High Cerebrospinal Fluid (CSF) Penetration and Potent Bactericidal Activity in CSF of NZ2114, a Novel Plectasin Variant, during Experimental Pneumococcal Meningitis

Abstract

Plectasin is the first defensin-type antimicrobial peptide isolated from a fungus and has potent activity against gram-positive bacteria. By using an experimental meningitis model, the penetration of plectasin into the cerebrospinal fluid (CSF) of infected and uninfected rabbits and the bactericidal activities in CSF of the plectasin variant NZ2114 and ceftriaxone against a penicillin-resistant Streptococcus pneumoniae strain (NZ2114 and ceftriaxone MICs, 0.25 and 0.5 microg/ml, respectively) were studied. Pharmacokinetic analysis showed that there was a significantly higher level of CSF penetration of NZ2114 through inflamed than through noninflamed meninges (area under the concentration-time curve for CSF/area under the concentration-time curve for serum, 33% and 1.1%, respectively; P = 0.03). The peak concentrations of NZ2114 in purulent CSF were observed approximately 3 h after the infusion of an intravenous bolus of either 20 or 40 mg/kg of body weight and exceeded the MIC >10-fold for a 6-h study period. Treatment with NZ2114 (40 and 20 mg/kg at 0 and 5 h, respectively; n = 11) caused a significantly higher reduction in CSF bacterial concentrations than therapy with ceftriaxone (125 mg/kg at 0 h; n = 7) at 3 h (median changes, 3.7 log(10) CFU/ml [interquartile range, 2.5 to 4.6 log(10) CFU/ml] and 2.1 log(10) CFU/ml [interquartile range, 1.7 to 2.6 log(10) CFU/ml], respectively; P = 0.001), 5 h (median changes, 5.2 log(10) CFU/ml [interquartile range, 3.6 to 6.1 log(10) CFU/ml] and 3.1 log(10) CFU/ml [interquartile range, 2.6 to 3.7 log(10) CFU/ml], respectively; P = 0.01), and 10 h (median changes, 5.6 log(10) CFU/ml [interquartile range, 5.2 to 5.9 log(10) CFU/ml] and 4.2 log(10) CFU/ml [interquartile range, 3.6 to 5.0 log(10) CFU/ml], respectively; P = 0.03) after the start of therapy as well compared to the CSF bacterial concentrations in untreated rabbits with meningitis (n = 7, P < 0.05). Also, significantly more rabbits had sterile CSF at 5 and 10 h when they were treated with NZ2114 than when they were treated with ceftriaxone (67% [six of nine rabbits] and 0% [zero of seven rabbits], respectively, at 5 h and 75% [six of eight rabbits] and 14% [one of seven rabbits], respectively, at 10 h; P < 0.05). Due to its excellent CSF penetration and potent bactericidal activity in CSF, the plectasin variant NZ2114 could be a promising new option for the treatment of CNS infections caused by gram-positive bacteria, including penicillin-resistant pneumococcal meningitis.