Hospital Practice
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Efficacy of Ceftaroline Fosamil for Bacteremia Associated With Community-Acquired Bacterial Pneumonia Alena Jandourek MD, Alexander Smith MS, Lily Llorens PhD, Dirk A. Thye MD, Paul B. Eckburg MD & H. David Friedland MD, MBA To cite this article: Alena Jandourek MD, Alexander Smith MS, Lily Llorens PhD, Dirk A. Thye MD, Paul B. Eckburg MD & H. David Friedland MD, MBA (2014) Efficacy of Ceftaroline Fosamil for Bacteremia Associated With Community-Acquired Bacterial Pneumonia, Hospital Practice, 42:1, 75-78 To link to this article: http://dx.doi.org/10.3810/hp.2014.02.1094
Published online: 13 Mar 2015.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Florida State University]
Date: 10 September 2015, At: 18:39
C l i n i c a l F e at u r e s
Efficacy of Ceftaroline Fosamil for Bacteremia Associated With Community-Acquired Bacterial Pneumonia
Downloaded by [Florida State University] at 18:39 10 September 2015
DOI: 10.3810/hp.2014.02.1094
Alena Jandourek, MD 1 Alexander Smith, MS 2 Lily Llorens, PhD 3 Dirk A. Thye, MD 4 Paul B. Eckburg, MD 5 H. David Friedland, MD, MBA 6 Director, Clinical Development; Associate Director, Biostatistics; 3 Senior Director, Biostatistics and Data Management, Cerexa, Inc., Oakland, CA a; 4Chief Executive Officer, InClin, San Mateo, CA; 5 Adjunct Clinical Assistant Professor, Infectious Diseases, Stanford University School of Medicine, Stanford, CA; 6Vice President, Clinical Sciences, Cerexa, Inc., Oakland, CA a a Cerexa, Inc., is a wholly-owned subsidiary of Forest Laboratories, Inc., New York, NY 1 2
Abstract
Objectives: Few publications of prospective studies have described patient outcomes in community-acquired bacterial pneumonia (CABP)-associated bacteremia. Our objective, in performing this subgroup analysis, was to assess outcomes in subjects with CABP-associated bacteremia in 2 randomized, double-blind clinical studies comparing treatment with ceftaroline fosamil versus ceftriaxone. Methods: Our analysis summarizes baseline subject demographics, distribution of baseline pathogens isolated from blood cultures, clinical response rates at Day 4, and clinical cure rates at end of therapy and test of cure (8 to 15 days after end of therapy) in subjects with bacteremic CABP in the ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone in hospitalized patients (FOCUS) studies. Results: In the FOCUS studies, 23 of 614 patients in the ceftaroline fosamil-treated group and 22 of 614 patients in the ceftriaxone-treated group had CABP-associated bacteremia. Baseline demographics were similar between groups. Streptococcus pneumoniae was the most common baseline bloodstream isolate. For subjects with CABP-associated bacteremia, clinical response/cure rates were similar at Day 4 (60.9% vs 59.1%), end of therapy (69.6% vs 72.7%), and test of cure (69.6% vs 68.2%) for ceftaroline fosamil and ceftriaxone, respectively. Conclusions: In subjects with CABP-associated bacteremia, ceftaroline fosamil demonstrated similar clinical outcomes at Day 4, end of therapy, and test of cure compared with ceftriaxone. Keywords: ceftaroline; ceftriaxone; bacteremia; community-acquired bacterial pneumonia
Introduction
Correspondence: Alena Jandourek, MD, Director, Clinical Development, Cerexa, Inc., 2100 Franklin St, Suite 900, Oakland, CA 94612. Tel: 510-285-9235 Fax: 510-217-4355 E-mail: [email protected]
Community-acquired bacterial pneumonia (CABP) is a serious infection associated with significant patient morbidity and mortality.1 Bacteremia related to CABP is indicative of disseminated infection and worsened patient prognosis.2–4 Streptococcus pneumoniae is consistently the most common cause of CABP,5,6 and # 30% of pneumococcal pneumonia cases are accompanied by bacteremia.7,8 Patients with pneumococcal bacteremia often have more comorbidities and higher disease severity than nonbacteremic patients.8 Worse patient outcomes may be compounded by inappropriate therapy selection.9,10 In 1 retrospective cohort study, ceftriaxone nonsusceptibility was an independent risk factor for 30-day mortality in patients with pneumococcal bacteremia.9 There are few publications of prospective studies that describe patient outcomes in CABP-associated bacteremia, and no prospective studies have described early clinical response (Day 4). Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against gram-positive pathogens, including multidrug-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus, as well as common gram-negative pathogens.11,12 Ceftaroline has greater binding
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 75 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 75
1/31/14 5:17 PM
Downloaded by [Florida State University] at 18:39 10 September 2015
Jandourek et al
affinity than ceftriaxone and comparator β-lactams for many penicillin-binding proteins (PBP) of S. pneumoniae, including those with mutations at the binding site.13,14 In the integrated analysis of 2 pivotal clinical trials, ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone in hospitalized patients (FOCUS) 1 and FOCUS 2, ceftaroline fosamil was noninferior to ceftriaxone in clinical cure rates at test of cure (TOC; 8 to 15 days after end of therapy [EOT]) for treatment of patients with CABP.15 Each individual study also demonstrated noninferiority for the primary endpoint.16,17 Clinical cure was defined as resolution of all signs and symptoms of pneumonia or improvement such that no further antimicrobial therapy was necessary. Patients had to be afebrile (temperature # 38°C orally or # 38.5°C rectally or tympanically) for 24 consecutive hours with a return of CABP signs and symptoms to baseline levels.15 An additional outcome considered in this analysis was clinical response rate at Day 4, which was defined by both symptom response (improvement in $ 1 and worsening in none of cough, dyspnea, chest pain, and sputum production) and clinical stability (temperature # 38°C, heart rate # 100 beats per minute, respiratory rate # 24 breaths per minute, systolic blood pressure $ 90 mm Hg, oxygen saturation $ 90%, and absence of confusion/disorientation). We performed our subgroup analysis to assess clinical response rates at Day 4 and clinical cure rates at EOT and TOC in subjects with bacteremic CABP in the FOCUS trials.
