of studies do. If you think about it, this is really what all studies should do, but it’s hard to do with healthcare privacy laws and all.3 – Cytotoxicity and Toxigenic Culture are the gold standards for lab tests that are often used for comparisons in papers4 – When compared to patient health, the presence of active toxin is the most important aspect.A webinar presented by the lead author of the study and UK guidelines is available online. It’s also available for PACE continuing education credits if anyone needs, and goes into detail about the study and what this new information means.Webinar by Dr. Mark Wilcox, co-author of the UK study & GuidelinesPlanche, et al. Lancet Infectious Diseases. E-pub Sept. 3, 2013.
28 C. difficile Testing Algorithm Positive for toxigenicC. difficile10-15%Reporting ResultsAdditional TestingPositive GDH Antigen and Negative Toxin10%There is no optimal test for C. diffNegative for toxigenicC. difficileNPV 99.8%75 – 80%
29 What Does GDH + , Toxin – Mean? C. difficile bacteria are present but toxin is not detectedCould be due to:Colonization with a nontoxigenic strainPatient is a carrier of a toxigenic strainToxin level is below the limit of detectionUK Study: GDH+, Tox- patients have similar outcomes to C. diff negative patients1 – It’s important to know this result isn’t wrong, it’s telling us something about the patient4 – They looked at this group as part of the big UK study, comparing their outcomes to the group with active disease that had toxin present and the group that didn’t have C. diff present at all. The patient health and clinical outcomes for GDH+/Tox- patients was similar to the group that didn’t have C. diff present, and was significantly different from the group that had active disease. So this raises questions about how best to manage patients who may be carriers.
30 Carrier Rates COMMON CARRIERS RATE Treating carriers is ineffective Healthy Adults1 – 3%People with recent healthcare exposure15 – 25%Residents of Long Term Care Facilities%Newborn Infants%Treating carriers is ineffectiveContributes to antibiotic overusePuts individual patient at risk of contracting CDIIdentification important for infection prevention
31 Antimicrobial Stewardship Directly Impacts C. difficile Rates AMS program instituted at VAMC HoustonRequired ID Doc approval for most antibioticsC. difficile infection rate dropped 42% solely from restricting inappropriate antibioticsStudy presented at ID Week, 201310% reduction in antibiotics = 17% reduction in C. diff ratePenicillins and β-lactams had most effectFluoroquinolone decrease had surprisingly small effectNuila, et al Infection Control and Hospital Epidemiology. 29(11):
32 C. difficile Testing Companion C. difficile toxins typically cause inflammationLactoferrin results can help differentiate carriers from active infectionsInflammationPresentNo InflammationLikely not active infectionCarrier, colonizedLikely active infection
33 Fecal WBC Smear False negatives from cell breakdown Need intact cells for microscopic identificationWBCs break down rapidly in stoolDigestive enzymes, cytotoxinsVariation from different users, different prep techniques, number of fields examined
34 WBC Testing Options - Lactoferrin Highly accurate marker of WBCs (neutrophils/PMNs)Elevated lactoferrin = WBCs are present, inflammation in GI tractStable marker of WBCsUnaffected by cell breakdownNon-subjective, no variation between users
35 Infection Control Recommendations Cohort CDI patientsC-IIIIsolationB-IIIHand HygieneA-IIContact PrecautionsA-ISHEA/IDSA Guidelines for C. difficile infection in adults ICHE 31(5)
36 Importance of Daily Cleaning Elderly relative living with you develops infectious diarrheaYour young children have daily contact with their ill grandparentDo you:Wait 10 days until the illness has resolved before cleaning the bathroom & other objects the person contactsDisinfect surfaces daily or after each use of the bathroom to prevent transmissionAt end of slide say: Healthcare workers are like children…they touch everything and they don’t always wash their handsThanks to Dr. Curtis Donskey, Case Western Reserve University, for this example
37 Points to Remember C. difficile testing is complex No One & Done solutionHigh carrier rate can complicate treatment and infection prevention decisionsInflammation testing can aid diagnosis
38 Points to Remember Proper rapid diagnosis of C. diff disease: Improves patient outcomesPrevent antibiotic overuseProtect vulnerable patients from antibiotic-related complicationsAntimicrobial stewardship plays a direct role in reducing C. difficile rates
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