Novel Management Strategies in the Treatment of Infections with MDROs (RP Berba) - PHICS 2019

NOVEL MANAGEMENT
STRATEGIES in the
TREATMENT of INFECTIONS
with MDROs?
Regina Berba MD

My Disclosures
• Chair, National Steering Committee on
Antimicrobial Stewardship since 2016 (DOH)
• Travel & study grants: US-Singapore govts, Pfizer,
MSD, Qiagen, Cathay, Unilab
• No money received for the MOOC of London
School/ travel & hotel subsidy from BD

• Definition: (by Google and many HCWs)
• microorganisms, predominantly bacteria, that are
resistant to one or more classes of antimicrobial agents
• Importance:
• Limited options for treatment
• Increase the length of stay and cost of hospitalization
• Increase admission to and stay in ICU
• High mortality rates
3
What are Multi-Drug Resistant
Organisms (MDROs)?
AGREE or DISAGREE?

The Simplest Approach
Resistant to > 1 drug
classes of drugs>2Non-susceptible to
The Not Quite As Simple But Now The Closest
Thing We Have to Universally Accepted Approach
Alan D. Junkins, PhD, D(ABMM)
Louisville, KY

XDR and PDR
Non-susceptible to at least 1 drug in
all but two or fewer classes
Non-susceptible to all
agents in all classes
Louisville, KY

What is a “class” of drugs?
Beta-lactams
Louisville, KY

Cephalosporins
Penicillins
Monobactams
Carbapenems
Louisville, KY

1st gen. CephalosporinsAminopenicillins
Monobactams Carbapenems
Ureidopenicillins
Carboxypenicillins
ß-lactamase resistant
penicillins
ß-lactamase inhibitor
combinations
2nd gen. Cephalosporins
3rd gen. Cephalosporins
4th gen. Cephalosporins
5th gen. Cephalosporins
Cefamycins
Louisville, KY

What is resistance to a class?
Bug A Bug B Bug C Bug D
Gentamicin R R R I
Tobramycin R R S S
Amikacin R S S S
Resistant to
this class?
Louisville, KY

ANTIBIOTICS: Miracle Drugs
Discovery of PENICILLIN by Sir Alexander Fleming &
its subsequent devt by Florey & Chain revolutionized
management of infectious disease
Armstrong GL et al, JAMA 1999;281(1):61-66
Crude mortality rates
for all causes,
noninfectious causes
and infectious
diseases over the
period 1900-1996.
↑Life expectancy

“Microbes are educated to resist
penicillin and a host of penicillin-
fast organisms is bred out… In such
cases the thoughtless person
playing with penicillin is morally
responsible for the death of the
man who finally succumbs to
infection with the penicillin-
resistant organism.
I hope this evil can be averted.”
Soon after…
the beginnings of MDROs was observed
Fleming A. New York Times. 26 June 1945:21.

https://www.cdc.gov/drugresistance/pdf/5-2013-508.pdf
Microbes
CAN BE very
smart

https://www.cdc.gov/drugresistance/pdf/5-2013-508.pdf

Resistant Strains
Rare
xx
Resistant Strains
Dominant
Antimicrobial
Exposure
xx
xx
xx
xx
xx
Selection for Resistant
Strains
CDC. Campaign to Prevent Antimicrobial Resistance in Healthcare Settings 2002
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5115a5.htm
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

“Survival of the
Fittest”
http://mostlyscience.com/wp-

If we don’t kill them the first time….
18

New Resistant Bacteria
Mutations
XX
Emergence of AMR
Susceptible Bacteria
CDC. Campaign to Prevent Antimicrobial Resistance in Healthcare Settings 2002
https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5115a5.htm
Resistant Bacteria
Resistance Gene Transfer
CDC
Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

At the Microbiology lab…
MDROs look like this

MEGA agar plate for Ecoli
Baym M, Lieberman TD, Kelsic ED et al Science 09 Sep 2016. Vol 353:6304: 1147-1151
“Bugs on Screen” hms.harvard.edu

