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

• Published in: Antimicrobial Agents and Chemotherapy 2011-11, Vol.55 (11), p.5325-5330
• Main Authors: Xiong, Yan Q, Hady, Wessam Abdel, Deslandes, Antoine, Rey, Astrid, Fraisse, Laurent, Kristensen, Hans-Henrik, Yeaman, Michael R, Bayer, Arnold S
• Format: Article
• Language: English
• Subjects: Animals; antibiotic resistance; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimicrobial Cationic Peptides; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - therapeutic use; Bacterial diseases; Biological and medical sciences; blood serum; body weight; Cardiology. Vascular system; daptomycin; dose response; Endocardial and cardiac valvular diseases; Endocarditis; Endocarditis - drug therapy; Endocarditis - microbiology; fungi; Gram-positive bacteria; Heart; Human bacterial diseases; in vivo studies; Infectious diseases; intravenous injection; kidneys; Medical sciences; methicillin; Methicillin-Resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - pathogenicity; Microbial Sensitivity Tests; Peptides; Peptides - chemistry; pharmacokinetics; Pharmacology; Pharmacology. Drug treatments; plate count; Rabbits; Random Allocation; relapse; saprophytes; spleen; Staphylococcal Infections; Staphylococcal Infections - drug therapy; Staphylococcal Infections - microbiology; Staphylococcal infections, streptococcal infections, pneumococcal infections; Staphylococcus aureus; vancomycin
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.00453-11

Cationic antimicrobial peptides (CAPs) 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 those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, 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 than vancomycin (P < 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy 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: fCmax/MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC), fAUC/MIC (where AUC is the area under the concentration-time curve), and f%T>MIC (%T>MIC is the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect (Emax) model (R2 > 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.