Assessment of time to clinical response, a proxy for discharge readiness, among hospitalized patients with community-acquired pneumonia who received either ceftaroline fosamil or ceftriaxone in two phase III FOCUS trials.
Adult; Aged; Anti-Bacterial Agents/*therapeutic use; Bacterial/*drug therapy; Ceftriaxone/*therapeutic use; Cephalosporins/*therapeutic use; Community-Acquired Infections/*drug therapy; Female; Humans; Male; Middle Aged; Pneumonia; Treatment Outcome
The primary driver of health care costs for patients with community-acquired pneumonia (CAP) is the hospital length of stay (LOS). Unfortunately, hospital LOS comparisons are difficult to make from phase III CAP trials because of their structured designs and prespecified treatment durations. However, an opportunity still exists to draw inferences about potential LOS differences between treatments through the use of surrogates for hospital discharge. The intent of this study was to quantify the time to a clinical response, a proxy for the time to discharge readiness, among hospitalized CAP patients who received either ceftaroline or ceftriaxone in two phase III CAP FOCUS clinical trials. On the basis of the Infectious Diseases Society of America and American Thoracic Society CAP management guidelines and recent FDA guidance documents for community-acquired bacterial pneumonia, a post hoc adjudication algorithm was constructed a priori to compare the time to a clinical response, a proxy for the time to discharge readiness, between patients who received ceftaroline or ceftriaxone. Overall, 1,116 patients (ceftaroline, n=562; ceftriaxone, n=554) from the pooled FOCUS trials met the selection criteria for this analysis. Kaplan-Meier analyses showed that ceftaroline was associated with a shorter time, measured in days, to meeting the clinical response criteria (P=0.03). Of the patients on ceftaroline, 61.0, 76.1, and 83.6% achieved a clinical response by days 3, 4, and 5, compared to 54.3, 69.8, and 79.3% of the ceftriaxone-treated patients. In the Cox regression, ceftaroline was associated with a shorter time to a clinical response (HR, 1.16, P=0.02). The methodology employed here provides a framework to draw comparative effectiveness inferences from phase III CAP efficacy trials. (The FOCUS trials whose data were analyzed in this study have been registered at ClinicalTrials.gov under registration no. NCT00621504 and NCT00509106.).
Lodise Thomas P; Anzueto Antonio R; Weber David J; Shorr Andrew F; Yang Min; Smith Alexander; Zhao Qi; Huang Xingyue; File Thomas M
Antimicrobial agents and chemotherapy
2015
2015-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1128/AAC.03643-14" target="_blank" rel="noreferrer noopener">10.1128/AAC.03643-14</a>
Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials.
Anti-Bacterial Agents/*therapeutic use; Bacterial/*drug therapy; Ceftriaxone/*therapeutic use; Cephalosporins/*therapeutic use; Community-Acquired Infections/*drug therapy; Humans; Pneumonia; Randomized Controlled Trials as Topic
BACKGROUND: We conducted a meta-analysis of clinical trials of adults hospitalized with pneumonia outcomes research team (PORT) risk class 3-4 community-acquired pneumonia (CAP) receiving ceftaroline fosamil versus ceftriaxone. METHODS: Three Phase III trials (clinicaltrials.gov registration numbers NCT00621504, NCT00509106 and NCT01371838) including 1916 hospitalized patients with CAP randomized 1:1 to empirical ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (1-2 g every 24 h) for 5-7 days were included in the meta-analysis. Primary outcome was clinical response at the test-of-cure visit (8-15 days after end of treatment) in the PORT risk class 3-4 modified ITT (MITT) and clinically evaluable (CE) populations. Data were tested for heterogeneity (chi(2) test) and, if not significant, results were pooled and OR and 95% CI constructed. A logistic regression analysis assessed factors impacting cure rate and treatment interactions. RESULTS: Clinical cure rates in each trial consistently favoured ceftaroline fosamil versus ceftriaxone, with no evidence of heterogeneity. In the meta-analysis, ceftaroline fosamil was superior to ceftriaxone in the MITT (OR: 1.66; 95% CI 1.34, 2.06; P \textless 0.001) and CE (OR: 1.65; 95% CI 1.26, 2.16; P \textless 0.001) populations. Results were consistent across various patient- and disease-related factors including patients' age and PORT score. Prior antimicrobial use within 96 h of starting study treatment was associated with diminished differences in cure rates between treatments. CONCLUSIONS: Ceftaroline fosamil was superior to ceftriaxone for empirical treatment of adults hospitalized with CAP. Receipt of prior antimicrobial therapy appeared to diminish the observed treatment effect.
Taboada Maria; Melnick David; Iaconis Joseph P; Sun Fang; Zhong Nan Shan; File Thomas M; Llorens Lily; Friedland H David; Wilson David
The Journal of antimicrobial chemotherapy
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/jac/dkv415" target="_blank" rel="noreferrer noopener">10.1093/jac/dkv415</a>
FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.
