MULTI-DRUG

RESISTANT ORGANISMS
(MDROs)
Dr Rahul S Kamble, MBBS, MD Microbiology
Diploma Infectious Diseases (UNSW, Australia)
Infection Control course (Harvard Medical School, USA)
International Clinical Tropical Medicine course
(CMC Vellore|Haukeland university McGill university)
International Vaccinology course (CMC Vellore)
Six Sigma Black Belt (Govt of India certified)
Auditor: JCI|NABH|NABL|CSSD|RBNQA|Texila university
PGDBA|PGDHM|PGDCR|PGDMR|PGDOM|
PGDMLS|PGDIM|PGDHI|PGDBI|PGDHA|CCDHHO
Consultant Clinical Microbiologist & Infectious Diseases
Project Lead - Antimicrobial Stewardship 1
Once upon a time, a scientist named Fleming discovered the miracle of
antibiotics…..e, a scientist named Fleming discovered the miracle of antibiotics…..

http://www.pbs.org/wgbh/nova/sciencenow/0303/04-arms-nf.html
 “…. the 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.”

- Sir Alexander Fleming, June 1945

Lynfield, The Continued Assault of Antibiotic-Resistance; IDSA Congressional briefing. Accessed 7.27.14 at http://www.idsociety.org/WHDbriefing/
                   MDRO (multidrug resistant organisms)

Multi-drug resistant organisms are bacteria that have developed

resistance to atleast one agent in three or more antimicrobial categories.

These antibiotics can no longer be used effectively to control or kill the

bacteria

MDROs are predominantly bacteria, but can also include viruses, fungi, or
parasites

The names of some MDROs identify resistance to only one drug agent, but
they are frequently resistant to multiple drugs
Source: http://www.ct.gov/dph/cwp. Accessed June 20, 2014 4
   Each year nearly 2 million patients in the United States get an infection
in a hospital. Of those patients, about 90,000 die as a result of their
infection. More than 70% of the bacteria that cause hospital-acquired
infections are resistant to at least one of the drugs most commonly used
to treat them. Persons infected with drug-resistant organisms are more
likely to have longer hospital stays and require treatment with second-
or third-choice drugs that may be less effective, more toxic, and/or
more expensive
Clinical importance of
MDROs
•In most instances, MDRO infections have clinical
manifestations that are similar to infections caused by
susceptible pathogens. However, options for treating
patients with these infections are often extremely limited.
Although antimicrobials are now available for treatment
of MRSA and VRE infections, resistance to each new agent
has already emerged in clinical isolates

•Similarly, therapeutic options are limited for ESBL-

producing isolates of gram-negative bacilli
 These limitations may influence antibiotic usage patterns in ways that suppress
normal flora and create a favorable environment for development of colonization
when exposed to potential MDR pathogens (i.e., selective advantage).

Increased lengths of stay, costs, and mortality also have been associated with
MDROs.

The type and level of care influence the prevalence of MDROs. ICUs especially
those at tertiary care facilities, may have a higher prevalence Of MDRO infections
than do non-ICU settings
Emergence of Antimicrobial Resistance

Resistant Bacteria
Susceptible
Bacteria

Resistance Gene
Transfer

N
e 8
w
The most challenging
MDROs in Healthcare
Methicillin-resistant Staphylococcus aureus
(MRSA)

Vancomycin-resistant enterococcus (VRE)

Extended-spectrum Beta-lactamase-producing
bacteria (ESBLs)

Carbapenem-resistant enterobacteriaceae (CRE)

9
1.Methicillin-Resistant
Staphylococcus Aureus (MRSA)
•     MRSA was first isolated in the United States in 1968.

• By the early 1990s, MRSA accounted for 20%-25% of

Staphylococcus aureus isolates from hospitalized patients.
In 1999, MRSA accounted for >50% of S. aureus isolates
from patients in ICUs in the National Nosocomial Infection
Surveillance (NNIS) system; in 2003, 59.5% of S. aureus
isolates in NNIS ICUs were MRSA .
   
 Methicillin-Resistant Staphylococcus aureus
(MRSA) Among Intensive Care Unit Patients,
1995-2004
• Staphylococcus aureus cultured from any specimen that tests oxacillin-resistant, cefoxitin-
resistant, or methicillin-resistant by standard susceptibility testing methods (AST) OR,
positive FDA approved direct testing from sampling (e.g. PCR)

• Resistant to Penicillins, Cephalosporins, Monobactams, Carbapenems.

