Ceftaroline in the Treatment of Complicated Skin and Soft Tissue Infections: in Vitro Joseph P

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EV0128 Contact information: Ceftaroline in the treatment of complicated skin and soft tissue infections: in vitro Joseph P. Iaconis, Ph.D. AstraZeneca Infection iMed susceptibility of baseline pathogens isolated in a phase III randomised clinical trial 35 Gatehouse Drive Waltham, MA, USA Email: [email protected] Edina Reiszner1, Jane Ambler2, Joseph P. Iaconis1 1AstraZeneca LP, Waltham, MA, USA; 2Formerly AstraZeneca LP, Waltham, MA, USA

• Enrolled patients were randomised 2:1 to receive ceftaroline fosamil 600 mg q8h • MIC distributions indicated that ceftaroline demonstrated good in vitro activity against breakpoints of ≤1 mg/L for ceftaroline fosamil 600 mg every 12 h [q12h]). Abstract or vancomycin (weight-based dosing) plus aztreonam 1 g q8h for 5–14 days, key Gram-positive and Gram-negative pathogens obtained at baseline (Table 2). No patients were enrolled that had infections with S. aureus with ceftaroline with the primary endpoint of clinical cure assessed at a test-of-cure visit 8–15 – The MIC distribution of ceftaroline against S. aureus (Figure 1) for isolates MICs >1 mg/L. days after the last dose of study drug treatment in the modified intention-to-treat Objectives: To evaluate the in vitro activity of ceftaroline (CPT), the active obtained in the COVERS trial trended one dilution lower compared with that – Among non-ESBL producing Enterobacteriaceae, 89.3% were susceptible to (MITT) and clinically evaluable populations. metabolite of the pro-drug ceftaroline fosamil (CPT-F) and comparators of global surveillance conducted in 2012–2013 (modal MICs were 0.25 and ceftaroline. (vancomycin [VA] and aztreonam [AZT]) against baseline pathogens from For all enrolled patients, appropriate cSSTI site specimens and blood samples • 0.5 mg/L respectively). – 81.7% (58/71) of all isolated Enterobacteriaceae had ceftaroline MICs at patients (≥18 years) enrolled in COVERS (CeftarOline versus Vancomycin and were obtained at baseline for culture, Gram-stain and susceptibility testing. – All S. aureus (including MRSA) isolates obtained in COVERS tested with or below the EUCAST and CLSI susceptibility breakpoint of ≤0.5 mg/L for aztrEonam tReating complicated Skin and soft tissue infection [cSSTI]), a Patients with ≥1 bacterial pathogen isolated from either a relevant cSSTI site ceftaroline MICs of ≤1 mg/L (susceptible using both CLSI and EUCAST ceftaroline fosamil 600 mg q12h. Phase III, multicentre, randomised, double-blind, comparative trial in Europe, and/or baseline blood sample, and who met protocol-defined minimum disease North America, Asia, and Latin America (NCT01499277). criteria, were included in the microbiological MITT (mMITT) population. Methods: Baseline specimens were collected from cSSTI patients with • All bacterial pathogens were identified by local laboratories to the genus and Table 2. Ceftaroline MIC distributions of key baseline pathogens isolated from site of skin infection or blood (mMITT population) evidence of systemic inflammatory response or underlying co-morbidities species level using confirmatory identification methods. A central laboratory randomised 2:1 to CPT-F (600 mg q8h) or VA (weight-based dosing regimen) (Covance Central Laboratory Services, IN, USA) confirmed pathogen Number (cumulative %) of pathogens