Pharmacokinetic-Pharmacodynamic Analysis for Efficacy of Ceftaroline Fosamil in Patients with Acute Bacterial Skin and Skin Structure Infections

BC-3781 is a novel semisynthetic pleuromutilin antibiotic inhibiting bacterial protein synthesis. BC-3781 has completed a phase 2 clinical trial in acute bacterial skin and skin structure infections (ABSSSI). Its antibacterial spectrum additionally covers the predominant pathogens causing community-acquired bacterial pneumonia (CABP). In this study, the antibacterial activity of BC-3781 was evaluated against a contemporary collection of 10,035 bacterial isolates predominately causing ABSSSI and CABP, among other infections, collected within the SENTRY Antimicrobial Surveillance Program worldwide in 2010. BC-3781 exhibited potent activity against organisms commonly isolated from ABSSSI such as Staphylococcus aureus (MIC 50/90 , 0.12/0.12 g/ ml; 99.8% inhibited at <0.5 g/ml), beta-hemolytic streptococci (MIC 50/90 , 0.03/0.03 g/ml; 99.3% inhibited at <0.5 g/ml), and coagulase-negative staphylococci (CoNS; MIC 50/90 , 0.06/0.12 g/ml; 97.8% inhibited at <1 g/ml). BC-3781 displayed similar MIC distributions among methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) S. aureus strains. BC-3781 was also active against Enterococcus faecium, with 76.3% of vancomycin-susceptible and 97.0% of vancomycin-resistant isolates being inhibited at BC-3781 concentrations of <1 g/ml. Beta-hemolytic and viridans group streptococci were highly susceptible to BC-3781, with 99.3% and 96.7% of isolates inhibited at <0.5 g/ml, respectively. Further, activity of BC-3781 against Streptococcus pneumoniae (MIC 50/90 , 0.12/0.25 g/ml), Haemophilus influenzae (MIC 50/90 , 1/2 g/ml), and Moraxella catarrhalis (MIC 50/90 , 0.12/0.25 g/ml) was not negatively influenced by ␤-lactamase production or resistance to other antimicrobial classes tested. In all, BC-3781 displayed a very potent antibacterial profile including the most prevalent bacterial pathogens causing ABSSSI and CABP, thus warranting further clinical development of this antibiotic in these and possibly other indications.

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Antimicrobial Activity of the Pleuromutilin Antibiotic BC-3781 against Bacterial Pathogens Isolated in the SENTRY Antimicrobial Surveillance Program in 2010

Paukner

Sader

Ivezić-Schoenfeld

et al. 2013

“…The second objective was to identify any patient descriptors associated with the interindividual variability in BC-3781 population PK parameters. The third, and most important, objective was to obtain accurate estimates of PK exposure in the phase 2 patients in order to facilitate the conduct of PK-PD analyses (13).…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Analyses for BC-3781 Using Phase 2 Data from Patients with Acute Bacterial Skin and Skin Structure Infections

Rubino

Bai

Bhavnani

et al. 2015

BC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.)

“…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.…”

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confidence: 99%

“…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.…”

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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

Self Cite

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...