ENTEROBATTERI RESISTENTI AI CARBAPENEMI (CRE) E NUOVI ANTIBIOTICI

1. ENTEROBATTERI RESISTENTI AI CARBAPENEMI (CRE) E NUOVI ANTIBIOTICI Francesco Menichetti Professore di Malattie Infettive, Università di Pisa, Presidente GISA

2. Disclosures 2017 • 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. Batteriemie Toscana, 2015     Bollettino ARS Toscana

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

5. 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

8. 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

9. The domino effect of the ESBL pandemic Dissemination of Enterics ProducingESBLs CarbapenemOveruse Dissemination of CarbapenemR Gram-negatives

11. The double domino effectof the CRE epidemic Idea: Gianni Rossolini Dissemination of CRE FurtherCarbapenemOveruse Colistinoveruse Dissemination of ColistinRstrains

12. 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

13. Comparing the Outcomes of Patients with Carbapenemase-Producing and Non-Carbapenemase-Producing Carbapenem-Resistant Enterobacteriaceae Bacteremia • The CRE resistance mechanism heterogeneity has clinical relevance as reliable phenotypic and genotypic carbapenemase assays are available. • Differences in outcomes between CP-CRE and non-CP-CRE infections would underscore the importance of delineating underlying resistance mechanisms in CRE as this may impact antibiotic treatment decisions (e.g., prioritizing who should receive newer CP-CRE active antibiotic agents). Clinical Infectious Diseases Advance Access published November 9, 2016

14. 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

15. Spectrum of β-lactamases carbapenemasi

16. Differentialfeatures ofacquiredcarbapenemases

17. Spectrum of Beta-Lactamase Inhibitors

18. Refertazione antibiogramma molecolare

19. Antibioticchoicedepending on genotype

20. New Agents to Treat Resistant Gram-Negative Bacteria

21. Ceftazidime/avibactam • Avibactamisa non-beta-lactam, diazabicyclooctane (DBO) beta-lactamase • Avibactamisa potentinhibitor of many beta-lactamases, protectingceftazidime from hydrolysis by gram-negative organismsproducingAmblerclass A and C beta-lactamases and some Amblerclass D enzymes. • Avibactamcannoteffectivelyinhibit metallo-beta-lactamases (AmblerclassB enzymes) • CAZ/AVI haspotent in vitro activityagainst KPC-producingK.Pneumoniae • Resistancehasbeenreported in a limitednumber of KPC- producingclinicalisolates with multiple resistancefactorsincluding multiple carbapenemases, overexpression of effluxpumps and reducedporinexpression. • The MIC of CAZ/AVI against KPC-3 wassignificantlyhigherthanagainst KPC-2 variants. The mechanisticbasis for thismay be more likelyresistance to ceftazidimethanresistance to avibactaminactivation.

22. Ceftazidime-avibactam MIC

23. Ceftazidime/avibactam • Overallsusceptibility of P. aeruginosato ceftazidime/avibactamisimproved relative to ceftazidime alone. • The observedreductions in MIC90 are more modestthanthoseobservedwith Enterobacteriaceae, with reportedsusceptibilitiesshowingsignificantinstitutionaland geographicalvariation. • Data examiningP. aeruginosaisolatesthat are ceftazidime and carbapenemnon-susceptibleshowedvaryingactivity to ceftazidime/avibactam, with resistanceapproaching 50% in some studies. • Ceftazidime/avibactamislessactiveagainstAcinetobacterspp.

24. Ceftazidime – Avibactam • Spectrum of activity: Gram-negatives, including MDR P. aeruginosa,ESBL-producing strains, KPC-Kp • EMA approval in June 2016 • Complicated Urinary Tract Infections, including Pyelonephritis • Complicated Intra-abdominal Infections (plus metronidazole) • Nosocomial pneumonia • Gram-negative infection with limited treatment option • IV dose: 2.5 g (2 g ceftazidime; 0.5 g avibactam) q8h (2-h infusion)

25. Ceftazidime/avibactam • The development of resistance to ceftazidime/avibactam (MIC ≥16 mg/L) was observed following relatively short courses of therapy. • Could the development of resistance be reduced by using a combination therapy approach ? • Is the reported early development of resistance a unique flaw of ceftazidime-avibactam or might it be seen with other new βL-βLIs combinations ? • How common will the mechanisms causing this phenotype be found in the clinic ? • Given much of the resistance reported has been seen in K. pneumoniae isolates, how commonly will this phenotype be seen 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 ?

