3/23/2012. Impact of Laboratory Testing on Detection and Treatment of Healthcare Associated Infection: The Case of CDI

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1 Impact of Laboratory Testing on Detection and Treatment of Healthcare Associated Infection: The Case of CDI L. Clifford McDonald, MD Lance R. Peterson, MD March 27,

2 Potential COI L. Clifford McDonald, MD None Lance R. Peterson, MD Research Grants» Bayer, Cepheid, NorthShore, GeneOhm, GSK, Johnson and Johnson, Merck, MicroPhage, Nanogen, Nanosphere, NIAID, Roche, 3M, Washington Square Health Foundation, Wyeth (Pfizer), Syntezza, Great Basin, AHRQ, CareFusion Consultations (in conjunction with research projects and new diagnostics)» Cepheid, GeneOhm, GSK, MicroPhage, Nanogen, Nanosphere, Roche, 3M, Wyeth (Pfizer), CareFusion Goals of the Presentation To understand why Clostridium difficile is a particular problem What is the disease? How is it important? To evaluate the diagnostic approach How good are the tests? What clinical criteria should be used? How do I implement the right test? To discuss the implications of testing format Best practices for sample selection Diagnostics (migration to more sensitive testing) Infection Control Pathogenesis of Clostridium difficile Infection (CDI) 1. Ingestion of spores transmitted from other patients via the hands of healthcare personnel and environment 4. Toxin A & B Production leads to colon damage +/- pseudomembrane 3. Altered lower intestine flora (due to antimicrobial use) allows proliferation of C. difficile in colon 2. Germination into growing (vegetative) form Sunenshine et al. Cleve Clin J Med. 2006;73: Sunenshine RH and McDonald LC. Clev Clinic J Med. 2006;73:

3 Initial (Wrong) and Modified Sequence C. difficile acquisition Antimicrobial (s) Hospitalization Asymptomatic C. difficile colonization CDI Antimicrobial C. difficile exposure Hospitalization Asymptomatic C. difficile colonization C. difficile infection (e.g., diarrhea) Figures courtesy of Stuart Johnson, Hines VA Colonization and Immunity to Clostridium difficile in Humans Unestablished Antibiotic perturbed- Microbiome, Microbiome, Non-immune Waning immunity, Innate resistance Disease susceptibility Degree of Colonization The period between exposure to C. difficile and the occurrence of CDI has been estimated in 3 studies to be a median of 2 3 days Cohen SH et al. Infect Control Hosp Epidemiol 2010; 31(5): Degree of Immunity Colonization in Later life due to antibiotics Age in years McDonald LC; created February 16, /149 (4%) communitydwelling elderly colonized Miyajima et al. PlosOne 2011 Both Colonization and Infection Increase with Duration of Exposure to Ward Setting Loo VG et al. N Engl J Med 2011;365:

4 Important Host Defense and Risk Factors for CDI Host Defense Intact/undisturbed lower intestinal microbiota Intact appendix? Infancy Humoral immune response Stomach acid? Spores are acid resistant Risk factors Medications that disrupt microbiota Antibiotics PPIs? Older age Immunosuppressant's Inflammatory bowel disease Tube feeds Factors increasing acquisition Proximity to other infected patients--hospitalization Clostridium difficile Infections (CDIs) and Deaths Reach and Remain at Historic Highs CDI hospitalizations Increased 3-fold Deaths linked to CDI 14,000 in 2007 $1 billion in medical costs CDIs in hospital patients only Epidemic strain First emerged in 2000 Causes more cases and severity Lucado J, et al, Available at Hall AJ et al.. Presentation at the 49th Annual Meeting of the Infectious Disease Society of America; October 22, 2011; Boston, MA. Dubberke ER et al. Clin Infect Dis 2008;46: McDonald LC et al. N Engl J Med 2005;353: Current Epidemic Strain of C. difficile BI/NAP1/027, toxinotype III Historically uncommon epidemic since 2000 More resistant to fluoroquinolones Higher MICs compared to historic strains and current non-bi/nap1 strains More virulent Increased toxin A and B production Polymorphisms in binding domain of toxin B McDonald et al. N Engl J Med. 2005;353: Warny et al. Lancet. 2005;366: Stabler et al. J Med Micro. 2008;57: Akerlund et al. J Clin Microbiol. 2008;46:

