1. Emerging Strategies to Address the Spread of Antibiotic Resistance in Healthcare
Alex Kallen, MD, MPH, FACP. FIDSA, FSHEA, MS
Chief, Prevention and Response Branch
Division of Healthcare Quality Promotion
August 6, 2019
No Disclosures

2. Objectives
Describe the burden of antibiotic resistance in the United States
Understand what we are learning about how antibiotic resistance spreads in healthcare and regionally
What are the new strategies to preventing spread of resistant pathogens

3. Background

4. Antibiotic resistance in the United States
Sickens >2 million people per year
Kills at least 23,000 people each year
Plus 15,000 each year from C. difficile
>$20B/year in healthcare costs

5. Antibiotic resistance: old challenge, new opportunity

7. Healthcare Pathogens

8. Emerging Antibiotic-Resistant Threats

9. Novel antimicrobial-resistant threats
Antimicrobial resistance is one of the biggest public health challenges of our time;
One of the tests we face is determining how to respond to new threats; ensuring both resources and infrastructure are in place early to slow the spread of transmission and get ahead of the problem.

11. Enterobacteriaceae
Large family of gram negative rods with >25 recognized genera
Most common family encountered in clinical microbiology labs
Most common are Klebsiella spp., Escherichia coli
Many historically have been susceptible to many antibiotics (including penicillins)
K. pneumoniae, scanning electron micrograph

12. Carbapenems
Broad spectrum “antibiotics of last resort” for highly resistant infections
Four approved carbapenems in US (imipenem, meropenem, doripenem, ertapenem)
Have always been able to rely on these for really sick people and for very resistant bacteria
Increasing use as resistant Enterobacteriaceae (ESBLs) emerged and spread in 1990’s
Resistance rare in US and due to collection of multiple mutations within the bacteria

13. Carbapenemases
Carbapenemases are enzymes that digest carbapenems and other related antibiotics (Penicillins)
Plasmid encoded
Can pass resistance vertically and horizontally
No/minimal fitness defect
Prior to the late 1990’s, only rarely found in the US
More common outside the US, but not primary driver of carbapenem resistance

14. Rise of Klebsiella pneumoniae carbapenemase (KPC)
Isolate collected in 1996 during an ICU surveillance project from NC
Plasmid-mediated
Plasmid associated with resistance to lots of other classes
Some, so resistant that no options to treat with standard drugs
Alex’s CRE talk
!st isolate collected in ICARE from north Carolina Hospital from Identified a novel class A beta-lactamase called KPC-1 14

15. Geographical of KPC-producing CRE, 2001-2017
KPC-CRE found in the US spread from 2 states in 2001 to 49 states, DC, and PR in 16 years
2001
2005
2006
2008
DC*
DC*
DC*
DC*
2010
2012
2014
2017
DC*
DC*
DC*
DC*
States with Klebsiella pneumoniae carbapenemase (KPC)-producing Carbapenem-resistant Enterobacteriaceae (CRE) confirmed by CDC
In addition, proportion of Klebsiella resistant to carbapenems increase from <1% to>10%
Division of Healthcare Quality Promotion

16. First reports of Candida auris
2009
Discovered during the course of a study to analyze antifungal yeast diversity in humans
Although there are more than 400 known species of Candida, C. auris had not been recognized prior to [NEXT] During the course of a study designed to survey the diversity of yeasts in humans and their susceptibility to antifungal drugs, this novel species was discovered in a sample taken from the external ear canal of a patient in Japan, and thus named auris.
[NEXT]

17. Global emergence of C. auris
2011
2009
2015
After 2009, Candida auris was reported across the globe, and interestingly in areas geographically isolated from each other. C. auris was detected in [NEXT] South Korea in 2011 and then [NEXT] India in In 2014 [NEXT], C. auris was found in South Africa, Kenya, and Kuwait. [NEXT] saw new cases in Pakistan, Venezuela, Israel, and the United Kingdom. Furthermore, these weren’t just ear infections, they were often bloodstream infections. Disconcertingly, many of these C. auris infections were clustered in hospitals over a short period of time, making them look like outbreaks. For example, one such instance included up to 30 patients in Pakistan. And this is highly unusual, because as I previously mentioned, outbreaks were not thought to be common with candidemia.
[NEXT]
2013
2014

