The ChalLenGe of C. difficile and multi-drug resistant organisms in long-term care Fred C. Tenover, Ph.D., D(ABMM) Vice President, Scientific Affairs Cepheid, Sunnyvale, CA, USA Consulting Professor of Pathology Stanford University School of Medicine Stanford, CA, USA Adjunct Professor of Epidemiology Rollins School of Public Heath Emory University, Atlanta, GA, USA

Disclosures My salary and benefits are paid by Cepheid, a molecular diagnostics company, and I am also a shareholder in Cepheid

Topics for Today Movement of MRSA in healthcare systems; setting the stage Clostridium difficile Epidemiology Infection Control Laboratory detection Multidrug-resistant gram-negative bacilli Conclusions

Nursing homes play an important role in the spread and control of infectious pathogens, such as MRSA , in Orange County, CA hospitals. Data indicate that nursing homes: Can multiply the effects of a hospital outbreak Can originate outbreaks that in turn affect multiple hospitals Make it even more difficult to trace the source of an outbreak. Even if hospitals maintain effective infection control, even a single nursing home with poor infection control can lead to hospital outbreaks.

Clostridium difficile - the Organism Clostridium difficile is a Gram- positive, anaerobic, spore-forming bacillus. Spore formation is critical to its prolonged survival in the environment and ability to spread. Requires bleach for adequate disinfection Alcohol hand gels not effective during outbreaks; requires soap and water

Pathogenicity Locus (PaLoc) Two toxins, A and B, cause disease; some strains lack A and are still virulent; non toxigenic strains lack the PaLoc Binary Toxin (cdtA and cdtB) is an additional virulence factor; it is encoded at a different place on the chromosome

Changing Epidemiology of Clostridium difficile Infection C. difficile causes 3 million cases of diarrhea and colitis in US per year linked and is linked to >23,000 in-hospital deaths per year. It is surpassing MRSA as most common cause of healthcare-associated infection in the US The incidence of CDI in U.S. hospitals nearly doubled from 2001 to 2010, with little evidence of recent decline Outbreaks of severe disease caused by epidemic strain of C. difficile (027/NAP1/BI) with increased virulence and fluoroquinolone resistance have been seen worldwide. Although elderly are still most frequently affected, more disease reported in “low-risk” persons, including healthy persons in community Food may play a role in transmission The epidemiology of C. diff-associated disease has gone through dramatic changes over the last several years. C.difficile-associated disease in the U.S. has been increasing in incidence over the last 1-2 decades according to analyses of surveillance data from the National Nosocomial Infection Surveillance system, the National Hospital Discharge survey, and individual healthcare systems. We have also seen reports from hospitals of more severe disease associated with complications including colectomies and deaths. A recently identified epidemic strain of C. difficile with increased virulence and antibiotic resistance has caused outbreaks of severe disease in North America and Europe. We are now seeing CDAD in people previously thought to be at low risk for the disease such as healthy persons with minimal or no exposure to healthcare settings and peripartum women. In the face of this changing epidemiology, interim surveillance definitions have recently been developed to provide standardized surveillance methods for those working on CDAD interventions in individual healthcare facilities and in public health. These definitions are likely to evolve as we gather more data on such things as community-onset and community-acquired CDAD, incubation periods, and recurrence rates.

Frequency of C. difficile Outbreaks in U.S. Hospitals Survey of 1714 Infection preventionists; reports from 289 hospitals, 386 outbreaks in prior 24 months Top 5 pathogens (>65% ): Norovirus, Staphylococcus aureus, Acinetobacter spp., Clostridium difficile and Pseudomonas aeruginosa. C. difficile outbreaks mostly on medical and surgical units (norovirus on behavioral and psychiatry units) Overall, outbreaks with top 5 organisms lasted weeks to months C. difficile outbreaks were the longest Rhinehart, E. 2012: Am J Infect Control 40:2-8

94% 6%

Diagnostic Methods- Reality Check

Tested for CDI in 2 time periods Clinical and laboratory characteristics of Clostridium difficile infection in patients with discordant diagnostic test results (Kaltsas et al. JCM 2012) Tested for CDI in 2 time periods 56 samples positive by PCR only 72 positive by direct cytotoxin and PCR. 72% of 027 strains detected by both methods For non- NAP1 strains, only 52% were positive by both methods (p< 0.05), i.e., PCR more sensitive for non-027 No significant differences in CDI symptoms and severity for 85% of cases positive by both assays and 84% of cases detected by PCR only “Suggests that PCR is NOT an overly sensitive test in persons with clinical indications for C. difficile testing.”

Detection of C. difficile Infection (CDI): Impact of Test Method on Infection Control Tenover FC et al. J. Molecular Diag. 2011 Nov;13(6):573-82. Assume 1000 patients are tested, 10% prevalence Test Method Average Cost/ Test Sensitivity No. of + Patients Missed Spec- ificity Patients in isolation with CDI Patients in isolation without CDI Patients with CDI not in Isolation* GDH/ EIA $18.00 55% 45 94% 55 54 NAAT $35.00 95% 5 96% 95 36 *Is it worth spending more money in microbiology to treat these patients before they develop serious CDI and spread C difficile to others?

