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The role of detecting and differentiating

beta-lactamases in antibiotic

stewardship

programs (ASP)

Nikolaos V. Sipsas, MD, PhD, FIDSA Medical School

National and Kapodistrian University of Athens, Greece

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Disclosure of speaker’s interests

(Potential) conflict of interest None

Potentially relevant company relationships in connection with event ¹

None

• Sponsorship or research funding²

• Fee or other (financial) payment³

• Shareholder⁴

• Other relationship, i.e. …⁵

Nothing to declare

Disclosure slide for speaker at EUCIC Local module for Infection Prevention and Control

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Outline

• Beta – lactamases

• Antimicrobial stewardship programs (AMS)

• Diagnostic stewardship

• Effect of detecting and differentiating beta-lactamases on AMS

• Conclusions

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Outline

• Conclusions

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By 2050: Antimicrobial resistant infections the leading cause of death

μέχρι το 2050

By 2050

 10 million people will die every year from infections by MDR pathogens

 The infections by MDR pathogens will cost the global economy more than $100 million

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Main reason of resistance:

β-lactamases with broad spectrum of activity

 The increase of Gram –ve pathogens resistance is mainly due to the presence of various β-lactamases with a broad

spectrum of activity

 Growing – heterogeneous group including:

 Extended-spectrum β- lactamases (ESBLs)

 Plasmid AmpCs

 Carbapenemases: KPCs, MBLs (IMP, VIM, NDM), OXA-types

Davies J & Davies D. Microbiol Mol Biol Rev 2010;74:417

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Health care-associated infections, in the USA, per year

• ESBL-producing Enterobacteriaceae, ~26,000

• Carbapenem-resistant Enterobacteriaceae , ~9,000

• MDR P. aeruginosa ~6,700

• Especially affected by MDRs Gram-ves

• cUTIs

• cIAIs

7

Hampton T. JAMA. 2013;310:1661–1663.

Zilberberg MD, et al. Infect Control Hosp Epidemiol. 2013; 34: 940–946.

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Beta - lactamases

Gould IM et al, Int J Antimicrobiol Agents 2009

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Major Groups of broad-spectrum beta- lactamases

Enzymes Classification Type Spectrum resistance Inhibitors Pathogens Endemic Areas

Extended-spectrum β-

lactamases Class A TEM, SHV, CTX-M

PER, GES Penicillins,

Cephalosporins Monobactams

Clavulanic acid Tazobactam Sulbactam

K. pneumoniae E. coli

P. aeruginosa

worldwide

Plasmidic AmpCs,

Chromosomal AmpCs Class C CMY, FOX, ACT, MOX,

ACC, DHA Penicillins,

Cephalosporins Cephamycins Monobactams

Boronic acid

Cloxacillin K. pneumoniae E. coli, others P. aeruginosa

worldwide

KPC carbapenemases Class A KPC Penicillins,

Cephalosporins Cephamycins Monobactams Carbapenems

Boronic acid Clavulanic acid (weak)

others

USAGreece Italy Israel China Metallo-

β-lactamases Class B IMP, VIM, NDM Penicillins,

Cephalosporins Cephamycins Carbapenems

Metal chelators

(e.g EDTA) K. pneumoniae E. coli, οthers P. aeruginosa

Greece, Italy, Spain (VIM) Japan (IMP), Taiwan (IMP) India (NDM), Balkan (NDM) worldwide

OXA-type

β-lactamases Class D OXA-48, OXA-181

OXA-1, -10, -13, -2, -18, -45

Penicillins Temocillin

β-lactamases inhibitor combinations

Carbapenems

NaCl K. pneumoniae

E. coli

P. aeruginosa

Turkey

Morocco Tunisia worldwide

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Gram (-) and mechanisms of resistance

Bonomo RA, et al. Clin Infect Dis 2006;43:S49-56,

Nicasio AM, et al.

Pharmacotherapy 2008;28:235-49

• Pseudomonas aeruginosa

• Production of AmpC, efflux pumps (MexAB-OprM, etc)

• Mutation of outer membrane porins (i.e loss of OprD)

• Production of Metallo-β-Lactamase s (e.g., blaVIM, bla_IMP)

• Mutations gyrA/parC

• Enzymes that modify aminoglycosides (AME)

• Production of ESBL/KPC

• Acinetobacter spp

• AmpC, ESBL (TEM-1, SHV-type, CTX-M-type)

• Production serine (bla_OXA), metallo (bla_VIM, bla_IMP) carbapenemases

• Mutation of outer membrane porins - Mutations gyrA/parC

• AME, efflux pumps

• Enterobacteriaceae (Klebsiella spp , E. coli, Enterobacter spp )

• ESBL, Klebsiella-producing-carbapenemase (KPC-2, -3, -4, etc.)

