1. Evaluation of the Efficacy of Intramuscular (IM) Administration of Ceftaroline (CPT) Against a Methicillin-Resistant Staphylococcus aureus (MRSA) Strain in a Rabbit Endocarditis Model (REM)
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Cédric Jacqueline
UPRES EA 3826
France
C. Jacqueline,1 J. Caillon,1 V. Le Mabecque,1 E. Batard,1 A.F. Miegeville,1 D. Biek,2 Y. Ge,2 and G. Potel1
B-1003
1 UPRES EA 3826, UER Médecine, Nantes, France, and 2 Cerexa, Inc. Alameda, CA, USA.
Abstract
Methods
Results
Pharmacokinetics of Ceftaroline 20 mg/kg After IM Administration or Short IV Infusion
Pharmacokinetics of Ceftaroline 20 mg/kg After IM Administration or Short IV Infusion
After IM administration of 5-, 20-, and 40-mg/kg doses, the Cmax increased approximately in proportion to dose (5.18, 15.75, and mg/L, respectively) and plasma half-life increasing from 0.74 to 1.14 hours (Figure 2).
Background: Ceftaroline is a novel, parenteral, broad-spectrum cephalosporin exhibiting bactericidal activity against gram-positive organisms, including MRSA and multidrug-resistant Streptococcus pneumoniae (MDRSP), as well as common gram-negative pathogens. CPT is currently in phase 3 development. We previously reported the highly bactericidal activity of IV CPT against MRSA in rabbit. The objective of this study was to compare the activity of 3 different doses of CPT with teicoplanin (TEC) after IM administration against a MRSA strain using a REM. Methods: MICs were 1 and 0.5 mg/L for CPT and teicoplanin (TEC), respectively. Preliminary PK studies were performed to determine the PK parameters of IM administration and facilitate dose selection. Animals were randomized to: no treatment (controls), CPT 5 mg/kg bid, CPT 20 mg/kg bid, CPT 40 mg/kg bid, or TEC 20 mg/kg bid. Results: The absolute bioavailability of IM CPT exceeded 90% of IV CPT (as measured by AUC). The Cmax of CPT at 5, 20, and 40 mg/kg increased approximately in proportion to dose (5.18, 15.75, and mg/L, respectively). The plasma elimination half-life was hours over the range tested. See Table 1 for bacterial titers in vegetations after 4 days of treatment. Conclusions: IM CPT demonstrated excellent bactericidal activity against the MRSA strain at 20 and 40 mg/kg, resulting in sterilization rates in vegetations of 80% and 100%, respectively. The results strongly support IM CPT as a promising and effective therapeutic option for the treatment of severe MRSA infections.
Figure 1. Ceftaroline fosamil is converted in vivo to the microbiologically active form, ceftaroline
Discussion - Conclusion
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 achieved previously with IV ceftaroline administered in a regimen simulating the human dose (ie, 600 mg twice daily).2
As expected, teicoplanin 20 mg/kg IM displayed activity against the MRSA strain, with a sterilization rate of 60%.
After a 4-day treatment regimen, IM ceftaroline demonstrated excellent bactericidal activity against the MRSA strain at 20-mg/kg and 40-mg/kg twice-daily doses in a rabbit endocarditis experimental model. These findings are consistent with a favorable IM pharmacokinetic profile and strongly support the development of IM ceftaroline as a promising and effective therapeutic option for the treatment of severe MRSA infections.
Six animals were divided into 2 groups, and a 20-mg/kg dose of the prodrug ceftaroline acetate was administered by IM injection into the right thigh or by a very short (2-minute) IV infusion via the marginal ear vein. Blood samples were obtained from the animals through a catheter positioned in the median artery of the ear (contralateral to the ear used for drug administration in the IV group) over 8 hours (5, 10, 15, 30, and 45 minutes, and 1, 2, 4, and 8 hours post-dose). Samples were centrifuged for 10 minutes at 5000g, and plasma samples were frozen until bioassay.
Results from the first phase of this investigation suggest that ceftaroline has an excellent pharmacokinetic profile after IM administration. Bioavailability of IM adminis tration exceeded 90% of IV infusion as calculated by area under the concentration-time curve (AUC) (Table 1).
