The role of Ceftaroline for the treatment of CAP (Community acquired pneumonia)

Transcription

1 The role of Ceftaroline for the treatment of CAP (Community acquired pneumonia) S t e l i o s A s s i m a k o p o u l o s Assistant Professor of Internal Medicine Dept. of Medicine, School of Health Sciences University of Patras Patras, Greece

2 Conflicts of Interest Advisory Board: Pfizer, GSK Lectures: Pfizer, Gilead Sciences, MSD The opinions expressed in this presentation belong to the presenter and do not necessarily reflect the views of the company. For all medicinal products mentioned, please refer to the approved Summaries of Product Characteristics

3 Pneumonia: Terms and classification CAP: Community-acquired pneumonia Outside of hospital ( 2 weeks from hospitalization) Not in extended-care facility HCAP: Healthcare-associated pneumonia Long-term or extended care facility, hemodialysis, outpatient chemo, wound care, etc. HAP: Hospital-acquired pneumonia 48 h from admission VAP: Ventilator-associated pneumonia 48 h from endotracheal intubation Kalil AC, et al. CID 2016:63 (5): e61-111

4 CAP: Epidemiology The most frequent Infectious cause of hospitalization and mortality in USA and E.U. 5 th most common cause of death in Europe 6 th to 8 th leading cause of death in the US Increased Incidence with age ~1 to 5 hospitalized pts will need ICU admission, where bacterial pathogens are increasingly isolated (S. pneumoniae, S.aureus, Enterobacteriaceae) CAP, community-acquired pneumonia Jain et al. N Engl J Med 2015;373:415 File & Low. Clin Pulm Med 2009;16:243 Welte Lancet Infect Dis 2015

5 CAP aetiology USA (EPIC study) 3 rd most common bacterial pathogen 3,8% of isolated pathogens CAP, community-acquired pneumonia Jain et al., N Engl J Med Jul 30;373(5):415-27

6 CAP aetiology according to age Jain et al., N Engl J Med Jul 30;373(5): Bacterial pathogens were detected in 14% of pts The prevalence of pneumococcal disease is 5% Pneumococcal CAP was almost 5 times as high among adults 65 years of age or older M. pneumoniae, L. pneumophila, and C. pneumoniae combined were detected in 4% Overall S. aureus was detected in 2% of adults Low prevalence of Enterobacteriaceae (1%) and other gram-negative bacteria S. pneumoniae, S. aureus were the most common bacterial aetiologies in pts over 50 years S. pneumoniae, S. aureus, and Enterobacteriaceae were significantly more common among severely ill patients, accounting for 16%

7 Which patient is at risk of death? - Age Ewig S, et al. Thorax 2009; 64:

8 Risk factors for clinical failure and poor outcome in CAP Prognostic factors associated with poor outcome in CAP: Age > 65 years Diabetes - Alcoholism Chronic Renal disease - Malignancy Heart failure - Poor nutritional status Chronic pulmonary disease - Swallowing disabilities CAP, community-acquired pneumonia 1. File TM Jr, et al. JAMA 2005;294: File TM Jr, Niederman MS. Infect Dis Clin North Am 2004;18:

9 Empiric antimicrobial therapy: Early yes, blind no Early treatment within 4-8 h from hospital arrival is associated with significantly lower 30-d mortality (Lee, et al., JAMA Feb 9;315(6): ) but before selection of antimicrobial treatment, we should consider several factors (stratification): Clinico-laboratory characteristics of CAP Severity of disease Co-morbidities associated with clinical failure and/or mortality risk Potential microbial aetiological factors Risk factors for antimicrobial resistance

10 To admit or not? CURB-65

11 To admit or not? Pneumonia Severity Index (PSI) DEMOGRAPHICS Age Gender Nursing home COMORBIDITIES Neoplasia Liver disease CHF Cerebrovascular Renal disease PHYSICAL EXAMINATION Mental confusion Respiratory rate SBP Heart rate Temperature LAB / IMAGING BUN, Glucose, sodium Haematocrit, pleural effusion, Arterial PH, Oxygenation Risk Class Mortality Admission Recommendation I 0.1 Outpatient II 0.6 Outpatient III 2.8 Outpatient/Brief Inpatient IV 8.2 Inpatient V 29.2 Inpatient Woodhead, Eur R J 2005, Fine, NEJM 1997, Restrepo, Curr Opin Infect Dis 2006

