Tommaso Giani, PhD e-mail: [email protected] Tel. +390577233855 P0723 Acvity of ceobiprole and comparators against hospital-acquired pneumonia pathogens from Italy, January-May 2016

Tommaso Giani1, Alberto Antonelli2, Marco Coppi2, Olga Lorenza Colavecchio2, Viola Conte1, Anne Santerre Henriksen4, Gian Maria Rossolini2, 3

1 Department of Medical Biotechnologies, University of Siena, Siena, Italy; 2 Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 3 Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy; 4 Basilea Pharmaceuca Int. Ltd, Basel, Switzerland

Introducon and purpose Results Table 1. Percentage of suscepble (S) isolates to ceobiprole and comparators DI among the most frequently isolated Gram- negaves isolated from HAP in Italy. • Hospital-acquired pneumonia (HAP) and community-acquired pneumonia (CAP) are among the most common • A total of 313 isolates of Gram-negave and Gram-posive isolates were collected CBP FEP CAZ PTZ MEM ERT CIP COL TIG GEN infecons treated in the hospital seng 1 • Of all the isolates, the most common species were P. aeruginosa (n=106, 34%), Klebsiella pneumoniae (n=63, 20%), S. K. pneumoniae (n=63) % S 35 38 36 40 62 57 38 78 79 63 • Successful outcomes of such infecons depend on rapid and adequate empirical anbioc therapy that could be aureus (n=42, 13%) and Escherichia coli (n=26, 8%) E. coli (n=26) % S 58 58 61 77 96 96 46 100 100 77

challenging especially in sengs, such as Italy, characterized by a high proporon of mul-drug resistant isolates • Overall 65 MRSA strains were collected from 12/13 centers • Ceobiprole is a 5th-generaon cephalosporin with an expanded-spectrum and potent acvity against Gram-posive 100 • Considering the most frequently isolated Enterobacteriaceae, ceobiprole showed an acvity similar to ceazidime and

and -negave bacteria. It is approved for markeng in various European and non-European countries for the cefepime, being acve against 35% and 58% of K. pneumoniae and E. coli, respecvely (Table 1) 80 treatment of HAP (excluding venlator-associated pneumonia) and CAP in adults 2 • MIC50 and MIC90 values of ceobiprole for P. aeruginosa were 8 mg/L and >16 mg/L, respecvely. Cumulave MIC • Ceobiprole has in vitro acvity against methicillin-resistant Staphylococcus aureus (MRSA) and other common distribuon indicated that ceobiprole showed a similar trend to ceazidime (Figure 2) 60 PTZ pathogens in pneumonia, e.g. Enterobacteriaceae not expressing extended spectrum β-lactamases (ESBLs) or • All methicillin-suscepble S. aureus (MSSA) isolates were suscepble to ceobiprole (Table 2A) CAZ carbapenemase and non-carbapenemase producing Pseudomonas aeruginosa 3 40 P.aeruginosa • All MRSA isolates were suscepble to vancomycin, teicoplanin and linezolid; ceobiprole had acvity against 95.3% of these inhibited CBP • The objecve of this study was to invesgate the in vitro acvity of ceobiprole and comparators against a collecon MEM isolates (Table 2B) 20 of clinical isolates putavely responsible for HAP, representave of the contemporary Italian epidemiology of %