Over 200 Mutations in just 12 days
Baym M, Lieberman TD, Kelsic ED et al Science 09 Sep 2016. Vol 353:6304: 1147-1151

HOW
DIFFICULT are
MDROs?
EXTREMELY
PROBLEMATIC
March 28, 1994

Among top 10 threats globally
1. Climate Change
2. Noncommunicable
Diseases
3. Global Influenza
pandemic
4. Fragile & Vulnerable
Settings
5.ANTIMICROBIAL
RESISTANCE

“AMR is a problem so serious that it threatens
the achievements of modern medicine.”
August 2015

2014 WHO Report on Global AMR
•A post-antibiotic era – in
which common infections
and minor injuries can kill –
far from being an apocalyptic
fantasy, is instead a very real
possibility for the 21st century.”

US CDC: The “AMR CRISIS”
• BIGGEST HEALTH
PROBLEM OF OUR TIME
• GREATEST HEALTH
CHALLENGE
• HIGHER MORTALITY
• LONGER LOS
• HIGHER COSTS
https://www.cdc.gov/drugresistance/biggest_threats.html

In the US, the White House classified Superbugs as
“THREATS”

URGENT THREATS
These bacteria are immediate public health
threats which require urgent action

SERIOUS THREATS
These bacteria are a serious concern and require prompt and sustained
action to ensure the problem does not grow.

Pseudomonas aeruginosa a
SERIOUS THREAT
CDC. Threat Report 2013. http://www.cdc.gov/drugresistance/threat-
report-2013/

MDR Acinetobacter is a
VERY SERIOUS THREAT
report-2013/

CRE THREAT
IS EXTREMELY SERIOUS
report-2013/

WHO PRIORITY PATHOGENS for
R&D of New Antibiotics
https://www.hygiene-in-practice.com/publication/who-priority-pathogens-list-the-most-dangerous-bacteria-in-the-world/

40
www.ritm.g
ov.ph
www.arsp.c
ANTIMICROBIAL RESISTANCE
SURVEILLANCE PROGRAM
2015 Annual Report
Antim
i
crobial Resistance Surveillance
Reference Laboratory
Research Institu te for Tropical Medicine
Department of Health
Philippines
Antimicrobial Resistance
Surveillance Program
2016 Data Summary Report
Antimicrobial Resistance Surveillance
Reference Laboratory
Research Institute for Tropical Medicine
Department of Health
Philippines

Distribution of 76,892 Isolates from 24 sentinel sites
RITM ARSP 2017
http://arsp.com.ph/publications/antimicrobial-resistance-surveillance-program-
2017-data-summary-report/

TOP 3 ISOLATES PER SPECIMEN TYPE
RITM ARSP 2017

THE “GOOD” BUGS
RITM ARSP 2017

Streptococcus pneumoniae
RITM ARSP 2017

Salmonella typhi
RITM ARSP 2017

Non-typhi Salmonella
RITM ARSP 2017

RITM ARSP 2018
Vibrio cholerae
RITM ARSP 2017

Neisseria gonorrhea
RITM ARSP 2017

...AND THE “SUPERBAD” BUGS
RITM ARSP 2017

RITM ARSP 2018
MRSAby Institution
RITM ARSP 2017

MRSA resistance to other agents
RITM ARSP 2017

E coli by Institution
RITM ARSP 2017

RITM ARSP 2018
Klebsiella pneumoniae
RITM ARSP 2017

ESBL Klebsiella pneumoniae by institutions
RITM ARSP 2017

Klebsiella pneumoniae in last 10 years
RITM ARSP 2017

Pseudomonas aeruginosa
RITM ARSP 2017

Acinetobacter baumanii
RITM ARSP 2017

RITM ARSP 2018
A baumanii in last 10 years
RITM ARSP 2017

DEFINITIONS of MDR & XDR
RITM ARSP 2017

MDR and XDR Abaumanii
RITM ARSP 2017

WHAT
SHOULD I
DO WITH
ALL THESE
SUPERBUG
S?