• New Delhi Metallo-Beta-Lactamase (NDM-1, -2)

• AmpC, Mutation of outer membrane porins

• plasmid mediated quinolone resistance gene (qnrA)

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Epidemiology of Enterobacteriaceae producing ESBLs

SMART study (intra-abdominal infections)

Hawser et al., AAC, 2011;55:3917-3921; Hoban et al., AAC, 2010;54:3043-3046

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The spread of CTX-M ESBLs has become irreversible: Why?

Hawkey PM, et al. J Antimicrob Chemother. 2009;64(suppl1):i3-I10.12

 The genetic environment & their presence in various conjugative plasmids

 The connection with successful bacterial clones Κ. pneumoniae & E. coli (ST131)

 Population movements and mostly healthy carriers

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L Silvia Munoz-Price , Laurent Poirel , Robert A Bonomo , Mitchell J Schwaber , George L Daikos , Martin Cormican ...

Global expansion of Klebsiella pneumoniae carbapenemases

The Lancet Infectious Diseases, Volume 13, Issue 9, 2013, 785 - 796

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Distribution of Carbapenemases in Europe

R Canton. Clin Microbiol Infect 2012; 18: 413–431

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Low sensitivity of ESBLs, AmpCs to current treatment options

 3^rd generation cephalosporins: sensitive to hydrolysis by ESBLs and AmpCs

 β-lactam + inhibitor β-lactamases: No activity in AmpC isolates

 Cefepime & piperacillin/tazobactam: in ESBL isolates,

correlation of therapeutic effect with bacterial load - inoculum effect

Carbapenems: treatment of choice

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ESBLs & in vitro susceptibility of lactamase inhibitors

Leclercq R et al. CMI 2011

Rule No Rule Comments

9.1 For Enterobacteriaceae intermediate or resistant to any third-generation (cefotaxime, ceftriaxone, ceftazidime) or

fourth-generation (cefepime) oxyimino- cephalosporin, AND susceptible to amoxycillin–clavulanate, ampicillin–

sulbactam or piperacillin–tazobactam, THEN report as tested and enclose a warning on uncertain therapeutic outcome

for infections other than urinary tract infections (GRADE B)

With the exception of urinary tract infections and

bloodstream infections secondary to this origin, the use

of these combinations in infections caused by ESBL

producers remains

controversial, and should be approached with caution.

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Vicious Cycle use of Carbapenems

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Increased multi-resistant enterobacteria (ESBL)

Cross transmission +spread of resistance

Selected strains resistant to carbapenems

Increased use of carbapenems

Increased carbapenem resistant isolates

Pseudomonas aeruginosa

Enterobacteriacaea Acinetobacter

Nordmann and Poirel. J Antimicrob Chemother. 2013;68:487-9.

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An increased use of carbapenems has been observed in the EU in recent years

• Trends in consumption of carbapenems in the European Union(EU)/European Economic Area (EEA) countries,

2010–2014 (expressed as DDD per 1000 inhabitants and per day)

EU/EEA refers to the corresponding population-weighted mean consumption, calculated by adding together the products of each country’s consumption in DDD per 1000 inhabitants and per day × country’s population as in Eurostat, and then dividing this sum by the total EU/EEA population. The green bars in the 2014 column provide a visual representation of the consumption of carbapenems. (a) These countries did not report data for all years during the period 2010‒2014; (b) Finland: data include consumption in remote primary healthcare centres and nursing homes; (c) Portugal: data relate to public hospitals only; (d) United Kingdom: data do not include consumption from UK-Wales (2013) or UK-Northern Ireland (2014). DDD, defined daily doses; n.a., not applicable (linear regression was not applied due to missing data); n.s., not significant

ECDC. Summary of the latest data on antibiotic consumption in the European Union. 2015. Available at: http://ecdc.europa.eu/en/eaad/antibiotics- news/Documents/antimicrobial-consumption-ESAC-Net-summary-2015.pdf (accessed April 2017).