80 and over; 80 and Over; Aged; Bacteria; Bacteria/isolation & purification; Bacterial – Drug Therapy; Bacterial/*drug therapy; Ceftriaxone – Administration and Dosage; Ceftriaxone – Adverse Effects; Ceftriaxone/administration & dosage/adverse effects; Cephalosporins – Administration and Dosage; Cephalosporins – Adverse Effects; Cephalosporins/*administration & dosage/*adverse effects; Community-Acquired Infections – Drug Therapy; Community-Acquired Infections/*drug therapy; Double-Blind Method; Double-Blind Studies; Female; Human; Humans; Infusions; Intravenous; Male; Middle Age; Middle Aged; Pneumonia; Randomized Controlled Trials; Treatment Outcome; Treatment Outcomes
OBJECTIVES: Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) \textgreater/= -10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. METHODS: Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504). RESULTS: Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (-0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar rates of AEs, serious AEs, deaths and discontinuations because of an AE. The most common AEs for ceftaroline fosamil-treated patients were diarrhoea, headache, insomnia and nausea, and the most common AEs for ceftriaxone-treated patients were hypokalaemia, hypertension, nausea and diarrhoea. CONCLUSIONS: Ceftaroline fosamil demonstrated high clinical cure and microbiological response rates in hospitalized patients with CAP of PORT risk class III or IV. Ceftaroline fosamil was well tolerated, with a safety profile similar to that of ceftriaxone and consistent with the cephalosporin class. In this study, ceftaroline fosamil was an effective and well-tolerated treatment option for CAP.
File Thomas M Jr; Low Donald E; Eckburg Paul B; Talbot George H; Friedland H David; Lee Jon; Llorens Lily; Critchley Ian A; Thye Dirk A
The Journal of antimicrobial chemotherapy
2011
2011-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1093/jac/dkr096" target="_blank" rel="noreferrer noopener">10.1093/jac/dkr096</a>
A new dosing paradigm: high-dose, short-course fluoroquinolone therapy for community-acquired pneumonia.
Community-Acquired Infections/*drug therapy; Fluoroquinolones/*administration & dosage/pharmacology/therapeutic use; Humans; Ofloxacin/administration & dosage/pharmacology/therapeutic use; Pneumococcal/*drug therapy; Pneumonia; Safety; Time Factors; Treatment Outcome
The goals of optimal antimicrobial therapy are to treat infection effectively, to improve the clinical condition of the patient, and to prevent the emergence of resistant bacterial strains. For ideal drug usage the World Health Organization recommends administering the correct drug by the best route, in the right amount, at optimum intervals for the appropriate period, and after an accurate diagnosis. This article discusses the use of high-dose, short-course fluoroquinolone therapy as an effective option for patients with community-acquired pneumonia.
File Thomas M Jr
Clinical Cornerstone
2003
1905-6
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s1098-3597(03)90026-3" target="_blank" rel="noreferrer noopener">10.1016/s1098-3597(03)90026-3</a>
Macrolide therapy for community-acquired pneumonia due to atypical pathogens: outcome assessment at an early time point.
80 and over; Adult; Aged; Anti-Bacterial Agents/adverse effects/*therapeutic use; Atypical pathogen; Bacterial/*drug therapy; Ceftaroline fosamil; Ceftriaxone/adverse effects/*therapeutic use; Cephalosporins/adverse effects/*therapeutic use; Chlamydial Pneumonia; Chlamydophila pneumoniae; Clinical Trials; Combination/adverse effects/methods; Community-Acquired Infections/*drug therapy; Community-acquired pneumonia; Double-Blind Method; Drug Therapy; Female; Humans; Legionella pneumophila; Macrolide; Macrolides/adverse effects/*therapeutic use; Male; Middle Aged; Mycoplasma; Mycoplasma pneumoniae; Phase III as Topic; Pneumonia; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome
BACKGROUND: Therapy directed against atypical pathogens in patients with community-acquired pneumonia (CAP) is often recommended. This post-hoc analysis evaluated the effect of addition of a macrolide to ceftaroline fosamil or ceftriaxone treatment in atypical CAP. METHODS: Two phase 3, double-blind, comparative safety and efficacy studies of ceftaroline fosamil vs. ceftriaxone, FOCUS 1 and FOCUS 2, enrolled adults with CAP. Only FOCUS 1 included 24-h adjunctive clarithromycin therapy for all patients on day 1. Day 4 and test-of-cure (TOC) outcomes were compared for adjunctive vs. no adjunctive therapy. RESULTS: Of 1240 enrolled patients, 130 patients with CAP due to atypical pathogens alone were included (FOCUS 1, n = 64; FOCUS 2, n = 66). Among patients infected with Mycoplasma pneumoniae and/or Chlamydophila pneumoniae alone, a higher clinical response rate was observed with clarithromycin plus ceftaroline fosamil or ceftriaxone compared with treatment without additional clarithromycin at day 4 [38/49 (77.6%; FOCUS 1) vs. 24/43 (55.8%; FOCUS 2)], but not at the TOC assessment [42/49 (85.7%; FOCUS 1) vs. 41/43 (95.3%; FOCUS 2)]. In patients infected with Legionella pneumophila alone, a higher clinical response rate with adjunctive clarithromycin therapy was observed at the TOC assessment alone [12/12 (100%; FOCUS 1) vs. 14/19 (73.7%; FOCUS 2)]. The unadjusted odds ratio of a favourable clinical response at day 4 with adjunctive clarithromycin vs. no adjunctive clarithromycin was 2.4 (95% confidence interval 1.1-5.1; P = 0.0299) for all pathogens combined. CONCLUSIONS: These results suggest that empirical antibiotic therapy against atypical pathogens may improve early clinical response rate. This hypothesis is best evaluated in a prospective trial.
File Thomas M Jr; Eckburg Paul B; Talbot George H; Llorens Lily; Friedland H David
International journal of antimicrobial agents
2017
2017-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ijantimicag.2017.01.043" target="_blank" rel="noreferrer noopener">10.1016/j.ijantimicag.2017.01.043</a>