Controversies in Guidelines for
the Control of MDR Gram-
negative bacteria in EU
countries
J.A. Otter, N.T. Mutters, E. Tacconelli, A. Gikas, A.H. Holmes
Clinical Microbiology and Infection
Volume 21, Issue 12, Pages 1057-1066 (December 2015)
DOI: 10.1016/j.cmi.2015.09.021

Fig. 1
Clinical Microbiology and Infection 2015 21, 1057-1066DOI: (10.1016/j.cmi.2015.09.021)
Copyright © 2015 Terms and Conditions

Jane D. Siegel, MD; Emily Rhinehart, RN MPH CIC;
Marguerite Jackson, PhD; Linda Chiarello, RN MS
The Healthcare Infection Control Practices Advisory Committee
(HICPAC)
• 2007 Guideline for Isolation
Precautions: Preventing
Transmission of Infectious Agents in
Healthcare Settings
Updated February 15, 2017
https://www.cdc.gov/infectioncon
trol/guidelines/mdro

Back to Basics
HAND HYGIENE PLUS PLUS PLUS

Isolation Precautions
• Standard precautions
• Masks for:
• Splash-generating procedures
• Patients with open tracheostomies
• Circumstances when there is evidence of transmission from heavily
colonized sources (e.g., burns)
• Contact precautions
• All patients with infections or previously identified as colonized
• Patients with ability to perform hand hygiene and without
draining wounds, diarrhea, uncontrolled secretions: establish
ranges of permitted ambulation, socialization and use of
common areas based on risk …
• Cohorting, in order of preference:
• Single patient room
• Cohort with patient with same MDRO
• Cohort with low-risk patient
67http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf

Other Basic Infection Control
Measures
• Environmental measures
• Increased cleaning of:
• Items in close proximity to patient, e.g., bed rails, over-bed
tables
• Frequently touched surfaces
• Monitoring
• Decolonization
68
http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf

Reservoirs for MDROs
Organism Reservoir Colonizes In hospital environment
Staphylococcus
aureus
Nares, skin Nares, skin Stethoscopes, pagers, bed spaces,
linens, wheelchairs, doorknobs,
workstations, telephones …
Enterococcus
species
Intestines Intestines Bed rails, linens, doorknobs,
bedpans, urinals, blood pressure
cuffs, stethoscopes, monitoring
equipment
Pseudomonas
aeruginosa
Soil, water,
plants
Axilla, ear,
perineum,
respiratory tract
Drains, toilets, showers, water in
patient equipment
Acinetobacter
species
Soil, water,
food
Pharynx,
especially
tracheostomy
Tap water, peritoneal dialysate
bath, urinals, washcloths, soap
dispensers
Enterobacteriaceae
(Klebsiella,
Enterobacter, E.Coli)
Intestines Oropharynx,
genitourinary
tract
Sinks, ultrasonography gel, bath
soap, water baths
69

Intensified MDRO Control Measures
• Obtain consultation
• Evaluate staffing and resources
• Educate
• Judicious antimicrobial use
• Active surveillance and pre-emptive contact
isolation
• Contact precautions for all colonized or infected
patients
70

Intensified MDRO Control Measures
• Stop new admissions to the unit or facility if
transmission continues
• Dedicated use of non-critical equipment
• Training for environmental staff
• Monitor cleaning
• Vacate units for intensive cleaning when previous
efforts fail
• Decolonization for MRSA (only) with expert
consultation
71

CLEANING AND DISINFECTION
OF HOSPITAL ENVIRONMENT

Simple Portfolio Pr
esentation
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THE ENVIRONMENT A VERY
IMPT SOURCE OF MDRO
~ Contaminated surfaces increase cross-transmission ~
Abstract: The Risk of Hand and Glove Contamination after Contact with a VRE (+) Patient
Environment. Hayden M, ICAAC, 2001, Chicago, IL.

