Drug resistant gram-negative bacteria

7/30/2019 Drug resistant gram-negative bacteria

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Dr.T.V.Rao MD

DRUG RESISTANT GRAM-NEGATIVE

BACTERIA

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Bugs, No Drugs: No ESKAPE

Enterococcus faecium (E), Staphylococcus aureus (S), Klebsiella

pneumoniae (K),Acinetobacter baumannii(A), Pseudomonas aeruginosa

(P), and Enterobacterspp. (E)ate-stage clinical development

pipeline remains unacceptably lean

Some important molecules for problematic pathogens

such as MRSA

Few novel molecules for other ESKAPE pathogens

No new drugs for infection due to multidrug-resistant Gram-negative

bacilli (eg,A. baumanniiand P. aeruginosa)

None represent more than an incremental advance over currently

available therapies

NO ESKAPE ? FROM PATHOGENS

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EXTENDED-SPECTRUM -LACTAMASES (ESBLS):

THE FORGOTTEN (AND UNDERRATED) MDR GNB

Most commonly identified in enterobacteriaceae

Plasmid-mediated

Impart decreased susceptibility to -lactam

antimicrobials

Often co-resistance to aminoglycosides,fluoroquinolones

Carbapenems are drugs of choice for invasive

infections due to ESBL-producers 08-12-2012DR.T.V.RAO MD 3


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ESBLs are enzymes

capable of

hydrolysing

penicillins, broad-

spectrum

cephalosporins and

Monobactams, andare generally derived

from TEM and SHV-

type enzymes

WHAT ARE ESBL

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ALEXANDER FLEMINGNOBEL LECTURE, DECEMBER 11, 1945

It arose simply from a fortunate occurrence which happened when I

was working on a purely academic bacteriological problem which had

nothing to do with antagonism, or moulds, or antiseptics, or

antibiotics.

www.nobelprize.org

Google images

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Abx Penicillin

Cephalosporin

Monobactam

Carbapenem

Bactericidal

WHAT IS A BETA-LACTAM?

Google Images

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Enterobacteriaceae

Resistance to

oxyimino-

cephalosporins andmonobactams but

not cephamycins and

carbamenems

Susceptible to

beta-lactamase

inhibitors

ESBLS

Oteo, et al., 201008-12-2012DR.T.V.RAO MD 7


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SHV

TEM

CTX-M

OXA

AmpC

GENES

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CLASSIFICATION Ambler Classification

Molecular class A D

A

Bush-Jacoby-Medeiros Classification

Functional group 1 4

2

2b

2be

Paterson and Bonomo, 200508-12-2012DR.T.V.RAO MD 9


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Mid 1980s

Variants of TEM and

SHV

Breakdown 3rd

generation

cephalosporins

Mainly in hospitalKlebsiella

Spread world wide

ESBL EVOLUTION

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ESBLs are often

located on

plasmids that aretransferable from

strain to strain and

between bacterialspecies.

WHERE ESBL ARE LOCATED

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Common ESBL worldwide, often produced by

Escherichia coli

Often causes UTI

Now reported in US Healthcare associated

Some community

Community-based ESBL infection raiseconcern for continued increases in

carbapenem use

CTX-M: ESBL EPIDEMIC

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WHY WE NEED ESBL DETECTION

ESBL-producing Enterobacteriaceae have been

responsible for numerous outbreaks of infection

throughout the world and pose challenging infection

control issues. Clinical outcomes data indicate thatESBLs are clinically significant and, when detected,

indicate the need for the use of appropriate

antibacterial agents.

Unfortunately, the laboratory detection of ESBLs can be

complex and, at times, misleading.

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ESBL PRODUCING BACTERIA ARE MORE

COMPLEX ?