(additionally to aminoglycosides, macrolides, tetracycline, chloramphenicol, and lincosamide)

Recognizing the signs and receiving treatment in early
stages reduces the chances of the infection becoming
severe
More severe and potentially life-threatening MRSA
infections occur in the hospital setting
• Bloodstream infections
• Surgical site infections
• Pneumonia

According to the CDC, these more serious infections have

been declining in hospitals for several years

22
Clinical Manifestations

Most MRSA infections are skin infections that

appear as pustules or boils which are often red,
swollen, painful, or have pus or other drainage

They can look like spider bites

They commonly occur at sites of visible skin

trauma, such as cuts and abrasions, and areas
covered by hair, such as the back of the neck, groin,
or beard

23
• MRSA skin infections can lead to:

• Abscesses

• Cellulitis

24
 Risk Factors
 Poor functional status Contributing to
 Conditions that cause skin breakdown
MRSA
Colonization/Infectio
 Presence of invasive devices n for all Facility
Types
 Prior antimicrobial therapy

 History of colonization
  Male gender  Pressure ulcers

 Urinary  Antibiotic therapy

Specific incontinence  Hospitalized within
Risk  Fecal incontinence the previous 6 months
Factors for
MRSA  Presence of wounds
What patients are more likely to  shed
MRSA and need contact precautions?

• Heavy draining wound

• Incontinent, diarrhea, colostomy
• Cannot/will not contain secretions and excretions
• Very poor hygiene
• Difficult behaviors that may increase the risk of
transmission
• Other
Treatment
Regimens for
MRSA Infection
Vancomycin is the drug of choice.

Disadvantages of Vancomycin
• expensive

• parenteral administration

• ototoxicity

• can potentiate

nephrotoxicity of
aminoglycosides
Treatment
Regimens for • Linezolid has been an alternative to Vancomycin treatment of
MRSA MRSA since 2000 and Administered orally

Infection
Colonization/carrier state of MRSA by
Healthcare Workers

Do not routinely culture staff for colonization with

MRSA
It may be needed as part of an outbreak
investigation
HCW epidemiologic link to transmission
Before culturing,
• Get expert consultation

• Have an action plan in place!

Outbreak control
• Contact precautions with
observation for compliance
• Hand hygiene
• If a decision has been made to
culture staff for nasal
colonization:
• Mupirocin has been shown to be
somewhat effective.
  Vancomycin-Resistant
Enterococcus (VRE)
• Enterococcus faecalis, Enterococcus faecium, or
Enterococcus species unspecified that is resistant to
vancomycin, by standard susceptibility testing methods
(AST) or by direct testing by FDA approved test e.g. PCR for
genes
• Resistance to Penicillins, Cephalosporins,
Monobactams,Carbapenems, Vancomycin
• Treatment
Linezolid
 A similar rise in prevalence has occurred with VRE . From 1990 to 1997,
the prevalence of VRE in enterococcal isolates from hospitalized patients
increased from <1% to approximately 15%

VRE accounted for almost 25% of enterococcus isolates in NNIS ICUs in

1999 and 28.5% in 2003 .
 Vancomycin-Resistant Enterococci (VRE) Among Intensive Care Unit Patients,1995-
2004
    Contact Precautions - culture negative prior to  discontinuing precautions?

 CDC now says we need to decide when to d/c  precautions but it may be
prudent to have  negative culture(s) prior to d/c of isolation
Why contact precautions for specific
organisms?

Environmental contamination
The Inanimate Environment Can Facilitate
Transmission
X represents VRE culture positive sites

Contaminated surfaces increase cross-transmission

Carbapenem-resistant
enterobacteriaceae (CRE)
•Any Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae,
or Enterobacter spp. testing resistant to imipenem, meropenem,
doripenem, or ertapenem by standard susceptibility testing
methods (AST). OR by production of a carbapenemase (i.e., KPC,
NDM, VIM, IMP, OXA-48) genes by PCR.

