pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models.

Nystatin, a polyene, is one of the oldest antifungal drugs with wide potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including , , , and . For each species group, three to four strains were selected. Minimum inhibitory concentration (MIC) testing was done by Clinical Laboratory Standards Institute (CLSI) methods. Single-dose kinetics for BSG005 were performed at four dose levels. The immunosuppressed mouse IPA model was used for studies. For all studies, we utilized the neutropenic disseminated candidiasis model. We used quantitative PCR to enumerate in the lung and colony forming units (CFU) counts for in the kidney. Treatment results were evaluated based on both area under the concentration-time curve (AUC)/MIC and maximum plasma concentration ()/MIC exposures. The BSG005 MIC was 1 mg/L against all strains. Escalating doses of BSG005 resulted in increased effect and, in general, the dose-response curves within each species were concordant. The median 96-h AUC/MIC associated with net stasis was lowest at 6.08 for . Increasing exposures were needed for same outcome for at 18.7, at 29.3, and at 102.4. /MIC targets for the four groups were 0.22, 0.48, 0.60, and 1.41. BSG005 demonstrated potent activity against a variety of fungal pathogens in the neutropenic mouse models. /MIC PK/PD targets were numerically lower than other polyene studies using the same infection models.