Antibacterial choice is often complicated by

multi-resistance. Many ESBLproducing

organisms also expressAmpC -lactamases and may be co-transferredwith

plasmids mediating aminoglycoside

resistance. In addition, there is anincreasing association between ESBL

production and fluoroquinolone resistance

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DYNAMICS OF ANTIBIOTIC

RESISTANCE


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1st generation

Extended-

spectrum With or w/o

beta-lactamase

inhibitor Broad spectrum

PENICILLINS

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CEPHALOSPORINS

Willey, et al., 2008

1st

2nd

3rd

4th

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Although in in vitro tests

ESBLs are inhibited by

-lactamase inhibitors such

as clavulanic acid, the

activity of -lactam/-lactamase inhibitor

combination agents is

influenced by the bacterial

inoculum, doseadministration regimen and

specific type of ESBL

present

ESBL DYNAMICS

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Beta-lactam

Beta-lactamase

Beta-lactamase

inhibitor

ESBL

THE FIGHT

Google Images

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THE FIGHT

BETA-LACTAM

cell

PG

NO

LYSIS08-12-2012DR.T.V.RAO MD 20

THE FIGHT


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THE FIGHT

BETA-LACTAMASE

cell

PG

NO

beta-lactamase

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THE FIGHT

BETA-LACTAMASE

cell

PG

NHO

OH

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THE FIGHT

BETA-LACTAMASE INHIBITOR

cell

PG

NO

beta-lactamase

Inhibitor

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THE FIGHT

BETA-LACTAMASE INHIBITOR

cell

PG

NO

beta-lactamase

Inhibitor

LYSIS08-12-2012DR.T.V.RAO MD 24


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WHAT ARE EXTENDED-SPECTRUM

-LACTAMASES?

ESBLs are enzymes that mediate

resistance to extended-spectrum (third

generation) cephalosporins (e.g.,ceftazidime, cefotaxime, and ceftriaxone)

and monobactams (e.g., aztreonam) but do

not affect cephamycins (e.g., cefoxitin andcefotetan) or Carbapenems (e.g.,

meropenem or imipenem

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WHY SHOULD CLINICAL LABORATORY PERSONNEL BE

CONCERNED ABOUT DETECTING THESE ENZYMES?

The presence of an ESBL-producing organism in a clinicalinfection can result in treatment failure if one of the above

classes of drugs is used. ESBLs can be difficult to detect

because they have different levels of activity against

various cephalosporins. Thus, the choice of whichantimicrobial agents to test is critical. For example, one

enzyme may actively hydrolyze ceftazidime, resulting in

ceftazidime minimum inhibitory concentrations (MICs) of

256 g/ml, but have poor activity on cefotaxime, producing

MICs of only 4 g/ml. If an ESBL is detected, all penicillins,

cephalosporins, and aztreonam should be reported as

resistant, even if in vitro test results indicate susceptibility08-12-2012DR.T.V.RAO MD 26


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HOW CAN CLINICAL LABORATORY

PERSONNEL CONFIRM ESBL PRODUCTION?

NCCLS recommends performing phenotypic confirmation of

potential ESBL-producing isolates of K. pneumoniae, K.

oxytoca, or E. coli by testing both cefotaxime and ceftazidime,

alone and in combination with clavulanic acid . Testing can be

performed by the broth micro dilution method or by diskdiffusion. For MIC testing, a decrease of > 3 doubling dilutions

in an MIC for either cefotaxime or ceftazidime tested in

combination with 4 g/ml clavulanic acid, versus its MIC when

tested alone, confirms an ESBL-producing organism. For diskdiffusion testing, a > 5 mm increase in a zone diameter for either

antimicrobial agent tested in combination with clavulanic acid

versus its zone when tested alone confirms an ESBL-producing

organism.08-12-2012DR.T.V.RAO MD 27


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CLINICAL STRATEGY TO DETECT

ESBL

CTX CTX/CLA

CAZ CAZ/CLA


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NCCLS suggests making

disks by adding 10 l of a

1000 g/ml stock solution

of clavulanic acid to

cefotaxime and ceftazidimedisks each day of testing .

In the future, commercial

manufacturers of

antimicrobial disks mayproduce disks containing

cefotaxime and ceftazidime

with clavulanic acid.

HOW SHOULD LABORATORY PERSONNEL TEST FOR

CEFOTAXIME AND CEFTAZIDIME IN COMBINATION WITH

CLAVULANIC ACID?

