Evaluation of the in vivo efficacy of intramuscularly administered ceftaroline fosamil, a novel cephalosporin, against a methicillin-resistant Staphylococcus aureus strain in a rabbit endocarditis model

Abstract

Sir, Ceftaroline fosamil is the prodrug form of a novel, parenteral, broad-spectrum cephalosporin, ceftaroline, exhibiting bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), as well as common Gram-negative pathogens. To date, Phase III trials using intravenous (iv) administration of ceftaroline fosamil (herein after referred to as ceftaroline) have been completed for complicated skin and skin structure infections and for community-associated pneumonia. Pathogens such as MRSA are becoming more virulent and are no longer confined to acute-care settings. Ceftaroline may be administered by both iv and intramuscular (im) routes, facilitating outpatient antibiotic therapy for MRSA. Recently, Ge et al. assessed the pharmacokinetic profile for iv and im ceftaroline treatment in different animal species, and demonstrated favourable pharmacokinetic profiles following im administration. Teicoplanin, a glycopeptide antibiotic, may be administered either intravenously or intramuscularly and was used as a positive control. The aim of the present study was to assess the in vivo activity of three different doses of ceftaroline against MRSA compared with teicoplanin after im administration in a rabbit model of endocarditis. In the present study, we used an MRSA strain (P9) isolated from blood cultures exhibiting heterogeneous high-level methicillin resistance (methicillin MIC1⁄4128 mg/L). MICs of ceftaroline, teicoplanin and vancomycin were 1, 0.5 and 1 mg/L, respectively. In vivo studies were performed with New Zealand white female rabbits weighing 2.5–3.0 kg. Animals were treated in accordance with institutional policies and the guidelines stipulated by the animal welfare committee. The Committee of Animal Ethics of the University of Nantes approved all animal experimentation in this study. Using a well-established rabbit endocarditis model, experimental endocarditis was induced with an inoculum of 10 cfu of the MRSA isolate. Treatment was started 24 h after inoculation and antibiotics (ceftaroline and teicoplanin) were administered twice daily using the im route for 4 days. Animals (10 per group) were randomly assigned to no treatment (controls), 40 mg/kg ceftaroline im twice daily, 20 mg/kg ceftaroline im twice daily, 5 mg/kg ceftaroline im twice daily or 20 mg/kg teicoplanin im twice daily. Animals were euthanized at the beginning of the treatment period (controls) or at the end of the im treatment (12 h after the last injection). Aortic valve vegetations were excised, weighed and homogenized in 0.5 mL of saline buffer and used for quantitative cultures on agar. Bacterial counts were determined after 24 h of incubation at 378C. The lower detection limit was 1 cfu per 50 mL of undiluted vegetation homogenate. Statistical analyses were performed with GraphPad Prism software (version 4.0; GraphPad Software, San Diego, CA, USA). Analysis of variance was used to compare the antibacterial effects (bacterial counts) between the different groups, followed by a Bonferroni’s test to compare groups two by two. A P value of ≤0.05 was considered significant. After im administration of 5, 20 and 40 mg/kg doses of ceftaroline, the Cmax increased approximately in proportion to the dose (5.18, 15.75 and 37.85 mg/L, respectively) and the plasma half-life increased from 0.74 to 1.14 h. The in vivo outcome after a 4 day treatment regimen and the rate of sterilization of the vegetations produced by the MRSA strain are shown in Table 1. A dose-dependent response was observed with sterilization rates for ceftaroline of 100%, 80% and 33% for the 40, 20 and 5 mg/kg ceftaroline doses, respectively. The difference between the 20 and 40 mg/kg doses was not statistically significant (P.0.05). In vivo bactericidal activity was consistent across all animals tested at the 40 mg/kg dose and for most animals (8/10) at the 20 mg/kg dose of ceftaroline. As a positive control, 20 mg/kg teicoplanin im demonstrated bactericidal activity, with a sterilization rate of 60%. Using murine thigh and lung infection models, Andes and Craig determined that the T.MIC was the pharmacokinetic– pharmacodynamic parameter that best correlated with efficacy of ceftaroline. In our study, the mean %T.MICs for a 1 mg/L target with 20 mg/kg ceftaroline given by im injection were 46% and 31% over 8 and 12 h, respectively. Using an infective endocarditis rabbit model, the %T.MICs attained with im administration were associated with bactericidal activity against MRSA after a 4 day treatment. The efficacy of im ceftaroline in the present study was similar to that