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 PathologyStanford University School of Medicine

Stanford, CA, USA

Adjunct Professor of EpidemiologyRollins 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

EpidemiologyInfection ControlLaboratory detection

Multidrug-resistant gram-negative bacilliEpidemiologyInfection ControlLaboratory detection

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)

Binary Toxin (cdtA and cdtB) is an additional virulence factor; it is encoded at a different place on the chromosome

Two toxins, A and B, cause disease; some strains lack A and are still virulent; non toxigenic strains lack the PaLoc

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

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

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 only72 positive by direct cytotoxin and PCR. 72% of 027 strains detected by both methodsFor 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.

TestMethod

Average Cost/ Test

SensitivityNo. 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 45

NAAT $35.00 95% 5 96% 95 36 5

Assume 1000 patients are tested, 10% prevalence

*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)

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

CID 2007; 45:1266-73(BI=NAP1/027)

Used direct cytotoxin testing (sensitivity 70%) – was this also an issue?

InfectionControl

interventions

Northeast (174) South (82) Midwest (77) West (175)0%

5%

10%

15%

20%

25%

30%

35%

40%

Top 7 PCR Ribotypes in US by Region (2011-2013) Cepheid HAI Consortium Data (n=503)

027 014/020 106 053 001 002 056

Potential Value of 027/NAP1/BI Call-out at time of C. difficile Testing; Hospital A Data

Month 1 CDI Results Month 4 CDI Results

C.diff tox B+; 027 negative C.diff tox B+; 027 negative C.diff tox B+; 027 positive C.diff tox B+; 027 negative C.diff tox B+; 027 negative C.diff tox B+; 027 negative C.diff tox B+; 027 negative C.diff tox B+; 027 negative C.diff tox B+; 027 negative

C.diff tox B+; 027 negative C.diff tox B+; 027 positive C.diff tox B+; 027 positive C.diff tox B+; 027 positive C.diff tox B+; 027 positive C.diff tox B+; 027 negative C.diff tox B+; 027 positive C.diff tox B+; 027 positive C.diff tox B+; 027 positive

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/

PAGE | 25

View of Beta-Lactamases (2013) The Road to Carbapenem Resistance

Class A TEM, SHV,

CTX-M, KPCs others

Class BMetallo-

enzymes, VIMNDM-1,others

Class CAmpCs, MIR, DHA,

FOX, and others

Class DOXA

ESBLS; Carba-

penemases OXA48, 162,

163, 181 carba-

penemases

Most are carba-

penemases

AmpC + porin change = carbapenem

resistance

More to detect than KPCs, but we must be able toDistinguish carbapenemase producers from porin changes

106Current #

212

142

14777

18113

363

3132

NDM 3a 9 NDM-1, NDM-2

8

48

Updated 9/5/13

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

(VIM-1)

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

VIM

Control

KPC-Producing K. pneumoniae and VIM-Producing Pseudomonas

aeruginosa from Long-Term Care

CROs are much more widely disseminated than often perceivedThe 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

THANK YOU

Questions?