Materials and Methods
The study designs of FOCUS 1 and FOCUS 2 (clinicaltrials.gov identifiers NCT00621504 and NCT00509106) were previously described.15,18 All randomized subjects who received any amount of study drug were included in the modified intent-to-treat (MITT) population, and the subgroup with CABP-associated bacteremia was defined as subjects with a pathogen consistent with pneumonia identified from blood cultures at baseline. For these subjects, 4 culture bottles were obtained from 2 separate venipunctures; repeat surveillance blood cultures were drawn until results were negative, and a central laboratory was used for verification and susceptibility testing. Our analysis includes summaries of baseline subject demographics, the distribution of baseline pathogens isolated from blood cultures, and outcomes at Day 4, EOT, and TOC for treatment with ceftaroline fosamil compared with ceftriaxone therapy in the bacteremic CABP subgroup. Data were analyzed using descriptive statistics only.
Results
In the FOCUS studies, 45 of 1228 subjects had CABPassociated bacteremia: 3.7% (23 of 614) in the ceftaroline fosamil-treated group and 3.6% (22 of 614) in the ceftriaxone-treated group. Low bacteremia rates in the FOCUS studies may have been due to limited enrollment of subjects with severe CABP and other patients who might have been at higher risk for bacteremia (eg, those who were immunosuppressed, required admission to the intensive care unit at baseline, were Pneumonia Outcomes Research Team [PORT] risk class V, had empyema, and/or a life-threatening illness). Demographic characteristics were similar between the 2 groups, although fever was more often seen in the ceftriaxone-treatment group (Table 1). The most common subject baseline bloodstream isolate was S. pneumoniae (Table 2). Other pathogens isolated included S. aureus, EschTable 1. Demographic and Baseline Characteristics of Subjects With Bacteremia at Baselinea by Treatment Group Characteristic
Ceftaroline Fosamil (n = 23)
Ceftriaxone (n = 22)
Mean age, years (SD) $ 65 Men, n (%) PORT risk class,b n (%) III IV Smoking history, n (%) Fever (. 38°C orally or . 38.5°C rectally or tympanically), n (%) Hypoxia (PAO2 , 60 mm Hg or O2 saturation , 90%), n (%) Fever or hypoxia, n (%) Both hypoxia and fever,c n (%) Radiology findings, n (%) Pleural effusiond Multilobar infiltrate Creatinine clearance (mL/min),e n (%) . 80 . 50 and # 80 . 30 and # 50 # 30
60.6 (16.1) 11 (47.8) 15 (65.2)
63.2 (16.2) 11 (50.0) 17 (77.3)
5 (21.7) 18 (78.3) 14 (60.9) 12 (52.2)
5 (22.7) 15 (68.2) 16 (72.7) 16 (72.7)
8 (34.8)
7 (31.8)
17 (73.9) 3 (13.0)
17 (77.3) 6 (27.3)
5 (21.7) 5 (21.7)
5 (22.7) 5 (22.7)
7 (30.4) 9 (39.1) 7 (30.4) 0
3 (13.6) 8 (36.4) 10 (45.5) 1 (4.5)
MITT population, pooled FOCUS data. In ceftriaxone arm, 1 subject had PORT risk class II, 1 subject had PORT risk class V. c Subjects who had fever but did not have PAO2 , 60 mm Hg or O2 saturation collected at baseline; and subjects who had hypoxia but did not have temperature collected at baseline were excluded. d Pleural effusion includes subjects with pleural effusion of any size on either right or left side. e Central lab values for subject creatinine clearance were used if available; otherwise, local lab values were used. Abbreviations: FOCUS, ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone; MITT, modified intent-to-treat; PORT, Pneumonia Outcomes Research Team, in hospitalized patients. a
b
76
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 76
1/31/14 5:17 PM
Ceftaroline for Bacteremia Associated With CABP
Table 2. Pathogens Identified at Baseline From Positive Blood Cultures,a,b by Treatment Group Pathogen
Ceftaroline Fosamil Ceftriaxone (n = 23), n (%) (n = 22), n (%)
Gram-positive organisms Streptococcus pneumoniae MDRSPc PSSP Staphylococcus aureus MRSA Gram-negative organisms Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Pseudomonas stutzeri
21 (91.3) 19 (82.6) 1 (4.3) 19 (82.6) 3 (13.0) 0 3 (13.0) 1 (4.3) 1 (4.3) 1 (4.3) 0
16 (72.7) 12 (54.5) 1 (4.5) 11 (50.0) 4 (18.2) 1 (4.5) 6 (27.3) 1 (4.5) 4 (18.2) 0 1 (4.5)
Subjects with . 1 pathogen isolated from a baseline blood culture could be counted in multiple categories. Two subjects in the ceftaroline fosamil-treated group had polymicrobial bacteremia, 1 with both S. pneumoniae and S. aureus, and 1 with both S. pneumoniae and E. coli. c Strains resistant to $ 2 antimicrobial classes, including penicillin, macrolides, tetracycline, fluoroquinolones, chloramphenicol, trimethoprim-sulfamethoxazole, and cephalosporins. Abbreviations: FOCUS, ceFtarOline Community-acquired pneUmonia trial vS ceftiaxone in hospitalized patients; MDRSP, multidrug-resistant S. pneumoniae; MITT, modified intent-to-treat; MRSA, methicillin-resistant S. aureus; PSSP, penicillinsusceptible S. pneumoniae.