18. Global emergence of C. auris
2011
case identified in US
Retrospective review identified 6 others (first in 2013)
2009
2015
After 2009, Candida auris was reported across the globe, and interestingly in areas geographically isolated from each other. C. auris was detected in [NEXT] South Korea in 2011 and then [NEXT] India in In 2014 [NEXT], C. auris was found in South Africa, Kenya, and Kuwait. [NEXT] saw new cases in Pakistan, Venezuela, Israel, and the United Kingdom. Furthermore, these weren’t just ear infections, they were often bloodstream infections. Disconcertingly, many of these C. auris infections were clustered in hospitals over a short period of time, making them look like outbreaks. For example, one such instance included up to 30 patients in Pakistan. And this is highly unusual, because as I previously mentioned, outbreaks were not thought to be common with candidemia.
[NEXT]
2013
2014

19. Candida auris Truly novel:
No C. auris in >7000 Candida isolates collected in U.S –20161
>30,000 Candida isolates collected from 4 continents,
No C. auris before 2009
Causes invasive infections with high mortality (60%)
Unlike most other Candida species
Colonizes skin
Transmitted person-to-person in healthcare
Not susceptible to many disinfectants used in hospitals

20. WGS of isolates from 4 regions
South Asia
Very different across regions
10,000s–100,000s SNPs
Virtually identical within regions
<100 SNPs
South Africa
Whole genome sequencing revealed four distinct clades corresponding to geographic regions, as shown in the figure here. [NEXT] Clades were very different across regions, on the magnitude of tens of thousands to hundreds of thousands of SNPs. [NEXT] However, within a geographic region, strains were highly related, with differences of less than 100 SNPs. Interestingly, this suggests a simultaneous emergence around the globe, rather than a spread from a singular location. This brings up more questions than answers and is still subject to our ongoing investigations.
[NEXT]
South America
East Asia

21. C. auris is highly resistant
Polyenes
Azoles
Echinocandins
Of the initially described Candida auris isolates, almost all were resistant to [NEXT] fluconazole and half to voriconazole. This is particularly important as azoles are an affordable antifungal treatment, and often the only available option in many parts of the world. One third were also resistant to [NEXT] amphotericin. A small percentage were further resistant to echinocandins [NEXT], leaving no traditional treatment options.
[NEXT]

22. A few isolates resistant to all three classes
Polyenes
Azoles
Echinocandins
Of the initially described Candida auris isolates, almost all were resistant to [NEXT] fluconazole and half to voriconazole. This is particularly important as azoles are an affordable antifungal treatment, and often the only available option in many parts of the world. One third were also resistant to [NEXT] amphotericin. A small percentage were further resistant to echinocandins [NEXT], leaving no traditional treatment options.
[NEXT]
35% resistant to amphotericin B
93% resistant to fluconazole
54% resistant to voriconazole
7% resistant to echinocandins
C. auris

23. C. auris clinical cases reported by state, United States, May 31, 2019, n=716
An additional 1342 asymptomatically colonized patients have been identified

24. Lessons learned
Resistance can emerge and spread silently if not looking for it
Spread can happen very quickly
Healthcare settings are frequently the amplification centers
Particularly early in an epidemic

25. What are We Learning about Controlling the Spread of Resistant Pathogens?

26. 1. Resistance is a regional problem
Traditional Approach
Promotion of prevention efforts independently implemented by individual health care facilities
Does not account for inter-facility spread through movement of colonized/infected patients

27. KPC outbreak in Chicago, 2008
Won et al. Clin Infect Dis 2011; 53:

28. Hospital transfers are a significant predictor of Clostridium difficile burden
“Clostridium difficile burden at a hospital level can be better understood by knowing how a hospital is connected to other hospitals in terms of patient transfers”
Simmering et al, Infect Control Hosp Epidemiol 2015;36: 28

29. Projected regional prevalence of CRE over a 5-year period,10-facility model
In 2015, CDC published a Vital Signs report in order to assess the impact of the coordinated approach in a simulated network of 10 health care facilities consisting of four acute care hospitals and six free-standing nursing homes serving adult patients.
Using mathematical modeling, a coordinated response in a region resulted in a cumulative 81% reduction in CRE acquisitions over a 5 year period, illustrating that coordinated, early interventions can slow the spread of emerging antimicrobial resistance within a region. The results have been confirmed in a similar model using Orange County healthcare facilities.