0 2 Figure 1. Geographical Methods distribuon of parcipang 0.5 1 2 4 8 16 >16 4 centres. Centers were as follow: MIC (mg/L) 1 Bacterial strains 1. Lecco; 2. Bolzano;3 Arezzo; 4. Figure 2. Cumulave MIC distribuon for P. aeruginosa isolates against an-pseudomonas β-lactams 13 • 13 different centers were involved in the study (locaon of the satellite centers is reported in Figure 1). During the Udine; 5. Florence; 6. Perugia; 7. 10 Ancona; 8. Rome; 9. Foggia;10. study period (January 1 – May 31, 2016), all satellite centers were asked to collect up to 25 consecuve, non- Torino;11. Cesena; 12. Catania; 13. Milan. Table 2. Suscepbility profiles and MIC50 and MIC90 of all MSSA (A) and MRSA (B) isolates against ceobiprole and comparators. MIC values are in mg/L. replicate clinical isolates, of all species, putavely responsible of HAP. During the same period, the collecng centers 11 A B also collected all MRSA isolates from HAP 5 7 TOT=42 CBP CLI ERY LEV LNZ OX TEC TGC SXT VA TOT=65 CBP CLI ERY LEV LNZ TEC TGC SXT VA • All isolates were sent to the reference laboratory for confirmaon of species idenficaon and minimum inhibitory 3 6 concentraon (MIC) tesng of ceobiprole and comparator molecules MIC50 0.25 0.12 0,5 0.25 2 0.5 0.5 0.25 ≤0.06 1 MIC50 1 0.12 >1 16 2 0,5 0.25 ≤0.06 1 Isolate idenficaon and anmicrobial suscepbility tesng 8 MIC90 0.5 0.12 >1 0.5 4 1 1 0.25 0.25 1 MIC90 2 >1 >1 >16 4 1 0.5 0.12 1 • Idenficaon of all collected isolates was performed using the MALDI-TOF Vitek-MS system (bioMérieux, Marcy 9 L’Etoile, France). To test the acvity of ceobiprole and comparators all collected isolates were subjected to MIC %S 100 95.2 71.4 95.2 100 92.8 100 100 100 100 %S 95.3 86.1 16.2 13.8 100 100 100 98.5 100 tesng by reference broth microdiluon procedure using custom plates (Thermo Fisher Scienfic) 4 • MIC results were interpreted as suscepble, intermediate and resistant according to EUCAST breakpoints according CBP: ceobiprole; CLI: clindamycin; ERY: erythromycin; LEV: levofloxacin; OX: oxacillin; TEC: teicoplanin; TGC: gecycline; SXT: trimethoprim/sulphametoxazole; VA: vancomicin; FEP: cefepime; CAZ: ceazidime; PTZ: piperacillin-tazobactam; MEM: meropenem; ERT: ertapenem; CIP: ciprofloxacin; COL: colisn; GEN: gentamicin (hp://www.eucast.org/clinical_breakpoints). The MRSA phenotype was confirmed by cefoxin broth microdiluon and, in case of discrepancy between central-laboratory and collecng-center results, a cefoxin screen test using Conclusions disk-diffusion, following EUCAST rules, was performed • Ceobiprole showed a broad spectrum of acvity against a collecon of contemporary Gram-negave and Gram-posive HAP clinical isolates 12 from Italy References • A high prevalence of both ESBL- and carbapenemase-producing Enterobacteriaceae was observed, affecng suscepbility against all 1 Torres A, et al. Treatment guidelines and outcomes of hospital-acquired and venlator-associated pneumonia. Clin. Infect. Dis. 2010 2 Scheeren TW. Ceobiprole medocaril in the treatment of hospital-acquired pneumonia. Futur Microbiol. 2015 anbiocs tested 3 Farrel, DJ, et al. Ceobiprole acvity against over 60,000 clinical bacterial pathogens isolated in Europe, Turkey, and Israel from 2005 to 2010. Anmicrob. Agents Chemother. 2014 Acknowledgements • This study confirmed that ceobiprole could be a valid therapeuc opon in case of HAP caused by MRSA. The MRSA included in this study 4 Clinical Laboratory Standards Instute. Methods for diluon anmicrobial suscepbility. Tests for bacteria that grow aerobically; Approved Funding for this researh was provided by Basilea Pharmaceuca Internaonal Ltd, Basel, will be subjected to Whole Genome Sequencing in order to assess their clonality, resistome and genec background of mecA gene standards. 10th ed. CLSI document M07-A10. Wayne, PA: CLSI; 2015 Switzerland. ASH is an employee of Basilea.