12 CURB-65 or PSI? PSI Comparison of PSI and CURB-65 CURB-65 Pros Well validated Reduces admissions and cost Comorbidities Cons Complex to calculate Not based on severity of disease Underestimates severity in young without comorbidities Pros Easy to remember Easy to calculate Severity Cons Not considering comorbidities Underestimates risk in aged with comorbidities 1. Lim WS, et al. Thorax 2003;58: Niederman MS, et al. Am J Respir Crit Care Med. 163, (2001).

13 Severe CAP: CAP admitted to ICU Criteria for ICU admission Severe CAP Major ( 1) Invasive mechanical ventilation Septic shock with the need for vasopressors Minor ( 3) Respiratory rate 30 breaths/min PaO2/FiO2 ratio 250 (PO2=52 mmhg, FiO2=0,21) Multilobar infiltrates Confusion/disorientation Uremia (BUN 20 mg/dl) Leukopenia (WBC <4000 cells/mm 3 ) Thrombocytopenia (platelets <100,000 cells/mm 3 ) Hypothermia (core T <36 C) Hypotension requiring aggressive fluid resuscitation Mandell LA, et al. IDSA/ATS Guidelines for CAP in Adults CID 2007; 44:S27 72

14 Severe CAP and specific microbial pathogens Risk factors for Pseudomonas Severe COPD (FEV1<30%) Bronchiectasis Cystic fibrosis Recent ICU admission Recent (3 months) antibiotics Corticosteroids > 10 mg prednisone for 1 month Risk factors for CA-MRSA colonization Relapsing SSTI History of MRSA infection Nasal carriage Contact sports Soldiers MSM Prisoners Homeless Long term care facilities Children < 2 years Antibiotics / hospital admission (3 months) MRSA >15-20% in community ( Greece 39.4% ECDC 2015) CAP, community-acquired pneumonia, MRSA: methicillinresistant Staphylococcus aureus, CA: community acquired Wunderink RG, N Engl J Med. 2014;370: Clinical features of MRSA-CAP CAP with septic shock Necrotic pneumonia Rapidly evolving pleural effusion Gross haemoptysis Post/Concurrent influenza Neutropenia Erythroderma Furuncle Young-healthy Severe CAP in Summer

15 MRSA Modern-day CAP pathogen 51 Staphylococcus aureus CAP cases in 19 states reported % MRSA Median age 16 years (range <1 to 81) 47% antecedent viral illness 11 of 33 (33%) tested had lab-confirmed influenza 51% died a median of 4 days from symptom onset Lesson: Must consider MRSA, MSSA coverage in severe CAP especially during flu season! CAP, community-acquired pneumonia, MRSA: methicillin-resistant Staphylococcus aureus, MSSA: methicillin-sensitive S. aureus Kallen, Ann Emerg Med Mar;53(3):

16 CA-MRSA pneumonia Panton-Valentine leucocidin (PVL) luks-pv, lukf-pv genes Induces pores in leucocytes Leucocyte destruction SSTI and necrotic pneumonia >85% of MRSA-CAP are PVL (+) vs. <5% in HA-MRSA Over 40% mortality Shallcross Laura, et al. Lancet Infect Dis 2013; 13: CAP, community-acquired pneumonia, MRSA: methicillin-resistant Staphylococcus aureus, CA: community acquired

17 Specific pathogens and clinical failure due to inappropriate initial empiric treatment Adapted from Micek ST, et al. Antimicrobial Agents Chemother 2007;51:

18 Resistant pathogens in CAP? Streptococcus pneumoniae S. pneumoniae clinical breakpoints in penicillin G (parenteral) for respiratory infections Previous Breakpoints Current Breakpoints Carriage isolates Invasive isolates Carriage isolates Invasive isolates Sensitive Intermediate resistance Resistant Modified from: Poulakou G, Katsarolis I, Matthaiopoulou I et al, IJAA 2007