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Increased use of carbapenem is related to increased

non-susceptibility to carbapenems among Enterobacteriaceae

CIRE, carbapenem-intermediate or –resistant Enterobacteriaceae, defined as isolates for which carbapenem MIC was ≥2 mg/L; DOT, days of therapy; Q1 to -4, first to fourth quarters

McLaughlin M, et al. Antimicrob Agents Chemother 2013;57:5131–3.

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Proportion of carbapenem-resistant Klebsiella pneumoniae isolates

Europe is indicative of a global problem:

increasing carbapenem resistance

Available at: http://ecdc.europa.eu/en/activities/surveillance/EARS-Net (accessed April 2017).

2005 2015

+ 10 yrs

Among all isolates of Enterobacteriaceae 7.6% were non-susceptible to carbapenems

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Carbapenem-sparing Tx for ESBL-producing organisms

• Ceftolozane / tazobactam

• Ceftazidime / avibactam

• Tigecycline is a non-beta-lactam drug that is a potential alternative for treatment of ESBL-producing strains

• Eravacycline also appears effective against ESBL-producing isolates, based on limited clinical data.

• Plazomicin is an advanced aminoglycoside that often retains activity against ESBL-producing isolates

• Fosfomycin retains activity against many ESBL-producing isolates, and can be effective for cystitis caused by ESBL-producing E. coli

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Outline

• Conclusions

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ASP

• Antimicrobial stewardship programs are means to

• address inappropriate antimicrobial use,

• manage costs,

• decrease drug resistance,

• prevent medication-related adverse events.

• Antimicrobial stewardship programs (ASPs) must be a fiduciary responsibility for all healthcare institutions, and they should be implemented in all healthcare facilities

Society for Healthcare Epidemiology, SHEA, 2012.

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GOALS OF ASPs

• Reduce resistance rates: This is an overarching target for all ASPs, but when resistance is endemic, the need to reduce resistance rates becomes more pressing.

• Control of outbreaks: In epidemics by resistant pathogens, ASPs should be part of a multidisciplinary program for the outbreak containment.

Samarkos M, Sipsas N. in Principles and practices of Antimicrobial Stewardship. CABI 2017

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GOALS OF ASPs

• Improve selection of initial antimicrobial therapy

• Reduce the duration of initial empirical antimicrobial therapy

• Optimize the efficacy of antimicrobials:

• pharmacokinetic/pharmacodynamic (PK/PD) data

• susceptibility data

• to select the most appropriate dose and schedule or antimicrobial combinations

Samarkos M, Sipsas N. in Principles and Practices of Antimicrobial Stewardship. CABI 2017

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Observed values and model predictions of

Carbapenems consumption pre- and post-AMS

implementation at Laiko Hospital, Athens, Greece.

Pre-intervention Post-intervention

10 15 20 25

Carbapenems consumption (DDDs/100 p-days) 2014 Nov 2015 Jan 2015 Mar 2015 May 2015 Jul 2015 Sep 2015 Nov 2016 Jan 2016 Mar 2016 May 2016 Jul 2016 Sep 2016 Nov 2017 Jan 2017 Mar 2017 May 2017 Jul 2017 Sep 2017 Nov 2018 Jan 2018 Mar 2018 May 2018 Jul 2018 Oct

Time

Solid line: predicted values

- Pre-intervention monthly slope: 0.18 (95% CI: 0.06, 0.29); p: 0.003 - Change at intervention: -8.99 (95% CI: -12.60, -5.38); p: <0.001 - Post-intervention monthly slope: -0.28 (95% CI: -0.54, -0.01); p: 0.041

Intervention starts: 2016 Oct Estimates on Carbapenems

consumption (DDDs/100 p- days) from an interrupted time- series model

Pre-intervention monthly slope:

0.18 (95% CI: 0.06, 0.29); p:

0.003

Change at intervention: -8.99 (95% CI: -12.60, -5.38); p:

<0.001

Post-intervention monthly slope : -0.28 (95% CI: -0.54, - 0.01); p: 0.041

Sipsas NV, personal communication

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Outline

• Conclusions

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Diagnostic stewardship

• It involves modifying the process of ordering, performing, and

reporting diagnostic tests to improve the treatment of infections and other conditions.

