1. I nuovi antibiotici per la chemioterapia di precisione nella terapia delle infezioni da gram-negativi MDR
Francesco Menichetti, MD
Professor of Infectious Diseases, University of Pisa
Director, Infectious Diseases Department, Cisanello Hospital, Pisa
President, Italian Group for Antimicrobial Stewardship (GISA)

2. Disclosures 2017-2018 Advisory Board: Angelini, MSD, Nordic Pharma
Speaker/chairman: Angelini, Astellas, Basilea, MSD, Pfizer
Events Sponsorship: Astellas, Gilead, MSD, BMS, Jansenn, ViiV, BioMerieux, Biotest, Becton-Dickinson, Nordic Pharma, Pfizer, Shionogi
Ongoing research protocol: Angelini, Astellas, Cidara, MSD, Shionogi, Theravance

3. MDR gram-negative bacilli, resistance mechanisms & therapeutic options
Pop-Vicas A & Opal SM Virulence 2013

4. Spectrum of β-lactamases
Classe A
Classe D
Classe B
Classe C
SHV
OXA
IMP
Amp C
TEM
VIM
CMY
CTX-M
NDM-1
FOX
KPC
MOX
Extended-Spectrum β-lactamases (ESBLs)
Metallo β-lattamasi
β-lactamases
carbapenemasi

5. Blood Isolates, Toscana 2015-2016
811
2087
ARS-SMART 2016

6. E. coli ESBL, 2016

7. K. pneumoniae ESBL, 2016

8. Treatment for ESBL infections
The Sanford Guide 2018
ESBL producing strains suspected by their resistance in vitro
to Piperacillin, Cefotaxime, Ceftriaxone, Ceftazidime, Aztreonam
Life-threatening:
Carbapenems
Mild/moderate, non bacteremic,
low-inoculum, low MIC:
Cefepime
Piperacillin/tazobactam
Limited clinical data:
Ceftolozane/tazobactam
Ceftazidime/avibactam
UTI uncomplicated: Fosfomycin Nitrofurantoin

9. The MERINO Trial: piperacillin-tazobactam versus meropenem for the definitive treatment of bloodstream infections caused by third-generation cephalosporin non-susceptible Escherichia coli or Klebsiella spp
Adult pts from 32 sites in 9 countries (Singapore, Australia and Turkey).
Pts included 378 (February 2014 to July 2017).
HAI: > 50% of the infections in the study group.
Urosepsis: 60.9% of the infections
E. coli responsible of 86.5% of the cases
Harris P et al. ECCMID 2018 oral presentation

10. MERINO trial: preliminary results
Harris P et al. ECCMID 2018 oral presentation

11. The MERINO Trial: piperacillin-tazobactam versus meropenem for the definitive treatment of bloodstream infections caused by third-generation cephalosporin non-susceptible Escherichia coli or Klebsiella spp
No difference between the two groups regarding subsequent infections of drug-resistant bacteria or C. difficile, but difference in mortality rate was significant.
Twenty-three patients (12.3%) treated with pip-tazo died by the 30-day mark compared with seven patients (3.7%) who had been treated with meropenem.
Pip-tazo was significantly less effective than MPN for potentially fatal BSI caused by ceftriaxone-resistant E. coli and K. pneumoniae and should be avoided
Harris P et al. ECCMID 2018 oral presentation

12. The domino effect of the ESBL pandemic
Dissemination of Enterics
producing ESBLs
Carbapenem-sparing regimens ?
Carbapenem Overuse
Dissemination of
Carbapenem R
Gram-negatives
Idea: Gianni Rossolini

13. 335 pts included; 249 received empiric CPSs and 86 OADs.
Most frequent OADs were AGs (43 pts) and FQs (20 pts).
Empiric therapy with OADs was not associated with increased mortality.
OADs were neither associated with 14-day clinical failure nor increased length of hospital stay.
This information allows more options to be considered for empiric therapy, at least for some patients, depending on ocal susceptibility patterns of ESBL-E.

14. Early administration of OADs for BSI due to ESBL-E does not seem to compromise outcome in comparison with carbapenems, and might be an option for empiric regimens for many patients, depending on local susceptibility patterns.
This may be particularly applied to the use of aminoglycosides in urinary tract sepsis potentially caused by ESBL-E and would justify the design of a randomized trial;
However, until more data are available, we would still recommend considering carbapenems (or BL-BLI) for patients at risk of ESBL-E presenting with septic shock or with a non–urinary tract source of sepsis.