• Resistant to imipenem, meropenem, doripenem, or ertapenem

• Treatment
• ceftazidime avibactam , gentamicin, amikacin, colistin,
tigecycline and fosfomycin
 • Bacterial enzymes capable of hydrolysing
Extended- and thus conferring resistance to all
spectrum beta- penicillins, first-, second-, & third generation
lactamase- cephalosporins, and aztreonam.
producing • Resitance to ceftriaxone or cefotaxime is the
screening criteria for ESBL
bacteria
• Treatment
(ESBLs)
• Carbapenems, BLBLIs (piptaz, zavicefta)
 •Enzymes produced by certain
bacteria that provide resistance to
certain antibiotics
Beta-
Lactamases:
What are they ? •Produced by both gram positive and
gram negative bacteria

•Found on both chromosomes and

plasmids
Beta-lactam Antibiotics

Examples

•Penicillin's:
–Penicillin, amoxicillin, ampicillin
•Cephalosporin's:
–Cephalexin,Cefuroxime,Ceftriaxone
•Carbapenems:
–Imipenem, meropenem
 • Mechanism of Action

Beta- • •Hydrolysis of beta-lactam ring of basic

penicillin structure
Lactamases • •Hydrolysis = adding a molecule of H2O
to C-N bond with enzyme action
• –This opens up the ring, thus making the
drug ineffective!
 The story is more complicated….

•Multiple antimicrobial resistance is often a characteristic of ESBL producing gram-negative bacteria.

•Ceftazidime

•Cefotaxime

•Ceftriaxone

•Aztreonam

•Genes encoding for ESBLs are frequently located on plasmids that also carry resistance genes for:

•Aminoglycosides

•Tetracycline

•TMP-SULFA

•Chloramphenicol

•Fluoroquinolones
Essential vocabulary for
phenotypic  detection of
ESBLs, AmpCs and 
carbapenemases 2/3
Essential vocabulary for phenotypic  detection of ESBLs,
AmpCs and  carbapenemases 3/3

FOT FOT FOT FOT FOT FOT FOT FOT POS

0.25 0.5 1 2 4 8 16 32 CTRL

F/C F/C F/C F/C F/C F/C F/C F/C F/C F/C F/C POS
0.06/4 0.12/4 0.25/4 0.5/4 1/4 2/4 4/4 8/4 16/4 32/4 64/4 CTRL
B E TA - L A C TA M A S E
PHENOTYPES: EFSA CRITERIA
Genotypic detection of
ESBLs, AmpCs and carbapenemases
FEATURES TO REMEMBER

•RESISTANCE TO BETA-LACTAM ANTIBIOTICS IN E. COLI (AND

OTHER  ENTEROBACTERIACEAE) IS MAINLY DUE TO ENZYMATIC
INACTIVATION OF THE DRUG

•ESBLS, AMPCS AND CARBAPENEMASES ARE ENZYMES THAT

INACTIVATE BETA-  LACTAM ANTIBIOTICS. THEY DIFFER FOR
SUBSTRATE SPECIFICITY

•PHENOTYPIC AND GENOTYPIC METHODS CAN BE USED FOR

DETECTION OF ESBLS,  AMPCS AND CARBAPENEMASES
ESBL?

• However: ESBL producing organisms are still susceptible to:

• •Cephamycins:
• –Cefoxitin
• –Cefotetan
• •Carbapenems:
• –Meropenem
• –Imipenem

• Carbapenem are becoming the therapeutic option of choice

ESBLs are
harbingers of
multi-drug
resistance
Colistin
Resistance
 Colistin resistance

• Limited clinical use due to nephro- and neurotoxicity  main use in production animal industry

• Resurgence in last decade due to MDR Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter spp.

Total consumption of colistin in humans (…) has doubled in some of EU/EEA countries between 2010 and 2014
following the rise in MDR Gram negative pathogens involved in healthcare-associated infections. – EMA, 2016

• Colistin is among the highest prioritized critically important antimicrobials (WHO)

Escherichia coli
Salmonella spp. Intrinsically resistant bacteria:
Klebsiella spp. Gram-positive bacteria
Acinetobacter spp. Proteus mirabilis
Enterobacter spp. Serratia marcescens
Pseudomonas aeruginosa Other
Haemophilus influenzae
Colistin resistance
•Acquired colistin resistance is mainly the consequence of Gene Publication
Gene
accession
Variants