Downloaded by [Florida State University] at 18:39 10 September 2015
b
erichia coli, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas stutzeri. The majority of subjects, with the exception of 2 in the ceftaroline fosamil-treated group, had monomicrobial bacteremia. For all subjects with bacteremia, the clinical response/cure rates were comparable between ceftaroline fosamil and ceftriaxone at all assessed time points (Day 4 [60.9% vs 59.1%], EOT [69.6% vs 72.7%], and TOC [69.6% vs 68.2%], respectively; (Table 3). For subjects with S. pneumoniae bacteremia, rates for improvement in $ 1 symptom (and no worsening in other symptoms) at Day 4 were similar between ceftaroline fosamil-treated and ceftriaxone-treated groups (84.2% and 83.3%, respectively). Clinical stability rates at Day 4 (68.4% vs 50.0%) and clinical cure rates at EOT (78.9% vs 75.0%) and TOC (78.9% vs 66.7%) were numerically higher for ceftaroline fosamil-treated compared with ceftriaxone-treated subjects, respectively (Table 3).
Discussion
Compared with the MITT population in the FOCUS studies, the subgroup of subjects with bacteremia were similar in age but had a higher incidence of moderate renal impairment (creatinine clearance level, 31–50 mL/min; 38% vs 15%).15 Additionally, a greater percentage of subjects with bacteremia had a PORT risk score of IV compared with the MITT population in the FOCUS studies (73% vs 38%).15 In the FOCUS studies, subjects with pneumococcal CABP (bacteremic and
Table 3. Response Rate at Day 4 EOT, TOC, for Subjects With Bacteremia at Baselinea Treated With Ceftaroline Fosamil or Ceftriaxone Visit Day 4b Overall Streptococcus pneumoniae Day 4 Symptom Improvementb,c Overall S. pneumoniae Day 4 Stability of Clinical Signsb Overall S. pneumoniae EOTb Overall S. pneumoniae TOCb Overall S. pneumoniae
Ceftaroline Fosamil (n = 23), n/N (%)
Ceftriaxone (n = 22), n/N (%)
14/23 (60.9) 11/19 (57.9)
13/22 (59.1) 6/12 (50.0)
20/23 (87.0) 16/19 (84.2)
19/22 (86.4) 10/12 (83.3)
16/23 (69.6) 13/19 (68.4)
13/22 (59.1) 6/12 (50.0)
16/23 (69.6) 15/19 (78.9)
16/22 (72.7) 9/12 (75.0)
16/23 (69.6) 15/19 (78.9)
15/22 (68.2) 8/12 (66.7)
MITT population, pooled FOCUS data. Number of responders/number of subjects in group (%). c Improvement in $ 1 clinical symptoms (and no worsening in others). Abbreviations: FOCUS, ceFtarOline Community-acquired pneUmonia trial vS ceftiaxone in hospitalized patients; EOT, end of therapy; MITT, modified intent-to-treat; TOC, test of cure.
a
b
non-bacteremic [sputum culture- or urine antigen-positive]) had clinical response rates at TOC of 85.5% in the ceftaroline fosamil-treated group versus 68.6% in the ceftriaxone-treated group,15 and the subgroup findings are consistent with the pneumococcal CABP response rates. The results described reflect subgroup analyses that are not sufficiently powered or designed to demonstrate noninferiority, however, they are hypothesis-generating for the subgroup of CABP subjects with bacteremia.
Conclusion
The data suggest that in the subset of subjects with CABPassociated bacteremia, ceftaroline fosamil demonstrated similar clinical outcomes at Day 4, EOT, and TOC compared with ceftriaxone. For subjects with S. pneumoniae bacteremia, which were the majority, the higher clinical outcomes appeared to be driven by improved stability in clinical signs at Day 4.