15. Ceftolozane demonstrates good activity against Enterobacteriaceae but its activity is limited against ESBLs.
Tazobactam is a potent, irreversible inhibitor of most ESBLs.
The MIC50/MIC90 of this agent for ESBL-producing E. coli are 0.5/4 μg/mL and for K. pneumoniae 4/>32 μg/mL
Differences in MIC distributions may be reflective of discrepancies in ESBL genes present.
The blaCTX-M genes predominate in E. coli, whereas there is often a preponderance of blaTEM/SHV in K. pneumoniae, with variations in local epidemiology.

16. Ceftolozane-tazobactam (in combination with metronidazole) was compared to meropenem for the treatment of complicated intra-abdominal infections in phase 2 and phase 3 trials that included 4 and 50 people, respectively, with ESBL-producing Enterobacteriaceae.
Although the limited number of ESBLs precluded a robust analysis, this compound performed similarly against ESBL-producing and non-ESBL producing isolates.

17. Efficacy of ceftolozane/tazobactam against urinary tract and
intra-abdominal infections caused by ESBL-producing Escherichia coli
and Klebsiella pneumoniae: a pooled analysis of Phase 3 clinical trials
At ceftolozane/tazobactam concentrations ≤2 mg/L, 95% of ESBL-E. coli and 56.7% of ESBL- K. pneumoniae were inhibited
Popejoy M, J Antimicrob Chemother, 2017; 72:

18. Ceftazidime-avibactam is usually more active in vitro against ESBL producers than ceftolozane-tazobactam.
The MIC50/MIC 90 for ESBL-producing E. coli are 0.12/0.25 μg/mL and for K. pneumoniae 0.5/1 μg/mL
Phase 2/3 studies compared ceftazidime-avibactam (plus metronidazole) vs meropenem for intra-abdominal infections, but did not specifically compare outcomes of ESBL-confirmed pathogens.
Data from a phase 3 study comparing ceftazidime-avibactam and doripenem in UTIs showed similar microbiological response for ceftazidime-resistant Enterobacteriaceae, most of which were ESBL producers

19. Carbapenem-resistant enterobacteriaceae (CRE): definition
CRE was defined as an Enterobacteriaceae isolate demonstrating resistance to any carbapenem (ertapenem, meropenem, imipenem, and/or doripenem), based upon antimicrobial susceptibility testing (AST).
Carbapenem resistance was defined as an Ertapenem MIC ≥2 mcg/ml and MPN and/or IP MIC ≥4 mcg/ml.
Clinical Infectious Diseases Advance Access published November 9, 2016

20. Meropenem use for CRE: MIC, please
For Meropenem MICs of ≤4 mcg/ml: standard-infusion of 2 grams t.i.d. considered active, based on existing pK/pD studies.
For Meropenem MICs of 8 mcg/ml: extended-infusion (2 grams t.i.d. over at least 3 hours) potentially active.
Modeling of extended-infusion strategies suggest that reasonable target attainment can be anticipated with meropenem MICs of up to 8 mcg/ml, and possibly 16 mcg/ml
Clinical Infectious Diseases Advance Access published November 9, 2016

21. K. pneumoniae CR,

22. The double domino effect of the CRE epidemic
Dissemination of CRE
Further Carbapenem Overuse
Colistin overuse
Dissemination of
Colistin R strains

23. K. pneumoniae Col-R,
Col-R: 8,1%

24. P. aeruginosa CR,

25. Acinetobacter spp. CR, Toscana 2015-2016

26. Comparing the Outcomes of Patients with Carbapenemase-Producing and Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Bacteremia
Carbapenem-resistant Enterobacteriaceae (CRE) bacteremia is associated with mortality up to 60%.
Carbapenem resistance can be mediated via: carbapenemase production (CP-CRE) or
production of ESBLs and/or AmpC cephalosporinases combined with altered membrane permeability (non-CP-CRE).
Need to know the outcomes associated with CRE bacteremia according to underlying resistance mechanisms.
Clinical Infectious Diseases Advance Access published November 9, 2016

