Decalogo: Tuscany's Proposal for ESBL Infections

1. Decalogo GISA e PTD: la proposta della Toscana per le infezioni da microrganismi produttori di ESBLs 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 • 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. The GISA Decalogue

4. Batteriemie Toscana, 2015 Bollettino ARS Toscana

5. E. Coli ESBL, 2015

6. K. pneumoniae ESBL, 2015

7. Spectrum of β-lactamases carbapenemasi

8. Spectrum of Beta-Lactamase Inhibitors

9. Antibioticchoicedepending on genotype

10. Risk factors for MDR gram-negative infections Bassetti et al. EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2016

11. Predictive scores for ESBL infections

12. Treatment for ESBL infections 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 The Sanford Guide 2017

13. Cefepime can be considered for nonsevere ESBL infections where the agent can achieve high concentrations to ensure PD targets (eg, UTIs with cefepime MICs ≤2 μg/mL). • We do not favor the use of cefepime for serious ESBL infections. • If cefepime is administered for nonsevere ESBLproducing infections with MICs of 4–8 μg/mL based on susceptibility criteria, we recommend administering 2 g every 8 hours, possibly as a continuous infusion.

14. βL-βLIs seems to be a reasonable options for low- to moderate-severity infections, those resulting from urinary or biliary sources, and infections with MICs <4 μg/mL. • For critically-ill pts, those with higher inoculum infections, and elevated MICs, it might be more appropriate to administer carbapenem therapy, at least initially. • If PTZ is administered to patients with invasive ESBL infections, we would recommend administering 4.5 g every 6 hours (or 4.5 g every 8 hours as extended infusion)

15. The Use of βL/βLIs for ESBL Infections: Defining the Right Patient Population Pranita D. Tamma, & Maria Virginia Villegas Caveat for βL/βLIs in invasive ESBL infections • in vitro observed inoculum effect • data from animal studies • co-expression of additional β-lactamases not effectively inhibited by β-lactamase inhibitors • concerns regarding inadequate PK/PD drug target attainment with standard β-lactam βL/βLI dosing regimens

17. The Use of βL/βLIs for ESBL Infections: Defining the Right Patient Population Pranita D. Tamma, & Maria Virginia Villegas • In the propensity-score matched empiric therapy group, 30-day mortality was 20% and 11% for the βL/βLI and carbapenem groups, respectively. • In the propensity-score matched definitive therapy group, 30-day mortality was 13% for the βL/βLI group and 7% for the carbapenem group, respectively. • The absolute differences in mortality reminds us that these cohorts were likely underpowered to identify differences in 30-day mortality, if such differences existed.

18. The Use of βL/βLIs for ESBL Infections: Defining the Right Patient Population Pranita D. Tamma, & Maria Virginia Villegas For neutropenic pts with: • mild-moderate infections • low inoculum infections • sources easily amenable to source control • Non K. pneumoniae ESBL βL/βLIs are a reasonable option for the treatment of ESBL bloodstream infections, when active in vitro and appropriately dosed.

20. Wefoundno statisticallysignificantdifferencein mortalityof adults with ESBL-PE BSI thatweretreatedempiricallywith carbapenemscompared with thosethatweretreatedwith BL/BLIs. • Thesedata do notsupport the wide use of empiriccarbapenems, and BL/BLIsseem to be effective for the managementofpatients with likely ESBL-PE BSI, and especially ESBL-E coli BSI, whilewaiting for susceptibilityresults. • However, the efficacyBL/BLIsmayvarybased on the specificpathogen, and the future studiesshould account for severity of illness, immune suppression, and include adequatenumber of patients with BSI due to ESBL pathogensotherthanE coli, and especiallyK pneumoniae.

21. Gutierrez-Gutierrez • Our results: strongly support the hypothesis that active BLBLIs are not inferior to carbapenems for the treatment of BSI due to ESBL-E in different clinical scenarios. • support previous data on BSI due to E. coli with a urinary and biliary tract source and suggest that BLBLIs if active in vitro, may be useful alternatives to carbapenems for the treatment of BSI due to any ESBL-E from any source, if used at appropriate doses. • Our data refer to susceptible isolates, which is relevant for targeted therapy; • It is also relevant for empirical decisions in which an evaluation of the patient’s individual risk for ESBL producers and the local epidemiology data on susceptibility are to be taken into account.

22. PTZ islessactivein vitro whentestedagainst a high inoculum of bacteria. • The resultsfrom some animal data suggesta lowerefficacythan for carbapenemsagainstisolatesproducing TEM-typeESBLsand some anecdotalfailures. • The MICs of carbapenems(exceptertapenem) are usuallyseveraldilutionsbelowthe breakpoints, whilethose of BLBLIs are frequentlynearer the breakpoint. • Aspecificanalysissuggestedthat PTZ may be lesseffectivein patientswith severe non-urinarytractbacteremicinfectionscausedby borderline-susceptible ESBL-producing E. coli. • Thisstudystatisticalpowerisstilllimitedand cannotexcludea potentialrelevantdifferencebetweencarbapenemsand BLBLIs. Gutierrez-Gutierrez

25. 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 mortality. OADs were neither associated with 14-day clinical failure nor 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.