5 NAP1 Remains a Major Player Epidemiology of Clostridium difficile in Chicago Hospitals, 2009 Black SR et al. Infect Control Hosp Epidemiol 2011;32(9): CDIs Largely Health Care Related: Most Develop Symptoms Outside Hospitals 94% health care related 75% of these outside hospitals Nursing home patients Patients in community Outpatient exposures only Recent inpatient exposure 25% hospital inpatients Post-discharge CDI common Most potent antibiotics used in hospitals Lasting effect on patients Source: CDC, MMWR;2012;61(Early Release): 1-6 Interdependence of Hospitals and Surrounding Facilities in Preventing CDI 52% of the CDIs diagnosed in hospitals are present on admission 36% (19% overall) recently discharged 48% hospital onset Likely result from inpatient care CDIs present on admission Source for intra-hospital transmission Source: CDC, MMWR;2012;61(Early Release): 1-6 5

6 Six Steps to Prevention of CDIs Prescribe and use antibiotics carefully Focus on an early and reliable diagnosis Isolate patients immediately Wear gloves and gowns for all contact with patient and patient care environment Assure adequate cleaning of the patient care environment, augment with EPA-registered C. difficile sporicidal disinfectant Notify facilities upon patient transfer Source: CDC, 2012 Current Testing Options - L Peterson and A Robicsek, Ann Int Med, 15:176-9, 2009 C. difficile Testing in the US 95% of USA testing is not cytotoxin or culture - LC McDonald et al, EID 12, , microbiology laboratories surveyed 4 (4%) routinely culture for C. difficile 20 culture for special reasons (not as a diagnostic test) - P Gilligan, ClinMicroNet, October 31 st,

7 Assessment of Multiple Tests Used toxigenic culture as the gold standard Sensitivities, specificities, positive and negative predictive values, respectively: Premier Toxins A & B 87% 48%, 98%, 88%, ImmunoCard Toxins A & B 87% 48%, 99%, 91%, Xpect C. difficile Toxin A/B 85% 48%, 84%, 46%, Triage C. difficile Panel (for toxin A) 84% 32%, 100%, 100%, LightCycler PCR (In-house test) 96% 86%, 97%, 90%, GDH assay combined with toxin A EIA was only 32% as sensitive as culture for toxigenic C. difficile - LM Sloan et al, JCM 46: , 2008 Comparison of CDI Tests Tested 1,000 non-formed stools Tested lactoferrin, 2 rtpcr tests, 4 EIA tests, 2 GDH tests (one combined with EIA), tissue culture cytotoxin 146 samples considered true positive Gold Standard is enriched toxigenic culture (2 methods; 136) or multiple positive tests and patient receiving oral Flagyl or Vancomycin (10/146) - LR Peterson et al, AJCP 136:372-80, 2011 C. difficile Toxin B Genome PCR target region - M Rupnik et al, FEMS Micro Lettr 178: , 1997; - M Rupnik et al, J Med Micro 54:113-7,

8 Comparison of CDI Tests Performance analysis of the evaluated CDI assays (For this analysis there were 146 true positive and 854 true negative tests). Statistic/ Lactoferrin EIA-1 EIA-2 EIA-3 EIA-4 GDH-1 GDH-2 Cyto- BD NS Culture Test (with (with toxicity rtpcr rtpcr GDH-1) EIA-4) Sensitivity (95% CI) ( ) (36.4- (38.3- (31.8- (37- (81- (76.3- (41.7- (89.1- (76.3- ( ) 55) 48.2) 53.6) 92.3) 89) 58.3) 97.4) 88.9) 96.5) Specificity (95% CI) ( ) ( ) (97.6- (98.1- (96.3- (99.1- (92.7- (91.6- (99.1- (97.8- ( ) 99.6) 98.5) 100) 96) 95.1) 100) 99.4) 99.2) - LR Peterson et al, AJCP 136:372-80, 2011 Two Step GDH-Cytotoxicity Assay GDH antigen assay (Techlab) used as a screen was compared culture and cytotoxicity on 439 non-formed samples 186 GDH and culture negative 253 GDH positive 112 stool cytotoxin + (20 culture - ) 141 stool cytotoxin (33 toxigenic culture + ) - ME Reller et al, JCM 45:3601-5, 2007 Two Step GDH-Cytotoxicity Assay: What Happened? Culture was using regular CCFA without prior anaerobic reduction following spore stimulation (>30% sensitivity loss) LS Mundy et al, AJCP 103:52-6, 1995 LR Peterson et al, EJCMID 15:330-6, 1996 Final stool cytotoxicity dilution as low as 1:20 dilution with no protein neutralization control (6-26% potential false positives) - RC Walker et al, DMID 5:61-9, 1986 If toxigenic culture is the Gold Standard the 2-step assay has a sensitivity of 77% - ME Reller et al, JCM 45:3601-5,

