Infezioni da Gram-negativi MDR nel Paziente Chirurgico:

Ruolo dei Nuovi Antibiotici

Francesco G. De Rosa

AINF-1204855-0004-ZER-W-04/2018

Disclosures

Consultant/Advisory Board

• Pfizer, MSD, AstraZeneca, Angelini

• Astellas Pharma, Basilea, Sanofi Aventis

Speaker fees

• Pfizer, MSD, Astellas Pharma, Novartis

• AstraZeneca, Thermo Fisher, Basilea

Global Prevalence of ESBL-producing E. coli (2011-2014)

CDDEP report, 2015

Classifying -lactamases Bush. Rev Inf Dis 1987;10:681; Bush et al. Antimicrob Agents Chemother 1995;39:; Bush.

Curr Opin Investig Drugs 2002;3:1284

OXA e.g. OXA-11,

-14, -15,

-16, -17

TEM/SHV/ CTX-M

KPC

Class A

(serine)

β-lactamases

Serine enzymes Metallo-enzymes

Class D

(serine)

Class C

(serine)

AmpC

Class B

IMP/VIM

The β-lactamase Family Bradford PA. Clin Microbiol Rev 2001;14:933–51; Jacoby GA. Clin Microbiol Rev 2009;22:161–82;

Stuart JC, Leverstein-Van Hall MA. Int J Antimicrob Agents 2010;36:205–10

ESBLs1 AmpC2 Carbapenemases3

Class C (serine)

e.g. CMY, LAT, FOX

Others OXA e.g. OXA-11,

-14, -15, -16, -17

CTX-M e.g. CTX-M-1,

-3, -10

TEM,SHV e.g. TEM-3,

SHV-2

VEB, GES, PER

Metallo (MBL) Serine

Class A Class D Class B

9 families: KPC, IMI,

SME, NMC PER, GES,

SFO, SFC, IBC

2 families: OXA, PSE

e.g. OXA-48

6 families: NDM, VIM,

IMP, GIM, SIM,

SPM e.g. VIM-1,

NDM-1

Class D (serine)

Class A (serine)

Escherichia coli: Resistenza alle Cefalosporine 3G (2006-2014)

EARS-NET

2014 Italia: 28.7%

Resistenza alle Cefalosporine 3G Europa, 2014

K. pneumoniae E. coli

EARS-NET

Escherichia coli: Resistenza ai Fluorochinoloni (2006-2014)

EARS-NET

2014 Italia: 43.9%

K. pneumoniae Abat C et al Springerplus 2016 May 17;5:631

• Non-motile, rod-shaped, Gram-negative bacterium

– Naturally present in the environment but equally in humans

– Possible colonization of human nasopharynx, skin & gastrointestinal tract • Berrazeg et al. 2013; Ramos et al. 2014

• Wide spectrum of diseases worldwide

• Responsible for large nosocomial outbreaks

– Transferred via the hands of hospital personnel • Ramos et al. 2014

• European Centre for Disease Prevention and Control 2013

• Public health challenge

• Extraordinary capacities for carrying and spreading a wide variety of resistance genes – ESBL like SHV, CTX and AmpC

• Harris et al. 2015

– Carbapenem resistance genes including NDM, KPC, IMP and VIM • Rolain et al. 2010; Nordmann and Carrer 2010

– Colistin resistance genes, especially mgrB, pmrA, pmrB, phoP and phoQ genes • Olaitan et al. 2014

• Costs & deaths associated with invasive diseases • Schwaber and Carmeli 2007; Daroukh et al. 2014

K. pneumoniae Abat C et al Springerplus 2016 May 17;5:631

Produzione di carbapenemasi:

Metallo-beta-lattamasi (IMP, VIM, NDM)

Carbapenemasi a serina (KPC)

Carbapenemasi di tipo OXA (OXA-48)

Perdita di porine

associata a

produzione di

ESBL / AmpC +++

Più alto livello di resistenza ai carbapenemi

Resistenza trasferibile

Episodi epidemici di grandi dimensioni (cloni ad alto rischio)

Meccanismi di Resistenza ai Carbapenemi negli Enterobatteri

Carbapenem-resistant Klebsiella pneumoniae

2009

EARS-NET

33%

2014

62%

31%

Mobilization of Carbapenemase-Mediated Resistance in Enterobacteriaceae

Mathers A. Microbiol Spectr 2016;4(3)