30. 2. Post-acute care can amplify spread
SNF
(n=14)
58% MDRO
carriage
vSNF
(n=4)
76% MDRO
carriage
Long lengths of stay, home-like environment
Sick patients, lots of hands-on care
Highly connected to other facilities through resident transfers
McKinnell JA et al. Clin Infect Dis. 2019; Feb 11. doi: /cid/ciz119. [Epub ahead of print]

31. Slide courtesy of Chicago Department of Public Health.

32. In nine months, the prevalence went from 1.5% (1/69) to 43% (29/67).
The health department is instrumental in helping the facility determine how best to cohort residents. A cohorting hierarchy decision was created with symptomatic Clostridium difficile at the top of the hierarchy requiring a private room. C. auris is next, then CP-CRE – preferably like mechanisms of resistance, and in an attempt to limit additional exposure potentially roommates of C. auris positive residents. In reality, it’s not always that neat with pros and cons for many of the combinations. C. auris negative residents are roomed with C. auris positive residents as a last resort.
Slide courtesy of Chicago Department of Public Health.

33. Cohorting becomes a struggle
Cohorting becomes a struggle. You can see over time how complicated the map has become. This is January 2018 again with C. auris and Carbapenem producing organisms. Patients may give verbal consent to the skin swabs for C. auris, but not consent to a rectal swab for CRE.
Slide courtesy of Chicago Department of Public Health.

34. CRE Prevalence in LTCF: By Type
Prevalence of CRE Carriage at admission to 4 acute care hospitals
33.3%
27.3%
8.3%
1.5%
0% from those admitted to the community
Prabaker K, et al. ICHE 2012; 33:

35. 3. Importance of colonization
Only about 1 in 10 people with a targeted MDRO will have a positive clinical culture
Colonized patients can still serve as a reservoir for transmission but might not be subject to
Identifying colonized patients is important during a response to halt transmission

36. 4. Aggressive approaches can decrease spread: the experience with CRE in Israel
KPCs likely originally from US identified in Israel beginning in late 2005
By early 2006, increase in cases
Initiated National effort to control CRE (initial response) in acute care hospitals
Mandatory reporting of patients with CRE
Mandatory isolation (CP) of CRE patients
Staff and patient cohorting
Task Force developed with authority to collect data and intervene

37. The Israel CRE experience
79% decrease from the last month to the first month

38. The Israel CRE experience: beyond the first year
Active surveillance for high-risk patients
Added long-term care facilities
Targeted interventions in facilities from which CRE-patients had been transferred
Intervened at 13 high-risk facilities (1/10th of LTCF beds in country)
Determine CRE prevalence among sample
Map infection control infrastructure and policies
Developed CRE control measures by ward type
Similar to acute care without cohorting or strict CP
Visited facilities to ensure implementation

39. Schwaber MJ et al. Clin Infect Dis 2014

40. New Interventions/Strategies to Slow the Spread of Resistant Pathogens in Healthcare Settings

41. 1. Containment
CDC’s Containment Strategy is an aggressive approach to stop the spread of emerging AR pathogens.
Based on identification of a single isolate not a cluster
Most effective when organism is rare
Often targeting a “mechanism” instead of a bacteria
CP-CRE, CP-Acinetobacter and Pseudomonas
Candida auris
Pan-resistant strains

42. Containment strategy Systematic public health response to slow the spread of emerging AR
DETECTION
INFECTION CONTROL
CONTACT SCREENING
Single case of emerging resistance:
Pan-R, carbapenemase-producing organisms, Candida auris
Onsite assessment using standardized tools
Available through ARLN
The Containment Strategy was launched a year ago and is a systematic and aggressive approach led by public health and designed to slow the spread of AR.
It has three central elements: detection, infection control, and contact screening.
Detection focuses on identifying emerging resistance and launching a public health investigation in response to a single case. This is differentiated from past approaches, in which the threshold was two or more clinical cases with suspicion for transmission. The containment strategy has been applied to pan-R isolates, Carbapenemase or MCR-producing Enterobacteriaceae, and the resistant yeast C. auris. This year, detection has been greatly enhanced by the ARLN, which is implementing capacity to detect many of these threats at 56 state and local public health laboratories. In 2017, over 9000 isolates were tested through the ARLN.
The infection control element includes on-site assessments at facilities where the patient has been admitted in the prior 30 days. All facility types are targeted, with a special emphasis on facilities that care for high acuity patients with longer lengths of stay, which have previously been shown to be amplifiers of transmission. CDC funding for HAI programs means that the response capacity to perform these assessments is available nationwide.
Contact screening aims to detect asymptomatic colonization, to stop the silent spread of AR. Healthcare contacts of index patients, such as roommates or other patients on a unit or wing, are screened to identify transmission. Prior to advent of the ARLN, contact screening was often limited because it is expensive and difficult to access; however, the ARLN now provides screening for carbapenemase-producing CRE and CRPA free of charge through 7 regional laboratories, resulting in over 2100 colonization screening tests performed in 2018.
CLICK
When transmission is identified, regular infection control assessments and point prevalence surveys are conducted until transmission stops.
Regular infection control assessments and point prevalence surveys until transmission stops