9 Why is EIA So Inferior? 2,296 unformed stools tested at 7 sites All strains typed by PCR-ribotyping EIA was significantly lower for detection of ribotypes 002, 027, and 106 (P < , P < , and P 0.004) Sensitivity of GDH algorithms for ribotypes other than 027 was lower than rtpcr (P < 0.001) - FC Tenover et al, JCM 48:3719, 2010 What is the Consequence of a Low Sensitivity Test? Understanding Predictive Value - T Planche et al. Lancet Infect Dis 8: ,

10 Making early and accurate diagnosis a reality Low sensitivity of EIAs leads to over testing Goldenberg and French. Journal of Hospital Infection 79 (2011) 4e7 Making early and accurate diagnosis a reality resulting in low lab prevalence and PPV Goldenberg and French. Journal of Hospital Infection 79 (2011) 4e7 Making early and accurate diagnosis a reality To realize benefit of NAAT need a rational testing strategy 19 studies, 7392 samples Mean sensitivity: 90% Mean specificity: 96% a 15-20% testing prevalence with a NAAT may be more achievable than a 8-12% prevalence with an EIA --LC McDonald Test only significant diarrhea >3 unformed stools in 24 hours Reject formed stool Allow only one test every 5-7 days No test for cure Deshpande et al. Clinical Infectious Diseases 2011;53(7):e81 e90 10

11 Accuracy of PCR CDI Diagnosis Meta-analysis of 19 studies (7392 samples) Overall sensitivity 90% (95% CI: 88% 91%), specificity 96% (CI: 96% 97%) At C. difficile prevalence of 10%, 10% 20% and 20% the positive predictive value and the negative predictive value were 71%, 79%, 93% and 99%, 98% and 96% FDA now requiring toxigenic culture for all new tests - A Deshpande et al, Clin Infect Dis 2011;53:e81 e90 Making early and accurate diagnosis a reality NAAT and non-naat surveillance rates not comparable ~30% of NHSN hospitals using NAAT Working to risk adjust these rates Incorporate into SIR Fong KS et al. Infect Control Hosp Epidemio 2011 Goldenber SA et al. Infect Control Hosp Epidemiol 2011 Can Test Positive Prevalence Act as a Specimen Quality Measure? When testing all specimens EIA positive test prevalence = 6.5% rtpcr positive test prevalence = 13.8% Toxigenic positive test prevalence = 13.6% - LR Peterson et al, AJCP 136:372-80, 2011 Suggests PCR positive prevalence should be twice that of EIA 11

12 What is a Positive Prevalence Goal? PCR Testing 16.7% ( %) 7.5% ( %) - DM Hacek and LR Peterson, unpublished data Assessing Specimen Quality When using rtpcr one tested samples per 7 days is sufficient in most cases (suggest expert consultation (Infectious Diseases, Gastroenterology) when more requested Stool should not be formed when tested Suggested positive test prevalence for indication of adequate sample screening At least 8-10% when using EIA At least 16-20% when using real-time PCR - LC McDonald and LR Peterson, 2011 Testing Approach GDH/EIA alone Impact of CDI Test Methods Days of No. of No. of Potential Average Sensitivity Specificity Patients in Patients in Patients with Positive False Environmental Cost/ of of Isolation Isolation CDI not in Tests Algorithm b Patients Algorithm b Positive Shedding and with CDI without CDI Isolation Missed Tests Treatment Delay $ % 45 94% Reflex to NAA for GDH+ EIA $ % % 55 1 Day 1: 55 Days 2 5: 85 Day 1: 54 Days 2 5: 55 Day 1: 45 Days 2 5: 15 Reflex to Toxigenic culture for GDH+ EIA $ % % 55 4 Day 1 4: 55 Days 5: 86 Day 1 4: 54 Days 5: 55 Day 1 4: 45 Days 5: 14 Reflex to Direct Cytotoxin for GDH+ EIA $ % % 55 2 Days 1 2: 55 Days 3 5: 77 Days 1 2: 54 Days 3 5: 55 Days 1 2: 45 Days 3 5: 23 NAAT alone $ % 5 96% b. Based on 1,000 Patients with 10% sample positivity - FC Tenover et al, J Mol Diagnostics, 2011 (Aug 18. [Epub ahead of print]) 12