26. Ceftazidime-avibactam Pros Cons β-lactam allergy Monotherapy potentially dangerous Combination with GM, ERT Empirical use ?? • Rapid bactericidal activity • Tissue distribution (lung) • Safety • Activity vs. ESBL and KPC • P. aeruginosa enhanced activity • Carbapenem-sparing strategy

27. Sinergismo CAZ/AVI + ErtapenemKPC-Kp

28. Sinergismo CAZ/AVI + carbapenemici/GMno sinergismo con colistinaKPC-Kp KPC-Kp

29. Sinergismo CAZ/AVI + carbapenemici/AG Ps.aeruginosa Ps. aeruginosa cazavi

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

31. Aztreonam/Avibactam • Aztreonam, the onlyclinicallyavailablemonobactam, is a beta-lactamantibioticnothydrolysed by metallo-beta-lactamases. • Aztreonamalone isreadilyhydrolysed by mostserine ESBLs and KPC carbapenemases. • The combination with avibactamthusimprovesthe activityagainst multi-drugresistantpathogensincludingstabilityagainst serine carbapenemases, metallo-beta-lactamases and some Class D beta-lactamases. • Aztreonam/avibactamhasshowedin vitro activityagainstESBL-, class C beta-lactamase-, metallo-beta-lactamase-, and KPC carbapenemase- producingstrainsof Enterobacteriaceae. • IsolatesproducingallobservedAmblerclasses of beta-lactamaseenzymeswereinhibited by aztreonam/avibactam, includingisolatesthatproduced IMP-, VIM-, and NDM-type metallo-beta lactamases in combination with multiple serine beta-lactamases.

32. Aztreonam/Avibactam • 2000 mg/375 mg o 600 mg /6 h • Attività in vitro (con Avibactam [4μg/mL]): -ESBL- E. coli, Klebsiella spp., Enterobacter spp., Proteus spp.: MIC 0,25 mg/L  ↓ x10 MIC atm -MBL- E. coli, Klebsiella spp., Enterobacter spp.: MIC 1 mg/L -AmpC- E. coli ed Enterobacter spp.: MIC 0,5-2 mg/L -KPC- e OXA- E. coli, Klebsiella spp., Enterobacter spp, Proteus spp.: MIC 1 mg/L -Providencia spp. • Non potenzia l’attività vs P. aeruginosa e A. baumannii Clinical Trial fase II per la tollerabilità in cIAI Falagas M.E. Expert Review 2016

33. Aztreonam/avibactam • Aztreonam-avibactamislesseffectivewhentestedagainststrains of P. aeruginosawith aztreonamMIC90 value 32 mg/L or 64 mg/L • The combinationdoesnot show significantactivity in vitro againstA. baumanniisolates. • A phase II clinical trial to determine the pharmacokinetics, safety, and tolerabilityof aztreonam/avibactam in the treatment of hospitalizedpatentswith cIAIiscurrentlybeingundertaken. • A numberofclinicalobservations have nowbeenpublishedevaluatingaztreonamcombinedwithceftazidime/avibactamshowingsuccessfuloutcomes in smallnumbersofpatientswithinfections due to NDM producingEnterobacteriaceae, carbapenemresistantPseudomonasaeruginosaand Stenotrophomonasmaltophilia. • Evaluation ofthe optimal time ofadministrationofaztreonam relative to theceftazidime/avibactam is lacking.

34. 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.

35. Meropenem/Vaborbactam • Vaborbactam is a novel cyclic boronic acid inhibitor of many class A, class C and some class D beta-lactamases. • This reversible inhibitor was designed to interact favorably with serine beta-lactamases, and KPC in particular. • 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

36. Cefiderocol • Cefiderocolis a novelsiderophorecephalosporinantibiotic with a catecholmoiety on the 3-position side chain. • The catechol side chainenablesferricironionbinding, and the resultingcomplex of cefiderocol and ironionsisactivelytransportedintobacteria via ferricirontransportersystems with subsequentdestruction of cellwallsynthesis. • 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 cefiderocolagainstcarbapenemasehydrolysis.

37. Cefiderocol • Cefiderocol was potent in vitro against Enterobacteriaceae including KPC-, NDM-, IMP-, VIM producing isolates. • The MIC values ranged from ≤0.125 to 4 μg/ml against all of the KPC producing strains. • Cefiderocol was found to be less active against some strains of E. coli which expressed NDM-1. • Cefiderocol showed potent in vitro activity against A. baumannii, P. aeruginosa and Stenotrophomonas maltophilia. • Activity include A. baumannii producing carbapenemases such as OXA-type beta-lactamases, and P. aeruginosa producing metallo-beta lactamases with MIC90 of 8 and 4, respectively.