• Dramatic increase of carbapenem-resistant Enterobacteriaceae – Few residual treatment options

– Poor outcomes

• Carbapenem resistance is often mediated by acquisition of: – Klebsiella pneumoniae carbapenemase [KPC]

– oxacillinase-48-like [OXA-48]

– New Delhi metallo-β-lactamase [NDM])

• Unique epidemiology and microbiology

• Encoding genes for most globally widespread carbapenemases – Typically carried on mobile pieces of DNA

– Free exchange between bacterial strains and species via horizontal genetransfer

Pseudomonas aeruginosa: Resistenza agli Antibiotici (2014)

Italia: 28.3%

Italia: 23.2%

FQ

AG CAZ

TZP

Italia: 31.5%

Italia: 24.9%

The Colistin Resistance mcr-1 Gene Going Wild Liakopoulos A et al. JAC 2016 Jun 20

• First report by Liu et al. of the plasmid-encoded mcr-1 gene conferring colistin resistance

• Liu YY, Wang Y, Walsh TR et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 2016; 16: 161–8.

• Now documented worldwide in food and food-producing animals, the environment and humans

• Skov RL, Monnet DL. Plasmid-mediated colistin resistance (mcr-1 gene): three months later, the story unfolds. Euro Surveill 2016; 21: pii¼30155

Ceftolozane/Tazobactam Overview

18

Class

Antipseudomonal cephalosporin + β-lactamase inhibitor

Fixed 2:1 ratio

Mechanism of action

Rapidly bactericidal

Inhibits cell wall synthesis

Active against organisms with porin deficiencies or mutations

Inhibits β-lactamases, broadens coverage to most ESBL-producing Enterobacteriaceae

In vitro activity

Pseudomonas aeruginosa, including drug-resistant strains

Escherichia coli, including ESBL-positive strains

Klebsiella pneumoniae, including ESBL-positive strains

Minimal activity against Gram-positive bacteria

Limited activity against anaerobes

No activity against KPC, MBL

Development stage

Completed Phase 3 trials for treatment of cIAI and cUTI

Phase 3 trial underway for nosocomial pneumonia

In vivo efficacy

Activity in mouse models of sepsis, pneumonia, urinary tract infection, burn wound infection, and thigh infection

Positive outcomes and adhered to an expected safety profile in Phase 2 and 3 trials in adult patients with cUTI and cIAI

Pharmacokinetics

Linear PK

Lung penetration

Rapid tissue distribution

Minimal accumulation

Extensive renal excretion

Low protein binding

Minimal CYP450 drug-drug interactions

+

Zhanel et al. Drugs. 2014;74:31-51.

Ceftolozane-Tazobactam: Place in Therapy

• Official Indications – IAI – Complicated UTI

• Microbiological activity – P. aeruginosa – ESBL

• Off-label • PK Advantages • Carbapenem-sparing strategies • Piperacillin-tazobactam alternatives

– Data from clinical trial vs ESBL-producing bacteria

Carbapenemase producers

ASPECT-cIAI

Clinical Response by ESBL Status (ME at TOC)

100 100 100 100 100 100

88,5

72,7

90

77,8 75

0 0

10

20

30

40

50

60

70

80

90

100

EnterobacteriaceaeESBL+

EnterobacteriaceaeCTX-M-14/15

E. coli ESBL+ E. coli CTX-M-14/15 K. pneumoniae ESBL+ K. pneumoniae CTX-M-14/15

Ceftolozane/tazobactam+metronidazole Meropenem

4/4

K. pneumoniae

22

CTX-M-14/15 is a subset of ESBL-producers. cIAI, complicated intra-abdominal infection; E. coli, Escherichia coli; ESBL, extended-spectrum β-lactamase; K. pneumoniae, Klebsiella pneumoniae; ME, microbiologically evaluable; TOC, test of cure. Eckmann et al. ECCMID 2 2014. Poster P0266a.

Clin

ical

cu

re (

%)

22/22 23/26 12/12 14/14 8/11

E. coli K. pneumoniae E. coli

18/20 9/9 7/9 6/6 3/4

ASPECT-cIAI

Clinical Response at TOC Visit by Infection Site

23 Eckmann et al. ECCMID 2014. Poster P0266a.

95% CI for the difference of ceftolozane/tazobactam [TOL/TAZ] + metronidazole – meropenem are calculated as Wilson score CIs. A patient can have more than 1 anatomical site of infection. Data as-observed approach used for calculation of Wilson score CIs.