Acknowledgments
The results of the FOCUS 1 and FOCUS 2 studies on which our subgroup analysis is based have been previously published. Our study was supported by Cerexa, Inc., Oakland, CA, USA (a wholly-owned subsidiary of Forest Laboratories,
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 77 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 77
1/31/14 5:17 PM
Jandourek et al
Inc., New York, NY, USA). Cerexa, Inc., was involved in the design, collection, analysis, interpretation of data, and decision to present these results. Scientific Therapeutics Information, Inc., provided editorial assistance, which was funded by Forest Research Institute, Inc.
Downloaded by [Florida State University] at 18:39 10 September 2015
Conflict of Interest Statement
Alena Jandourek, MD, is an employee of Cerexa, Inc., Oakland, CA (a wholly-owned subsidiary of Forest Laboratories, Inc., New York, NY); Alexander Smith, MS, is an employee of Forest Laboratories, Inc., New York, NY, and receives stock/stock options in the company; Lily Llorens, PhD, is an employee of Cerexa, Inc., Oakland, CA (a whollyowned subsidiary of Forest Laboratories, Inc., New York, NY), and receives stock/stock options; Dirk A. Thye, MD, was previously an employee of Cerexa, which was acquired by Forest Laboratories; Paul B. Eckburg, MD, has nothing to declare; H. David Friedland, MD, MBA, is an employee of Forest Laboratories, Inc., and receives stock/stock options.
References 1. US Department of Health and Human Services. Centers for Disease Control. National Center for Health Statistics. Xu JQ, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: Final Data for 2007. National Vital Statistics Report. 2010;58(19):1–135. http://www.cdc.gov/nchs/data/ nvsr/nvsr58/nvsr58_19.pdf. Accessed Sept 30, 2013. 2. Lark RL, Saint S, Chenoweth C, Zemencuk JK, Lipsky BA, Plorde JJ. Four-year prospective evaluation of community-acquired bacteremia: epidemiology, microbiology, and patient outcome. Diagn Microbiol Infect Dis. 2001;41(1–2):15–22. 3. Metersky ML, Waterer G, Nsa W, Bratzler DW. Predictors of inhospital vs postdischarge mortality in pneumonia. Chest. 2012; 142(2):476–481. 4. Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24(4):584–602. 5. Mandell LA, Wunderink RG, Anzueto A; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–S72.
6. Richter SS, Heilmann KP, Dohrn CL, Riahi F, Beekmann SE, Doern GV. Changing epidemiology of antimicrobial-resistant S treptococcus pneumoniae in the United States, 2004–2005. Clin Infect Dis. 2009; 48(3):e23–e33. 7. Blasi F, Mantero M, Santus P, Tarsia P. Understanding the burden of pneumococcal disease in adults. Clin Microbiol Infect. 2012;18 (Suppl 5):7–14. 8. Palma I, Mosquera R, Demier C, Vay CA, Famiglietti A, Luna CM. Impact of bacteremia in a cohort of patients with pneumococcal pneumonia. J Bras Pneumol. 2012;38(4):422–430. 9. Choi S-H, Chung J-W, Sung H, et al. Impact of penicillin nonsusceptibility on clinical outcomes of patients with nonmeningeal Streptococcus pneumoniae bacteremia in the era of the 2008 Clinical and Laboratory Standards Institute penicillin breakpoints. Antimicrob Agents Chemother. 2012;56(9):4650–4655. 10. Lujan M, Gallego M, Fontanals D, Mariscal D, Rello J. Prospective observational study of bacteremia pneumococcal pneumonia: Effect of discordant therapy on mortality. Crit Care Med. 2004;32(3):625–631. 11. Flamm RK, Sader HS, Farrell DJ, Jones RN. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrob Agents Chemother. 2012;56(6):2933–2940. 12. Morrissey I, Ge Y, Janes R. Activity of the new cephalosporin ceftaroline against bacteraemia isolates from patients with community-acquired pneumonia. Int J Antimicrob Agents. 2009;33(6):515–519. 13. Kosowska-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other β-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2010;54(5):1670–1677. 14. Moisan H, Pruneau M, Malouin F. Binding of ceftaroline to penicillinbinding proteins of Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother. 2010;65(4):713–716. 15. File TM Jr, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, double-blind, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis. 2010;51(12):1395–1405. 16. File TM Jr, Low DE, Eckburg PB, et al, on behalf of the FOCUS 1 investigators. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother. 2011; 66(Suppl 3):iii19–iii32. 17. Low DE, File TM Jr, Eckburg PB, et al; FOCUS 2 investigators. FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother. 2011;66(Suppl 3):iii33–iii44. 18. Eckburg PB, Friedland HD, Llorens L, et al. Day 4 clinical response of ceftaroline fosamil versus ceftriaxone for community-acquired bacterial pneumonia. Infect Dis Clin Pract. 2012;20(4):254–260.