at MIC, mg/L and AZT(1000 mg q8h) for 5–14 days. Isolates were shipped to a central identifications and susceptibility test results. Susceptibility testing was performed ≤ ≥ laboratory (CCLS, USA); bacterial identification, susceptibility testing, including in accordance with CLSI methodology. N 0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 extended-spectrum β-lactamase (ESBL) phenotypic screen and confirmatory S. aureus 217 0 0 0 2 (0.9) 41 (19.8) 121 (75.6) 48 (97.7) 5 (100.0) 0 0 0 0 0 tests were performed using broth microdilution method (CLSI M100-S21). • The presence of extended-spectrum β-lactamase (ESBL) among Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis isolates MSSA 163 0 0 0 2 (1.2) 41 (26.4) 115 (96.9) 5 (100.0) 0 0 0 0 0 0 Results: A total of 524 baseline isolates cultured from 384 patients (mMITT was determined by CLSI phenotype MIC broth microdilution test and/or the CLSI MRSA 54 0 0 0 0 0 6 (11.1) 43 (90.7) 5 (100.0) 0 0 0 0 0 population: 248 CPT-F- and 136 VA/AZT-treated patients) diagnosed with ESBL confirmatory MIC broth microdilution test. Streptococcus pyogenes 25 25 (100.0) 0 0 0 0 0 0 0 0 0 0 0 0 the following cSSTIs: 141 (36.7%) cellulitis; 72 (18.8%) traumatic or surgical wound infection; 124 (32.3%) major cutaneous abscess; 45 (11.7%) burns; and S. agalactiae 16 3 (18.8) 13 (100.0) 0 0 0 0 0 0 0 0 0 0 0 2 (0.5%) unidentified source were tested. The predominant pathogens across Results S. dysgalactiae 12 9 (75.0) 2 (91.7) 0 1 (100.0) 0 0 0 0 0 0 0 0 0 both treatment arms were Staphylococcus aureus (165 methicillin-susceptible The MITT population comprised 761 patients, from whom 524 bacterial isolates Enterobacteriaceae 71 0 1 (1.4) 11 (16.9) 19 (43.7) 15 (64.8) 10 (78.9) 2 (81.7) 2 (84.5) 2 (87.3) 0 1 (88.7) 4 (94.4) 4 (100.0) [MSSA] and 54 methicillin-resistant [MRSA]), followed by β-haemolytic • were cultured from 384 patients in the mMITT population (ceftaroline fosamil, E. coli 30 0 1 (3.3) 5 (20.0) 7 (43.3) 4 (56.7) 4 (70.0) 2 (76.7) 1 (80.0) 1 (83.3) 0 1 (86.7) 3 (96.7) 1 (100.0) streptococci (25 S. pyogenes, 16 S. agalactiae, 12 S. dysgalactiae), and n=248; vancomycin plus aztreonam, n=136). ESBL-positive 4 0 0 0 0 0 0 0 0 0 0 0 3 (75.0) 1 (100.0) Streptococcus anginosus group. Enterobacteriaceae (namely Escherichia coli, Klebsiella pneumoniae [KP] and Proteus mirabilis [PM]) were cultured • The incidence of baseline pathogens was generally balanced across the ESBL-negative 26 0 1 (3.8) 5 (23.1) 7 (50.0) 4 (65.4) 4 (80.8) 2 (88.5) 1 (92.3) 1 (96.2) 0 1 (100.0) 0 0 less frequently. CPT has no activity against ESBL-producing strains. Minimum treatment groups (Table 1): Klebsiella pneumoniae 12 0 0 0 4 (33.3) 1 (41.7) 2 (58.3) 0 0 1 (66.7) 0 0 1 (75.0) 3 (100.0) inhibitory concentration (MIC) summary data and percent susceptibility (%S) – The majority of pathogens were isolated from cellulitis and major cutaneous ESBL-positive 3 0 0 0 0 0 0 0 0 0 0 0 1 (33.3) 2 (100.0) for study drugs against baseline pathogens are reported in the table. abscess specimens, and most were Gram-positive monomicrobial infections. ESBL-negative 8 0 0 0 4 (50.0) 1 (62.5) 5 (87.5) 0 0 1 (100.0) 0 0 0 0 Infections were predominantly community-acquired (94.1%). Pathogen CPT (mg/L) VA (mg/L) AZT (mg/L) ESBL-indeterminate 1 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0) – S. aureus was the most frequently isolated pathogen (55.6% ceftaroline MIC MIC