27. Comparing the Outcomes of Patients with Carbapenemase-Producing and Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Bacteremia
In a cohort of 83 CRE bacteremic patients, the odds of dying within 14 days were four times greater for carbapenemase-producing (CP) CRE compared with non-CP-CRE patients, adjusting for severity of illness, underlying medical conditions, and differences in antibiotic regimens.
Clinical Infectious Diseases Advance Access published November 9, 2016

28. Differential features of acquired carbapenemases
KPC-type
OXA-48-like
MBLs
Amber class A D B
CARBAPENEMASE
ACTIVITY
Strong
Weak
SPECTRUM
Extended (most beta-lactams)
Broad
(penicillins, NS cephems)
Extended, most beta-lactams exc.monobactams
INHIBITION
PBA
Avibactam
Relebactam
Vaborbactam
EDTA

29. Spectrum of Beta-Lactamase Inhibitors
Tazobactam
Avibactam
Vaborbactam
Relebactam
Class A narrow-spectrum
Class A ESBLs
Class A carbapenamases (KPC)
Some class C enzymes
Some class D enzymes
(OXA-48)
Class B enzymes (MBLs)

30. Refertazione antibiogramma molecolare
ATB MOLECOLARE
SPECIE
REFERTO
KPC +
NDM –
VIM –
OXA –
CTX-M -
Enterobatteri
Presenza di un gene per carbapenemasi tipo KPC: elevata probabilità di resistenza a tutti i betallatamici escluso ceftazidime/avibactam
KPC –
Assenza dei più comuni geni per ESBL e carbapenemasi: possibile sensibilità a CFSP di 3° e 4° generazione ed a combinazioni con inibitori di betalattamasi; probabile sensibilità a carbapenemi

31. Antibiotic choice depending on genotype
ESBL
AmpC
KPC
OXA
NDM
Carbapenems
Ceftazidime-avibactam
Ceftolozane-tazobactam
Cefepime
Colistin
Tigecycline
Aminoglycosides
Piperacillin/tazobactam
Fosfomicina

32. Expanded spectrum of β-lactamase inhibition
J Antimicrob Chemother 2016; 71:

33. Ceftazidime – Avibactam
Spectrum of activity: Gram-negatives, including MDR P. aeruginosa, ESBL-producing strains, KPC- Kp
EMA approval in June 2016
c-UTI, including Pyelonephritis
C-IAI (plus metronidazole)
Nosocomial pneumonia
Gram-neg. infection with limited treatment option
IV dose: 2.5 g (2 g ceftazidime; 0.5 g avibactam) q8h (2-h infusion)

34. Ceftazidime/avibactam potential drawbacks
The development of resistance to CAZ/AVI (MIC ≥16 mg/L) was observed following relatively short courses of therapy.
Reducing the development of resistance by using a combination therapy approach ?
Early development of resistance a unique flaw of CAZ/AVI or might it be seen with other new βL-βLIs combinations ?
Much of the resistance reported seen in K. pneumoniae isolates, how common will this phenotype in non- Klebsiellae spp. harbouring KPCs ?
In geographical areas where MBLs are observed at higher rates, what is the overall utility of ceftazidime/avibactam in clinical practice ?

35. News antibiotics for CP-CRE
KPC
OXA-48
VIM/IMP/NDM
Ceftazidime Avibactam
Meropenem Vaborbactam
Imipenem Relebactam
Aztreonam Avibactam
Cefiderocol
Plazomicina
Eravacycline
Active
Activity depending on MICs and/or target concentrations
Not active

36. Ceftazidime/Avibactam
Aztreonam/Avibactam
Aztreonam
Non gravato da reazioni allergiche crociate con altri β-lattamici (eccetto ceftazidime)
Idrolizzato da ESBL, AmpC e
KPC
NON idrolizzato da MBLs
Avibactam
Inibitore non β-lattamico
NON Idrolizzato da:
ESBL
AmpC β-lattamasi
Aztreonam
Ceftazidime/Avibactam
Falagas M.E. Expert Review 2016

37. Imipenem/Relebactam
Relebactam (MK7655) is a piperidine analogue diazabicyclooctane beta-lactamase inhibitor designed to have inhibitory activity against class A and class C beta-lactamases.
In KPC-producing K. pneumoniae the addition of relebactam resulted in lowering imipenem MICs by up to 64-fold.
More modest potentiation was seen with other ESBL- and AmpC producing strains.
Little or no reduction was seen in OXA-48-producing K. pneumoniae or OXA-23-producing A. baumannii, suggesting relebactam, unlike avibactam, does not have significant activity against class D enzymes
Imipenem MICs were reduced from ≥16 mg/L to 2 mg/L in the presence of relebactam when imipenem-resistant P. aeruginosa isolates were tested.