•LPS modifications/ number

•inaccessibility

mcr-1 Liu Y, 2016 KP347127 1.2 to 1.15

 CHROMOSOMAL MUTATIONS
•Chromosomal mutations affecting PhoPQ and PmrAB t mcr-2 Xavier BB, 2016 LT598652 2.2

•wo-component systems, etc. mcr-3 Yin W, 2017 KY924928 3.2 to 3.25

 MCR GENES mcr-4 Carattoli A, 2017 MF543359 4.2 to 4.6

• Since the discovery of

plasmid-mediated mcr-5 Borowiak M, 2017 KY807921 5.2 and 5.3
colistin resistance in
2015, interest in this
mcr-6 AbuOun M, 2018 MF176240.1 None
phenotype increased
exponentially because of
high risk of fast mcr-7 Yang Y, 2018 MG267386.1 None

dissemination of
resistance mcr-8 Wang X, 2018 MG736312.1 8.2 and 8.4
Detection of
Colistin
Resistance
Phenotypic
methods
Phenotypic methods
Phenotypic methods
 Quality control is essential

Quality control of colistin must be performed both with a susceptible QC strain (E. coli ATCC 25922
or P. aeruginosa ATCC 27853) and with the colistin-resistant E. coli NCTC 13846 (mcr-1 positive).

QC strain Colistin MIC

target values

E. coli ATCC 25922 0.25 – 2 mg/L

P. aeruginosa ATCC 27853 0.5 – 4 mg/L

4 mg/L
E. coli NCTC 13846 (only occasionally 2 or 8 mg/L)

References: CLSI M100 and www.EUCAST.org

Genotypic
methods
Genotypic Methods
Genotypic Methods
Highlights
 Antimicrobial Resistance:
Key Prevention Strategies
Susceptible pathogen Pathogen
Prevent Prevent
Transmission Infection
Infection
Antimicrobial
Resistance

Effective
Optimize Diagnosis
Use & Treatment

Antimicrobial Use
 Steps to Prevent Antimicrobial
Resistance:                     
Prevent Infection
1. Vaccinate
1 2 3 4 5 6 7 8 9
2. Get the catheters
out Use Practice Use Treat Treat Know Stop Isolate Break
Diagnose and Treat • Use • Practice • Use local • Treat • Treat • Know when • Stop • Isolate the • Break the
Infection Effectively Antimicrobi
als Wisely
antimicrobi
al control
data infection,
not
infection,
not
to say “no”
to vanco
treatment
when
pathogen chain of
• contagion
contamina colonizatio infection is
tion n  cured or
unlikely 

3. Target the pathogen

4. Access the experts
 Prevent Infection
Step 1: Vaccinate

Fact: Pre-discharge influenza and pneumococcal vaccination

of at-risk hospital patients and influenza vaccination of
healthcare personnel will prevent infections.

Actions:
give influenza / pneumococcal vaccine to at-risk patients before discharge
get influenza vaccine annually
 Need for Healthcare Personnel Immunization
Programs: Influenza Vaccination Rates (1996-97)

% Vaccinated

All adults > 65 yrs. of age 63%

Healthcare personnel at high
38%
risk*
All healthcare personnel** 34%
Need for Hospital-Based Vaccination:
Post-discharge Vaccination Status of Hospitalized Adults

Influenza Pneumococcal Population Vaccine Vaccine

Age 18-64 years17% vaccinated 31% vaccinated
with medical risk*

Age > 65 years* 45% vaccinated 68% vaccinated

Hospitalized for
pneumonia 35% vaccinated 20% vaccinated
during influenza
season**
 Prevent Infection
Step 2: Get the catheters out

•Fact: Catheters and other invasive devices are the # 1

exogenous cause of hospital-onset infections.

•Actions:
• use catheters only when essential
• use the correct catheter
• use proper insertion & catheter-care protocols
• remove catheters when not essential

 Link to: Guidelnes for the Prevention of Intravascular Catheter-related Infections

Step 2: Get the catheters out

Biofilm on Intravenous Catheter Connecter 24 hours after Insertion

Scanning
Electron Micrograph
Diagnose & Treat Infection Effectively
Step 3: Target the pathogen

Fact: Appropriate antimicrobial therapy

saves lives.

