scholarly journals Pharmacokinetics and Concentration-Dependent Efficacy of Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

2016 ◽  
Vol 60 (5) ◽  
pp. 2718-2726 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Patriss W. Moradi ◽  
Gittel E. Strauss ◽  
Aspasia Katragkou ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Prolonged Survival ◽  
Pulmonary Injury ◽  
Pulmonary Aspergillosis ◽  
Lower Serum ◽  
Time Curve ◽  
Content Type ◽  
Fungal Burden ◽  
Dose Dependent ◽  
Significant Concentration

ABSTRACTWe studied the pharmacokinetics and efficacy of the broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration ofAspergillus fumigatusinoculum; study subjects included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (ISA; BAL4815) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg (of body weight)/day, with an initial loading dose of 90 mg/kg (ISA90), and untreated rabbits (UC). There were significant concentration-dependent reductions of residual fungal burden (log CFU/gram) and of organism-mediated pulmonary injury, lung weights, and pulmonary infarct scores in ISA40- and ISA60-treated rabbits in comparison to those of UC (P< 0.001). ISA20-treated (P< 0.05), ISA40-treated, and ISA60-treated (P< 0.001) rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40- and ISA60-treated animals demonstrated a significant decline of serum (1→3)-β-d-glucan levels (P< 0.05) and galactomannan indices (GMIs) during therapy following day 4 in comparison to progressive GMIs of UC (P< 0.01). There also were significantly lower concentration-dependent GMIs in bronchoalveolar lavage (BAL) fluid from ISA40- and ISA60-treated rabbits (P< 0.001). There was a direct correlation between isavuconazole plasma area under the concentration-time curve from 0 to 24 h (AUC0–24) and residual fungal burdens in lung tissues, pulmonary infarct scores, and total lung weights. In summary, rabbits treated with isavuconazole at 40 and 60 mg/kg/day demonstrated significant dose-dependent reduction of residual fungal burden, decreased pulmonary injury, prolonged survival, lower GMIs in serum and BAL fluid, and lower serum (1→3)-β-d-glucan levels.

scholarly journals Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Matthew W. McCarthy ◽  
Laura L. Kovanda ◽  
Myo H. Zaw ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Single Agent ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Injury ◽  
Pulmonary Aspergillosis ◽  
Fungal Cell ◽  
Fungal Burden ◽  
Improved Outcomes ◽  
Simultaneous Inhibition ◽  
Dose Dependent

ABSTRACT Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-β-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits (P < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone (P < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone (P < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-β-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights (r = 0.764; P < 0.001), and pulmonary infarct score (r = 0.911; P < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-β-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent.

scholarly journals Antifungal Efficacy of Caspofungin (MK-0991) in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits: Pharmacokinetics, Drug Disposition, and Relationship to Galactomannan Antigenemia

2002 ◽  
Vol 46 (1) ◽  
pp. 12-23 ◽  
Author(s):  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Andreas H. Groll ◽  
Tin Sein ◽  
Robert L. Schaufele ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Invasive Pulmonary Aspergillosis ◽  
Tetrazolium Salt ◽  
Pulmonary Injury ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden ◽  
Galactomannan Antigen ◽  
Improvement In Survival ◽  
Dose Dependent ◽  
Antifungal Efficacy