43. Hospitals/Clinical Laboratories
Antimicrobial Resistance Laboratory Network (ARLN): laboratory support for Containment
Hospitals/Clinical Laboratories
Public Health Laboratories
50 States
5 Local Health Departments
CRE/CRPA isolates
PHD
Species identification
Confirmatory AST
Phenotypic screening for carbapenemase production
Carbapenemase mechanism testing
mcr-1 testing (some labs)
Rectal Swabs
CRE and CRPA Colonization Screening
Regional Lab
ARLN

44. The Containment strategy
Activity
2017
2018
Isolates tested by AR Lab Network (CRE, CRPA)
11,557
22,622
Colonization screening swabs tested by AR Lab Network
2,022
10,577
Isolates submitted to CDC for reference testing, by year (CRE, CRPA, CRAB)
539
790
CDC-supported AR containment responses, by year
152
158

45. 2. Addressing antibiotic resistance locally: State HAI/AR programs
In all 50 States, Puerto Rico, and 5 large cities
Work includes:
Containment
HAI/ C difficile prevention programs
Healthcare outbreak response
Surveillance
Improving antibiotic use
Improving infection control practices in facilities
Detect & Contain
Improve Abx Use
Prevent Infections
Patient Safety

46. 3. Infection Control Assessment and Response (ICAR) activities, 2015-2019
CDC funding and technical support to state and local health departments
Structured approach for assessing current infection prevention and control (IPC) programs using CDC developed tools
Outreach to all healthcare facilities (outpatient, NH, etc.)
Developing capacity for health departments serve as an IPC resource for healthcare facilities
Continues within CDC ELC grant
Targets high-acuity post acute care settings
F/u visit to address gaps

47. ICAR Targets: initial phase (May 2018)
53 funded HDs targeted 4,914 facilities for ICAR assessments over 3 year period
Health department programs completed 5,411 assessments nationwide
Setting
Number completed
Acute care hospitals, included critical access, LTACHs
1260
Long-term care, included nursing homes (NHs), assisted-living (ALFs), intermediate care facilities (ICFs)
2563
Outpatient, included ASCs, urgent care, general and specialty clinics
788
Dialysis
800
CDC unpublished data, May/June 2018

48. ICAR: Common gaps in addressing resistant threats (nursing homes)
Limited hand hygiene adherence and available stations/supplies
Lack of PPE availability and improper use
Lack of supplies for cleaning and disinfection
Limited interfacility communication, especially regarding MDROs and precautions

49. 4. Source control Colonization Decolonization and Source Control
Transmission can occur from colonized patients
Colonized patients may progress to clinical infection
Colonization difficult to detect or act on
sites can differ
Screening not common
Decolonization and Source Control
Decolonization: use of an antimicrobial agent often in combination with a topical antiseptic to completely eliminate organism from colonized patients
Source Control: use of antimicrobials or antiseptics to reduce the burden of colonization in patients without complete elimination
(Note these interventions might be particularly important to target in facilities for which nvHAP is a common underlying syndrome for patients with HO MRSA BSIs)

50. Source control
MRSA - Typically done using an intranasal antistaphylococcal agent + topical antiseptic
Intranasal Mupirocin (antibiotic)
Topical Chlorhexidine
CRE – topical chlorhexidine
Future – GI tract?
(Note these interventions might be particularly important to target in facilities for which nvHAP is a common underlying syndrome for patients with HO MRSA BSIs)

51. Source control: REDUCE MRSA trial
(Note these interventions might be particularly important to target in facilities for which nvHAP is a common underlying syndrome for patients with HO MRSA BSIs)
50-60% of ICUs have adopted some decolonization strategy
Other evaluations in acute care and nursing homes

