DRUG RESISTANT GRAM-NEGATIVE

BACTERIA
Dr.T.V.Rao MD

DR.T.V.RAO MD

08-12-2012

NO ESKAPE ? FROM PATHOGENS

Bugs, No Drugs: No ESKAPE Enterococcus faecium (E), Staphylococcus aureus (S), Klebsiella pneumoniae (K), Acinetobacter baumannii (A), Pseudomonas aeruginosa (P), and Enterobacter spp. (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. baumannii and P. aeruginosa) None represent more than an incremental advance over currently available therapies
DR.T.V.RAO MD 08-12-2012

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

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

WHAT ARE ESBL

ESBLs are enzymes capable of hydrolysing penicillins, broadspectrum cephalosporins and Monobactams, and are generally derived from TEM and SHVtype enzymes
DR.T.V.RAO MD

08-12-2012

ALEXANDER FLEMING
NOBEL 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

DR.T.V.RAO MD

08-12-2012

WHAT IS A BETA-LACTAM?
Abx
Penicillin Cephalosporin Monobactam Carbapenem

Bactericidal

Google Images

DR.T.V.RAO MD

08-12-2012

ESBLS
Enterobacteriaceae Resistance to oxyiminocephalosporins and monobactams but not cephamycins and carbamenems

Susceptible to beta-lactamase inhibitors

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

Oteo, et al., 2010

GENES
SHV TEM CTX-M OXA AmpC
DR.T.V.RAO MD 08-12-2012

CLASSIFICATION
Ambler Classification Molecular class A D

A
Bush-Jacoby-Medeiros Classification Functional group 1 4 2 2b 2be
DR.T.V.RAO MD

Paterson and Bonomo, 2005

08-12-2012

ESBL EVOLUTION
Mid 1980s Variants of TEM and SHV Breakdown 3rd generation cephalosporins Mainly in hospital Klebsiella Spread world wide
DR.T.V.RAO MD 08-12-2012

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WHERE ESBL ARE LOCATED

ESBLs are often located on plasmids that are transferable from strain to strain and between bacterial species.
DR.T.V.RAO MD 08-12-2012

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Common ESBL worldwide, often produced by Escherichia coli Often causes UTI Now reported in US
Healthcare associated Some community

CTX-M: ESBL EPIDEMIC

Community-based ESBL infection raise concern for continued increases in carbapenem use
DR.T.V.RAO MD 08-12-2012

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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 that ESBLs 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.
DR.T.V.RAO MD 08-12-2012

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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 an increasing association between ESBL production and fluoroquinolone resistance
DR.T.V.RAO MD 08-12-2012

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DYNAMICS OF ANTIBIOTIC RESISTANCE

DR.T.V.RAO MD

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PENICILLINS
1st generation Extendedspectrum

With or w/o beta-lactamase inhibitor Broad spectrum

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

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CEPHALOSPORINS
4th 3rd 2nd

1st
DR.T.V.RAO MD 08-12-2012

Willey, et al., 2008

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ESBL DYNAMICS
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, dose administration regimen and specific type of ESBL present
DR.T.V.RAO MD 08-12-2012

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THE FIGHT
Beta-lactam
Beta-lactamase

Beta-lactamase inhibitor
ESBL
Google Images

DR.T.V.RAO MD

08-12-2012

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THE FIGHT

BETA-LACTAM
PG

O
DR.T.V.RAO MD

N
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cell
LYSIS
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THE FIGHT

BETA-LACTAMASE
PG

beta-lactamase N
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cell
21

O
DR.T.V.RAO MD

THE FIGHT

BETA-LACTAMASE
PG

O OH

NH

cell
DR.T.V.RAO MD 08-12-2012

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THE FIGHT

BETA-LACTAMASE INHIBITOR
PG

beta-lactamase N Inhibitor
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cell
23

O
DR.T.V.RAO MD

THE FIGHT

BETA-LACTAMASE INHIBITOR
PG

beta-lactamase Inhibitor

O
DR.T.V.RAO MD

N
08-12-2012

cell
LYSIS
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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 and cefotetan) or Carbapenems (e.g., meropenem or imipenem
DR.T.V.RAO MD 08-12-2012

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WHY SHOULD CLINICAL LABORATORY PERSONNEL BE CONCERNED ABOUT DETECTING THESE ENZYMES?

The presence of an ESBL-producing organism in a clinical infection 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 which antimicrobial 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 susceptibility
DR.T.V.RAO MD 08-12-2012

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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 disk diffusion. 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 disk diffusion 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.
DR.T.V.RAO MD 08-12-2012

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CLINICAL STRATEGY TO DETECT ESBL

CTX/CLA CTX CAZ

CAZ/CLA

HOW SHOULD LABORATORY PERSONNEL TEST FOR CEFOTAXIME AND CEFTAZIDIME IN COMBINATION WITH CLAVULANIC ACID? NCCLS suggests making disks by adding 10 l of a 1000 g/ml stock solution of clavulanic acid to cefotaxime and ceftazidime disks each day of testing . In the future, commercial manufacturers of antimicrobial disks may produce disks containing cefotaxime and ceftazidime with clavulanic acid.
DR.T.V.RAO MD 08-12-2012