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Common ESBL worldwide, often produced by

Escherichia coli

Often causes UTI

Now reported in US Healthcare associated

Some community

Community-based ESBL infection raise concern

for continued increases in carbapenem use

CTX-M: ESBL EPIDEMIC

Urban, Diag Micro Infect Dis, 2010; Sjlund-Karlsson, EID, 201108-12-2012DR.T.V.RAO MD 30


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CARBAPENEM RESISTANCE

Emerging problem in Pseudomonasaeruginosa,Acinetobacter baumannii,Enterobacteriaceae (CRE)

Risk factors include ICU stay, prolongedexposures to healthcare, indwelling devices,antibiotic exposures

Long-term acute care centers (LTACs)

Severely limits treatment options

Increased use of older, toxic agents such ascolistin

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KLEBSIELLA PNEUMONIAECARBAPENEMASES (KPCS)

Plasmid-mediated carbapenemases

KPC-producing strains ofKlebsiella pneumonia and other

enterobacteriaceae

KPC-2, KPC-3

Endemicity in many locales in the US

Hyperendemicity in NYC

24% of K. pneumoniae infections were due to KPCs in 2

hospitals

Country-wide outbreak ongoing in Israel, Greece, Columbia and

others

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KPCS (CONT)

Might appear susceptible to imipenem ormeropenem, but with borderline MICs per 2009 CLSI

breakpoints

Usually Ertapenem resistant Modified Hodge test

Usually only susceptible to colistin, Tigecycline and

select aminoglycosides Easily spread in hospitals (often requires Cohorting of

staff and patients to control)

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Other isolates ofEnterobacteriaceae, suchas Salmonella species andProteus mirabilis, andisolates of Pseudomonasaeruginosa produceESBLs. However, at thistime, methods for screeningand phenotypicconfirmatory testing of

these isolates have notbeen determined byNCCLS.

DO ISOLATES OTHER THAN K. PNEUMONIAE,

K. OXYTOCA, OR E. COLI PRODUCE ESBLS?

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HOW SHOULD CEPHALOSPORIN AND

PENICILLIN RESULTS BE REPORTED?

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If an isolate is confirmed as an ESBL-producer by the

NCCLS-recommended phenotypic confirmatory test

procedure, all penicillins, cephalosporins, and

aztreonam should be reported as resistant. This listdoes not include the Cephamycins (cefotetan and

cefoxitin), which should be reported according to their

routine test results. If an isolate is not confirmed as an

ESBL-producer, current recommendations suggestreporting results as for routine testing. Do not change

interpretations of penicillins, cephalosporins, and

aztreonam for isolates not confirmed as ESBL

BACTERIA NOT TO TEST FOR


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Acinetobacter

Often S to clavulanate

alone

S. maltophila +ve resultby inhibition of L-2

chromosomal b-

lactamase, ubiquitous

in the species

BACTERIA NOT TO TEST FOR

ESBLS

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NEW DELHI METALLO BETA LACTAMASE 1


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NEW DELHI METALLO-BETA-LACTAMASE-1

(NDM-1)

Carbapenemases mediating broad spectrumresistance

Usually found in Klebsiella pneumonia, E. coli

Initially identified in India, Pakistan, Bangladesh

Recovered in Australia, France, Japan, Kenya,

North America, Singapore, Taiwan, and the United

Kingdom, Australia, Canada

Recovered in the US (Massachussetts, Illinois and

California)08-12-2012DR.T.V.RAO MD 37


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MDR GNB IN LONG TERM CARE

Quinolone resistance increasingly common in

hospitals, long-term care and in some community

settings

B-lactam resistance established in hospitals, many

long-term care settings

Risk factors in long-term care for resistant Gram-

negative bacilli

Indwelling devices Poor functional status

Pressure ulcers/wounds

Antimicrobial/quinolone exposure

Prior hospitalization 08-12-2012DR.T.V.RAO MD 38

STRATEGIES TO CONTROL THE


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Contact

precautions/hand

hygiene

Environment andsource control

Antibiotic stewardship

Enhanced infectioncontrol measures

Bundles

STRATEGIES TO CONTROL THE

SPREAD OF MDR GNB

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ROLE OF THE ENVIRONMENT

Environmental sources of contamination/infection

Increasingly recognized as sources of infection

Particularly important with pathogens such asClostridium difficile, Norovirus,Acinetobacterspp.

