Previous pharmacodynamic studies using in vivo candidiasis models have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC is a good descriptor of the echinocandin exposure-response relationship. Further studies investigating the 24-h AUC/MIC target for a stasis endpoint identified free-drug 24-h AUC/MIC against Candida albicans and were similar for two echinocandins, anidulafungin and micafungin. The current studies expand investigation of a third echinocandin (caspofungin) and compare the pharmacodynamic target among C. albicans, Candida glabrata, and Candida parapsilosis. Treatment studies were conducted with six C. albicans, nine C. glabrata, and 15 C. parapsilosis strains with various MICs (anidulafungin, 0.015 to 4.0 g/ml; caspofungin, 0.03 to 4.0 g/ml; and micafungin, 0.008 to 1.0 g/ml). Efficacy was closely tied to MIC and the 24-h AUC/MIC. Therapy against C. parapsilosis required more of each echinocandin on a mg/kg basis. Caspofungin required less drug on a mg/kg basis for efficacy against all of the organisms than did the other two drugs. However, the 24-h AUC/MIC targets were similar among the echinocandins when free drug concentrations were considered, suggesting the relevance of protein binding. The targets for C. parapsilosis (mean, 7) and C. glabrata (mean, 7) were significantly lower than those for C. albicans (mean, 20) for each echinocandin. The results suggest that current susceptibility breakpoints and the consideration of organism species in these determinations should be reexplored.Experimental antifungal pharmacodynamic investigations have been important for the design of optimal dosing strategies and the development of susceptibility breakpoints (1, 2, 5, 17). Several studies have begun to focus on the most recently approved antifungal drug class, the echinocandins (9,11,14,21,22,34,57). Results of these pharmacodynamic experiments have demonstrated concentration-dependent killing and have shown prolonged postantifungal effects. Both concentrationassociated pharmacodynamic indices, the 24-h area under the concentration-time curve (AUC)/MIC and the C max /MIC, have been linked to treatment efficacy. More recently, investigations have attempted to identify the pharmacodynamic target or the drug exposure relative to the MIC needed for treatment efficacy (9, 14). Several observations were made in studies with two echinocandins in experimental models of disseminated Candida albicans. The pharmacodynamic targets were similar between the two echinocandins as long as free drug concentrations were considered, suggesting the relevance of protein binding. However, only a few "high" MIC organisms were available for investigation at the time, and the studies did not include the species demonstrating the least susceptibility in vitro, Candida parapsilosis. The present studies expand evaluation to include all three FDA-approved echinocandins as well as in depth exploration of the pharmacodynamic target for C. parapsilosis. The results from these experiments provide pharmacodyna...

Candida device infections are common and invariably associated with biofilm growth. Exploratory microarray studies were undertaken to identify target genes associated with biofilm formation from an in vivo catheter model over time. We compared mRNA levels from C. albicans grown in an in vivo central venous catheter biofilm model at 12h (intermediate growth) and 24h (mature) to in vitro planktonic cells without a biofilm substrate using C. albicans oligo-arrays. 124 transcripts were similarly upregulated at the 12 and 24h timepoints. Ontology categories most highly represented included energy/metabolism (12%), carbohydrate (10%) and protein (13%) synthesis and modification, and transport (6%). Numerous genes were previously identified from in vitro biofilm studies. These genes included those associated with hyphal growth, amino acid metabolism, adherence, drug resistance, ergosterol biosynthesis, and β-glucan synthesis. In the current data set, adherence genes were unique to the earlier timepoint. Differences between the current in vivo biofilm expression data and that previously reported from in vitro models, including alterations in metabolism and carbohydrate processing, may be due to the continuous availability of nutrients from host serum and the incorporation of the host-pathogen interaction.

APX001 is the prodrug of APX001A, which is a first-in-class small molecule with a unique mechanism of action that inhibits the fungal enzyme Gwt1 in the glycosylphosphatidylinositol (GPI) biosynthesis pathway. The goal of the present study was to determine which pharmacokinetic/pharmacodynamic (PK/PD) index and magnitude best correlated with efficacy in the murine disseminated candidiasis model for ( = 5), ( = 5), and ( = 4). MIC values ranged from 0.002 to 0.03 mg/liter for , from 0.008 to 0.06 mg/liter for, and from 0.004 to 0.03 mg/liter for Plasma APX001A pharmacokinetic measurements were performed in mice after oral administration of 4, 16, 64, and 256 mg/kg of body weight APX001. Single-dose pharmacokinetic studies exhibited maximum plasma concentration () values of 0.46 to 15.6 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC) values of 0.87 to 70.0 mg · h/liter, and half-lives of 1.40 to 2.75 h. A neutropenic murine disseminated candidiasis model was utilized for all treatment studies, and drug dosing was by the oral route. Dose fractionation was performed against K1, with total doses ranging from 4 to 1,024 mg/kg/day of APX001 fractionated into regimens of dosing every 3, 6, 8, and 12 h for a 24-h treatment duration. Nonlinear regression analysis was used to determine which PK/PD index best correlated with efficacy on the basis of the reduction in the number of CFU/kidney at 24 h. The 24-h free-drug AUC/MIC ratio (AUC/MIC) was the PK/PD index that best correlated with efficacy (coefficient of determination [] = 0.88). Treatment studies with the remaining strains utilized regimens of 1 to 256 mg/kg of APX001 administered every 6 h for a 24-h duration with and a 96-h study duration with and The dose required to achieve 50% of the maximum effect (ED) and stasis AUC/MIC targets were as follows: for, 3.67 ± 3.19 and 20.60 ± 6.50, respectively; for , 0.38 ± 0.21 and 1.31 ± 0.27, respectively; and for, 7.14 ± 4.54 and 14.67 ± 8.30, respectively. The present studies demonstrated and APX001A and APX001 potency, respectively, against ,, and These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints. The identification of a lower AUC/MIC ratio target for suggests that species-specific susceptibility breakpoints should be explored.

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Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrumbeta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC 0 -∞ ) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R 2 ϭ 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.