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20 Few studies have evaluated the role of other potentially MDR pathogens in CAP such as Enterobacteriaceae and Acinetobacter Limited data are available regarding real MDR pathogens, which include ESBLs A different approach from the original classification focusing on a broad group of MDR pathogens is drifted to a more focus approach on specific pathogens such as MRSA and P. aeruginosa

21 Inpatient Empiric CAP treatment Inpatients in ward Respiratory fluoroquinolone ß-lactam (cefotaxime/ceftriaxone or ampicillin/sulbactam) + macrolide Inpatients in ICU ß-lactam + macrolide ß-lactam + Respiratory fluoroquinolone Pseudomonas (if concerns exists) anti-pseudomonal/pneumococcal ß-lactam (pip/tazo or cefepime) + cipro/levofloxacin (750 mg) anti-pseudomonal/pneumococcal ß-lactam (pip/tazo or cefepime) + aminoglycoside + macrolide Penicillin-allergic: can substitute aztreonam CA-MRSA: Add vancomycin or linezolid CA-MSSA: antistaphylococcal penicillin (Nafcillin) CAP, community-acquired pneumonia, MRSA: methicillinresistant Staphylococcus aureus, MSSA: methicillin-sensitive S. aureus, CA: community acquired Mandell LA, et al. IDSA/ATS Guidelines for CAP in Adults CID 2007; 44:S27 72, File TM, et. al. CID (12):

22 Is any treatment option superior? In moderate CAP there is no difference in outcome and mortality (90 d) between (a) monotherapy with β-lactam, (b) monotherapy with respiratory quinolone, and (c) combination of β-lactam with macrolide (Postma DF, et al. N Engl J Med 2015; 372: ) In severe CAP numerous studies have shown that the combination of β-lactam with a macrolide is superior of other choices including the combination of ceftriaxone with a respiratory quinolone (Ο Brien, et al. Respir Investig 2015 Sep;53(5):201-9)

23 Ceftaroline: a new treatment option for CAP FOCUS 1 & 2: study design PORT III and IV severity classification 1:1 randomization End of treatment (EOT) Patients aged 18 years with CAP and PORT risk class III/IV requiring hospitalisation Ceftaroline 600 mg IV q12h (400 mg q12h for moderate renal impairment) (5 7 days of therapy) Ceftriaxone 1 g IV q24h 10% non-inferiority design TOC (Test of cure) 8 15 days after EOT LFU (Late follow-up) days after EOT All patients in FOCUS 1 received 2 doses (24 h course) of adjunctive clarithromycin (500 mg q12h) starting with first dose of study drug CAP, community-acquired pneumonia; EOT, end of treatment; IV, intravenous; LFU, late follow-up; PORT, Pneumonia Outcomes Research Team; q12h, every 12 hours; q24h, every 24 hours; TOC, test of cure; 1. File TM, et al. Clin Infect Dis 2010;51: ; 2. Eckburg PB, et al. Infect Dis Clin Pract 2012;20:254-60

24 FOCUS 1 & 2: Main Inclusion and Exclusion Criteria Main inclusion criteria Radiographically-confirmed pneumonia (new or progressive pulmonary infiltrate[s] consistent with bacterial pneumonia) AND Acute illness (duration 7 days) AND PORT score >70 and <130 (ie, PORT Risk Class III or IV) Requiring initial hospitalization, or treatment in an emergency room or urgent care setting Requiring treatment with IV antimicrobials Main exclusion criteria Requiring admission to an ICU CAP suitable for outpatient therapy with an oral antimicrobial agent Known or suspected MRSA, Pseudomonas sp. or atypicals Prior antimicrobial therapy for current CAP except for: Single dose of short-acting antibiotic for CAP Healthcare- or hospital-associated pneumonia CAP, community-acquired pneumonia; ICU, intensive care unit; IV, intravenous; MRSA, methicillin-resistant Staphlycoccus aureus; PORT, Pneumonia Outcome Research Team; File TM, et al. Clin Infect Dis 2010;51:

25 Percentage of patients (%) Percentage of patients (%) FOCUS 1 & 2: Results: Primary Outcomes CAP primary outcome (clinical cure at TOC): MITT population CAP primary outcome (clinical cure at TOC): CE population Ceftraroline Ceftriaxone FOCUS 1 FOCUS 2 FOCUS 1 and 2 0 FOCUS 1 FOCUS 2 FOCUS 1 and 2 Difference (n/n) 244/ / / / / /573 Difference (n/n) 194/ / / / / /449 CI 6.2 (-0.2, 12.6) -5.9 (-1.0, 12.7) 6.0 (1.4, 10.7) CI 8.4 (1.4, 15.4) 4.9 (-2.5, 12.5) 6.7 (1.6, 11.8) Ceftaroline demonstrated consistently high clinical cure rates in patients with moderate-to-severe CAP CAP, community-acquired pneumonia; CE, clinically evaluable; CI, confidence interval; MITT, modified intent-to-treat; TOC, test of cure File TM, et al. Clin Infect Dis 2010;51:

26 PP-ZFO-EUR-0022 Date of preparation: March 2018 FOCUS: primary outcomes Both the FOCUS 1 and 2 trials demonstrated that ceftaroline was noninferior to ceftriaxone 1g in the treatment of CAP FOCUS 1 and 2: primary outcome CE and MITTE populations Favours ceftriaxone 1g Favours ceftaroline fosamil Integrated FOCUS Studies MITTE Population FOCUS 2 MITTE Population FOCUS 1 MITTE Population Integrated FOCUS Studies CE Population FOCUS 2 CE Population FOCUS 1 CE Population Difference in clinical cure rates (%) CAP, community-acquired pneumonia; CE, clinically evaluable; FOCUS; ceftaroline Community-acquired pneumonia trial vs ceftriaxone in hospitalised patients; MITTE, modified intent-to-treat efficacy. File TM, et al. Clin Infect Dis 2010;51:

27 PP-ZFO-EUR-0022 Date of preparation: March 2018 FOCUS: clinical cure at TOC by subgroup Cure Rates (CE Population), n/n (%) Ceftaroline Ceftriaxone 1g Difference PORT risk class III 249/287 (86.8) 217/274 (79.2) 7.5 (1.3, 13.8) PORT risk class IV 138/172 (80.2) 132/175 (75.4) 4.7 (-4.1, 13.5) Prior antibiotic treatment 152/185 (82.2) 158/194 (81.4) 0.7 (-7.2, 8.6) No prior antibiotic treatment 235/274 (85.8) 191/255 (74.9) 11.2 (4.5, 18.0) >50 years of age 304/362 (84.0) 278/351 (79.2) 4.8 (-.09, 10.6) 65 years of age 195/232 (84.1) 177/219 (80.8) 3.4 (-3.7, 10.5) 75 years of age 90/111 (81.1) 83/105 (79.0) 3.3 (-7.4, 14.1) Mild renal impairment (CrCL, 51-80mL/min) Moderate renal impairment (CrCL, 31-50mL/min) 133/164 (81.1) 115/151 (76.2) 5.3 (-3.8, 14.4) 62/75 (82.7) 50/63 (79.4) 3.5 (-9.7, 17.2) Ceftaroline demonstrated favourable clinical cure rates irrespective of age, PORT score, prior antibiotic treatment or renal status (TOC: treatment of care) CAP, community-acquired pneumonia; CE, clinically evaluable; CrCL, creatinine clearance; FOCUS; ceftaroline Community-acquired pneumonia trial vs ceftriaxone in hospitalised patients; PORT; Pneumonia Outcomes Research Team; TOC, test of cure. File TM, et al. Clin Infect Dis 2010;51:

