Francesco Menichetti, MD Professor of Infectious Diseases, University of Pisa

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) www.antimicrobialstewardship.net

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 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 producingstrainssuspected by theirresistance 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: FosfomycinNitrofurantoin

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 • Adultpts from 32 sites in 9 countries(Singapore, Australia and Turkey). • Ptsincluded 378 (February 2014 to July 2017). • HAI: > 50% of the infections in the studygroup. • Urosepsis: 60.9% of the infections • E. coliresponsible of 86.5% of the cases Harris Pet al. ECCMID 2018 oralpresentation

10. MERINO trial: preliminaryresults Harris Pet al. ECCMID 2018 oralpresentation

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 differencebetween the twogroupsregardingsubsequentinfections of drug-resistantbacteria or C. difficile, butdifference in mortality rate wassignificant. • Twenty-threepatients(12.3%) treated with pip-tazodied by the 30-day markcompared with sevenpatients(3.7%) whohadbeentreated with meropenem. • Pip-tazowassignificantlylesseffectivethan MPN for potentiallyfatal BSI caused by ceftriaxone-resistantE. coli and K. pneumoniae and should be avoided Harris Pet al. ECCMID 2018 oralpresentation

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-Eand 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) wascompared to meropenem for the treatment of complicated intra-abdominalinfections in phase 2 and phase 3 trials thatincluded4 and 50 people, respectively, with ESBL-producingEnterobacteriaceae. • Although the limitednumber of ESBLsprecluded a robustanalysis, this compound performedsimilarlyagainst ESBL-producing and non-ESBL producingisolates.

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: 268-72

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-resistantenterobacteriaceae (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, 2015- 2016

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

23. K. pneumoniae Col-R, 2015- 2016 Col-R: 8,1%

24. P. aeruginosa CR, 2015- 2016

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-resistantEnterobacteriaceae (CRE) bacteremiaisassociated with mortality up to 60%. • Carbapenemresistance can be mediated via: carbapenemase production (CP-CRE) or • production of ESBLs and/or AmpCcephalosporinasescombined with altered membrane permeability(non-CP-CRE). • Need to know the outcomesassociated with CRE bacteremiaaccording to underlyingresistancemechanisms. Clinical Infectious Diseases Advance Access published November 9, 2016

27. Comparingthe Outcomes of Patients with Carbapenemase-Producing and Non-Carbapenemase-ProducingCarbapenem-ResistantEnterobacteriaceaeBacteremia • 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. Differentialfeaturesof acquiredcarbapenemases

29. Spectrum of Beta-Lactamase Inhibitors

30. Refertazione antibiogramma molecolare

31. Antibioticchoicedepending on genotype

32. Expanded spectrum of β-lactamase inhibition J Antimicrob Chemother 2016; 71:2713-22

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/avibactampotentialdrawbacks • 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

36. 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 • KPC 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 • Cefiderocolisa siderophorecephalosporinantibiotic with a catecholmoiety on the 3-position side chain. • The catechol side chainenablesferricironionbinding, and the resultingcomplexisactivelytransportedintobacteria via ferricirontransportersystems with subsequentdestruction of cellwall. • Cefiderocolhasbeenshown to be potent in vitro againstgram-negative organisms, includingCRE and MDR P. aeruginosa and A. baumannii. • Thisactivityisconsidered to be due to the efficientuptake via the activesiderophoresystemsand alsoto the high stability of cefiderocolagainst CPS hydrolysis.

40. Terapia empirica carbapenem-sparing per MDR gram-neg

41. Terapia mirata carbapenem-sparing in infezioni gravi da gram-neg

42. New approach to MDR gram-neg. infections

43. New approach to MDR gram-neg. infections

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) www.antimicrobialstewardship.net

45. www.antimicrobialstewardship.net 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.