52. Source control for MDRO prevention
Setting & Decolonization Agents
Study
Effect on MRSA/MSSA
Notes
Non-ICU hospitals
CHG/mupirocin
ABATE (baseline)
Huang, Lancet 2019
No change MRSA/VRE clinical cx/all-cause BSI;
In patients with devices, ↓30% MRSA clinical cx and all-cause BSI
Patients with devices were 11% of hospitalized population, but 38% of MRSA and VRE cultures; 58% of all BSIs
LTACH
Daily CHG
Hayden et al, CID 2015
↓50% CRE transmission; ↓56% CRE bacteremia; ↓32% all-cause BSI
Uptake uncertain
MRSA colonized patients discharged from hospitals
CHG + mupirocin
Project CLEAR
Huang et al, NEJM 2019
↓30% MRSA infections
CHG + mupirocin 10 days/month for 6 months. Education component
Regional intervention based on network analysis (acute care hospitals, LTACHs, NHs)
CHG + nasal iodophor
SHIELD-Orange Cty
ongoing
Baseline:
65% of NH pts have ≥1 MDRO; 80% of LTACH pts ≥1 MDRO (published Clin Infect Dis Feb 2019)
Regional intervention based on network analysis (LTACHs, NHs)
CHG bathing
PROTECT (Chicago)
Bundled intervention including hand hygiene, XDRO registry, etc.
(Note these interventions might be particularly important to target in facilities for which nvHAP is a common underlying syndrome for patients with HO MRSA BSIs)

53. 5. Screening
Clinical cultures only identify about 10% of those colonized with an MDRO
Unrecognized colonized patients can still be a source for transmission
Uses
During a Containment response – to halt transmission
Surveillance – to identify new pathogens before they spread
CDC has developed tools to assist with this process

55. 6. Transmission-based Precautions in nursing homes
Department of Health and Human Services. Centers for Medicare and Medicaid Services. Revisions to Appendix PP Interpretive Guidance for Long Term Care Facilities. Rev. 173,
CDC/HICPAC. Guideline for Isolation Precautions: Preventing transmission of Infectious Agents in Healthcare Settings, 2007.
CDC/HICPAC. Management of multidrug-resistant organisms in healthcare settings,

56. 6. Transmission-based Precautions in nursing homes
Works well for some infections like Influenza or scabies
Works less well for MDROs
Department of Health and Human Services. Centers for Medicare and Medicaid Services. Revisions to Appendix PP Interpretive Guidance for Long Term Care Facilities. Rev. 173,
CDC/HICPAC. Guideline for Isolation Precautions: Preventing transmission of Infectious Agents in Healthcare Settings, 2007.
CDC/HICPAC. Management of multidrug-resistant organisms in healthcare settings,

57. CDC guidance is not always clear
“Healthcare is provided in various settings outside of hospitals, including facilities such as LTCFs… Each setting has unique circumstances and population risks… While this Guideline does not address each setting, the principles and strategies may be adapted and applied…”
“Consider the individual resident’s clinical situation and prevalence or incidence of MDRO in the facility when deciding whether to implement or modify Contact Precautions in addition to Standard Precautions for a patient infected or colonized with a target MDRO.”
CDC/HICPAC. Guideline for Isolation Precautions: Preventing transmission of Infectious Agents in Healthcare Settings
CDC/HICPAC. Management of multidrug-resistant organisms in healthcare settings,

58. Resident Quality of Life
Preventing spread of MDROs
Need: Clarification about how/when to use PPE and room restriction
Need: Clarification about managing prolonged carriage of MDROs
Resident Quality of Life
Resident Safety

59. Personal protective equipment in nursing homes to prevent spread of multidrug-resistant organisms (MDRO)

60. Updated framework for use of PPE and room restriction for MDRO colonized or infected residents in nursing homes
Contact Precautions
Presence of acute diarrhea, draining wounds, secretions or excretions that are unable to be covered or contained
With rare and highly resistant pathogens (e.g., novel resistance mechanisms for which no current treatment options exist (pan-resistant))
On units or in facilities where, despite attempts to control the spread of MDROs, ongoing transmission is documented or suspected
Enhanced Barrier Precautions
During high-contact care activities when Contact Precautions does not apply
Dressing
Bathing/showering
Transferring
Providing hygiene
Changing linens
Changing briefs or assisting with toileting
Device care or use of a device: central line, urinary catheter, feeding tube, tracheostomy
Wound care: any skin opening requiring a dressing
Gown/gloves on every room entry
Room restriction
Gown/gloves for high-contact care
NO room restriction

61. Summary
Resistant pathogens continue to emerge and healthcare settings continue to serve as sites for amplification
Spread occurs across the continuum of healthcare and preventing spread of these organisms within a region requires broad facility engagement
Novel approaches that challenge assumptions about how healthcare are provided in different settings are needed
Facilities, healthcare personnel, public health, and survey agencies all have important roles in facilitating these efforts

62. Thank you!
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