• These steps are referred to as:

• Pre-analytic,

• analytic

• Post-analytic interventions

Morgan JD et al. JAMA 2017

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J Clin Microbiol. 2017; 55: 715–723.

• Roles of diagnostic and antimicrobial stewardship in the implementation of rapid molecular infectious disease diagnostics in the clinical setting.

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J Clin Microbiol. 2017; 55(11): 3306–3307.

The AID stewardship model

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Outline

• Conclusions

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Different beta – lactamases offer different resistance patterns

Early identification allows prescription of appropriate

antimicrobials

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Beta-lactamase inhibitors

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In vitro coverage against ESBLs

Inhibitory activity of β-lactamase inhibitors against various β-lactamases

1. Livermore et al. J Antimicrob Chemother. 2010;65:1972-4. 2. Titelman et al. Diag Microbiol Infect Dis. 2011;70:137-41.

3. Drawz and Bonomo. Clin Microbiol Rev. 2010;23:160-201. 4. Jacoby and Munoz-Price. N Engl J Med. 2005;352:380-91. 5. Shadid et al. Crit Rev Microbiol. 2009;35:81-108. 6. Ceftolozane/Tazobactam SmPC 2017.

7. Zhanel et al. Drugs. 2013;73:159-77.

-: No inhibitory activity +: Inhibitory activity

β-lactamase enzyme

AmpC CTX-M SHV TEM KPC MBL

Sulbactam³ -/+^a + + + - -

Clavulanic acid^4,5 - + + + - -

Tazobactam^3,6 - + + + - -

Avibactam⁷ + + + + + -

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Beta-lactamases and spectrum of resistance

Enzymes Classification Type Spectrum resistance Inhibitors Pathogens Endemic Areas

Extended-spectrum β-

lactamases Class A TEM, SHV, CTX-M

PER, GES Penicillins,

Cephalosporins Monobactams

Clavulanic acid Tazobactam Sulbactam

P. aeruginosa

worldwide

Plasmidic AmpCs,

Chromosomal AmpCs Class C CMY, FOX, ACT, MOX,

ACC, DHA Penicillins,

Cephalosporins Cephamycins Monobactams

Boronic acid

Cloxacillin K. pneumoniae E. coli, others P. aeruginosa

worldwide

KPC carbapenemases Class A KPC Penicillins,

Cephalosporins Cephamycins Monobactams Carbapenems

Boronic acid Clavulanic acid (weak)

others

USAGreece Italy Israel China Metallo-

β-lactamases Class B IMP, VIM, NDM Penicillins,

Cephalosporins Cephamycins Carbapenems

Metal chelators

(e.g EDTA) K. pneumoniae E. coli, οthers P. aeruginosa

Greece, Italy, Spain (VIM) Japan (IMP), Taiwan (IMP) India (NDM), Balkan (NDM) worldwide

OXA-type

β-lactamases Class D OXA-48, OXA-181

OXA-1, -10, -13, -2, -18, -45

Penicillins Temocillin

β-lactamases inhibitor combinations

Carbapenems

NaCl K. pneumoniae

E. coli

P. aeruginosa

Turkey

Morocco Tunisia worldwide

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Beta-lactamase identification and AMS aims

• Improve selection of initial antimicrobial therapy

• Reduce the duration of initial empirical antimicrobial therapy

• Address inappropriate antimicrobial use

• Decrease drug resistance

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The new paradigm

These strategies should include :

Rapid bacterial

identification Rapid antibiotic resistance profiling

Antibiotic therapy adaptation by an

antimicrobial stewardship team

New strategies should be developed to select the most suitable antibiotic

therapy to improve patient care.

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Rapid molecular techniques to identify resistant pathogens are

revolutionizing antibiotic stewardship

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Rapid bacterial identification and AMS

• Recent studies have shown a positive impact on clinical management of patients with BSI when rapid bacterial identification by MALDI-TOF MS is used in conjunction with advice from an antimicrobial

stewardship team

• MALDI-TOF with AMS intervention

• decreased time to organism identification (84.0 vs 55.9 hours, P < .001)

• improved time to effective antibiotic therapy (30.1 vs 20.4 hours, P = .021)

• optimal antibiotic therapy (90.3 vs 47.3 hours, P < .001).

Huang AM, et al. Impact of rapid organism identification via matrix- assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 2013;57:1237–1245.