78
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 78
1/31/14 5:17 PM
ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20
Efficacy of Ceftaroline Fosamil for Bacteremia Associated With Community-Acquired Bacterial Pneumonia Alena Jandourek MD, Alexander Smith MS, Lily Llorens PhD, Dirk A. Thye MD, Paul B. Eckburg MD & H. David Friedland MD, MBA To cite this article: Alena Jandourek MD, Alexander Smith MS, Lily Llorens PhD, Dirk A. Thye MD, Paul B. Eckburg MD & H. David Friedland MD, MBA (2014) Efficacy of Ceftaroline Fosamil for Bacteremia Associated With Community-Acquired Bacterial Pneumonia, Hospital Practice, 42:1, 75-78 To link to this article: http://dx.doi.org/10.3810/hp.2014.02.1094
Published online: 13 Mar 2015.
Submit your article to this journal
Article views: 5
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [Florida State University]
Date: 10 September 2015, At: 18:39
C l i n i c a l F e at u r e s
Efficacy of Ceftaroline Fosamil for Bacteremia Associated With Community-Acquired Bacterial Pneumonia
Downloaded by [Florida State University] at 18:39 10 September 2015
DOI: 10.3810/hp.2014.02.1094
Alena Jandourek, MD 1 Alexander Smith, MS 2 Lily Llorens, PhD 3 Dirk A. Thye, MD 4 Paul B. Eckburg, MD 5 H. David Friedland, MD, MBA 6 Director, Clinical Development; Associate Director, Biostatistics; 3 Senior Director, Biostatistics and Data Management, Cerexa, Inc., Oakland, CA a; 4Chief Executive Officer, InClin, San Mateo, CA; 5 Adjunct Clinical Assistant Professor, Infectious Diseases, Stanford University School of Medicine, Stanford, CA; 6Vice President, Clinical Sciences, Cerexa, Inc., Oakland, CA a a Cerexa, Inc., is a wholly-owned subsidiary of Forest Laboratories, Inc., New York, NY 1 2
Abstract
Objectives: Few publications of prospective studies have described patient outcomes in community-acquired bacterial pneumonia (CABP)-associated bacteremia. Our objective, in performing this subgroup analysis, was to assess outcomes in subjects with CABP-associated bacteremia in 2 randomized, double-blind clinical studies comparing treatment with ceftaroline fosamil versus ceftriaxone. Methods: Our analysis summarizes baseline subject demographics, distribution of baseline pathogens isolated from blood cultures, clinical response rates at Day 4, and clinical cure rates at end of therapy and test of cure (8 to 15 days after end of therapy) in subjects with bacteremic CABP in the ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone in hospitalized patients (FOCUS) studies. Results: In the FOCUS studies, 23 of 614 patients in the ceftaroline fosamil-treated group and 22 of 614 patients in the ceftriaxone-treated group had CABP-associated bacteremia. Baseline demographics were similar between groups. Streptococcus pneumoniae was the most common baseline bloodstream isolate. For subjects with CABP-associated bacteremia, clinical response/cure rates were similar at Day 4 (60.9% vs 59.1%), end of therapy (69.6% vs 72.7%), and test of cure (69.6% vs 68.2%) for ceftaroline fosamil and ceftriaxone, respectively. Conclusions: In subjects with CABP-associated bacteremia, ceftaroline fosamil demonstrated similar clinical outcomes at Day 4, end of therapy, and test of cure compared with ceftriaxone. Keywords: ceftaroline; ceftriaxone; bacteremia; community-acquired bacterial pneumonia
Introduction
Correspondence: Alena Jandourek, MD, Director, Clinical Development, Cerexa, Inc., 2100 Franklin St, Suite 900, Oakland, CA 94612. Tel: 510-285-9235 Fax: 510-217-4355 E-mail: [email protected]
Community-acquired bacterial pneumonia (CABP) is a serious infection associated with significant patient morbidity and mortality.1 Bacteremia related to CABP is indicative of disseminated infection and worsened patient prognosis.2–4 Streptococcus pneumoniae is consistently the most common cause of CABP,5,6 and # 30% of pneumococcal pneumonia cases are accompanied by bacteremia.7,8 Patients with pneumococcal bacteremia often have more comorbidities and higher disease severity than nonbacteremic patients.8 Worse patient outcomes may be compounded by inappropriate therapy selection.9,10 In 1 retrospective cohort study, ceftriaxone nonsusceptibility was an independent risk factor for 30-day mortality in patients with pneumococcal bacteremia.9 There are few publications of prospective studies that describe patient outcomes in CABP-associated bacteremia, and no prospective studies have described early clinical response (Day 4). Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with in vitro bactericidal activity against gram-positive pathogens, including multidrug-resistant S. pneumoniae and methicillin-resistant Staphylococcus aureus, as well as common gram-negative pathogens.11,12 Ceftaroline has greater binding
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 75 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 75
1/31/14 5:17 PM
Downloaded by [Florida State University] at 18:39 10 September 2015
Jandourek et al
affinity than ceftriaxone and comparator β-lactams for many penicillin-binding proteins (PBP) of S. pneumoniae, including those with mutations at the binding site.13,14 In the integrated analysis of 2 pivotal clinical trials, ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone in hospitalized patients (FOCUS) 1 and FOCUS 2, ceftaroline fosamil was noninferior to ceftriaxone in clinical cure rates at test of cure (TOC; 8 to 15 days after end of therapy [EOT]) for treatment of patients with CABP.15 Each individual study also demonstrated noninferiority for the primary endpoint.16,17 Clinical cure was defined as resolution of all signs and symptoms of pneumonia or improvement such that no further antimicrobial therapy was necessary. Patients had to be afebrile (temperature # 38°C orally or # 38.5°C rectally or tympanically) for 24 consecutive hours with a return of CABP signs and symptoms to baseline levels.15 An additional outcome considered in this analysis was clinical response rate at Day 4, which was defined by both symptom response (improvement in $ 1 and worsening in none of cough, dyspnea, chest pain, and sputum production) and clinical stability (temperature # 38°C, heart rate # 100 beats per minute, respiratory rate # 24 breaths per minute, systolic blood pressure $ 90 mm Hg, oxygen saturation $ 90%, and absence of confusion/disorientation). We performed our subgroup analysis to assess clinical response rates at Day 4 and clinical cure rates at EOT and TOC in subjects with bacteremic CABP in the FOCUS trials.