27. 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.

28. 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.

29. 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.

32. Raccomandazioni GISA (versione preliminare) B. Viaggi, F.Menichetti Ceftolozane/tazobactam

33. Ceftolozane/Tazobactam Il farmaco è registrato per le seguenti indicazioni: • Infezioni intra-addominali complicate (c-IAI), in associazione al metronidazolo • Infezioni complicate delle vie urinarie (c-UTI) • Somministrazione IV alla dose di 1,5 g ogni 8 ore • Il farmaco è prescrivibile soltanto dallo specialista infettivologo o da clinico designato dal CIO, e viene fornito dalla Farmacia previa compilazione della scheda AIFA

34. Obiettivi delle raccomandazioni • Identificare i pazienti elegibili nell’ambito delle c-IAI • Identificare i pazienti elegibili nell’ambito delle c-UTI • Identificare altre potenziali indicazioni • Ottenere informazioni dal laboratorio di microbiologia • Gestire la scheda AIFA • Considerare il costo del farmaco

35. Ceftolozane/Tazobactam nelle c-IAI Infezioni intra-addominali complicate, extra-biliari, acquisite in comunità, in pazienti con shock settico, o anziani fragili, o fattori di rischio per MDR (utilizzo empirico, in associazione al MNZ) Infezioni intra-addominali complicate, correlate all’assistenza, in alternativa ai carbapenemici o Pip/tazo, se epidemiologia locale indica E-ESBL > 40% e P. aeruginosa MDR > 20% (utilizzo empirico, in associazione al MNZ)

36. Ceftolozane/Tazobactam nelle c-IAI • Infezioni intra-addominali complicate, biliari, nelle forme CA se età avanzata, paziente fragile, sepsi grave; e nelle forme nosocomiali, in alternativa a carbapenemici o Pip/tazo (utilizzo empirico, in associazione al MNZ) • Utilizzo mirato, previa documentazione microbiologica, in alternativa ai carbapenemici • NEC (enterocolite neutropenica) terapia empirica, in associazione

37. 2. Ceftolozane/tazobactam nelle c-UTI: Terapia mirata se P.aeruginosaMDR e sensibile al C/T, (no MBL) Terapia empirica nel paziente con sepsi severa /shock settico in alternativa a carbapenemici o Pip/tazo (no colonizzazione KPC) Terapia empirica nel paziente con sepsi severa/shock settico colonizzato da E-ESBL, in alternativa a carbapenemici

38. 3. Altre Potenziali indicazioni Terapia mirata per infezioni gravi da E-ESBL produttori, in alternativa ai carbapenemici (off-label) Terapia mirata delle VAP da P.aeruginosaMDR: 3 g IV ogni 8 ore (off-label) Sepsi da P. aeruginosaMDR, anche paziente neutropenico (terapia mirata; terapia empirica se epidemiologia locale congrua, in associazione con AG) (off-label)

39. 4. Ceftolozane/tazobactame laboratorio di microbiologia E-test “unreliable”, per falsi positivi Sistemi automatizzati ancora non aggiornati Brodo-diluizione in agar: test di riferimento Test molecolari necessari x escludere MBL

40. 5. GESTIONE Scheda aifa Definire raccomandazioni terapeutiche condivise da altri specialisti (ad es. ICU, onco-ematologi) che siano “regola” per l’Azienda e per la Farmacia ospedaliera Consentire l’utilizzo iniziale per 48-72 ore secondo raccomandazioni, poi rivalutare il caso su base clinica e microbiologica Favorire l’adozione di un sistema di “alert” microbiologico che includa isolamenti di P. aeruginosa da sangue, urine e BAL Definire un protoocollo diagnostico con il laboratorio di microbiologia

41. 6. costo

42. Ceftolozane/tazobactam Pro Cons Beta lactam allergy E-TEST unreliable No MBL/KPC activity Combination needed (AG) ? Data on pneumonia pending AIFA form Use in empiric antibiotic regimen • Bactericidal activity • Tissue distribution – Lung • Safety • High activity against ESBLs & P.aeruginosa • Carbapenem-sparing-regimen

43. Although evidence thus far suggests a potential role for these new cephalosporin/β-lactamase inhibitor antibiotics against ESBL-producing organisms, clinical data remain limited. • Additionally, the significant expense of utilizing these new cephalosporin/β-lactamase inhibitor agents is a limiting factor when alternative, less costly options are available.

44. 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

45. Conclusioni Conoscere ed utilizzare i nuovi antibiotici: un dovere per il clinico ed una opportunità per il paziente !! • AMR: "a call for action” • Un impegno a più livelli • Forte sostegno politico (advocacy) • Chiaro impegno istituzionale (piani e risorse) • Governo clinico, equo e multidisciplinare • Programma di stewardship antimicrobica in ospedale e nel territorio • Sinergismo tra società scientifica e realtà politico/istituzionali www.antimicrobialstewardship.net

46. 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.