Bleach preparations are more effective for somepathogens (still need cleaning)

Latest technology being tested: UV light,

hydrogen peroxide vapor08-12-2012DR.T.V.RAO MD 40


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ENVIRONMENTAL CLEANING Adequacy of cleaning of patients rooms

suboptimal

Improve monitoring and feedback of efficacy of

cleaning

Direct observation and culturing not efficient, time-

consuming and expensive

Other options: ATP bioluminescence andfluorescent dyes

Monitor process, efficacy of cleaning08-12-2012DR.T.V.RAO MD 41


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SUPPLEMENTS TO ROUTINE ENVIRONMENTAL

CLEANING

Disinfection units that decontaminate

environmental surfaces

Must remove debris and dirt in order forthese units to be effective

Two most common methods

UV light

Hydrogen peroxide (HP)

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Broad-spectrumantimicrobial disinfectant

Preferred agent for skinpreparation prior to

insertion of vascularcatheter and prior tosurgery

Studied for source control,

decrease in degree ofcontamination of patientsby problem hospitalpathogens

CHLORHEXIDINE GLUCONATE (CHG)

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ENHANCED INFECTION CONTROL PROCESSES

Active Surveillance

Use of screening cultures to identify patients colonized with

pathogens (usually MDR) of interest

Goal is to prevent spread in the hospital by identifying patients who

are colonized and intervening to prevent spread Most experience is with Gram positive pathogens

Limited use for some pathogens (due to low sensitivity)

Cohorting of patients

Dedicated staff

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ANTIMICROBIAL STEWARDSHIP - GOALS

Optimize appropriate use of antimicrobials The right agent, dose, timing, duration, route

Optimize clinical outcomes

Reduce emergence of resistance

Limit drug-related adverse events

Minimize risk of unintentional consequences

Help reduce antimicrobial resistance

The combination of effective antimicrobial stewardship andinfection control has been shown to limit the emergence andtransmission of antimicrobial-resistant bacteria

Dellit TH et al. Clin Infect Dis. 2007;44(2):159177; . Drew RH. J Manag Care Pharm.2009;15(2 Suppl):S18S23; Drew RH et al. Pharmacotherapy. 2009;29(5):593607.

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A bundle is a structuredway of improving theprocesses of care andpatient outcomes: a

small, straightforwardset of evidence-basedpractices that, whenperformed collectivelyand reliably, have been

proven to improvepatient outcomes.

Resar R, Joint Commission Journalon ualit and Patient Safet .

BUNDLES

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CONCLUSIONS MDR GNB are growing in prevalence in multiple

geographic locales Occur in a variety of healthcare associated

settings

Even in the community Antimicrobial stewardship is here to stay

Problem is compounded by dry pharmaceutical

pipeline Novel methods to control spread of MDROs are

attractive but not clearly effective/cost-effective

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NEW DELHI METALLO BETA LACTAMASE 1


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NEW DELHI METALLO-BETA-LACTAMASE-1

(NDM-1)

Carbapenemases mediating broad spectrumresistance

Usually found in Klebsiella pneumonia, E. coli

Initially identified in India, Pakistan, Bangladesh

Recovered in Australia, France, Japan, Kenya,

North America, Singapore, Taiwan, and the United

Kingdom, Australia, Canada

Recovered in the US (Massachussetts, Illinois and

California)08-12-2012DR.T.V.RAO MD 48


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STILL THE BEST WAY TO PREVENT SPREAD OF

INFECTIONS AND DRUG RESISTANCE IS

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VISIT ME FOR MORE ARTICLES OF INTEREST

ON INFECTIOUS DISEASES

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Programme Created by Dr.T.V.Rao MD

for Microbiologists in the Developing

World

Email

[email protected]

Drug resistant gram-negative bacteria

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