38. Plazomicin • Plazomicinisan AG derivative of sisomicinthatinhibitsproteinsynthesisby binding to the ribosomal 30S subunit of bacteria. • Plazomicinhasbeensynthesized to be activeagainstmostbacteriacontainingAG-modifyingenzymes (AME). • Plazomicinhasbeenshown to be broadlyactiveagainstEnterobacteriaceae, includingcarbapenem-resistantisolates, and more potentwhencompared with amikacin, gentamicin and tobramycin. • Resistancehasbeennoted in MDR isolatesthat express 16S rRNAmethyltransferaseswhichmodify the ribosomalbinding site

39. Plazomicin • Plazomicin was active in vitro against MDR Enterobacteriaceae isolates producing a variety of carbapenemases and ESBLs, • Plazomicin exhibited MIC range and MIC90 values significantly lower than other aminoglycosides. • Against carbapenem-resistant K. Pneumoniae isolates, mainly ST258 clones, the plazomicin MIC was 0.125–1 μg/ml. • Higher MICs to plazomicin were observed in isolates that expressed a combination of specific AMEs. • Plazomicin was not potent against amikacin-, gentamicin-, and tobramycin-resistant, NDM-producing Enterobacteriaceae isolates with expression of 16S rRNA methylases and its MIC value ranged from 64 to ≥256 μg/ml,

40. Plazomicin • Plazomicinislessactiveagainst non-fermentative gram-negative bacteriacompared with Enterobacteriaceae. • Against MDR P. aeruginosaisolates, plazomicinMICsweresimilar to MICs for otheraminoglycosides. • Significantlyimprovedactivitywasseen in OXA producingA. baumanniiisolatescompared with otheraminoglycosides, with plazomicinMICs 16-32 fold lower.

41. Eravacycline • Eravacycline is a novel, synthetic fluorocycline tetracycline. that binds to the bacterial ribosome and inhibits the bacterial protein synthesis. • With a chemical structure similar to that of tigeycline, it evades many resistance mechanisms seen for other tetracyclines, with no loss of antibacterial activity in the presence of tetracycline ribosomal protection proteins and most tetracycline specific efflux pumps. • However elevated MICs were noted for eravacycline against isolates in the presence of a tet(A) efflux pump, and in a strain with overexpression of tet(X), a tetracycline inactivating monooxygenase. • Two chemical modifications at C – 7 and C-9 of the tetracycline core broaden the spectrum of activity of eravacycline, maintaining activity against multi drug resistant bacteria. • Eravacycline can be dosed orally and parenterally, with oral bioavailability estimated at 28% in phase I studies .

42. Eravacycline • Eravacycline has activity against Enterobacteriaceae including strains that exhibited carbapenem resistance associated with KPC-, OXA- and NDM- production. • The MIC50/90 of the drug was 0.25/0.5 μg/ml against E. coli isolates that were non-susceptible to third generation cephalosporins and fluoroquinolones. • There is often a correlation between tigecycline and eravacycline susceptibilities, but in one study eravacycline was shown to be 2- to 4-fold more active than tigecycline against carbapenem-resistant Enterobacteriaceae and A. baumannii isolates. • Eravacycline is not significantly active against Burkholderia spp. or P. aeruginosa.

43. Trial of new antibiotics in c-UTIs

44. Trial of new antibiotics in c-IAIs

45. Nuove opportunità antibiotiche anti-CP-CRE

46. New approach to MDR gram-neg. infections

47. New approach to MDR gram-neg. infections

48. Antimicrobialstewardship • AS, definedascoordinatedeffortsto improve the appropriate use of antibiotics, willhavean importantrole in sustaining the currenttrajectory of healthcare. • Appropriate use of antibioticsthroughAS aimsto decreaseselective pressure for multidrug-resistantorganismsin order to preserve the utility of currentlyavailableagents. • AS leads to improvedpatientoutcomes, increasedpatientsafety, and decreasedrisk of Clostridiumdifficile infection.

49. 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.

50. Chirurgia Medici di Medicina Generale; Pediatri Medicina Veterinaria Onco-ematologia Medicina interna Medicina intensiva Trapianti ATELIERS GISA Infettivologi Microbiologi Farmacologi Farmacisti ospedalieri Igienisti www.antimicrobialstewardship.net