FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia

Low, Donald E.; File, Thomas M.; Eckburg, Paul B.; Talbot, George H.; Friedland, H. David; Lee, Jon; Llorens, Lily; Critchley, Ian A.; Thye, Dirk; Corral, Jorge; Giugno, Eduardo; Arzac, Maria del Rosario Gonzalez; Maurizi, Diego; Altclas, Javier; Ambasch, Germán; Jasovich, Abel; Minguez, Angel Ramon; Oliva, María Eugenia; Teglia, Osvaldo; Bergallo, Carlos; Mastruzzo, María; Morera, Graciana; Scapellato, Pabio Gustavo; Lamberghini, Ricardo; Mykietiuk, Analía; Remolif, Christian; Monge, Manuel Jose Barros; Barker, Maria Isabel Enriqueta Campos; Steinmann, Sara Mireya Chernilo; Gutierrez, Pablo Antonio Gaete; Vejar, Sylvia Susana Muñoz; Arellano, Mario Andres Calvo; Anania, Carolina Eugenia Chahin; Cruz, Arturo Jáuregui; Tapia, Gerardo Amaya; Kaldman, Moises Acuna; Noriega, Eduardo Rodríguez; Prado, Eduardo; Ramos, Carlos A.; Andreeva, Irina V.; Абышев, Р. А.; Antonovsky, Yuri; Balyuzek, Marina; Esina, Alla L.; Gorelov, Alexander; Хрусталев, О.А.; Kozlov, Roman; Novozhenok, Vladislav; Popova, Veronika B.; Sobchenko, Svetlana; Trofimov, V. I.; Yakovlev, S B; Жидков, К. П.; Ambert, Luminta Gabriela; Fierbinteau, Carmen Georgeta; Ionescu, Valentina; Muresan, Mihai Marius; Tănăseanu, Cristina; Georgiev, Ognian; Hodzhev, Valdimir; Marinov, Rosen; Metev, Hristo; Peneva, M; Popov, Dimitar; Simeonova, Milkana; Krastiņš, Ivars; Lovcinovsk, Viktors; Silins, Viesturs; Svarcberga, Vita; Bargon, Joachim; Bauer, T.; Bergmann, Rolf; Meyer, Felicity J.; Mueller, Thomas; Welte, Tobias; Gläeser, Sven; Hammerl, Peter; Kern, Hartmut; Krueger, Stefan; Kujath, P.; Lies, Achim; Schaberg, T.; Schmalz, Oliver; Schütte, Wolfgang; Chazan, Ryszarda; Górecka, Dorota; Rogala, Barbara; Antczak, Adam; Grodzicki, Tomasz; Jahnz—Rö, Karina; Milanowski, Janusz; Nalepa, P; Wróbel-Rajzer, Malgorzata; Szelerska-Twardosz, Hanna; Grzelewska-Rzymowska, Iwona; Kachel, Tomasz; Marciniak, Andrzej; Panaszek, Bernard; Szczeklik, Andrzej; Kozielski, Jerzy; Harat, Rafał; Jastrzebsk, Dariusz; Juszczak, Jacek; Labij, Violetta; Vetter, N; Bolitschek, J; Eckmayr, Josef; Molnár, Sándor; Pápai-Székely, Zsolt; Szegedi, János; Vinkler, Ilona; Borscchivskyy, Mykhaylo; Dziublyk, Oleksandr; Dzyak, G. V.; Kraydaschenko, Oleg; Mostovoy, Yuriy; Rudyk, Iurii; Sushko, Viktor; Візір, Вадим Анатолійович; Bhattacharya, Amal; Chakrapan, Mahabala; D’Souza, George; Malpani, G.S.; Mehta, Parthiv; Rao, KL Narasimha; Talwar, Deepak

doi:10.1093/jac/dkr097

Cited by 174 publications

(163 citation statements)

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“…This study was approved by the AMCH Institutional Review Board committee (protocol 3216), and a waiver of informed consent was obtained. The study criteria were modeled after those of the ceftaroline fosamil versus ceftriaxone CAP phase III (FOCUS) trials (7)(8)(9)(10). Patients were included if they had the presence of a new or increasing pulmonary infiltrate(s) on chest radiograph or other imaging technique along with at least 3 of the following clinical features: new or increased cough, purulent sputum or change in sputum character, auscultatory findings consistent with pneumonia (e.g., rales, egophony, consolidation), dyspnea, tachypnea or hypoxemia, an oral temperature of Ͼ38°C (Ͼ38.5°C rectally or tympanically) or hypothermia (Ͻ35°C), a white blood cell count of Ͼ10,000 cells/mm 3 or Ͻ4,500 cells/mm 3 , and Ͼ15% immature neutrophils (bands) (6).…”

Section: Methodsmentioning

confidence: 99%

“…In the past, efficacy assessments involved patients with CAP. This is a critical distinction, since the etiology of CAP is often unknown in both clinical trials and clinical practice (5)(6)(7)(8)(9)(10)(11). In clinical trials, a bacterial pathogen is identified in only 25% of cases (7)(8)(9)(10)(11).…”