ABSTRACT The antifungal efficacy, pharmacokinetics, and safety of caspofungin (CAS) were investigated in the treatment and prophylaxis of invasive pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of 1, 3, or 6 mg of CAS/kg of body weight/day (CAS1, CAS3, and CAS6, respectively) or 1 mg of deoxycholate amphotericin B (AMB)/kg/day intravenously for 12 days starting 24 h after endotracheal inoculation. Prophylaxis (CAS1) was initiated 4 days before endotracheal inoculation. Rabbits treated with CAS had significant improvement in survival and reduction in organism-mediated pulmonary injury (OMPI) measured by pulmonary infarct score and total lung weight (P < 0.01). However, animals treated with CAS demonstrated a paradoxical trend toward increased residual fungal burden (log CFU per gram) and increased serum galactomannan antigen index (GMI) despite improved survival. Rabbits receiving prophylactic CAS1 also showed significant improvement in survival and reduction in OMPI (P < 0.01), but there was no effect on residual fungal burden. In vitro tetrazolium salt hyphal damage assays and histologic studies demonstrated that CAS had concentration- and dose-dependent effects on hyphal structural integrity. In parallel with a decline in GMI, AMB significantly reduced the pulmonary tissue burden of A. fumigatus (P ≤ 0.01). The CAS1, CAS3, and CAS6 dose regimens demonstrated dose-proportional exposure and maintained drug levels in plasma above the MIC for the entire 24-h dosing interval at doses that were ≥3 mg/kg/day. As serial galactomannan antigen levels may be used for therapeutic monitoring, one should be aware that profoundly neutropenic patients receiving echinocandins for aspergillosis might have persistent galactomannan antigenemia despite clinical improvement. CAS improved survival, reduced pulmonary injury, and caused dose-dependent hyphal damage but with no reduction in residual fungal burden or galactomannan antigenemia in persistently neutropenic rabbits with invasive pulmonary aspergillosis.

scholarly journals Antifungal Efficacy, Safety, and Single-Dose Pharmacokinetics of LY303366, a Novel Echinocandin B, in Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

1998 ◽  
Vol 42 (11) ◽  
pp. 2898-2905 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Andreas H. Groll ◽  
Aaron Bell ◽  
Diana P. Callender ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Injury ◽  
Plasma Drug ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Drug Levels ◽  
Plasma Drug Levels ◽  
Echinocandin B ◽  
Improvement In Survival ◽  
Antifungal Efficacy

ABSTRACT LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-β-d-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due toAspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden ofA. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of ≥5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated rabbits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

scholarly journals Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-β-D-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Aspasia Katragkou ◽  
Bo Bo Win Maung ◽  
Ethan Naing ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Rabbit Model ◽  
Prolonged Survival ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden ◽  
Treatment Groups ◽  
Glucan Synthesis ◽  
Synthase Inhibitor

ABSTRACT Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1→3)-β-d-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with antimold triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well-established persistently neutropenic New Zealand White (NZW) rabbit model of experimental IPA. Treatment groups included untreated control (UC) rabbits and rabbits receiving ibrexafungerp at 2.5 (SCY2.5) and 7.5 (SCY7.5) mg/kg of body weight/day, isavuconazole at 40 (ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced an in vitro synergistic interaction. There were significant in vivo reductions of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40 treatment groups versus those of the SCY2.5-treated, SCY7.5-treated, and UC (P < 0.01) groups. Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of the SCY2.5-, SCY7.5-, ISA40-treated, or UC (P < 0.05) groups. Serum galactomannan index (GMI) and (1→3)-β-d-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those of animals treated with SCY7.5 or ISA40 (P < 0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, and lower GMI and (1→3)-β-d-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an antimold triazole for treatment of IPA.

scholarly journals Comparative Pharmacodynamics of Posaconazole in Neutropenic Murine Models of Invasive Pulmonary Aspergillosis and Mucormycosis

2014 ◽  
Vol 58 (11) ◽  
pp. 6767-6772 ◽  
Author(s):  
Russell E. Lewis ◽  
Nathaniel D. Albert ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Rhizopus Oryzae ◽  
Invasive Pulmonary Aspergillosis ◽  
High Dose ◽  
Murine Models ◽  
Total Drug ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Content Type ◽  
Pulmonary Mucormycosis ◽  
Concentration Time