DIFFERENT CLASSIFICATIONS
DISINFECTANTS: What to Use
Use same basic terminology &
classification scheme
• To categorize medical
devices
• critical, semi-critical,
and noncritical
• To define antimicrobial
potency for processing
surfaces
• sterilization, and
high-, intermediate-
and low-level
CDC and FDA:
EPA uses manufacturer's
microbiological activity claims
• Doesn’t use the terms
intermediate- and low-
level disinfectants as
used in CDC
guidelines
EPA

Staphyloc
occus
aureus
Salmonella
cholerasuis
Pseudomonas
auruginosa
LOOK FOR THE
LABELS
To be labeled as an EPA hospital disinfectant,
the product must pass Association of AOAC
effectiveness tests VS 3 target organisms

EPA REGISTRATION OF
DISINFECTANTS
Potency against M Tb recognized as
a substantial benchmark
However, the tuberculocidal claim is
used only as a benchmark to measure
germicidal potency
• Tuberculosis is not transmitted via environme
ntal surfaces but by the airborne route
• Thus, use of products on environmental surfa
ces plays no role in preventing the spread of t
uberculosis
CDC. Regulatory Framework for Disinfectants and Sterilants. MMWR 2003; 52(RR17);62-64.
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5217a2.htm. Accessed July 4, 2014

EPA registration of disinfectants
• Because mycobacteria have among the
highest intrinsic levels of resistance
among the vegetative bacteria, viruses,
and fungi, any germicide with a
tuberculocidal claim on the label is
considered capable of inactivating a
broad spectrum of pathogens, including
such less-resistant organisms as blood-
borne pathogens (e.g., HBV, HCV, and
HIV)
• It is this broad-spectrum
capability, rather than the
product's specific potency
against mycobacteria, that is
the basis for protocols and
regulations dictating use of
tuberculocidal chemicals for
surface disinfection

CDC designates any EPA-
registered hospital disinfectant
• without a tuberculocidal
claim as a low-level
disinfectant
• with a tuberculocidal claim
as an intermediate-level
disinfectant
•

Disinfectants for Hospital Surfaces
and other non-critical items
• Chlorine-based products
• Sporicidal
• Corrosive
• Respiratory irritant
• Inactivation by organic matter
• Phenolics
• Bactericidal, fungicidal, virucidal, tuberculocidal
• Tissue irritant
• Hyperbilirubinemia in neonatal nursery
79
Practical Healthcare Epidemiology, 3rd Edition;
http://www.cdc.gov/hicpac/pdf/guidelines/Disinfection_Nov_2008.pdf

Disinfectants for Hospital Surfaces
and other non-critical items
• H2O2
• Bactericidal, fungicidal, virucidal, sporicidal
• Chemical irritant
• Quaternary ammonium compounds
• Bactericidal, fungicidal, virucidal against lipophilic (enveloped)
viruses
• Not sporicidal, tuberculocidal or active against hydrophilic
viruses.
• Inactivated by water hardness and cotton
• 70-90% alcohol
• Virucidal, tuberculocidal
• Lack sporicidal action and cannot penetrate
protein-rich materials
• Damage some surfaces after repeated use
80
Practical Healthcare Epidemiology, 3rd Edition;
http://www.cdc.gov/hicpac/pdf/guidelines/Disinfection_Nov_2008.pdf

Surveillance
• Routine clinical cultures (antibiograms)
• Detect emergence of new MDROs
• Facility- or unit- specific summary antimicrobial
susceptibility reports
• Monitor for changes
• MDRO incidence (new isolates per 1000 patient
days or per month)
• Monitor trends / evaluate impact of prevention
• Does not distinguish colonization from infection

Surveillance
• MDRO infection rates
• Requires clinical data
• Helpful in defining clinical impact
• Molecular typing
• Confirm clonal transmission
• Evaluate interventions in facility

Active Surveillance Cultures
• Prospective identification of colonized persons
• Coupled with intervention can reduce transmission
• Resource intensive
• Methods
• MRSA: nares > perirectal and wound
• VRE: stool, rectal or perirectal
• MDR-GNB: peri-rectal or rectal alone or in combination
with oropharyngeal, endotracheal, inguinal, or wound

Example – universal
surveillance for MRSA in
3 affiliated hospitals
Ann Intern Med, 2008; 148:409-418.
86