Materials and Methods
The study designs of FOCUS 1 and FOCUS 2 (clinicaltrials.gov identifiers NCT00621504 and NCT00509106) were previously described.15,18 All randomized subjects who received any amount of study drug were included in the modified intent-to-treat (MITT) population, and the subgroup with CABP-associated bacteremia was defined as subjects with a pathogen consistent with pneumonia identified from blood cultures at baseline. For these subjects, 4 culture bottles were obtained from 2 separate venipunctures; repeat surveillance blood cultures were drawn until results were negative, and a central laboratory was used for verification and susceptibility testing. Our analysis includes summaries of baseline subject demographics, the distribution of baseline pathogens isolated from blood cultures, and outcomes at Day 4, EOT, and TOC for treatment with ceftaroline fosamil compared with ceftriaxone therapy in the bacteremic CABP subgroup. Data were analyzed using descriptive statistics only.
Results
In the FOCUS studies, 45 of 1228 subjects had CABPassociated bacteremia: 3.7% (23 of 614) in the ceftaroline fosamil-treated group and 3.6% (22 of 614) in the ceftriaxone-treated group. Low bacteremia rates in the FOCUS studies may have been due to limited enrollment of subjects with severe CABP and other patients who might have been at higher risk for bacteremia (eg, those who were immunosuppressed, required admission to the intensive care unit at baseline, were Pneumonia Outcomes Research Team [PORT] risk class V, had empyema, and/or a life-threatening illness). Demographic characteristics were similar between the 2 groups, although fever was more often seen in the ceftriaxone-treatment group (Table 1). The most common subject baseline bloodstream isolate was S. pneumoniae (Table 2). Other pathogens isolated included S. aureus, EschTable 1. Demographic and Baseline Characteristics of Subjects With Bacteremia at Baselinea by Treatment Group Characteristic
Ceftaroline Fosamil (n = 23)
Ceftriaxone (n = 22)
Mean age, years (SD) $ 65 Men, n (%) PORT risk class,b n (%) III IV Smoking history, n (%) Fever (. 38°C orally or . 38.5°C rectally or tympanically), n (%) Hypoxia (PAO2 , 60 mm Hg or O2 saturation , 90%), n (%) Fever or hypoxia, n (%) Both hypoxia and fever,c n (%) Radiology findings, n (%) Pleural effusiond Multilobar infiltrate Creatinine clearance (mL/min),e n (%) . 80 . 50 and # 80 . 30 and # 50 # 30
60.6 (16.1) 11 (47.8) 15 (65.2)
63.2 (16.2) 11 (50.0) 17 (77.3)
5 (21.7) 18 (78.3) 14 (60.9) 12 (52.2)
5 (22.7) 15 (68.2) 16 (72.7) 16 (72.7)
8 (34.8)
7 (31.8)
17 (73.9) 3 (13.0)
17 (77.3) 6 (27.3)
5 (21.7) 5 (21.7)
5 (22.7) 5 (22.7)
7 (30.4) 9 (39.1) 7 (30.4) 0
3 (13.6) 8 (36.4) 10 (45.5) 1 (4.5)
MITT population, pooled FOCUS data. In ceftriaxone arm, 1 subject had PORT risk class II, 1 subject had PORT risk class V. c Subjects who had fever but did not have PAO2 , 60 mm Hg or O2 saturation collected at baseline; and subjects who had hypoxia but did not have temperature collected at baseline were excluded. d Pleural effusion includes subjects with pleural effusion of any size on either right or left side. e Central lab values for subject creatinine clearance were used if available; otherwise, local lab values were used. Abbreviations: FOCUS, ceFtarOline Community-acquired pneUmonia trial vS ceftriaxone; MITT, modified intent-to-treat; PORT, Pneumonia Outcomes Research Team, in hospitalized patients. a
b
76
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 76
1/31/14 5:17 PM
Ceftaroline for Bacteremia Associated With CABP
Table 2. Pathogens Identified at Baseline From Positive Blood Cultures,a,b by Treatment Group Pathogen
Ceftaroline Fosamil Ceftriaxone (n = 23), n (%) (n = 22), n (%)
Gram-positive organisms Streptococcus pneumoniae MDRSPc PSSP Staphylococcus aureus MRSA Gram-negative organisms Escherichia coli Haemophilus influenzae Klebsiella pneumoniae Pseudomonas stutzeri
21 (91.3) 19 (82.6) 1 (4.3) 19 (82.6) 3 (13.0) 0 3 (13.0) 1 (4.3) 1 (4.3) 1 (4.3) 0
16 (72.7) 12 (54.5) 1 (4.5) 11 (50.0) 4 (18.2) 1 (4.5) 6 (27.3) 1 (4.5) 4 (18.2) 0 1 (4.5)
Subjects with . 1 pathogen isolated from a baseline blood culture could be counted in multiple categories. Two subjects in the ceftaroline fosamil-treated group had polymicrobial bacteremia, 1 with both S. pneumoniae and S. aureus, and 1 with both S. pneumoniae and E. coli. c Strains resistant to $ 2 antimicrobial classes, including penicillin, macrolides, tetracycline, fluoroquinolones, chloramphenicol, trimethoprim-sulfamethoxazole, and cephalosporins. Abbreviations: FOCUS, ceFtarOline Community-acquired pneUmonia trial vS ceftiaxone in hospitalized patients; MDRSP, multidrug-resistant S. pneumoniae; MITT, modified intent-to-treat; MRSA, methicillin-resistant S. aureus; PSSP, penicillinsusceptible S. pneumoniae.