Subgroup in CE population Subgroup in ME population

Primary site of infection

15

Favors TOL/TAZ

30 45 60 75 0 -15 -30 -45 -60 -75

Favors meropenem

Anatomical site of infection

Bowel (small or large)

Other site of IAI

Appendix

Biliary-cholecystitis

Colon

Other

Parenchymal (liver)

Parenchymal (spleen)

Small bowel

Stomach/duodenum

Primary site of infection

15

Favors TOL/TAZ

30 45 60 75 0 -15 -30 -45 -60 -75

Favors meropenem

Anatomical site of infection

Bowel (small or large)

Other site of IAI

Appendix

Biliary-cholecystitis

Colon

Other

Parenchymal (liver)

Parenchymal (spleen)

Small bowel

Stomach/duodenum

ASPECT-cUTI Key Primary and Secondary Analysis Endpoints at TOC Visit

NI m

argi

n

Ceftolozane/ tazobactam

n/N (%)

Levofloxacin n/N (%)

Percentage difference (95% CI)

Percentage difference (99% CI)

306/398 (76.9) 275/402 (68.4) 8.5 (2.3 to 14.6) 8.5 (0.4-16.5)

284/341 (83.3) 266/353 (75.4) 8.0 (2.0 to 14.0) 8.0 (0.01-15.8)

95% CI

ME population

mMITT population

Ceftolozane/tazobactam – levofloxacin (difference [%])

n/N (%) n/N (%) (95% CI)

320/398 (80.4) 290/402 (72.1) 8.3 (2.4 to 14.1)

294/341 (86.2) 274/353 (77.6) 8.6 (2.9 to 14.3)

-10 -5 5 10 15 0

ME population

mMITT population

20

-10 -5 5 10 15 0 20 Microbiological eradication

-10 -5 5 10 15 0

ME population

mMITT population

20

Clinical cure n/N (%) n/N (%) (95% CI)

366/398 (92.0) 356/402 (88.6) 3.4 (-0.7 to 7.6)

327/341 (95.9) 329/353 (93.2) 2.7 (-0.8 to 6.2)

Composite cure

24 Wagenlehner et al. ECCMID 2014. Poster eP449.

Primary end point

In Vitro Susceptibility to Ceftazidime-Avibactam of Carbapenem-Nonsusceptible Enterobacteriaceae Isolates Collected during the INFORM Global Surveillance Study (2012- 2014) de Jonge BL et al

AAC 2016; 60(5): 3163-9

• Susceptibility to CAZ-AVI

– 98% • Meropenem-nonsusceptible & MBL-negative isolates

– 98% • Isolates with KPC or OXA-48-like β-lactamases both alone and in

combination with ESBLs and/or AmpC β-lactamases

– 95% • Meropenem-nonsusceptible, carbapenemase-negative isolates

• CAZ-AVI activity compromised only in isolates with metallo-β-lactamases

In vitro activity of Ceftazidime-avibactam Vs. Specific β-lactamases Bradford PA. Clin Microbiol Rev 2001;14:933–51; Jacoby GA. Clin Microbiol Rev 2009;22:161–82;

Stuart JC, Leverstein-Van Hall MA. Int J Antimicrob Agents 2010;36:205–10

ESBLs1 AmpC2

Class C (serine)

e.g. CMY, LAT, FOX

Others OXA e.g. OXA-11,

-14, -15, -16, -17

CTX-M e.g. CTX-M-1,

-3, -10

TEM,SHV e.g. TEM-3,

SHV-2

VEB, GES, PER

Class D (serine)

Class A (serine)

Carbapenemases3

Metallo (MBL) Serine

Class A Class D Class B

9 families: KPC, IMI,

SME, NMC PER, GES,

SFO, SFC, IBC

2 families: OXA, PSE

e.g. OXA-48

6 families: NDM, VIM,

IMP, GIM, SIM,

SPM e.g. VIM-1,

NDM-1

In vitro activity of Ceftazidime-avibactam Vs. Specific β-lactamases Bradford PA. Clin Microbiol Rev 2001;14:933–51; Jacoby GA. Clin Microbiol Rev 2009;22:161–82;