MIC MIC MIC MIC K. oxytoca 8 0 0 1 (12.5) 4 (62.5) 2 (87.5) 1 (100.0) 0 0 0 0 0 0 0 90 90 90 fosamil; 58.8% vancomycin plus aztreonam). The incidences of MSSA and ESBL-negative 8 0 0 1 (12.5) 4 (62.5) 2 (87.5) 1 (100.0) 0 0 0 0 0 0 0 n /%S range n /%S range /%S range MRSA were 43.1% and 12.5% respectively in the ceftaroline fosamil group, S. aureus 137 0.5/100 0.06–1 80 1/100 ≤0.25–1 NT NT and 43.4% and 16.2% in the vancomycin plus aztreonam group. Other Gram- Proteus mirabilis 11 0 0 4 (36.4) 4 (72.7) 2 (90.9) 0 0 0 0 0 0 0 1 (100.0) positive aerobes isolated in ≥1% of total patients included: Streptococcus ESBL-negative 10 0 0 4 (40.0) 4 (80.0) 2 (100.0) 0 0 0 0 0 0 0 0 β-haemolytic 0.015/ ≤0.008– 0.015/ ≤0.008– 36 17 NT NT streptococci 100 0.015 100 0.06 anginosus group (7.3%), S. pyogenes (6.5%), Enterococcus faecalis (4.9%), ESBL-indeterminate 1 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0) S. agalactiae (4.2%), S. dysgalactiae (3.1%), Streptococcus mitis group (1.6%), S. anginosus ≤0.008– ND/ Morganella morganii 7 0 0 2 (28.6) 3 (71.4) 2 (100.0) 0 0 0 0 0 0 0 0 21 0.03/100 3 0.5 NT NT Actinomyces (1.0%), and Enterococcus faecium (1.0%). group 0.03 100 Enterobacter cloacae 12 0 0 0 2 (16.7) 5 (58.3) 3 (83.3) 1 (91.7) 1 (100.0) 0 0 0 0 0 E. coli ESBL- ≤0.03– – Enterobacteriaceae (most commonly E. coli) were identified in 21.6% of For isolates where n≥10, light shading indicates MIC ; dark shading indicates MIC ; green shading indicates MIC /MIC 15 2/86.7 0.015–8 11 NT NT 0.12/100 50 90 50 90 negative 0.25 primary infection site or blood specimens. Monomicrobial infections caused by Enterobacteriaceae constituted <7% of all infections. KP ESBL- ND/ ≤0.03– 5 ND/80 0.06–2 3 NT NT negative 100 0.06 PM ESBL- ND/ 8 ND/100 0.03–0.12 2 NT NT ≤0.03 Table 1. Baseline infection composition (mMITT population) Figure 1. Ceftaroline MIC distribution for S. aureus isolates (MSSA and negative 100 MRSA) obtained in the Phase III COVERS clinical trial and from SSTI Conclusions N = total number of patients per treatment group, n= number of isolates Number (%) of patients specimens in the 2012–2013 AWARE surveillance program 3,5,6 ND = Not determined (<10 isolates) Ceftaroline fosamil Vancomycin plus • Consistent with previous multinational studies in patients with cSSTI, the NT= Not tested (N=248) aztreonam COVERS clinical trial isolates most frequently isolated pathogens in COVERS were S. aureus followed by Conclusion: The predominant pathogens in this study were S. aureus followed (N=136) 80 Asia (n=21) β-haemolytic and S. anginosus group streptococci. by β-haemolytic and S. anginosus group streptococci. CPT demonstrated Monomicrobial European Union (n=66) Latin America (n=7) 100% of these Gram-positive pathogens were susceptible to ceftaroline. 100% susceptibility against these Gram-positive pathogens (MSSA, MIC90 Gram-positive 144 (58.1) 79 (58.1) North America (n=49) • 60 Other European countries (n=68) Ceftaroline also demonstrated good in vitro activity against non-ESBL 0.25 mg/L and MRSA MIC90 1 mg/L, not shown). Against non-ESBL producing MRSA 25 (10.1) 16 (11.8) Enterobacteriaceae, 89.3% were CPT-susceptible. CPT has good in vitro Rest of the world (n=6) producing Enterobacteriaceae. Gram-negative 27 (10.9) 20 (14.7) activity against common cSSTI pathogens. Polymicrobial 40 • S. aureus MIC distributions from the 2012–2013 global surveillance trended one