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Rapid antibiotic resistance profiling and AMS

• The Beta-LACTA^TMtest (BLT) is a new chromogenic test for detecting 3GC-resistant isolates

• Vrioni G, et al. Performance of the b-LACTA test for rapid detection of expanded-

spectrum cephalosporin-nonsusceptible enterobacteriaceae. J Glob Antimicrob Resist.

2017;10:285–288.

• A recent study evaluated the clinical impact of combined strategies associating:

• Rapid identification of Gram-negative bacilli (GNB) by MALDI-TOF MS

• Rapid detection of 3GC resistance by BLT, directly from blood culture,

• on early antibiotic therapy adaptation by an AST as well as the establishment of infection control measures.

Mizrahi A, et al. Infect Dis (Lond). 2018;50:668-677

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Rapid antibiotic resistance profiling and AMS

• During an 18-months period, we prospectively evaluated the clinical impact of rapid bacterial identification by MALDI-TOF MS technology combined with an antimicrobial stewardship team (AST) intervention.

• Furthermore, during an 8-months period, we combined this strategy with the rapid detection of third-generation cephalosporin (3GC)

resistance by the Beta-LACTA^TM test (BLT) directly on blood cultures.

• We then evaluated the theoretical impact of BLT on antibiotic therapy adaptation and establishment of infection control measures.

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Rapid antibiotic resistance profiling and AMS

• Antimicrobial susceptibility testing, compared to the theoretical adaptation with BLT result

• The antibiotic therapy adaptation was delayed by 28.1 hours and

• the establishment of infection control measures was delayed by 35 hours

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• We compared, the antimicrobial choice of the local AMST as informed :

• of the Gram-stain result

• of the MALDI-TOF MS results only (option H)

• of the combined MALDI-TOF MS and BLT results (option A)

• Compared to the gold standard, options H and A did not lead to a significant reduction of carbapenem prescription (9/131, 6/131 and 12/131, P=0.57 and P=0.65, respectively)

Depret et al. J Med Microb 2018; 67:183-9

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• We describe two cases of bacteremia that were both initially identified by genotypic testing as carbapenem-resistant Acinetobacter spp. and subsequently identified

phenotypically as carbapenem-susceptible A. radioresistens.

• The genotypic results prompted unnecessary broad-spectrum antibiotic use and infection control concerns.

A.C. Brady et al. Diagnostic Microbiology and Infectious Disease 85 (2016) 488–489

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Limitations of rapid techniques for resistance profiling and effect on AMS

• Two patients with GN bacteremia

• Verigene BC-GN test was performed and identified Acinetobacter spp., OXA positive.

• Verigene BC-GN is a nucleic acid-based test which rapidly and

accurately identifies Gram-negative pathogens directly from positive blood culture bottles and probes for the genetic resistance markers that encode OXA (OXA-23, OXA-40, OXA 48, OXA-58), KPC, NDM, VIM, and IMP carbapenemases along with CTX-M extended-spectrum β-

lactamase

Sullivan KV, et al. J Clin Microbiol 2014; 52(7):2416–21.

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Limitations of rapid techniques for resistance profiling and effect on AMS

• In both patients the AMS team changed initial empirical

cephalosporin treatment to:

• Ampicillin – sulbactam

• colistimethate sodium, meropenem, and

minocycline

• The organism was subsequently identified as highly drug-

susceptible A. radioresistens using Vitek 2

A.C. Brady et al. Diagnostic Microbiology and Infectious Disease 85 (2016) 488–489

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Outline

• Conclusions

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Conclusions

• Antimicrobial resistance is emerging as a major public health threat

• The increase of Gram –ve pathogens resistance is mainly due to the presence of various β-lactamases with a broad spectrum of activity

• The presence of beta-lactamases is the driving force for

overconsumption of carbapenems, which leads to increase in carbapenem resistance– vicious cycle

• Antimicrobial stewardship along with diagnostic stewardship and infection control are the pillars for reduction of resistance

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Conclusions

• Rapid molecular techniques to identify resistant pathogens are revolutionizing AMS

• A new paradigm for antimicrobial therapy

• Rapid bacterial identification

• Rapid resistance profiling

• Antibiotic therapy adaptation by an antimicrobial stewardship team

• Rapid bacterial identification allows for optimization of AMS programs

• Identification and differentiation of beta-lactamases allows for early adaptation of antimicrobial therapy

• AMS teams should be aware of the limitations of rapid molecular techniques