38. Meropenem/Vaborbactam
Vaborbactam is a novel cyclic boronic acid inhibitor of many class A, class C and some class D beta-lactamases.
Vaborbactam acts via the creation of a covalent (dative) bond between its boron moiety and the serine hydroxyl of beta lactamase.
The addition of vaborbactam at 8 μg/ml to meropenem resulted in ≥ 16-fold reduction in MICs for KPC producing E. coli, K. pneumoniae, and Enterobacter spp. isolates.
In a limited number of strains, the combination appeared to have reduced activity against KPC-producing K.pneumoniae isolates with diminished expression of porin genes ompK35 and ompK36.
Little effect on A. baumannii containing OXA-type carbapenemases or P. aeruginosa was observed

39. Cefiderocol
Cefiderocol is a siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain.
The catechol side chain enables ferric iron ion binding, and the resulting complex is actively transported into bacteria via ferric iron transporter systems with subsequent destruction of cell wall.
Cefiderocol has been shown to be potent in vitro against gram-negative organisms, including CRE and MDR P. aeruginosa and A. baumannii.
This activity is considered to be due to the efficient uptake via the active siderophore systems and also to the high stability of cefiderocol against CPS hydrolysis.

40. Terapia empirica carbapenem-sparing per MDR gram-neg
Sepsi/shock settico
Epidemiologia locale KPC/ESBLs/P.aeruginosa
Fattori di rischio KPC/ESBLs/P.aeruginosa
Colonizzazione KPC/ESBLs/P.aeruginosa
Terapia empirica carbapenem-sparing per MDR gram-neg
No sepsi/shock settico
No epidemiologia locale MDR
No FR/colonizzazione MDR
Piperacillina/tazobactam
Sepsi/shock settico
No EL,FR, coloniz. KPC
EL/FR/colonizzazione ESBL o P.aeruginosa
Ceftolozane/tazobactam
(da preferire al meropenem se regime carbapenem-sparing)
Epidemiologia locale/FR/colonizzazione KPC
Ceftazidime/avibactam
* Fattori di rischio specifici (FR): vedi scores preditivi
Rivalutazione 48/72 h (risposta clinica/microbiologia)

41. Terapia mirata carbapenem-sparing in infezioni gravi da gram-neg
Urosepsi
Sepsi biliare
Infez. Intraddominali complicate
HAV/VAP
Batteriemia
Terapia mirata carbapenem-sparing in infezioni gravi da gram-neg
Antibiogramma molecolare
ESBL –
KPC –
MBL –
OXA -
Piperacillina/tazobactam
ESBL +
Ceftolozane/tazobactam
(da preferire al meropenem in regime carbapenem-sparing; in caso di HAV/VAP usare dose doppia)
KPC +
Ceftazidime/avibactam
MBL +
Ceftazidime/avibactam + aztreonam
Rivalutazione 48/72 h (risposta clinica/microbiologia)

42. New approach to MDR gram-neg. infections
Infections due to KPC-CP
Meropenem/vaborbactam
Plazomicin
Ceftazidime/avibactam
Imipenem/relebactam
Colistin
no more !!

43. New approach to MDR gram-neg. infections
Acinetobacter
Cefiderocol
MBLs
Aztreonam-Ceftazidime/ Avibactam

44. Conoscere i nuovi antibiotici: un dovere per il clinico
…..ed un’opportunità per i pazienti…….
Curiosità, non pigrizia prescrittiva
Modello di stewardship condivisa
Raccomandazioni terapeutiche condivise
Gestione della scheda AIFA
Ruolo armonico delle società scientifiche
Sistema nazionale delle LG (ISS)

45.
Presidente Onorario: Prof. Johnatan Cohen
Società Scientifica multidisciplinare, promuove la cultura dell’ASP intesa come GOVERNO CLINICO DELLA TERAPIA ANTIMICROBICA attraverso il confronto equo tra esperti e prescrittori.