Gram-positive 22 (8.9) 10 (7.4) Isolates, % dilution higher than those from COVERS, and MRSA isolates with ceftaroline MICs ≥2 mg/L were not obtained in COVERS, but were seen in the Asian, with MRSA 3 (1.2) 4 (2.9) 20 Background with anaerobe 4 (1.6) 1 (0.7) European and Latin American surveillance. However, population pharmacokinetic Gram-negative 8 (3.2) 5 (3.7) modelling and PTA analyses support a breakpoint for S. aureus of ≤2 mg/L for • Complicated skin and soft tissue infections (cSSTI) are a substantial cause of 0 ceftaroline fosamil 600 mg q12h, and ≤4 mg/L for 600 mg q8h.7 1,2 with anaerobe 1 (0.4) 0 morbidity and antimicrobial usage worldwide. Pathogens frequently associated ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 Mixed Gram-positive and Gram-negative 47 (19.0) 22 (16.2) with cSSTI include Gram-positive bacteria, in particular Staphylococcus MIC, mg/L • These data indicate that ceftaroline fosamil 600 mg q12h has a spectrum aureus including methicillin-resistant (MRSA) and -susceptible (MSSA) strains; with MRSA 4 (1.6) 2 (1.5) of activity and target attainment that covers the majority of common Gram- streptococci, including β-haemolytic species; and Gram-negative bacteria, with anaerobe 17 (6.9) 7 (5.1) 2012–2013 AWARE surveillance SSTI isolates positive and Gram-negative cSSTI pathogens. 3 including some Enterobacteriaceae. Number of pathogens identified 80 Asia (n=2369) 1 171 (69.0) 99 (72.8) European Union (n=5369) • COVERS (CeftarOline versus Vancomycin and aztrEonam tReating cSSTI), a Latin America (n=1605) Phase III, multicentre, randomised, double-blind trial (NCT01499277), evaluated 2 44 (17.7) 28 (20.6) North America (n=1742) 60 Other European countries (n=603) References the safety and efficacy of ceftaroline fosamil 600 mg 120-min intravenous (IV) 3 21 (8.5) 6 (4.4) Rest of the world (n=1502) infusion every 8 h (q8h) versus vancomycin plus aztreonam in patients with ≥4 12 (4.8) 3 (2.2) 1. Zervos MJ et al. J Clin Microbiol. 2012;50:238–245. 4 2. Garau J et al. Clin Microbiol Infect. 2013;19:E377–E385. cSSTI in Europe, North America, Asia and Latin America. Specimen source 40 3. Dryden MS. J Antimicrob Chemother. 2010;65(Suppl 3):iii35–iii44.

In this analysis we present the microbiological characteristics of pathogens Isolates, % • Cellulitis 90 (36.3) 51 (37.5) 4. Dryden MS et al. ECCMID 2015. Abstract O193. obtained at baseline from patients in COVERS. Major cutaneous abscess 85 (34.3) 39 (28.7) 20 5. Corey GC et al. J Antimicrob Chemother. 2010;65(Suppl 4):iv41–iv51. Traumatic or surgical wound infection 43 (17.3) 29 (21.3) 6. Wilcox MH et al. J Antimicrob Chemother. 2010;65(Suppl 4):iv53–iv65. Burns 29 (11.7) 16 (11.8) 7. Li J et al. ECCMID 2015. Abstract P1384. Methods 0 Unidentified 1 (0.4) 1 (0.7) Adult patients with cSSTI (including cellulitis, traumatic or surgical wound infection, ≤0.03 0.06 0.12 0.25 0.5 1 2 4 8 • Blood 12 (4.8) 15 (11.0) Disclosures major cutaneous abscess, or burn infection) of sufficient severity to warrant MIC, mg/L hospitalisation and IV antimicrobial therapy for ≥5 days were eligible for inclusion. ER and JI are employees of AstraZeneca. JA is a former employee of AstraZeneca.

This study was supported by AstraZeneca. Medical writing support was provided by Mark Waterlow of Prime Medica Ltd, Knutsford, Cheshire, UK, funded by AstraZeneca. Presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases, 25–28 April 2015, Copenhagen, Denmark.