ABSTRACTWe used two established neutropenic murine models of pulmonary aspergillosis and mucormycosis to explore the association between the posaconazole area under the concentration-time curve (AUC)-to-MIC ratio (AUC/MIC) and treatment outcome. Posaconazole serum pharmacokinetics were verified in infected mice to ensure that the studied doses reflected human exposures with the oral suspension, delayed-release tablet, and intravenous formulations of posaconazole. Sinopulmonary infections were then induced in groups of neutropenic mice withAspergillus fumigatusstrain 293 (posaconazole MIC, 0.5 mg/liter) orRhizopus oryzaestrain 969 (posaconazole MIC, 2 mg/liter) and treated with escalating daily dosages of oral posaconazole, which was designed to achieve AUCs ranging from 1.10 to 392 mg · h/liter. After 5 days of treatment, lung fungal burden was analyzed by quantitative real-time PCR. The relationships of the total drug AUC/MIC and the treatment response were similar in both models, with 90% effective concentrations (EC90s) corresponding to an AUC/MIC threshold of 76 (95% confidence interval [CI], 46 to 102) for strain 293 versus 87 (95% CI, 66 to 101) for strain 969. Using a provisional AUC/MIC target of >100, these exposures correlated with minimum serum posaconazole concentrations (Cmins) of 1.25 mg/liter for strain 293 and 4.0 mg/liter for strain 969. The addition of deferasirox, but not liposomal amphotericin or caspofungin, improved the activity of a suboptimal posaconazole regimen (AUC/MIC, 33) in animals with pulmonary mucormycosis. However, no combination was as effective as the high-dose posaconazole monotherapy regimen (AUC/MIC, 184). Our analysis suggests that posaconazole pharmacodynamics are similar forA. fumigatusandR. oryzaewhen indexed to pathogen MICs.

scholarly journals Efficacy of the Investigational Echinocandin ASP9726 in a Guinea Pig Model of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 59 (5) ◽  
pp. 2875-2881 ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Satoru Matsumoto ◽  
Rosie A. Bocanegra ◽  
Monica L. Herrera ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Quantitative Pcr ◽  
Guinea Pigs ◽  
Plasma Concentrations ◽  
Invasive Pulmonary Aspergillosis ◽  
Pig Model ◽  
Pulmonary Aspergillosis ◽  
Content Type ◽  
Fungal Burden ◽  
Guinea Pig Model

ABSTRACTASP9726 is an investigational echinocandin within vitroactivity againstAspergillusspecies. We evaluated the pharmacokinetics and efficacy of this agent in an established guinea pig model of invasive pulmonary aspergillosis. ASP9726 plasma concentrations were measured in guinea pigs administered either a single dose or multiple doses of this agent at 2.5, 5, and 10 mg/kg of body weight/day by subcutaneous injection. Immunosuppressed guinea pigs were inoculated withA. fumigatusAF293, and ASP9726 (2.5, 5, and 10 mg/kg/day), voriconazole (10 mg/kg by oral gavage twice daily), or caspofungin (3 mg/kg/day by intraperitoneal injection) was administered for 8 days. Changes in fungal burden were measured by enumerating CFU and by quantitative PCR of specimens from within the lungs, as well as by analysis of serum (1→3)-β-d-glucan and galactomannan. Lung histopathology was also evaluated. ASP9726 plasma concentrations increased in a dose-proportional manner, and the drug was well tolerated at each dose. Each dose of ASP9726, voriconazole, and caspofungin significantly reduced pulmonary fungal burden as measured by quantitative PCR and by determining (1→3)-β-d-glucan and galactomannan levels, but only voriconazole significantly reduced numbers of CFU. ASP9726 at 5 mg/kg also significantly improved survival. Histopathology demonstrated morphological changes in hyphae in animals exposed to ASP9726 and caspofungin, consistent with the activities of the echinocandins. These results suggest that ASP9726 may be efficacious for the treatment of invasive pulmonary aspergillosis.

scholarly journals Posaconazole Pharmacodynamic Target Determination against Wild-Type andCyp51Mutant Isolates of Aspergillus fumigatus in anIn VivoModel of Invasive Pulmonary Aspergillosis

2012 ◽  
Vol 57 (1) ◽  
pp. 579-585 ◽  
Author(s):  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jaimie VanHecker ◽  
David R. Andes
Keyword(s):  
Dose Range ◽  
Invasive Pulmonary Aspergillosis ◽  
Free Drug ◽  
Lung Homogenate ◽  
Study Endpoint ◽  
Pharmacokinetic Data ◽  
Wild Type ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Content Type

ABSTRACTInvasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10A. fumigatusisolates, including 4Cyp51wild-type isolates and 6 isolates carryingCyp51mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy, mice had 5.59 ± 0.19 log10Aspergillusconidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 ± 0.29 log10CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ± 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ± 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results, with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 to 0.5 mg/liter.