13 What Can the Laboratory Provide? Reliable detection of toxin-producing C. difficile in a submitted stool sample Elimination of formed stool testing without reasonable explanation Elevates likely disease prevalence in tested population and improves test performance Education of physicians on the limitation of current laboratory tests for CDI With current testing the laboratory cannot diagnose CDI Physician Understanding of CDI Katz and colleagues found 39% of tests for CDI could be avoided if simple clinical rules were used for patient selection - DA Katz et al, Am J Med 100:487-95, 1996 Study by Peterson and colleagues found >50% of stools were from patients without significant diarrhea and/or antibiotic use - LR Peterson et al, 45: , 2007 What Can Clinicians Provide? Careful evaluation of patients to assure they are at risk for CDI Minimally at least 3 loose stools in one day Preferred antibiotic exposure in prior 2-3 months Preferred unlikely other reason for diarrhea Preferred healthcare exposure in prior 2-3 months Document these findings in the medical record 13

14 What about Guidelines for CDI? SHEA/IDSA Perform testing on unformed stool Do not test asymptomatic patients or for test of cure Stool culture is the most sensitive test Toxigenic culture is the Gold Standard for CDI testing EIA is suboptimal for diagnostic testing GDH followed by cell cytotoxicity or toxigenic culture is a potential option for testing (2-step procedure) rtpcr may be the optimal test more data needed Repeat testing is of limited value - SH Cohen et al, ICHE 31:431-55, 2010 Current CDC Guidance (08/16/2010) Suspect CDI in patients who have received antibiotics in the previous 8-12 weeks and have 3 or more diarrheal stools in 24-hours The current testing gold standard is a toxigenic culture, but turnaround time is slow Rapid tests that approach the sensitivity and specificity of toxigenic culture include PCR tests or 2-step testing paradigms that use rapid antigen assays with confirmation - C Gould, 14

15 NorthShore Case Study Setting: a 4-hospital, 1,000 bed, university affiliated healthcare organization Historical testing based on EIA run each day on overnight shift Patients placed into isolation at the time an order for CDI testing originated Hypothesis: Disseminated CDI testing by PCR done on demand 24 hours per day can eliminate the need for pre-emptive isolation, increase detection of CDI, and lower cost Current NorthShore CDI Testing (Number Tested and Isolated) 7,102 EIA tests ordered per year 5,598 tests performed in 2009 representing 4,366 different patients (22% of tests are repeats) 1,504 duplicates/previous positive cancelled 660 Cytotoxin tests ordered representing 660 repeat patients Isolation days needed 3,842 patients in isolation for 1 day 88% negative EIA tests 581 patients in isolation for an additional 2 days Negative EIA + Negative Cytotoxin Test - R Thomson and I Dusich, 2010 NorthShore CDI Testing and Isolation Cost 7,102 EIA tests ordered and 5,598 done in ,504 EIA cancelled: 2 min labor = $1.00 5,598 EIA processed $5.12 reagents and 3 min labor ($1.50) = $ cytotoxin ordered and processed $6.85 and 5 minutes ($2.50) labor = $ LR Peterson et al, CID 45: ,