Downloaded by [Florida State University] at 18:39 10 September 2015
b
erichia coli, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas stutzeri. The majority of subjects, with the exception of 2 in the ceftaroline fosamil-treated group, had monomicrobial bacteremia. For all subjects with bacteremia, the clinical response/cure rates were comparable between ceftaroline fosamil and ceftriaxone at all assessed time points (Day 4 [60.9% vs 59.1%], EOT [69.6% vs 72.7%], and TOC [69.6% vs 68.2%], respectively; (Table 3). For subjects with S. pneumoniae bacteremia, rates for improvement in $ 1 symptom (and no worsening in other symptoms) at Day 4 were similar between ceftaroline fosamil-treated and ceftriaxone-treated groups (84.2% and 83.3%, respectively). Clinical stability rates at Day 4 (68.4% vs 50.0%) and clinical cure rates at EOT (78.9% vs 75.0%) and TOC (78.9% vs 66.7%) were numerically higher for ceftaroline fosamil-treated compared with ceftriaxone-treated subjects, respectively (Table 3).
Discussion
Compared with the MITT population in the FOCUS studies, the subgroup of subjects with bacteremia were similar in age but had a higher incidence of moderate renal impairment (creatinine clearance level, 31–50 mL/min; 38% vs 15%).15 Additionally, a greater percentage of subjects with bacteremia had a PORT risk score of IV compared with the MITT population in the FOCUS studies (73% vs 38%).15 In the FOCUS studies, subjects with pneumococcal CABP (bacteremic and
Table 3. Response Rate at Day 4 EOT, TOC, for Subjects With Bacteremia at Baselinea Treated With Ceftaroline Fosamil or Ceftriaxone Visit Day 4b Overall Streptococcus pneumoniae Day 4 Symptom Improvementb,c Overall S. pneumoniae Day 4 Stability of Clinical Signsb Overall S. pneumoniae EOTb Overall S. pneumoniae TOCb Overall S. pneumoniae
Ceftaroline Fosamil (n = 23), n/N (%)
Ceftriaxone (n = 22), n/N (%)
14/23 (60.9) 11/19 (57.9)
13/22 (59.1) 6/12 (50.0)
20/23 (87.0) 16/19 (84.2)
19/22 (86.4) 10/12 (83.3)
16/23 (69.6) 13/19 (68.4)
13/22 (59.1) 6/12 (50.0)
16/23 (69.6) 15/19 (78.9)
16/22 (72.7) 9/12 (75.0)
16/23 (69.6) 15/19 (78.9)
15/22 (68.2) 8/12 (66.7)
MITT population, pooled FOCUS data. Number of responders/number of subjects in group (%). c Improvement in $ 1 clinical symptoms (and no worsening in others). Abbreviations: FOCUS, ceFtarOline Community-acquired pneUmonia trial vS ceftiaxone in hospitalized patients; EOT, end of therapy; MITT, modified intent-to-treat; TOC, test of cure.
a
b
non-bacteremic [sputum culture- or urine antigen-positive]) had clinical response rates at TOC of 85.5% in the ceftaroline fosamil-treated group versus 68.6% in the ceftriaxone-treated group,15 and the subgroup findings are consistent with the pneumococcal CABP response rates. The results described reflect subgroup analyses that are not sufficiently powered or designed to demonstrate noninferiority, however, they are hypothesis-generating for the subgroup of CABP subjects with bacteremia.
Conclusion
The data suggest that in the subset of subjects with CABPassociated bacteremia, ceftaroline fosamil demonstrated similar clinical outcomes at Day 4, EOT, and TOC compared with ceftriaxone. For subjects with S. pneumoniae bacteremia, which were the majority, the higher clinical outcomes appeared to be driven by improved stability in clinical signs at Day 4.