28 Percentage of patients (%) Percentage of patients (%) FOCUS 1 & 2 Results: by Pathogen CAP: Clinical cure at TOC by pathogen (mmitte population) Gram-positive Ceftaroline Ceftriaxone Gram-negative Streptococcus pneumoniae Staphylococcus MSSA aureus MSSA 0 Haemophilus influenzae Haemophilus parainfluenzae parainfluenzae Klebsiella pneumoniae Escherichia coli Difference (n/n) 59/69 48/70 18/25 18/30 Difference (n/n) 17/20 20/24 16/17 15/18 14/15 10/13 10/12 9/13 Note: Available clinical data cannot substantiate efficacy against PNSP; Patients with confirmed/suspected CAP caused by MRSA at baseline were excluded from the trials there is no experience with ceftaroline fosamil in MRSA CAP. CAP, community-acquired pneumonia; mmitte, microbiological modified intent-to-treat efficacy; MRSA, methicillin-resistant Staphlycoccus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; PNSP, penicillin-non-susceptible Streptococcus pneumoniae; TOC, test of cure File TM, et al. Clin Infect Dis 2010;51:

29 PP-ZFO-EUR-0022 Date of preparation: March 2018 FOCUS: clinical responders (by Day 4) By-patient clinical response at Day 4 Ceftaroline fosamil N (%) FOCUS 1 FOCUS 2 FOCUS 1 and 2 Ceftriaxone N (%) Ceftaroline fosamil N (%) Ceftriaxone N (%) Ceftaroline fosamil N (%) Ceftriaxone N (%) N Responder (clinical stability and improvement of 49 (71.0) 41 (56.9) 58 (68.2) symptoms) Non-responder 20 (29.0) 31 (43.1) 27 (31.8) 32 (38.6) 47 (30.5) 63 (40.6) Crude difference (95% CI) 14.1 (-1.9 to 29.3) 6.8 (-7.7 to 21.0) 51 (61.4) 107 (69.5) 92 (59.4) 10.1 (-0.6 to 20.6) Day 4 clinical response rates were 69.5% (107/154) for ceftaroline fosamil and 59.4% (92/155) for ceftriaxone (difference 10.1%; 95% CI, -0.6% to 20.6%) Integrated analysis was stratified by study. Analyses were exploratory and conducted retrospectively. CI, confidence interval; EmMITT, exploratory microbiological modified intent-to-treat; FOCUS; ceftaroline Community-acquired pneumonia trial vs ceftriaxone in hospitalised patients. Eckburg PB, et al. Infect Dis Clin Prac 2012;20(4):

30 Asia CAP Study objectives To assess the efficacy and safety of ceftaroline fosamil (600 mg every 12 h) compared with ceftriaxone (2 g every 24 h) for the treatment of Asian patients admitted to hospital with CAP Zhong NS, et al. Lancet Infect Dis 2015;15:

31 Study design Asia CAP Phase III, multicentre, randomised, double-blind, active-comparator Multinational (64 centres): China (23), India (13), South Korea (16), Taiwan (7) and Vietnam (5) 1:1 randomization EOT Patients aged 18 years with CAP and PORT risk class III / IV requiring hospitalisation Ceftaroline 600 mg IV q12h (400 mg q12h for moderate renal impairment) (5 7 days of therapy) Ceftriaxone 2 g IV q24h 10% non-inferiority design TOC 8 15 days after EOT LFU days after EOT CAP, community-acquired pneumonia; CE, clinically evaluable; EOT, end of treatment; IV, intravenous; LFU, late follow-up; PORT, Pneumonia Outcomes Research Team; q12h, every 12 hours; q24h, every 24 hours; TOC, test of cure Zhong NS, et al. Lancet Infect Dis 2015;15:161-71

32 Asia CAP Most common pathogens identified at baseline (mmitt) Pathogen, n (%) Streptococcus pneumoniae Klebsiella pneumoniae Haemophilus influenzae Escherichia coli MSSA Ceftaroline 600 mg q12h (n=80) 24 (30) 18 (23) 12 (15) 4 (5) 5 (6) Ceftriaxone 2 g q24h (n=96) 18 (19) 20 (21) 8 (8) 9 (9) 7 (7) Note: Patients with confirmed/suspected CAP caused by MRSA at baseline were excluded from the pivotal trials there is no experience with ceftaroline fosamil in MRSA CAP. Available clinical data cannot substantiate efficacy of ceftaroline against PNSP CAP, community-acquired pneumonia; mmitt, microbiological modified intent-to-treat; MRSA, methicillin-resistant Staphlycoccus aureus; MSSA, methicillin-sensitive Staphylococcus aureus; PNSP, penicillin-non-susceptible Streptococcus pneumoniae Zhong NS, et al. Lancet Infect Dis 2015;15:

33 Asia CAP Clinical cure at TOC in CE population Ceftaroline 600 mg q12h n/n (%) Ceftriaxone 2 g q24h n/n (%) Difference % (95% CI) Clinical cure 217/258 (84.1) 178/240 (74.2) 9.9 (2.8, 17.1) Primary endpoint was met The 95% CI in the CE population was above 10%, thus the non-inferiority of ceftaroline versus ceftriaxone was demonstrated within Asian CAP patients Statistical analysis: As non-inferiority was established and the lower limit of the 95% CI was >0%, ceftaroline was considered to be superior to ceftriaxone Zhong NS, et al. Lancet Infect Dis 2015;15:

34 Asia CAP Clinical cure at TOC in patient subgroups (CE) CI, confidence interval; PORT, Pneumonia Outcomes Research Team; TOC, test of cure Zhong NS, et al. Lancet Infect Dis 2015;15:161-71

35 Asia CAP Summary of AEs (adverse events) AE, n (%) Ceftaroline 600 mg q12h (n=381) Ceftriaxone 2 g q24h (n=383) Any AE 172 (45) 163 (43) Any treatment-related AE 31 (8) 25 (7) Any severe AE 30 (8) 29 (8) Any treatment-related severe AE 0 (0) 1 (<1) Deaths 3 (1) 4 (1) Deaths due to treatmentrelated AE 0 (0) 0 (0) Zhong NS, et al. Lancet Infect Dis 2015;15:

36 Asia CAP: Summary Ceftaroline was superior to ceftriaxone for the treatment of Asian patients with PORT III IV CAP Consistent with the results of FOCUS 1 and FOCUS 2 Key study differences between Asia CAP and FOCUS 1 & 2: Asian patients versus European/North American patients Comparator: ceftriaxone 2 g q24h (versus 1 g q24h in FOCUS 1 & 2) Study protocol did not allow initial treatment with clarithromycin Pre-planned superiority analysis if primary endpoint was met Ceftaroline should be considered as an alternative empirical treatment regimen to ceftriaxone in Asian patients with CAP 1. Zhong NS, et al. Lancet Infect Dis 2015;15:161-71; 2. File TM Jr, et al. J Antimicrob Chemother 2011;66(Suppl 3):iii19-32; 3. Low DE, et al. J Antimicrob Chemother 2011;66(Suppl 3):iii33-44.

37 ASIA-CAP: Potential explanations of Ceftaroline superiority compared with Ceftriaxone 1. Affinity to PBPs Lower MICs of ceftaroline against key Gram-positive pathogens (Streptococcus pneumoniae and MSSA) isolated from patients 2. Serum Protein binding Protein-binding is a pivotal determinant of drug tissue penetration Serum protein-binding: Ceftaroline ~20% vs. Ceftriaxone 95% 3. Infusion Duration Infusion Duration if prolonged may lead to higher tissue concentrations over time Infusion time: Ceftaroline 1 hour vs. Ceftriaxone 30 min 4. ELF penetration/concentrations In healthy volunteers ceftaroline s concentration in ELF is almost 23% of plasma concentrations Ceftriaxone s penetration has not be measured in humans (reported to be very low in animal models) Note: Patients with confirmed/suspected CAP caused by MRSA at baseline were excluded from the pivotal trials there is no experience with ceftaroline fosamil in MRSA CAP. Available clinical data cannot substantiate efficacy of ceftaroline against PNSP. MSSA, methicillin-sensitive Staphylococcus aureus; MIC, minimal inhibitory concentration; PBP, Protein Binding Protein, PNSP, penicillin-non-susceptible Streptococcus pneumoniae Zhong NS, et al. Lancet Infect Dis. 2015;15: , Welte T. Lancet Infect Dis. 2015;15:

38 CAPTURE registry Ceftaroline Assessment Program and Teflaro Utilization REgistry A multicentre, retrospective registry of patients in the US receiving ceftaroline designed to: Gain insights into the real-world effectiveness of ceftaroline Provide clinical outcome data on patient populations not included or with limited inclusion in phase 3 clinical trials Provide clinical outcome data on bacterial pathogens not included or with limited inclusion in phase 3 clinical trials Examine other outcome data not collected in phase 3 clinical trials such as hospital duration and healthcare costs Carreno JJ, et al. Infect Dis Ther. 2014;3:123 32

39 Clinical success rate (%) PP-ZFO-EUR-0022 Date of preparation: March 2018 CAPTURE Registry: clinical success in elderly patients with CAP Clinical success rates for CAP patients by age group Age 65 years Age <65 years Ceftaroline fosamil is a treatment option for CAP in elderly patients The overall clinical success rate was similar in 268 patients >65 years of age compared with 260 patients <65 years of age Approximately one quarter of patients over the age of 65 were found to have 2 comorbidities (26%) The most common comorbidity found in elderly patients was structural lung disease (51%) NOTE: Clinical success is defined as the following: clinical cure with no further need for antibiotic therapy or clinical improvement with switch to oral agents at the end of ceftaroline fosamil treatment. There are no clinical data to support the use of ceftaroline fosamil for MRSA in CAP caution is advised when treating such patients. Available clinical data cannot substantiate efficacy of ceftaroline against PNSP. CAP, community-acquired pneumonia; CAPTURE, Ceftaroline Assessment Program and Teflaro Utilization Registry; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillinsensitive Staphylococcus aureus, PNSP: penicillin-non-susceptible Streptococcus pneumoniae 1. Udeani G, et al. Hosp Pract 2014;42:109 15, 2. SmpC Zinforo Dec 2017

40 Clinical success rate (%) CAPTURE Registry: CAP Clinical Success in the ICU versus General Medical Ward 138 evaluable patients were admitted to ICU 256 were treated in general medical wards 78% of ICU and 74% of general medical ward patients had underlying comorbidities Clinical success rates with Ceftaroline in patients admitted to the ICU or general medical ward All patients MRSA MSSA S. S. pneumoniae pneumoniae First-line therapy Second-line therapy Monotherapy Concurrent therapy ICU General medical ward NOTE: Clinical success is defined as the following: clinical cure with no further need for antibiotic therapy or clinical improvement with switch to oral agents at the end of ceftaroline fosamil treatment. There are no clinical data to support the use of ceftaroline fosamil for MRSA in CAP caution is advised when treating such patients. Available clinical data cannot substantiate efficacy of ceftaroline against PNSP. CAP, community-acquired pneumonia; CAPTURE, Ceftaroline Assessment Program and Teflaro Utilization Registry; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus, PNSP: penicillin-non-susceptible Streptococcus pneumoniae, ICU, intensive care unit; 1. Maggiore C, et al. Ther Clin Risk Manag 2015;11: SmpC Zinforo Dec 2017

41 Ceftaroline - conclusions Proven clinical efficacy in with moderate to severe CAP including patients with comorbidities and elderly patients Consistent clinical cure rates against relevant pathogens Associated with early clinical response at Day 4 Superior efficacy vs. ceftriaxone 2 g in Asia CAP study (in FOCUS trials ceftaroline was effective as ceftriaxone1g q24hr) Safety profile and tolerability similar to other cephalosporins Which patient? CAP, community-acquired pneumonia 1. Zhong NS, et al. Lancet Infect Dis 2015;15: File TM Jr, et al. J Antimicrob Chemother 2011;66(Suppl 3):iii Low DE, et al. J Antimicrob Chemother 2011;66(Suppl 3):iii SmpC Zinforo Dec Scott LJ. Drugs (2016) 76:

42 Thank you!