New insights in antibiotic and antifungal therapy in the compromised host

New insights in antibiotic and antifungal therapy in the compromised host Claudio Viscoli University of Genova Ospedale Policlinico San Martino, Genova

Potential conflicts of interest (last 5 years) Received payments as speaker/moderator in national or international meetings sponsored by Pfizer, Gilead, MSD, Astellas, Basilea, Angelini, Novartis Received payments for DRC in a registration study by Astellas Received grants for participation in national or international advisory boards by Gilead, Astellas, MSD, Pfizer, Basilea, Nordic, Novartis Obtained research grants for my institution from Pfizer, MSD, Gilead Expert in EMA-SAG on antibiotics/antifungals Member of several local boards (Genoa, Liguria, Italy) on Infection Control and Antibiotic Stewardship, HIV, Hospital Formulary

Un approccio pratico Un bacillo Gram-negativo per quanto riguarda le beta-lattamine attualmente a nostra disposizione può essere : Sensibile a tutte (cefalosporine III generazione, penicilline protette e carbapenemi) Sensibile ai carbapenemi e, di solito, anche al ceftolozanotazobactam e ceftazidime-avibactam, dubbia la possibilità di trattare con pip-tazo (sede, MIC, dose massima) e resistente alle cefalosporine di III generazione (è il cosiddetto ESBLproduttore) Resistente a tutte (attraverso vari meccanismi, di cui il più comune dei quali è la produzione di carbapenemasi)

Activity of β-lactams and β-lactam/β-lactamase inhibitors by type of β-lactamase Enterobacteriaceae Drug ESBL AmpC KPC MBL Oxa-48 Pseudomonas MDR Acinetobacter MDR Piperacillin-Tazobactam -/+ -/+ - - - - - Ceftazidime - - - - + - - Meropenem ++ ++ - - - - - Ceftazidime-Avibactam ++ ++ ++ - + + - Ceftolozane-Tazobactam + - - - - ++ - Aztreonam-Avibactam ++ ++ ++ ++ + + - Imipenem-relebactam ++ ++ ++ -? + - Meropenemvaborbactam ++ ++ ++ -? + - Cefepime-zidebactam ++ ++ ++ ++ ++ ++ - Cefiderocol (siderophore β-lactam) ++ ++ ++ ++ ++ ++ +

How do we treat infections by ESBLproducer Gram-negative rods? It depends on the site of infection and consequently on the expected drug concentrations First choice is a carbapenem Ceftolozane-tazobactam and ceftazidime-avibactam are also active What about piperacillin-tazobactam?

Piperacillin-tazo in ESBL producers Confusion in breakpoints Conflicting data in observational studies Activity and efficacy may depend on punctual MIC, dose and site of infection At last ECCMID in Madrid results of the only randomized study were presented

«MERINOS» study Pip-tazo (4.5 q6) vs meropenem (1 q8) in BSI due to ESBL K. Pneumoniae or E.coli that are S to pip-tazo by local laboratories Hypothesis: pip-tazo is non-inferior (5%) Primary outcome: 30 day mortality Results Pip-tazo 12.3% (23/187) Meropenem 3.7% (7/191) 95% CI 3.4-14.5 P. Harris et al, ECCMID 2018; abstract 01121

Ceftolozane Tazobactam New cephalosporin plus old β-lactamase inhibitor Active on ESBL-producing Gram-neg rods Pseudomonas aeruginosa Not active on anaerobes, KPC-Kp, metallo-β-lactamases (NDM, VIM) Approved for Complicated Urinary Tract Infections, including Pyelonephritis Complicated Intra-abdominal Infections (plus metronidazole) Dosage 1.5 g (1 g ceftolozane; 0.5 g tazobactam) q8h (1-h infusion) Ongoing Clinical trials in VAP with double dose Few data on ESBL specifically and on MDR Pseudomonas

Ceftazidime Avibactam Old cephalosporin plus new, broader-spectrum beta-lactamase inhibitor Active on - ESBL-producing Gram-neg rods, KPC-Kp, MDR Pseudomonas aeruginosa Not active on - Anaerobes, metalloβ-lactamases producers Approved for - Complicated Urinary Tract Infections, including Pyelonephritis - Complicated Intra-Abdominal Infections (plus metronidazole) - Hospital-Acquired Pneumonia - Infections by Gram-neg rods for which there are limited treatment options Dosage - 2.5 g (2 g ceftazidime; 0.5 g avibactam) q8h (2-h infusion)

