Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function

Canut, Andrés; Isla, Arantxazu; Rodríguez-Gascón, Alicia

doi:10.1016/j.ijantimicag.2014.12.023

Cited by 36 publications

(15 citation statements)

References 22 publications

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“…Evidence assessing the effectiveness of antimicrobials other than vancomycin for the treatment of serious infections caused by MRSA isolates in patients with renal impairment is limited [19–21]. Only a few review studies, all with methodological limitations, attempted to address this question.…”

Section: Discussionmentioning

confidence: 99%

Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis

Liu¹,

Capitano

Stein

et al. 2017

BMC Nephrol

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BackgroundThe primary objective of this study is to assess whether baseline renal function impacts treatment outcomes of linezolid and vancomycin (with a dose-optimized regimen) for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia.MethodsWe conducted a retrospective cohort analysis of data generated from a prospective, randomized, controlled clinical trial (NCT 00084266). The analysis included 405 patients with culture-proven MRSA pneumonia. Baseline renal function was stratified based on creatinine clearance.Clinical and microbiological success rates and presence of nephrotoxicity were assessed at the end of treatment (EOT) and end of study (EOS). Multivariate logistic regression analyses of baseline patient characteristics, including treatment, were performed to identify independent predictors of efficacy. Vancomycin concentrations were analyzed using a nonlinear mixed-effects modeling approach. The relationships between vancomycin exposures, pharmacokinetic-pharmacodynamic index (trough concentration, area under the curve over a 24-h interval [AUC0–24], and AUC0–24/MIC) and efficacy/nephrotoxicity were assessed in MRSA pneumonia patients using univariate logistic regression or Cox proportional hazards regression analysis approach.ResultsAfter controlling for use of vasoactive agents, choice of antibiotic therapy and bacteremia, baseline renal function was not correlated with clinical and microbiological successes in MRSA pneumonia at either end of treatment or at end of study for both treatment groups. No positive association was identified between vancomycin exposures and efficacy in these patients. Higher vancomycin exposures were correlated with an increased risk of nephrotoxicity (e.g., hazards ratio [95% confidence interval] for a 5 μg/ml increase in trough concentration: 1.42 [1.10, 1.82]).ConclusionsIn non-dialysis patients, baseline renal function did not impact the differences in efficacy or nephrotoxicity with treatment of linezolid versus vancomycin in MRSA pneumonia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-017-0581-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis

Liu¹,

Capitano

Stein

et al. 2017

BMC Nephrol

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“…The study concluded that the 600 mg q12h regimen was adequate against most clinical isolates; however, more frequent dosing (i.e., q8h) or the use of combination therapy may be more suitable for serious, deep-seated infections due to MRSA. In addition, a literature-based analysis of pharmacokinetic and microbiological data by Canut et al concluded that in patients with normal renal function, 600 mg q12h should be adequate to treat CABP caused by a number of organisms, including MSSA (24). However, in the case of MRSA, they concluded that ceftaroline fosamil at 600 mg q8h as a 2-h infusion may be more appropriate.…”