Cmax was decreased with IM administration compared with IV infusion as ceftaroline was slowly released from the IM injection site (Table I; Figure 2).
In Vivo Activity of Ceftaroline After IM Administration
The bacterial titers in vegetations following a 4-day treatment regimen for the 40 mg/kg, 20 mg/kg and 5 mg/kg doses of IM ceftaroline and IM teicoplanin are shown in Table II.
The sterilization rate of vegetations produced by the MRSA strain are indicated in Figure 3.
Ceftaroline fosamil
Ceftaroline
Figure 2. Ceftaroline concentrations after intramuscular (IM) and intravenous (IV) administration in the rabbit (mean ± standard deviation).
Table I. Pharmacokinetic parameters following single-dose IM administration or short IV infusion of ceftaroline (mean ± standard deviation)
■ = 5-mg/kg IM dose
▲= 20-mg/kg IM dose
● = 40-mg/kg IM dose
 = 20-mg/kg IV dose
In Vivo Activity of Ceftaroline After IM Administration
Pharmacokinetic parameter
Ceftaroline 20 mg/kg
IM administration
IV administration
Cmax (mg/L)
16.08 ± 0.69
84.03 ± 7.45
Tmax (minutes) 30 5
t1/2 (hours)
0.90 ± 0.28
0.18 ± 0.00
AUC0-8h (mg.h/L)
26.47 ± 2.89
29.16 ± 3.89
%T>MICa (8-h period)
46.3 ± 2.0
22.5 ± 1.9
%T>MICa (12-h period)
30.9 ± 1.3
15.0 ± 1.3
Using a well-established rabbit endocarditis model,1 experimental endocarditis was induced with an inoculum of 108 CFU of a MRSA strain with heterogeneous high-level methicillin resistance (methicillin MIC = 128 mg/L). Treatment was started 24 hours 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), ceftaroline 40 mg/kg IM twice daily, ceftaroline 20 mg/kg IM twice daily, ceftaroline 5 mg/kg IM twice daily, or teicoplanin 20 mg/kg IM twice daily.
Introduction
Ceftaroline, the bioactive metabolite of ceftaroline fosamil, is a novel, parenteral, broad-spectrum cephalosporin exhibiting bactericidal activity against gram-positive organisms, as well as gram-negative pathogens (Figure 1).
The goals of our experiments were to compare the pharmacokinetic parameters of ceftaroline after IV and IM administration and evaluate the in vivo activity of 3 different doses of ceftaroline against MRSA compared with teicoplanin as a positive control after IM administration by using an aortic valve endocarditis rabbit model.
Figure 3. Sterilization rate (%) of vegetation produced by the MRSA strain after 4 days of treatment
a Methicillin-resistant Staphylococcus aureus strain with ceftaroline MIC = 1 mg/L
References
Table II. Bacterial titers in vegetations after 4 days of treatment
Mean ± SD log10 CFU/g of vegetation (n)
Controls
8.99 ± 0.47 (10)
IM CPT (40 mg/kg bid)
2.45 ± 0.14 (10)a,c
IM CPT (20 mg/kg bid)
3.14 ± 1.38 (10)a,b
IM CPT (5 mg/kg bid)
5.26 ± 2.73 (9)a
IM TEC (20 mg/kg bid)
3.07 ± 0.66 (10)a,b
Durack, D.T., and P.B. Beeson Experimental bacterial endocarditis, II: survival of a bacteria in endocardial vegetations. Br. J. Exp. Pathol. 53:50-53.
Jacqueline, C., J. Caillon, V. Le Mabecque, et al. In vivo efficacy of ceftaroline (PPI-0903), a new broad-spectrum cephalosporin compared with linezolid and vancomycin against methicillin-resistant and vancomycin-intermediate Staphylococcus aureus in a rabbit endocarditis model. Antimicrob. Agents Chemother. 2007;51:
(n): no. of animals; a: P < vs controls; b: P < 0.05 vs IM CPT (5 mg/kg bid); c: P < vs IM CPT (5 mg/kg bid); Bonferroni’s test after analysis of variance.