Stuart JC, Leverstein-Van Hall MA. Int J Antimicrob Agents 2010;36:205–10

ESBLs1 AmpC2

Class C (serine)

e.g. CMY, LAT, FOX

Others OXA e.g. OXA-11,

-14, -15, -16, -17

CTX-M e.g. CTX-M-1,

-3, -10

TEM,SHV e.g. TEM-3,

SHV-2

VEB, GES, PER

Class D (serine)

Class A (serine)

Carbapenemases3

Metallo (MBL) Serine

Class A Class D Class B

9 families: KPC, IMI,

SME, NMC PER, GES,

SFO, SFC, IBC

2 families: OXA, PSE

e.g. OXA-48

6 families: NDM, VIM,

IMP, GIM, SIM,

SPM e.g. VIM-1,

NDM-1

Carbapenem Sparing Strategies

• Piperacillin-tazobactam

• Cephalosporins

– Ceftazidime, cefepime

– Ceftolozane-tazobactam

• Ertapenem

• Alone or in combination with aminoglycosides

– Especially for urinary tract infections or BSI

Ertapenem in ESBL-producing Enterobacteriaceae BSI: A Multinational Pre-registered Cohort Study

Gutiérrez-Gutiérrez B et al for REIPI/ESGBIS/INCREMENT Group. JAC 2016; 71:1672

• Comparison of monotherapy with ertapenem or other carbapenems – Empirical and targeted therapies were analysed

– Outcome variables were cure/improvement rate at day 14 and all-cause 30 day mortality

– Empirical therapy cohort (ETC) 195 patients

– Targeted therapy cohort (TTC) 509 patients

• Cure/improvement rates of erta or other carba, respectively: – ETC: 90.6% and 75.5% (P = 0.06)

– TTC: 89.8% and 82.6% (P = 0.02)

• 30 day mortality – ETC: 3.1% and 23.3% (P = 0.01

– TTC: 9.3% and 17.1% (P = 0.01)

Ertapenem in ESBL-producing Enterobacteriaceae BSI: A Multinational Pre-registered Cohort Study

Gutiérrez-Gutiérrez B et al for REIPI/ESGBIS/INCREMENT Group. JAC 2016; 71:1672

• Comparison of monotherapy with ertapenem or other carbapenems – Empirical and targeted therapies were analysed

– Outcome variables were cure/improvement rate at day 14 and all-cause 30 day mortality

– Empirical therapy cohort (ETC) 195 patients

– Targeted therapy cohort (TTC) 509 patients

• Cure/improvement rates of erta or other carba, respectively: – ETC: 90.6% and 75.5% (P = 0.06)

– TTC: 89.8% and 82.6% (P = 0.02)

• 30 day mortality – ETC: 3.1% and 23.3% (P = 0.01

– TTC: 9.3% and 17.1% (P = 0.01)

• Sensitivity analyses were consistent – Except for patients with severe sepsis/septic shock

Non-significant trend favouring other carbapenems.

• Ertapenem as effective as other carba in ETC & TTC – Further studies are needed for patients with severe sepsis/septic shock

Ertapenem in ESBL-producing Enterobacteriaceae BSI: A Multinational Pre-registered Cohort Study

Gutiérrez-Gutiérrez B et al for REIPI/ESGBIS/INCREMENT Group. JAC 2016; 71:1672

Ertapenem in ESBL-producing Enterobacteriaceae BSI: A Multinational Pre-registered Cohort Study

Gutiérrez-Gutiérrez B et al for REIPI/ESGBIS/INCREMENT Group. JAC 2016; 71:1672

A Multinational, Preregistered Cohort Study of β-Lactam/β-Lactamase Inhibitor Combinations for Treatment of Bloodstream Infections Due to

Extended-Spectrum-β-Lactamase-Producing Enterobacteriaceae Gutiérrez-Gutiérrez B et al AAC 2016;60(7):4159-69

• Styuy of Empirical-therapy (ET) Vs targeted-therapy (TT)

– ET = 365 patients

– TT = 601 patients

• The main outcome variables:

– Cure/improvement at day 14 & all-cause 30-day mortality

• The cure/improvement rates with BLBLIs and carbapenems

– ETC: 80.0% and 78.9%

– TTC: 90.2% and 85.5%

• The 30-day mortality rates

– ETC 17.6% and 20%

– TTC 9.8% and 13.9%

• BLBLIs, if active in vitro

– As effective as carbapenems

– Regardless of the source and specific species AINF-1204855-0004-ZER-W-04/2018