Infection Control Strategies
Classic Example: Evanston Northwestern Healthcare
• 3 hospitals
• 40,000 annual admissions
• 450 staff physicians
• Contact isolation for MRSA-colonized persons
• Private room or cohort
• Gowns and gloves for all room entries
• Dedicated equipment, e.g., stethoscopes
87
Ann Intern Med, 2008; 148:409-418

Study Design
Ann Intern Med, 2008; 148:409-418
Timeframe Period 1 (Aug 1,
2003 – July 31,
2004)
Period 2 (Aug 1,
2004 – July 31,
2005)
Period 3 (Aug 1,
2005 – April 2007)
Strategy No active
surveillance
ASC at ICU
admission
ASC at any
admission
Admissions tested
(%)
0 (0%) 3334 (75.9%) 62,035 (84.4%)
Positive test results 0 277 (8.3%) 3926 (84.4%)
Contact precautions
for MRSA
yes yes yes
Routine
decolonization
no no Mupirocin,
chlorhexidine
MRSA per 10,000
patient-days
(95% CI)
8.9
(7.6 – 10.4)
7.4
(6.1 – 9.0)
3.9
(3.2 – 4.7)
88
Ann Intern Med, 2008; 148:409-418

Ann Intern Med, 2008; 148:409-41889

Nosocomial outbreak of
infection with Pan-drug-
resistant Acinetobacter
baumannii in a tertiary
care university hospital
Infect Control Hosp Epidemiol, 2009; 30:257-263.
90

Case Definition
• “A case patient was defined as any inpatient who
had a pan-drug-resistant A baumannii isolate
recovered from a clinical or surveillance sample
obtained at least 48 hours after ICU admission
{from April 9, 2002 to March 9, 2003}.”
91
• Infect Control Hosp Epidemiol, 2009; 30:257-263.

92

Interventions to Control Pan-Drug-
Resistant Acinetobacter baumannii
• Environmental decontamination
• Environmental survey
• Revision of cleaning protocols
• Active surveillance for PDRAB
• Rectal and pharyngeal swabs of roommates
• Educational programs for the staff
• Display of posters illustrating isolation measures
and antimicrobial use recommendations
93

Successful control of an
outbreak of Carbapenemase-
producing Klebsiella
pneumoniae in a long term
acute care hospital
Infect Control Hosp Epidemiol, 2010; 31: 341-347.
94

95

Bundled Intervention
• Daily chlorhexidine baths for all patients
• 2% chlorhexidine from the jawline downward
• Observational study of terminal cleaning
• Bedrails, IV pumps, poles, respiratory tubing, etc. not
cleaned at all
• Environmental cleaning
• Cleaning personnel - clean all surfaces
• Respiratory therapy - nightly cleaning of all mechanical
ventilator surfaces and O2 valves
• Nursing – disinfect all shared objects
• All bedside curtains replaced
96

Bundled Intervention
• Surveillance cultures on new admissions
• Surveillance rectal swabs on all patients
• Isolation and contact precautions
• High risk patients placed in pre-emptive contact
isolation (CI) on admission until documented (-)
• (+) patients placed in CI
• Personnel education
• Environmental cultures to monitor cleaning
97

98

• To evaluate patients before and after their DAILY CHG BATHS
to determine rates of skin colonization with KPC
• Tested skin sites included
• Inguinal
• Upper back
• Antecubital
• Axilla
• Neck
Effectiveness of Routine Daily Chlorhexidine Gluconate Bathing in Reducing Klebsiella
pneumoniae Carbapenemase-Producing Enterobacteriaceae Skin Burden among Long-Term
Acute Care Hospital Patients (Lin et al., 2014)
Daily Chlorhexidine BATHING for KPC

Results
• 56% of patients had at least one skin site positive
for KPC immediately before bathing
• 32% of patients had at least one skin site positive
for KPC after bathing
pneumoniae Carbapenemase-Producing Enterobacteriaceae Skin Burden among Long-
Term Acute Care Hospital Patients (Lin et al., 2014)

Results
•Notable colonization rates occurred at axillary (39%) and
inguinal (37%) sites before bathing
•After bathing, colonization rates were 10% overall,
representing a 51% decrease from rates before bathing.
pneumoniae Carbapenemase-Producing Enterobacteriaceae Skin Burden among Long-
Term Acute Care Hospital Patients (Lin et al., 2014)