scholarly journals APX001 Pharmacokinetic/Pharmacodynamic Target Determination againstAspergillus fumigatusin anIn VivoModel of Invasive Pulmonary Aspergillosis

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Miao Zhao ◽  
Alexander J. Lepak ◽  
Karen Marchillo ◽  
Jamie Vanhecker ◽  
Hiram Sanchez ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Dose Fractionation ◽  
Coefficient Of Determination ◽  
Dose Selection ◽  
Pulmonary Aspergillosis ◽  
Time Curve ◽  
Minimum Effective Concentration ◽  
Content Type

ABSTRACTAPX001, the prodrug of APX001A, is a first-in-class antifungal agent that has a potent activity againstAspergillus fumigatus. The goal of current study was to determine the pharmacodynamic (PD) index and target of APX001 in an immunocompromised murine model of invasive pulmonary aspergillosis against 6 A. fumigatusisolates. Minimum effective concentration (MEC) values ranged from 0.03 to 0.06 mg/liter. Dose fractionation was performed against isolate AF293 using total doses of APX001 ranging from 81 to 768 mg/kg of body weight/day fractionated into every 3-, 6-, and 8-h regimens over a 96-h treatment duration. Efficacy was assessed byA. fumigatusquantitative PCR (qPCR) of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h area under the concentration-time curve (AUC)/MEC ratio was the pharmacokinetic (PK)/PD index that best correlated with efficacy (coefficient of determination [R2] = 0.79). Treatment studies with the remaining strains utilized regimens of 40 to 1,536 mg/kg of APX001 administered every 3 h for a 96-h duration. Exposure-response relationships for all strains were similar, and the median free drug AUC/MEC PK/PD targets for stasis and 1-log-kill endpoints were 47.6 and 89.4, respectively. The present studies demonstratedin vitroandin vivoAPX001A/APX001 potency againstA. fumigatus. These results have potential relevance for clinical dose selection and evaluation of susceptibility breakpoints.

scholarly journals The Fungal Cyp51-Specific Inhibitor VT-1598 DemonstratesIn VitroandIn VivoActivity againstCandida auris

2018 ◽  
Vol 63 (3) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Shawn R. Lockhart ◽  
Laura K. Najvar ◽  
Elizabeth L. Berkow ◽  
Rosie Jaramillo ◽  
...  
Keyword(s):  
Specific Inhibitor ◽  
Candida Auris ◽  
Once Daily ◽  
Content Type ◽  
Fungal Burden ◽  
Invasive Infections ◽  
Trough Concentrations ◽  
Dose Dependent

ABSTRACTCandida aurisis an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluatedin vitroandin vivoagainstC. auris. Susceptibility testing was performed against 100 clinical isolates ofC. aurisby broth microdilution. Neutropenic mice were infected intravenously withC. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstratedin vitroactivity againstC. auris, with a mode MIC of 0.25 μg/ml and MICs ranging from 0.03 to 8 μg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused byC. auris.

scholarly journals In VivoPharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

2015 ◽  
Vol 59 (10) ◽  
pp. 6568-6574 ◽  
Author(s):  
Alexander J. Lepak ◽  
Ajit Parhi ◽  
Michaela Madison ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Methicillin Resistance ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Cellular Division ◽  
Content Type ◽  
Concentration Time ◽  
Dependent Activity ◽  
Dose Dependent

ABSTRACTAntibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5Staphylococcus aureusisolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (Cmax) were relatively linear over the doses studied. All organisms exhibited an MIC of 1 mg/liter. Dose fractionation demonstrated the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) to be the PD index most closely linked to efficacy (R2= 0.72). Dose-dependent activity was demonstrated against all 5 isolates, and the methicillin-resistance phenotype did not alter the pharmacokinetic/pharmacodynamic (PK/PD) targets. Net stasis was achieved against all isolates and a 1-log10kill level against 4 isolates. PD targets included total drug 24-h AUC/MIC values of 122 for net stasis and 243 for 1-log10killing. TXA-709 and TXA-707 are a promising novel antibacterial class and compound forS. aureusinfections. These results should prove useful for design of clinical dosing regimen trials.

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