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Common ESBL worldwide, often produced by Escherichia coli Often causes UTI Now reported in US
Healthcare associated Some community

CTX-M: ESBL EPIDEMIC

Community-based ESBL infection raise concern for continued increases in carbapenem use
Urban, Diag Micro Infect Dis, 2010; Sjlund-Karlsson, EID, 2011
DR.T.V.RAO MD 08-12-2012

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CARBAPENEM RESISTANCE
Emerging problem in Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacteriaceae (CRE) Risk factors include ICU stay, prolonged exposures to healthcare, indwelling devices, antibiotic exposures
Long-term acute care centers (LTACs)

Severely limits treatment options

Increased use of older, toxic agents such as colistin
DR.T.V.RAO MD 08-12-2012

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KLEBSIELLA PNEUMONIAE CARBAPENEMASES (KPCS)

Plasmid-mediated carbapenemases
KPC-producing strains of Klebsiella 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
*
DR.T.V.RAO MD 08-12-2012

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KPCS (CONT)
Might appear susceptible to imipenem or meropenem, 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)
DR.T.V.RAO MD 08-12-2012

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DO ISOLATES OTHER THAN K. PNEUMONIAE, K. OXYTOCA, OR E. COLI PRODUCE ESBLS?

Other isolates of Enterobacteriaceae, such as Salmonella species and Proteus mirabilis, and isolates of Pseudomonas aeruginosa produce ESBLs. However, at this time, methods for screening and phenotypic confirmatory testing of these isolates have not been determined by NCCLS.

DR.T.V.RAO MD

08-12-2012

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HOW SHOULD CEPHALOSPORIN AND PENICILLIN RESULTS BE REPORTED?

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 list does 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 suggest reporting results as for routine testing. Do not change interpretations of penicillins, cephalosporins, and aztreonam for isolates not confirmed as ESBL
DR.T.V.RAO MD 08-12-2012

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BACTERIA NOT TO TEST FOR ESBLS

Acinetobacter
Often S to clavulanate alone

S. maltophila +ve result by inhibition of L-2 chromosomal blactamase, ubiquitous in the species

DR.T.V.RAO MD

08-12-2012

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NEW DELHI METALLO-BETA-LACTAMASE-1

Carbapenemases mediating broad spectrum resistance
Usually found in Klebsiella pneumonia, E. coli

(NDM-1)

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

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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 Gramnegative bacilli
Indwelling devices
Poor functional status Pressure ulcers/wounds Antimicrobial/quinolone exposure
DR.T.V.RAO MD

Prior hospitalization

08-12-2012

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STRATEGIES TO CONTROL THE SPREAD OF MDR GNB

Contact precautions/hand hygiene Environment and source control Antibiotic stewardship Enhanced infection control measures

Bundles
DR.T.V.RAO MD 08-12-2012

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ROLE OF THE ENVIRONMENT

Environmental sources of contamination/infection
Increasingly recognized as sources of infection

Particularly important with pathogens such as Clostridium difficile, Norovirus, Acinetobacter spp. Bleach preparations are more effective for some pathogens (still need cleaning) Latest technology being tested: UV light, hydrogen peroxide vapor
DR.T.V.RAO MD 08-12-2012

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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, timeconsuming and expensive

Other options: ATP bioluminescence and fluorescent dyes

Monitor process, efficacy of cleaning
DR.T.V.RAO MD 08-12-2012

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SUPPLEMENTS TO ROUTINE ENVIRONMENTAL CLEANING Disinfection units that decontaminate environmental surfaces
Must remove debris and dirt in order for these units to be effective Two most common methods
UV light
Hydrogen peroxide (HP)
DR.T.V.RAO MD 08-12-2012

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CHLORHEXIDINE GLUCONATE (CHG)

Broad-spectrum antimicrobial disinfectant Preferred agent for skin preparation prior to insertion of vascular catheter and prior to surgery Studied for source control, decrease in degree of contamination of patients by problem hospital pathogens
DR.T.V.RAO MD 08-12-2012

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

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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 and infection control has been shown to limit the emergence and transmission 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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BUNDLES
A bundle is a structured way of improving the processes of care and patient outcomes: a small, straightforward set of evidence-based practices that, when performed collectively and reliably, have been proven to improve patient outcomes.

DR.T.V.RAO MD

Resar R, Joint Commission Journal on Quality and Patient Safety.

08-12-2012

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 MDR GNB are growing in prevalence in multiple geographic locales Occur in a variety of healthcare associated settings
Even in the community

CONCLUSIONS

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

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NEW DELHI METALLO-BETA-LACTAMASE-1

Carbapenemases mediating broad spectrum resistance
Usually found in Klebsiella pneumonia, E. coli

(NDM-1)

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

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STILL THE BEST WAY TO PREVENT SPREAD OF INFECTIONS AND DRUG RESISTANCE IS

DR.T.V.RAO MD

08-12-2012

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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

doctortvrao@gmail.com

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08-12-2012

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