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)

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

The GISA Decalogue

Batteriemie Toscana, 2015 Bollettino ARS Toscana

E. Coli ESBL, 2015

K. pneumoniae ESBL, 2015

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 Amp C β-lactamases carbapenemasi

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

Antibiotic choice depending on genotype ESBL AmpC KPC OXA NDM Carbapenems Ceftazidime-avibactam Ceftolozane-tazobactam Cefepime Colistin Tigecycline Aminoglycosides Piperacillin/tazobactam Active Activity depending on MICs and/or target concentrations Not active

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

Predictive scores for ESBL infections

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

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.

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)

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

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.

For neutropenic pts with: mild-moderate infections 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.

We found no statistically significant difference in mortality of adults with ESBL-PE BSI that were treated empirically with carbapenems compared with those that were treated with BL/BLIs. These data do not support the wide use of empiric carbapenems, and BL/BLIs seem to be effective for the managementof patients with likely ESBL-PE BSI, and especially ESBL-E coli BSI, while waiting for susceptibility results. However, the efficacy BL/BLIs may vary based on the specific pathogen, and the future studies should account for severity of illness, immune suppression, and include adequate number of patients with BSI due to ESBL pathogens other than E coli, and especially K pneumoniae.

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.

PTZ is less active in vitro when tested against a high inoculum of bacteria. The results from some animal data suggest a lower efficacy than for carbapenems against isolates producing TEM-type ESBLs and some anecdotal failures. The MICs of carbapenems (except ertapenem) are usually several dilutions below the breakpoints, while those of BLBLIs are frequently nearer the breakpoint. A specific analysis suggested that PTZ may be less effective in patients with severe non-urinary tract bacteremic infections caused by borderline-susceptible ESBL-producing E. coli. This study statistical power is still limited and cannot exclude a potential relevant difference between carbapenems and BLBLIs. Gutierrez-Gutierrez

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.

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.

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.

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.

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

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

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

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)

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

2. Ceftolozane/tazobactam nelle c-UTI: Terapia mirata se P.aeruginosa MDR 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

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.aeruginosa MDR: 3 g IV ogni 8 ore (off-label) Sepsi da P. aeruginosa MDR, anche paziente neutropenico (terapia mirata; terapia empirica se epidemiologia locale congrua, in associazione con AG) (off-label)

4. Ceftolozane/tazobactam e 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

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

6. costo

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

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.

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

Conclusioni 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 Conoscere ed utilizzare i nuovi antibiotici: un dovere per il clinico ed una opportunità per il paziente !! www.antimicrobialstewardship.net

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.