Does the Nose Know? The Diagnosis of Clostridium difficile-Associated Diarrhea by Smell Johansen et al. found that nurses were able to predict correctly the presence of Clostridium difficile disease in 31 of 37 cases (sensitivity, 84%; specificity, 77%), using a mixture of patient signs, symptoms, and history, including stool odor. The positive and negative predictive values of the characteristic odor for CDAD were 77% and 82%, respectively. Nurses are an important part of control strategies for C. difficile

Using PCR Only versus a GDH screen: Review of Published Data Multiple recent studies (against toxigenic culture) show GDH sensitivity ranges from 42-98%, perhaps due to differences in strain types Published PCR sensitivities ranges from 86-97% Major problem with the two-step algorithm, i.e., screening with GDH and testing GDH+/EIA- samples PCR: Misses 10-15% of positive samples upfront (i.e., those that are GDH-negative to start) These patients do not get treated and can continue to infect other patients

Molecular methods superior to GDH-based algorithms for detecting CDI (PCR vs GDH) Molecular methods superior to GDH-based algorithms for detecting CDI

GDH screening decreases sensitivity of detection of CDI cases by 8-12%

(BI=NAP1/027) Infection Control interventions CID 2007; 45:1266-73 Infection Control interventions Used direct cytotoxin testing (sensitivity 70%) – was this also an issue?

Potential Value of 027/NAP1/BI Call-out at time of C Potential Value of 027/NAP1/BI Call-out at time of C. difficile Testing; Hospital A Data C.diff tox B+; 027 negative C.diff tox B+; 027 positive C.diff tox B+; 027 negative C.diff tox B+; 027 positive Month 1 CDI Results Month 4 CDI Results Would you find these data helpful in your hospital?

Dr. Dale Gerding’s Predictions for C. difficile Epidemiology My pick is C 5th Decennial Conference on Healthcare Associated Infections, Atlanta 2010

Long Term Care Facilities often Serve as Reservoirs of MDROs 356 cases of KPC-producing Klebsiella pneumoniae in Los Angeles nursing homes

CDC Data on Carbapenem Resistant Enterobacteriaceae http://www.cdc.gov/vitalsigns/hai/cre/

View of Beta-Lactamases (2013) The Road to Carbapenem Resistance Class A TEM, SHV, CTX-M, KPCs others Class B Metallo- enzymes, VIM NDM-1,others Class C AmpCs, MIR, DHA, FOX, and others Class D OXA ESBLS; Carba- penemases Most are carba-penemases AmpC + porin change = carbapenem resistance OXA48, 162, 163, 181 carba- penemases More to detect than KPCs, but we must be able to Distinguish carbapenemase producers from porin changes PAGE | 25

Updated 9/5/13 NDM 3a 9 NDM-1, NDM-2 Current # 106 212 142 147 7 7 18 11 3 363 48 31 32 8 NDM 3a 9 NDM-1, NDM-2

(VIM-1) The patient was a woman from the US who developed diarrhea during a Mediterranean cruise and was hospitalized in Greece Klebsiella pneumoniae isolate with VIM-2 was resistant to all antimicrobials usually used to treat Klebsiella (no antibiogram given) Facilities that have not identified cases of Carbapenem-resistant Enterobacteriaceae (CRE) should: Undertake periodic laboratory reviews to identify cases Patients with CRE should be managed using contact precautions Patients exposed to CRE patients (e.g., roommates) should be screened with surveillance cultures

Multiple Broad-Spectrum Beta-Lactamase Targets for Comprehensive Surveillance (Mangold et al. JCM Accepts 2013) Concern regarding frequent transfer of residents from long-term acute care facilities (LTACHs) who are colonized with MDROs into hospitals. Two-thirds of residents from two area LTACHs colonized with KPC producers. Used active surveillance to identify patients with MDRO carriage, and contact tracing and PFGE to monitor for MDRO transmission Surveillance included PCR for KPC, NDM, VIM, IMP, and CTX-M beta-lactamase genes performed on rectal swabs from residents of two (culture too slow) Despite high colonization rated, to date, only one MDRO transmission to an existing hospital patient has been detected during nearly 4 years.

Alpha Evaluation of Xpert MDRO Rectal Swab Surveillance Assay 328 samples (5 hospitals; US and Spain) 53 Xpert MDRO positive 11 VIM positive results (10 DNA sequence +) 43 KPC positive results (42 DNA sequence +) 1 sample contained both VIM and KPC 276 Xpert MDRO negative 256 organisms susceptible to all carbapenems 20 organisms non-susceptible to at least one carbapenem All 20 negative by Check Points microarray for carbapenemase genes

KPC-Producing K. pneumoniae and VIM-Producing Pseudomonas aeruginosa from Long-Term Care Control CROs are much more widely disseminated than often perceived The reservoirs are huge.

Preventing Lethal Hospital Outbreaks of Antibiotic-Resistant Bacteria MDROs are transmitted primarily on the hands of healthcare workers who do not practice effective hand washing after every contact with patients and the environment “We urgently need screening media or real time genetic tests that can be deployed quickly to identify patients who are colonized with MDROs” Antibiotic stewardship is a critical part of control Sandora and Goldmann: New Engl J Med 2012:367:2168-70

Conclusions Long-term care facilities play a key role in transmission and control of MDROs C. difficile continues to be an infection control challenge in the US; tests with high sensitivity and specificity are crucial Spread of carbapenem-resistant organisms is on the rise in the US but can be controlled with active surveillance

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