Acknowledgments
The results of the FOCUS 1 and FOCUS 2 studies on which our subgroup analysis is based have been previously published. Our study was supported by Cerexa, Inc., Oakland, CA, USA (a wholly-owned subsidiary of Forest Laboratories,
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 77 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 77
1/31/14 5:17 PM
Jandourek et al
Inc., New York, NY, USA). Cerexa, Inc., was involved in the design, collection, analysis, interpretation of data, and decision to present these results. Scientific Therapeutics Information, Inc., provided editorial assistance, which was funded by Forest Research Institute, Inc.
Downloaded by [Florida State University] at 18:39 10 September 2015
Conflict of Interest Statement
Alena Jandourek, MD, is an employee of Cerexa, Inc., Oakland, CA (a wholly-owned subsidiary of Forest Laboratories, Inc., New York, NY); Alexander Smith, MS, is an employee of Forest Laboratories, Inc., New York, NY, and receives stock/stock options in the company; Lily Llorens, PhD, is an employee of Cerexa, Inc., Oakland, CA (a whollyowned subsidiary of Forest Laboratories, Inc., New York, NY), and receives stock/stock options; Dirk A. Thye, MD, was previously an employee of Cerexa, which was acquired by Forest Laboratories; Paul B. Eckburg, MD, has nothing to declare; H. David Friedland, MD, MBA, is an employee of Forest Laboratories, Inc., and receives stock/stock options.
References 1. US Department of Health and Human Services. Centers for Disease Control. National Center for Health Statistics. Xu JQ, Kochanek KD, Murphy SL, Tejada-Vera B. Deaths: Final Data for 2007. National Vital Statistics Report. 2010;58(19):1–135. http://www.cdc.gov/nchs/data/ nvsr/nvsr58/nvsr58_19.pdf. Accessed Sept 30, 2013. 2. Lark RL, Saint S, Chenoweth C, Zemencuk JK, Lipsky BA, Plorde JJ. Four-year prospective evaluation of community-acquired bacteremia: epidemiology, microbiology, and patient outcome. Diagn Microbiol Infect Dis. 2001;41(1–2):15–22. 3. Metersky ML, Waterer G, Nsa W, Bratzler DW. Predictors of inhospital vs postdischarge mortality in pneumonia. Chest. 2012; 142(2):476–481. 4. Weinstein MP, Towns ML, Quartey SM, et al. The clinical significance of positive blood cultures in the 1990s: a prospective comprehensive evaluation of the microbiology, epidemiology, and outcome of bacteremia and fungemia in adults. Clin Infect Dis. 1997;24(4):584–602. 5. Mandell LA, Wunderink RG, Anzueto A; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–S72.
6. Richter SS, Heilmann KP, Dohrn CL, Riahi F, Beekmann SE, Doern GV. Changing epidemiology of antimicrobial-resistant S treptococcus pneumoniae in the United States, 2004–2005. Clin Infect Dis. 2009; 48(3):e23–e33. 7. Blasi F, Mantero M, Santus P, Tarsia P. Understanding the burden of pneumococcal disease in adults. Clin Microbiol Infect. 2012;18 (Suppl 5):7–14. 8. Palma I, Mosquera R, Demier C, Vay CA, Famiglietti A, Luna CM. Impact of bacteremia in a cohort of patients with pneumococcal pneumonia. J Bras Pneumol. 2012;38(4):422–430. 9. Choi S-H, Chung J-W, Sung H, et al. Impact of penicillin nonsusceptibility on clinical outcomes of patients with nonmeningeal Streptococcus pneumoniae bacteremia in the era of the 2008 Clinical and Laboratory Standards Institute penicillin breakpoints. Antimicrob Agents Chemother. 2012;56(9):4650–4655. 10. Lujan M, Gallego M, Fontanals D, Mariscal D, Rello J. Prospective observational study of bacteremia pneumococcal pneumonia: Effect of discordant therapy on mortality. Crit Care Med. 2004;32(3):625–631. 11. Flamm RK, Sader HS, Farrell DJ, Jones RN. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrob Agents Chemother. 2012;56(6):2933–2940. 12. Morrissey I, Ge Y, Janes R. Activity of the new cephalosporin ceftaroline against bacteraemia isolates from patients with community-acquired pneumonia. Int J Antimicrob Agents. 2009;33(6):515–519. 13. Kosowska-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other β-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother. 2010;54(5):1670–1677. 14. Moisan H, Pruneau M, Malouin F. Binding of ceftaroline to penicillinbinding proteins of Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother. 2010;65(4):713–716. 15. File TM Jr, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, double-blind, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis. 2010;51(12):1395–1405. 16. File TM Jr, Low DE, Eckburg PB, et al, on behalf of the FOCUS 1 investigators. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother. 2011; 66(Suppl 3):iii19–iii32. 17. Low DE, File TM Jr, Eckburg PB, et al; FOCUS 2 investigators. FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother. 2011;66(Suppl 3):iii33–iii44. 18. Eckburg PB, Friedland HD, Llorens L, et al. Day 4 clinical response of ceftaroline fosamil versus ceftriaxone for community-acquired bacterial pneumonia. Infect Dis Clin Pract. 2012;20(4):254–260.
78
© Hospital Practice, Volume 42, Issue 1, February 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
09_Jandourek.indd 78
1/31/14 5:17 PM