Section: Discussionmentioning

confidence: 99%

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

Riccobene¹,

Pushkin²,

Jandourek³

et al. 2016

Antimicrob Agents Chemother

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c Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with bactericidal activity against Grampositive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to (i) evaluate ceftaroline concentrations in human plasma and epithelial lining fluid (ELF) and (ii) develop a population pharmacokinetic (PK) model for plasma and ELF to be used in PK/pharmacodynamic (PD) target attainment simulations. Ceftaroline concentrations in ELF and plasma at steady state (day 4) were measured in healthy adult subjects for two dosages: 600 mg every 12 h (q12h) and 600 mg every 8 h (q8h). Both were well tolerated with no serious adverse events. The penetration of free ceftaroline into ELF, assuming 20% protein binding in plasma and no protein binding in ELF, was Ϸ23%. The population PK model utilized a two-compartment model for both ceftaroline fosamil and ceftaroline. Goodness-of-fit criteria revealed the model was consistent with observed data and no systematic bias remained. At 600 mg q12h and a MIC of 1 mg/liter, 98.1% of simulated patients would be expected to achieve a target free drug concentration above the MIC (fT>MIC) in plasma of 42%, and in ELF 81.7% would be expected to achieve a target fT>MIC of 17%; at 600 mg q8h, 100% were predicted to achieve an fT>MIC in plasma of 42% and 94.7% to achieve an fT>MIC of 17% in ELF. The literature and data suggest the 600 mg q12h dose is adequate for MICs of <1 mg/liter. There is a need for clinical data in patients with MRSA pneumonia and data to correlate PK/PD relationships in ELF with clinical outcomes. C eftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin antibiotic with bactericidal activity against Gram-positive organisms, including penicillin-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA) (1, 2). Ceftaroline is also active in vitro against Gram-negative organisms such as Haemophilus influenzae and Moraxella catarrhalis and non-extended-spectrum ␤-lactamaseproducing Enterobacteriaceae (1, 2). Ceftaroline fosamil is approved in the United States for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), with approval in Europe for similar indications. At a dosage of 600 mg every 12 h (q12h), ceftaroline fosamil demonstrated noninferiority to ceftriaxone given at 1 g q24h in the treatment of patients with moderate to severe CABP in two phase 3 clinical studies (ClinicalTrials registration no. NCT00621504 and NCT00509106) (3-5). Ceftaroline fosamil (600 mg q12h) has also been demonstrated to be superior to ceftriaxone (2 g q24h) in the treatment of Asian patients with community-acquired pneumonia (ClinicalTrials registration no. NCT01371838) (6), and in a recent meta-analysis ceftaroline fosamil was shown to be superior to ceftriaxone as an empirical treatment for adult patients hospitalized with PORT risk class 3 to 4 community-acquired pneumonia (7). Ceftaro...

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“…Regarding the dosage of ceftaroline, it has been previously proposed that 600 mg every 8 hours instead of every 12 hours would be more effective in patients with normal renal function, especially if the risk of MRSA infection is high [17]. The tolerance of this regimen was compared to standard therapy by Cheng et al [18], who found a comparable safety profile.…”

Section: Discussionmentioning

confidence: 99%

Ceftaroline fosamil: clinical experience after 23-month prescription in a tertiary hospital

Álvarez¹,

Merino²,

Corral³

et al. 2021

Rev Esp Quimioter

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Objective. To determine the indications, success rate and adverse effects of ceftaroline fosamil treatment in a tertiary hospital. Material and methods. In total, 84 cases from February 2018 to December 2019 were retrospectively analysed. No exclusion criteria were applied. Results. Eighty-four patients, with a median age of 70 years, of which, 6.7% (56) were male, were treated with ceftaroline fosamil for a median of 14 days. Most indications were off-label, including 29 endocarditis (34.5%), 14 bacteraemia (16.6%), 5 Central nervous system (CNS) infections (6%) and 19 osteoarticular infections (22.6%). Staphylococcus aureus was the most frequently isolated microorganism, including 28 methicillin-sensitive S. aureus (MSSA; 33.3%) and 14 methicillin-resistant S. aureus (MRSA; 16.7%), followed by coagulase-negative Staphylococcus (23, 27.4%). The main reason for ceftaroline fosamil prescription was the failure of previous treatment (41.7% of cases). Treatment was successful in 60/84 patients (71.4%) and failed clinically or microbiologically in 14 (16.7%). Eight patients died for a reason not related to the infection and two were found to have a non-infectious condition. Twenty-two of thirty-five (62.8%) patients prescribed ceftaroline because of failure of previous treatment improved, including eight endocarditis and seven bacteraemia. Adverse effects were reported in five patients (5.9%) including neutropenia, thrombocytopenia, transaminases elevation and creatinine elevation; all except one were mild and all resolved after discontinuation of treatment. Conclusions. Ceftaroline fosamil is a well-tolerated cephalosporine, effective against multi- resistant gram-positive and many gram-negative microorganisms. Our experience suggests that it is effective as a rescue or first-line therapy in other indications than those currently approved.

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Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function

Cited by 36 publications

References 22 publications

Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis

Clinical outcomes of linezolid and vancomycin in patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus stratified by baseline renal function: a retrospective, cohort analysis

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects

Ceftaroline fosamil: clinical experience after 23-month prescription in a tertiary hospital

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