Carbapenemases Amber class Produced by Resistance pattern Class A Klebsiella pneumoniae carbapenemase (KPC-Kp) K. Pneumoniae and other Enterobacteriaceae Occasionally other Gramneg. pathogens, including P. aeruginosa R carbapenems, ceftazidime, cefepime, pip-tazo, Cefto-tazo S cafta-avi Class B or metallo-βlactamase (MBL) New Delhi (NDM) Verona Integron-encoded (VIM) Imipenemase (IMP) Class D carbapenemhydrolizing β-lactamases OXA 23, 24, 40, 58 Class D carbapenemhydrolizing β-lactamases OXA 48 Acinetobacter Enterobacteriaceae Pseudomonas R all β-lactams Acinetobacter R carbapenems, but may be S to ceftazidime, cefepime Enterobacteriaceae R carbapenems (less than KPC-Kp), but maybe S to ceftazidime, cefepime

Bonomo RA et al, CID 2017 ahead of printing

How do we treat KPC-Kp?

Mortality in BSI KPC-Kp by treatment Tumbarello M, et al, JAC 2015

Mortality in BSI KPC-Kp by susceptibility to colistin and meropenem Tumbarello M, et al, JAC 2015

Tumbarello M, et al, JAC 2015

Things are changing New drugs arriving for KPC-Kp

Ceftazidime Avibactam Old cephalosporin plus new, broader-spectrum beta-lactamase inhibitor Active on - ESBL-producing Gram-neg rods, KPC-Kp, MDR Pseudomonas aeruginosa Not active on - Anaerobes, metalloβ-lactamases producers Approved for Only EMA - Complicated Urinary Tract Infections, including Pyelonephritis - Complicated Intra-Abdominal Infections (plus metronidazole) - Hospital-Acquired Pneumonia - Infections by Gram-neg rods for which there are limited treatment options Dosage - 2.5 g (2 g ceftazidime; 0.5 g avibactam) q8h (2-h infusion)

CID, 2016 37 CRE infections; used in monotherapy Clinical success 59% 30 days survival 76% Recurrence among success 23% Microbiological failure 27% (30% due to acquired resistance)

Ceftazidime/avibactam in carbapenem- resistant infections 38 CRE infections;66% in combination 73.7% experienced clinical and/or microbiological cure No data on recurrence Temkin E et al. Antimicrob Agents Chemother. 2017 Jan 24;61(2): pii: e01964-16.

Meropenem-vaborbactam FDA approval Tango I

TANGO II: focus on CRE Meropenem-vaborbactam (M-V) vs Best Available Therapy (BAT) BAT was combo with polymyxins, carbapenems, aminoglycosides, tigecycline; or monotherapy with ceftazidime-avibactam) for CRE Eligibility: Not treated yet Treated but failing Randomized 2:1 Hypothesis: no formal hypothesis Primary outcome: 30 day mortality and clinical success (TOC) 40

TANGO II: results 77 patients randomized (52 M-V and 25 BAT) 47 micro confirmed CRE (32 M-V and 15 BAT) In the mcre-mitt population EOT M-V 65.6% (31/32) BAT 33.3 (5/15) TOC M-V 59.4% (19/32) BAT 26.7% (4/15)33.3 (5/15) +32.3%; 95% CI, 3.3% to 61.3% P=.03 +32.7%; 95% CI, 4.6 % to 60.8% P=.02 M/V much better tolerated that BAT Stopped early for superior benefit/risk

Antibiotics developed by The Medicine Company now acquired by Melinta

What about fungi? Only 2 points Role of PET-CT in mold infections Candida auris

Altini C, et al

Candida auris

Resistance patterns Fluconazole Easily misidentified 100% as C. haemulonii, Other triazoles C. famata, C. sake, 3-73% Saccharomyces Amphotericin cerevisiae B and others 13-35% Almost all susceptible to echinocandins About 40% resistant to 2 drugs Few of them R to all families

Why a worrisome phenomenon Potential to cause outbreaks High mortality, apparently higher than other Candida strains Resistance profile Apparent interhuman transmission Spreading patter similar to MDR bacteria Biofilm formation and ability to survive on inhanimated surfaces Need for screening and isolation Lamoth and Kontoyiannis, JID 2017,

Grazie per l attenzione

Giannella et al. Clin Microbiol Infect 2014