16 NorthShore CDI Testing and Isolation Cost 88% of tests negative: 3,842 patients in isolation for 1 day and 581 for 2 more days (1,162 days) At least 5,004 not needed isolation days at $30 per day (additional days for weekends) = $150,120 - LR Peterson et al, Jt Com J Qual Pat Saf 33:732-8, 2007 TA Lee et al, ICHE 26:39-46, 2005 NorthShore CDI Testing Summary Current costs 5,598 EIA tests done, 1,504 cancelled = $38, cytotoxin tests = $6,171 5,004 not needed isolation days = $150,120 If de-centralize testing can spend above funds to perform 4,366 tests (if isolate when positive) $194,854 for 4,366 tests (1 test/patient) = $44.63/test Assume supply cost at $43.63 if $1 for labor If stay centralized then $44,734 for 4,366 tests and will still isolate on order $44,734 for 4,366 tests (1 test/patient) = $10.25/test Assume supply cost at $9.25 if $1 for labor Option One (Centralized Goal $9.25/test) 600 tests/month planned No charge for equipment or service 3 kits/month for $15,000 $25/test for supplies 16

17 Option Two (Centralized Goal $9.25/test) 600 tests/month planned $60,000 for equipment (1) and service $10,000 for service per year thereafter 600 tests/month for $18,000 $38.33/test for supplies in year one $31.39/test for supplies in following years Option Three (De-Centralized Goal $43.63/test) 600 tests/month planned $175,485 for equipment (4) and service $29,000 for service per year thereafter 600 tests/month for $18,000 $54.37/test for supplies in year one $34.03/test for supplies in following years Option Four (De-Centralized Goal $43.63/test) 600 tests/month planned No charge for equipment (4) and service 600 tests/month for $22,800 $38.00/test for supplies each year 17

18 Summary of Options (Multiple Hospitals) Option Structure Centralized Centralized De- Centralized De- Centralized Target $ $9.25 $9.25 $43.63 $43.63 Proposed $ $25 $38.33/ $31.39 $54.37/ $34.03 $38.00 Summary of Options (Single Hospital) Negative IC Impact of Using PCR Potential for increased detection of CDI cases - DM Hacek et al, AJIC 38:350,

19 What Actually Happened? Hospital 1 Start PCR Start PCR 21 of 26 (81%) outpatients in last 3 months admitted from home What Actually Happened? Hospital 2 Start PCR Start PCR 16 of 24 (67%) outpatients in last 3 months at 2 other NorthShore hospitals admitted from home Re-Admission for CDI After Discharge in California Assessed re-admission for up to 12 weeks In 2000 to 2007 hospital-onset CDI increased from 15 to 22 per 10,000 admissions When including post discharge CDI events, incidence doubled (29 to 52 per 10,000 admits) CR Murphy et al. 33;2012:

20 US Hospital CDI Risk Stratification In 85 hospitals with 1,351,156 unique patients; 2,022,213 admissions; 9,803 cases of CDI were identified 50.6% were Hospital Onset (HO-CDI) 23.0% were Community Onset/No Hospital Contact (CO- NHA) CO-NHA prevalence on admission was associated with HO CDI across all facilities As states mandate public reporting of HO CDI rates, they should include the collection of CO-NHA CDI admission prevalence for risk-stratification -MD Zilberberg et al. ICHE 32:649-55, 2011 What to Do Next: Solving the Problem Evaluate hand hygiene practice and availability of soap and water versus gels Assess antibiotic use Consider room bleaching (already in place) Look for disease clusters (typing) Test is too sensitive reevaluate lab assay Are the right patients being tested Determine where outpatients are coming from and consider surveillance screening/isolation Implement universal bleaching as an environmental cleaning tool Other ideas??? Diagnosis of CDI Appropriate clinical presentation At least 3 loose stools in 1 day AND Positive reliable diagnostic assay 1. Pseudomembranes seen at lower gastrointestinal endoscopy (for colitis) or 2. Toxin (B) or tcdb detected in the stool or 3. A stool culture positive for the presence of a toxin B- producing C. difficile If repeat testing is needed within 7 days perform it using a different assay format use the most sensitive test first 20

21 In Conclusion CDAD/CDI appears to be increasing and may be more virulent Careful diagnosis is necessary Apply appropriate clinical criteria for testing Do not perform multiple tests within 1 week Use the most sensitive test first rtpcr is that technology Perform 1 test per week per patient Do not perform test of cure assay Enhanced physician education is needed More Information More Information 21

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