Dataset Information

Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.

ABSTRACT: Objectives:To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600?mg q8h by 2?h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4?mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate?=?2?mg/L and resistant >2?mg/L). Methods:A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600?mg q12h by 1?h iv infusion or 600?mg q8h by 2?h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1?log10 kill and 35% fT>MIC for 2?log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study. Results:The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600?mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ?2?mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600?mg q8h dosage regimen against S. aureus with ceftaroline MICs ?4?mg/L. Conclusions:The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

SUBMITTER: Das S

PROVIDER: S-EPMC6337900 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.

Das Shampa S Li Jianguo J Iaconis Joseph J Zhou Diansong D Stone Gregory G GG Yan Jean Li JL Melnick David D

The Journal of antimicrobial chemotherapy 20190201 2

<h4>Objectives</h4>To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L).<h4>Methods</h4>A ...[more]

PMID: 30380060

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Project description:INTRODUCTION:Acute bacterial skin and skin structure infections (ABSSSIs) remain among the most common infectious processes seen in the clinical setting. For patients with complicated ABSSSIs deemed to require intravenous antibiotics, vancomycin remains the mainstay therapy. Ceftaroline has been shown to be non-inferior to vancomycin and may result in faster resolution of signs of infection. METHODS:Multicenter, prospective, open-label, randomized trial of ceftaroline versus vancomycin for the treatment of adult patients admitted for management of ABSSSIs from April 2012 to May 2016; 166 patients in the clinically evaluable (CE) group were needed to determine a 20% difference in primary outcome of clinical response at day 2 or 3 of antibiotics. Clinical response was defined as cessation of spread of lesion and improvement in systemic signs/symptoms of infection. A secondary outcome was a ≥ 20% reduction in lesion size at day 2 or 3 of antibiotics. RESULTS:One hundred seventy-four patients were enrolled in the intention-to-treat (ITT) group and 108 were CE. Among CE patients, 54 were randomized to ceftaroline and 54 to vancomycin. Baseline characteristics were similar except patients in the ceftaroline arm were older and had a non-significantly higher degree of comorbidities (median Charlson score 2 vs. 4, respectively). Cellulitis was the most common type of ABSSSI (85.2% vs. 79.6%, respectively). Rapid diagnostic testing of available cultures (n = 55) demonstrated high agreement with clinical microbiology for identification of Staphylococcus aureus (100%) and MRSA (100%). There was no significant difference in primary outcome of day 2 or 3 clinical response (50.0% vs. 51.9%). CONCLUSION:Early clinical response between vancomycin- and ceftaroline-treated ABSSSIs was similar. Patients with ABSSSIs rarely remained hospitalized for > 2-3 days, thus limiting our ability to critically assess clinical outcomes. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT02582203. FUNDING:Allergan plc.

Project description:AimExploratory analyses evaluated patient characteristics and outcomes among patients with complicated skin and soft tissue infection (cSSTI) in the phase 3 COVERS study who were admitted to an intensive care unit (ICU).MethodsAdults with cSSTI (surface area ≥ 75 cm2) and evidence of systemic inflammation and/or underlying comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h [q8h]) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g q8h) for 5-14 days. Clinical response and ICU length of stay (LOS) within first hospitalization were evaluated in the modified intent-to-treat (MITT) and clinically evaluable (CE) populations; a Cox proportional hazards model identified factors associated with increased hospital LOS.ResultsOverall, 42 of 761 randomized patients were admitted to the ICU (ceftaroline fosamil, n = 32; vancomycin plus aztreonam, n = 10) prior to, or at start of, study treatment. Baseline differences between the ICU and non-ICU populations were indicative of more severe disease in ICU patients; within this subset, there were also some notable imbalances between treatment groups. Clinical cure rates at test-of-cure (ceftaroline fosamil vs. vancomycin plus aztreonam) were generally similar in the non-ICU and ICU subsets (MITT population 79% vs. 79% and 69% vs. 90.0%, respectively; CE population 87% vs. 85% and 80% vs. 89%, respectively). Median ICU LOS was 8 vs. 13 days, respectively. ICU admission was a risk factor predicting increased hospital LOS (P < 0.001).ConclusionsClinical outcomes for patients admitted to the ICU were generally similar to non-ICU patients, despite more severe baseline disease, with shorter median treatment duration in the ceftaroline fosamil group. ICU admission was associated with longer hospital LOS. Given the small sample size and unbalanced patient and disease characteristics within the ICU subgroup, differences between treatment groups should be interpreted with caution.Trial registrationClinicalTrials.gov identifier, NCT01499277.

Project description:IntroductionMeticillin-resistant staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant infections worldwide. Its prevalence remains high in the Greek hospital setting. Complicated skin and soft tissue infections (cSSTIs) due to MRSA are associated with prolonged hospitalization, additional healthcare costs and significant morbidity. The purpose of this study was to conduct a cost analysis and a budget impact analysis relative to different management scenarios for MRSA-cSSTIs from a hospital perspective.MethodsEqual efficacy was assumed for the pharmacotherapies under evaluation and resource use was elicited via an expert panel of seven local infectious disease specialists. The model was based on a previously published economic model that was adapted for the Greek hospital setting and included a decision tree for the management of hospitalized patients with MRSA-cSSTIs, which simulated costs and outcomes for the duration of hospitalization according to the therapeutic scenario. Inpatient costs consisted of hospitalization, diagnostic/laboratory testing, physician visits and antibiotic treatment.ResultsCurrent economic impact of MRSA-cSSTIs for the inpatient setting in Greek hospitals was estimated at €29,196,218. Total per patient cost according to first-line agent was €2,457, €2,762, €2,850, €3,494 and €3,094 and mean length of stay was 9.2, 12.5, 10.3, 13.0 and 14.0 days for linezolid, vancomycin, daptomycin, tigecycline, and teicoplanin, respectively. An estimated 10,287 MRSA-cSSTI patients are treated annually in Greek hospitals. Thus, increasing the use of linezolid by 11% over a 3-year period (current use 19%; 3 year projection 30%), for the management of MRSA-cSSTIs, could result in 3-year savings of €896,065.ConclusionManagement of MRSA-cSSTI requires intensive resource use; overall healthcare costs differ according to the chosen first-line treatment. In light of considerable budget constraints, development of hospital strategies which facilitate early discharge, such as the introduction of clinical criteria and guidelines for switching from intravenous to oral MRSA-cSSTI therapy, could result in substantial savings for the Greek hospital budget.

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Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.

Publications

Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.

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