Multidrug resistant Acinetobacter baumannii infection,
colonization, and transmission related to a long-term care
facility providing subacute care (Mortensen et al., 2014)
• To investigate A. baumannii infection, colonization, and transmission
within and beyond a LTC facility
• The California Department of Public Health had noticed clusters of
patients being admitted to 2 local hospitals with MDR A. baumannii
infections – patients were predominantly coming from 1 particular
LTCF
MDRO COLONIZATION

ADVANCES IN ENVIRONMENTAL CLEA
NING
H202 VAPOR
01
.
UV LIGHT
02 ROBOTICS
03

http:www.uptodate.com
ANTIBIOTIC MA
NAGEMENT of M
DROs

TREATING MDROs
AS EARLY AS 2012, we alread
y know that treating MDROs
can be very challenging
In 2012 the Emerging Infection Network (E
IN) conducted a survey of members in 22
states regarding experiences treating CRE
infections
The conclusion: there are few antimic
robials to treat CRE and all have subs
tantial limitations
.
Challenges in the Management of Infections due to Carbapenem-Resistant
Enterobacteriaceae (Drekonja et al., 2014)

ANTIBIOTIC MANAGEMENT For
MDR Acinetobacter baumanii
1
2
3
4
5
COLISTIN
POLYMIXIN B
MINOCYCLINE
COMBINATION usually with CARBAPENEM
TIGECYCLINE

Other Novel Strategies for MDR Abau
PNEUMONIA
INHALED COLISTIN
PROLONGED INFUSION OF CARBAPE
NEM
CRBSI
Removal of Catheter is necessary.
Bloodstream Infection fr Abau
Prognosis usually bad prognosis
Meningitis
Higher dose of carbapenems.
Bacteremias and UTIs
Prudent to avoid tigecycline

CARPANEM- RESISTANT ENTEROBACT
ERIACEAE or CRE
KPC
Name Here
MBLs
Name Here
Klebsiella
pneumoniae
carbapenemases
Metallo-beta
-lactamases.
Carbapenemases D New Delhi
MBL-1
.
NDMOXA 48

ANTIBIOTIC MANAGEMENT of C
REs
1
2
3
4
5
For MBLs: COLISTIN or POLYMIXIN
For MBLs: COMBINATION WITH CARBAPENEM
For KPC: CEFTAZIDIME-AVIBACTAM
COMBINATION usually with AZTREONAM
For KPC: MEROPENEM-VABORBACTAM

ANTIBIOTIC MANAGEMENT FOR
ESBLs
1
2
3
4
5
CARBAPENEMS
POLYMIXIN B
MINOCYCLINE
COMBINATION usually with CARBAPENEM
TIGECYCLINE

ANTIBIOTIC MANAGEMENT FOR
MRSA
1
2
3
4
5
VANCOMYCIN
LINEZOLID
CLINDAMYCIN
SOURCE CONTROL
COTRIMOXAZOLE
DECOLONIZATION
6

WHY WE NEED TO FIND SOLUTIONS
FOR AMR
• ALL THESE
CAN HAPPEN
WITHIN OUR
LIFETIME
https://amr-review.org/

IN TIME, each one
of us will have to
be engaged in
the fight against
AMR ….

We got to be part of this
For OUR PATIENTS
FOR OURSELVES
FOR OUR CHILDREN

WHAT EACH OF US CAN DO TO
FIGHT AMR
HELP
PREVENT
INFECTIONS.
VACCINATE
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01
IMPROVE
ANTIMICROBIAL
PRESCRIBING
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KEEP
UPDATED
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PREVENT
INFECTIONS
IF THERE ARE LESS
INFECTIONS THEN
LESS ANTIBIOTICS
WILL BE USED
IMMUNIZE
CONTACT
PRECAUTION

Thank you for
your attention.
For Questions: rpberba@gmail.com

Novel Management Strategies in the Treatment of Infections with MDROs (RP Berba) - PHICS 2019

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