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confidence: 99%

“…One of the criticisms of the FOCUS trials was the restricted use of concomitant macrolide therapy, which was permitted only in the FOCUS 1 trial and was limited to 24 h (7)(8)(9). This is inconsistent with the empirical regimens currently recommended by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), CMS, and ATS/IDSA (6,18).…”

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confidence: 99%

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Relationship between Time to Clinical Response and Outcomes among Pneumonia Outcomes Research Team (PORT) Risk Class III and IV Hospitalized Patients with Community-Acquired Pneumonia Who Received Ceftriaxone and Azithromycin

Zasowski

Butterfield

McNutt

et al. 2014

Antimicrob Agents Chemother

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Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P ‫؍‬ 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indictor of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Relationship between Time to Clinical Response and Outcomes among Pneumonia Outcomes Research Team (PORT) Risk Class III and IV Hospitalized Patients with Community-Acquired Pneumonia Who Received Ceftriaxone and Azithromycin

Zasowski

Butterfield

McNutt

et al. 2014

Antimicrob Agents Chemother

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“…The objective of the analyses described herein was to conduct similar such PK-PD analyses for efficacy by using data from two phase III studies of patients with CABP (ClinicalTrials.gov registration numbers NCT00621504 and NCT00509106) in which the efficacy and safety of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h were evaluated (6,7).…”

mentioning

confidence: 99%

“…Patients were also required to have radiographic evidence of pneumonia, to have acute illness with at least three clinical signs or symptoms consistent with lower respiratory tract infection, and to be in Patient Outcome Research Team (PORT) risk class III or IV. Additional details regarding the inclusion and exclusion criteria for these studies are provided elsewhere (6,7).…”

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confidence: 99%

Pharmacokinetic-Pharmacodynamic Analyses for Efficacy of Ceftaroline Fosamil in Patients with Community-Acquired Bacterial Pneumonia

Bhavnani

Hammel

Wart

et al. 2013

Antimicrob Agents Chemother

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c Pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy using phase III trial data from patients treated with a ceftaroline fosamil dosing regimen of 600 mg intravenously (i.v.) every 12 h (q12h) for 5 to 7 days for community-acquired bacterial pneumonia (CABP) were conducted. High clinical and microbiological success rates (84.7 and 86.3%, respectively) and percentages of time during the dosing interval that free-drug steady-state concentrations remained above the MIC (f%T>MIC) (98.4% had f%T>MIC values of >63.3) were observed among 124 microbiologically evaluable patients. As a result, significant PK-PD relationships could not be identified. These data provide support for the use of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h to treat patients with CABP. R esults of pharmacokinetic (PK)-pharmacodynamic (PD)analyses have increasingly been used to support drug development, both early in development to make decisions about dosing regimens and then in late-stage development to confirm these decisions (1). Such analyses were carried out for ceftaroline fosamil, a water-soluble prodrug of ceftaroline (2). Ceftaroline is a broad-spectrum cephalosporin with activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), including methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae, respectively. Ceftaroline fosamil is approved by the FDA for the treatment of patients with ABSSSI and CABP and for similar such indications in Europe (3,4,5).By using data from ceftaroline-treated patients with ABSSSI enrolled in two phase II and two phase III studies, PK-PD efficacy analyses were carried out (2). The results of these analyses demonstrated a relationship between ceftaroline exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remained above the MIC (f%TϾMIC) and microbiological response. Given that a ceftaroline fosamil dosing regimen of 600 mg given intravenously (i.v.) every 12 h (q12h) provided exposures associated with the upper plateau of the PK-PD relationship identified for efficacy, these data provided support for the use of this dosing regimen for the treatment of patients with ABSSSI. The objective of the analyses described herein was to conduct similar such PK-PD analyses for efficacy by using data from two phase III studies of patients with CABP (ClinicalTrials.gov registration numbers NCT00621504 and NCT00509106) in which the efficacy and safety of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h were evaluated (6, 7).In each of the above-described phase III studies, patients received two consecutive infusions of 300 mg of ceftaroline fosamil i.v. q12h, each infused over 30 min for a total dose of 600 mg and a total infusion time of 60 min, with dose adjustments for patients with moderate renal impairment. The total duration of treatment was 5 to 7 days. Patients were eligible fo...

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Antibiotic Against Gram‐Negative Bacteria

Faiyaz

Gupta

2019

High Value Fermentation Products

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FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia

Cited by 174 publications

References 17 publications

Relationship between Time to Clinical Response and Outcomes among Pneumonia Outcomes Research Team (PORT) Risk Class III and IV Hospitalized Patients with Community-Acquired Pneumonia Who Received Ceftriaxone and Azithromycin

Relationship between Time to Clinical Response and Outcomes among Pneumonia Outcomes Research Team (PORT) Risk Class III and IV Hospitalized Patients with Community-Acquired Pneumonia Who Received Ceftriaxone and Azithromycin

Pharmacokinetic-Pharmacodynamic Analyses for Efficacy of Ceftaroline Fosamil in Patients with Community-Acquired Bacterial Pneumonia

Antibiotic Against Gram‐Negative Bacteria

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