THE CHALLENGE OF C DIFFICILE AND MULTIDRUG RESISTANT

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 THE CHALLENGE OF C. DIFFICILE AND MULTI-DRUG RESISTANT ORGANISMS IN LONG -TERM CARE

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,

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 �

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

 • Nursing homes play an important role in the spread and control of

• 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 Grampositive, anaerobic, sporeforming bacillus. �

Clostridium difficile - the Organism Clostridium difficile is a Grampositive, anaerobic, sporeforming 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 (Pa. Loc) Two toxins, A and B, cause disease; some strains lack

Pathogenicity Locus (Pa. Loc) Two toxins, A and B, cause disease; some strains lack A and are still virulent; non toxigenic strains lack the Pa. Loc Binary Toxin (cdt. A and cdt. B) 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

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/NAP 1/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

Frequency of C. difficile Outbreaks in U. S. Hospitals Survey of 1714 Infection preventionists;

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%

94% 6%

Diagnostic Methods- Reality Check

Diagnostic Methods- Reality Check

Clinical and laboratory characteristics of Clostridium difficile infection in patients with discordant diagnostic test

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- NAP 1 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

Detection of C. difficile Infection (CDI): Impact of Test Method on Infection Control Tenover FC et al. patients J. Molecular 2011 Nov; 13(6): 573 -82. Assume 1000 are Diag. tested, 10% prevalence Sensitivity Specificity $18. 00 55% 45 94% 55 54 45 $35. 00 95% 5 96% 95 36 5 GDH/ EIA NAAT Method Patients with CDI not in Isolation* No. of + Patients Missed Average Cost/ Test Patients in isolation without CDI Patients in isolation with CDI *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

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

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+/EIAsamples 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

(PCR vs GDH) 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%

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

(BI=NAP 1/027) CID 2007; 45: 1266 -73 Infection Control interventions Used direct cytotoxin testing

(BI=NAP 1/027) CID 2007; 45: 1266 -73 Infection Control interventions Used direct cytotoxin testing (sensitivity 70%) – was this also an issue?

Top 7 PCR Ribotypes in US by Region (2011 -2013) Cepheid HAI Consortium Data

Top 7 PCR Ribotypes in US by Region (2011 -2013) Cepheid HAI Consortium Data (n=503) 40% 35% 30% 25% 20% 15% 10% 5% 0% Northeast (174) 027 South (82) 014/020 106 Midwest (77) 053 001 002 West (175) 056

Potential Value of 027/NAP 1/BI Call-out at time of C. difficile Testing; Hospital A

Potential Value of 027/NAP 1/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 Month 1 CDI Results � � � � � C. diff tox B+; 027 negative C. diff tox B+; 027 positive C. diff tox B+; 027 positive 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 5 th

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

Long Term Care Facilities often Serve as Reservoirs of MDROs 356 cases of KPC-producing

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/

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 Class B TEM,

View of Beta-Lactamases (2013) The Road to Carbapenem Resistance Class A Class B TEM, SHV, CTX-M, KPCs others Metalloenzymes, VIM NDM-1, others Amp. Cs, MIR, DHA, FOX, and others ESBLS; Carbapenemases Most are carbapenemases Amp. C + porin change OXA 48, 162, = carbapenem 163, 181 resistance carba- Class C Class D OXA penemases More to detect than KPCs, but we must be able to Distinguish carbapenemase producers from porin changes PAGE | 25

Updated 9/5/13 Current # 106 212 147 7 7 18 11 3 363 48

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

(VIM-1) The patient was a woman from the US who developed diarrhea during a

(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 Carbapenemresistant 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)

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;

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 VIMProducing Pseudomonas aeruginosa from Long-Term Care VIM KPC Control CROs

KPC-Producing K. pneumoniae and VIMProducing Pseudomonas aeruginosa from Long-Term Care VIM KPC 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

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

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

THANK YOU Questions?

THANK YOU Questions?