Heart Care Info - Heart Disease Prevention & Treatment

Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, in Experimental Endocarditis due to Methicillin-Resistant Staphylococcus ...

YQ Xiong, W Abdel Hady, A Deslandes... - Antimicrobial Agents ..., 2011 - Am Soc Microbiol Page 1. Efficacy of NZ2114, a Novel Plectasin-Derived Cationic Antimicrobial Peptide Antibiotic, 1 in Experimental Endocarditis due to Methicillin-Resistant Staphylococcus aureus 2 3 4 ... 13 14 Running title: MRSA endocarditis model and antimicrobial peptides 15 16 17 ...

Cationic antimicrobial peptides (CA Ps) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungus, Pseudoplectania nigrella. NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated: i) the in vivo pharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114; and ii) the in vivo efficacy of NZ2114 in comparison with two conventional antibiotics, vancomycin or daptomycin, in a rabbit experimental endocarditis model (IE) due to a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC33591). All NZ2114 regimens (5, 10 and 20 mg/kg, iv, twice daily for three days), significantly decreased MRSA densities in cardiac vegetations, kidneys and spleen vs. untreated controls, except in one scenario (5 mg/kg vs. splenic MRSA counts). The efficacy of NZ2114 was clearly dose-dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy vs. vancomycin (P < 0.001), and similar efficacy to daptomycin. Of importance, only NZ2114 (at 10 and 20 mg/kg regimen) prevented post-therapy relapse in cardiac vegetations, kidneys and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. These in vivo efficacies were equivalent and significantly correlated with three PK indices investigated: f Cmax/MIC, f AUC/MIC and f%T>MIC, as analyzed by a sigmoid Emax model (R2 > 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggest the potential for further development of this compound for treating serious MRSA infections.