Actions:
target definitive therapy to known
target empiric therapy to likely
culture the patient pathogens and antimicrobial
pathogens and local antibiogram
susceptibility test results
 Inappropriate Antimicrobial Therapy:
Impact on Mortality

17.7% mortality Relative Risk = 2.37

No. Infected

(95% C.I. 1.83-3.08; p < .001)

Patients

42.0% mortality # Survivors

# Deaths
Inappropriate Appropriate
Therapy Therapy
 Inappropriate Antimicrobial Therapy: Prevalence among Intensive Care Patients

Inappropriate
45.2% Antimicrobial Therapy
% inappropriate

(n = 655 ICU patients with infection

34.3%
Community-onset infection
17.1% Hospital-onset infection

Hospital-onset infection after

initial community-onset infection

Patient Group
Step 4: Access the experts

Fact: Infectious diseases

expert input  improves the
outcome of serious
infections.
Infectious Diseases Expert Resources

Infectious Diseases
Specialists
Healthcare Infection Control
Epidemiologists Professionals

Clinical Optimal
Pharmacists Patient Care
Clinical
Clinical Pharmacologists
Microbiologists
Surgical Infection
Experts
 Use Antimicrobials Wisely

Step 5: Practice antimicrobial control

Fact: Programs to improve antimicrobial use are effective.

Step 6: Use local data

• Fact:
The prevalence of resistance can vary by time, locale, patient
population, hospital unit, and length of stay.
 
Step 7: Treat infection, not contamination

• Fact: A major cause of antimicrobial overuse is “treatment” of contaminated cultures.

• Actions:
• use proper antisepsis for blood & other cultures
• culture the blood, not the skin or catheter hub
• use proper methods to obtain & process all cultures
•
Step 8: Treat infection, not colonization

• Fact: A major cause of antimicrobial overuse is treatment of

colonization.

• Actions:
• treat bacteremia, not the catheter tip or hub
• treat pneumonia, not the tracheal aspirate
• treat urinary tract infection, not the indwelling catheter
 Fact:

Step 9: Know • Vancomycin overuse promotes emergence,

selection, and spread of resistant
when to say pathogens.

“no” to Vanco
Step 10: Stop antimicrobial treatment

• Fact: Failure to stop unnecessary antimicrobial treatment contributes to

overuse and resistance. 

• Actions:
• when infection is cured
• when cultures are negative and infection is unlikely
• when infection is not diagnosed
 Step 11: Isolate the pathogen

Fact: Patient-to-patient spread of Actions:

pathogens can be prevented.
use standard infection control precautions
contain infectious body fluids
• (use approved airborne/droplet/contact
isolation precautions)
when in doubt, consult infection control experts
Step 12: Break the chain of contagion

• Fact: Healthcare personnel can spread antimicrobial-resistant

pathogens from patient-to-patient.
Improved Patient Outcomes associated with Proper Hand Hygiene

Ignaz Philipp
Semmelweis
(1818-65)
Chlorinated lime hand antisepsis
Prevention and Control of MDRO
transmission

•   Successful control of MDROs has been documented  using a variety of combined interventions.
These include:
•   - Improvements in hand hygiene,
•   - Use of Contact Precautions until patients are culture-negative for a target MDRO,
•   - Active surveillance cultures (ASC), 
•   - Education,
•   - Enhanced environmental cleaning, and improvements in communication about patients with
MDROs within and between healthcare facilities.
Infection control practices and the
campaign to prevent multi-drug resistance

• Problem!
• Unrestricted use of antibiotics in the community:
• Role of physicians-evidence based guidelines and protocols
• Role of pharmacists-policies (antibiotics should not be over the counter
drugs!)
• Role of public-education
• Role of the ministry of health-rules and regulations
Infection control practices and the
campaign to prevent multi-drug resistance

• Problem!
• Lack of National Nosocomial Infection Surveillance (NNIS) system (governmental and non-governmental)
• Problem!
• Do we have adequate Infectious Diseases Expert Resources ?
• - Infectious Diseases Specialists
• - Infection Control Professionals
• - Clinical Pharmacologists
• - Clinical Microbiologists
• - Health care Epidemiologists
Protect patients…protect healthcare
personnel… promote quality healthcare!

55
THANK YOU