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.

Invasive pulmonary aspergillosis (IPA) continues to rise in concert with increasing numbers of immune suppression techniques to treat other medical conditions and transplantation. Despite these advances, morbidity and mortality rates remain unacceptably high. One strategy used to optimize outcomes is antifungal pharmacodynamic (PD) examination. We explored the pharmacodynamics of a new triazole in development, isavuconazole, in a murine neutropenic IPA model. Ten A. fumigatus isolates were used, including four wild-type isolates and six cyp51 mutants. The MIC range was 0.125 to 8 mg/liter. Following infection, groups of mice were treated orally with the prodrug (BAL8557) at 40 to 640 mg/kg/12 h for 7 days. Efficacy was determined by quantitative PCR of lung homogenates. At the start of therapy, mice had 4.97 log 10 conidial equivalents (CE)/ml of lung homogenate, and this increased to 6.82 log 10 CE/ml of lung homogenate in untreated animals. The infection model was uniformly lethal in untreated control mice. The PD target endpoints examined included the static-dose AUC/MIC ratio and the 1-log 10 killing AUC/MIC ratio. A stasis endpoint was achieved for all isolates with an MIC of <1 mg/liter and 1-log 10 killing in all isolates with an MIC of <0.5 mg/liter, regardless of the presence or absence of the cyp51 mutation. The static-dose range was 65 to 617 mg/ kg/12 h. The corresponding median free-drug AUC/MIC ratio was near 5. The 1-log 10 killing dose range was 147 to 455 mg/kg/12 h, and the corresponding median free-drug AUC/MIC ratio was 11.1. These values are similar to those previously reported for other triazoles.

bPharmacodynamic (PD) studies with triazoles in the neutropenic murine disseminated candidiasis model have been performed extensively for Candida albicans. They have consistently shown that the pharmacodynamic index most closely correlated with efficacy is the ratio of the 24-h area under the concentration-time curve (AUC) to the MIC, and a target 24-h free-drug AUC/MIC ratio near 25 is associated with 50% of maximal microbiologic efficacy. We utilized this model to investigate the pharmacodynamics of isavuconazole. Isavuconazole pharmacokinetics were linear over the dose range studied. Oral-gastric doses of 640, 160, 40, and 10 mg of prodrug/kg of body weight produced peak levels of 0.51 to 25.4 mg/ liter, an elimination half-life of 1 to 5 h, and an AUC from 0 h to infinity (AUC 0-ؕ ) of 0.9 to 287 mg · h/liter. The AUC/MIC ratio was the pharmacodynamic index that correlated best with efficacy ( R 2 , 0.84). Pharmacodynamic target studies were performed using 4 C. albicans isolates with both a 24-h and a 96-h treatment duration. The strains were chosen to include previously characterized fluconazole-resistant strains. The mean 50% effective doses (ED 50 ) (expressed in mg/kg of body weight/12 h) and associated 24-h free-drug AUC/MIC ratios were 89.3 ؎ 46.7 and 67.7 ؎ 35 for the 24-h treatment and 59.6 ؎ 22 and 33.3 ؎ 25.5 for the 96-h treatment. These differences were not statistically significant. Pharmacodynamic targets for two non-albicans Candida species were also explored. The mean ED 50 (expressed in mg/kg/12 h) and associated 24-h free-drug AUC/MIC ratios were 31.2 and 6.2 for Candida tropicalis (n ‫؍‬ 1) and 50.5 and 1.6 for Candida glabrata (n ‫؍‬ 2). These PD targets were significantly different from C. albicans targets (P, 0.04). Isavuconazole PD targets for C. albicans are similar to those observed in this model with other triazoles. However, the PD targets for non-albicans Candida species were more than 10-fold lower than those for C. albicans (P, 0.04). This difference is similar to the species-specific PD relationships for the echinocandins. The lower PD targets for these species in this model will be important to consider in the analysis of clinical trial data and during the development of susceptibility breakpoints.

Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the in vivo pharmacodynamic activity of omadacycline against Streptococcus pneumoniae. Four strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.5, 2, 8, and 32 mg/kg. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 72 to 102%. Omadacycline demonstrated net cidal activity in relation to the initial burden against all four strains. The pharmacokinetic/pharmacodynamic index AUC/MIC correlated well with efficacy (R 2 ϭ 0.74).

Eravacycline is a novel fluorocycline antibiotic with potent activity against a broad range of pathogens, including strains with tetracycline and other drug resistance phenotypes. The goal of the studies was to determine which pharmacokinetic/ pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli isolates were utilized for the studies. MICs were determined using CLSI methods and ranged from 0.125 to 0.25 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after administration of 2.5, 5, 10, 20, 40, and 80 mg/kg of body weight. Pharmacokinetic studies exhibited maximum plasma concentration (C max ) values of 0.34 to 2.58 mg/liter, area under the concentration-time curve (AUC) from time zero to infinity (AUC 0 -∞ ) values of 2.44 to 57.6 mg · h/liter, and elimination half-lives of 3.9 to 17.6 h. Dose fractionation studies were performed using total drug doses of 6.25 mg/kg to 100 mg/kg fractionated into 6-, 8-, 12-, or 24-h regimens. Nonlinear regression analysis demonstrated that the 24-h free drug AUC/MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy (R 2 ϭ 0.80). In subsequent studies, we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC needed for the efficacy of eravacycline varied among pathogens. Mice were treated with 2-fold increasing doses (range, 3.125 to 50 mg/kg) of eravacycline every 12 h. The mean fAUC/MIC magnitudes associated with the net stasis and the 1-log-kill endpoints were 27.97 Ϯ 8.29 and 32.60 Ϯ 10.85, respectively. KEYWORDS eravacycline, pharmacodynamics, Escherichia coli D iseases due to antibiotic-resistant bacteria are emerging at an alarming rate worldwide, warranting the development of new antimicrobial agents. Eravacycline is a novel synthetic fluorocycline that belongs to the tetracycline class of antibacterial agents and is currently in development for the treatment of complicated intraabdominal infection (cIAI) (1) and complicated urinary tract infection (cUTI) (2). Oral and intravenous formulations have been developed. As with other tetracyclines, eravacycline inhibits bacterial protein synthesis through binding to the 30S ribosomal subunit and demonstrates potent and broad-spectrum antimicrobial activity. Importantly, the drug maintains activity against many drug-resistant bacteria, including bacteria exhibiting tetracycline-specific efflux and ribosomal protection (2).Escherichia coli organisms are the predominant pathogens in intra-abdominal infections (3) and urinary tract infections, accounting for 47 to 94% of isolates (4). Given this,