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

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.

Download Full-text

Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01364-15 ◽

2015 ◽

Vol 60 (1) ◽

pp. 278-287 ◽

Cited By ~ 13

Author(s):

Helen Box ◽

Joanne Livermore ◽

Adam Johnson ◽

Laura McEntee ◽

Timothy W. Felton ◽

...

Keyword(s):

Invasive Pulmonary Aspergillosis ◽

Pathogenic Fungi ◽

Time Profile ◽

Wild Type ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Target Values ◽

Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

Download Full-text

Pharmacokinetic-Pharmacodynamic Characterization of Omadacycline against Haemophilus influenzae Using a One-Compartment In Vitro Infection Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02265-19 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 2

Author(s):

Brian D. VanScoy ◽

Elizabeth A. Lakota ◽

Haley Conde ◽

Jennifer McCauley ◽

Lawrence Friedrich ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Antimicrobial Agents ◽

Nonlinear Least Squares ◽

Infection Model ◽

Least Squares Regression ◽

Total Drug ◽

Time Curve ◽

Content Type ◽

Concentration Time

ABSTRACT Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including Haemophilus influenzae, which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against H. influenzae using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment in vitro infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five H. influenzae isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log10 CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination (r2) of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for H. influenzae.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01279-12 ◽

2012 ◽

Vol 57 (1) ◽

pp. 579-585 ◽

Cited By ~ 42

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.

Download Full-text

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02367-19 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Sujata M. Bhavnani ◽

Jeffrey P. Hammel ◽

Elizabeth A. Lakota ◽

M. Courtney Safir ◽

Brian D. VanScoy ◽

...

Keyword(s):

Compartment Model ◽

Simulated Patients ◽

Population Pharmacokinetic ◽

Total Drug ◽

Target Attainment ◽

Time Curve ◽

Content Type ◽

Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PKPD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

Download Full-text

Three-Dimensional Light Sheet Fluorescence Microscopy of Lungs To Dissect Local Host Immune-Aspergillus fumigatus Interactions

mBio ◽

10.1128/mbio.02752-19 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 7

Author(s):

Jorge Amich ◽

Zeinab Mokhtari ◽

Marlene Strobel ◽

Elena Vialetto ◽

Dalia Sheta ◽

...

Keyword(s):

Animal Models ◽

Fluorescence Microscopy ◽

Aspergillus Fumigatus ◽

Invasive Pulmonary Aspergillosis ◽

Fungal Growth ◽

Light Sheet ◽

Murine Models ◽

Pulmonary Aspergillosis ◽

Content Type ◽

Light Sheet Fluorescence Microscopy

ABSTRACT Aspergillus fumigatus is an opportunistic fungal pathogen that can cause life-threatening invasive lung infections in immunodeficient patients. The cellular and molecular processes of infection during onset, establishment, and progression of A. fumigatus infections are highly complex and depend on both fungal attributes and the immune status of the host. Therefore, preclinical animal models are of paramount importance to investigate and gain better insight into the infection process. Yet, despite their extensive use, commonly employed murine models of invasive pulmonary aspergillosis are not well understood due to analytical limitations. Here, we present quantitative light sheet fluorescence microscopy (LSFM) to describe fungal growth and the local immune response in whole lungs at cellular resolution within its anatomical context. We analyzed three very common murine models of pulmonary aspergillosis based on immunosuppression with corticosteroids, chemotherapy-induced leukopenia, or myeloablative irradiation. LSFM uncovered distinct architectures of fungal growth and degrees of tissue invasion in each model. Furthermore, LSFM revealed the spatial distribution, interaction, and activation of two key immune cell populations in antifungal defense: alveolar macrophages and polymorphonuclear neutrophils. Interestingly, the patterns of fungal growth correlated with the detected effects of the immunosuppressive regimens on the local immune cell populations. Moreover, LSFM demonstrates that the commonly used intranasal route of spore administration did not result in complete intra-alveolar deposition, as about 80% of fungal growth occurred outside the alveolar space. Hence, characterization by LSFM is more rigorous than by previously used methods employing murine models of invasive pulmonary aspergillosis and pinpoints their strengths and limitations. IMPORTANCE The use of animal models of infection is essential to advance our understanding of the complex host-pathogen interactions that take place during Aspergillus fumigatus lung infections. As in the case of humans, mice need to suffer an immune imbalance in order to become susceptible to invasive pulmonary aspergillosis (IPA), the most serious infection caused by A. fumigatus. There are several immunosuppressive regimens that are routinely used to investigate fungal growth and/or immune responses in murine models of invasive pulmonary aspergillosis. However, the precise consequences of the use of each immunosuppressive model for the local immune populations and for fungal growth are not completely understood. Here, to pin down the scenarios involving commonly used IPA models, we employed light sheet fluorescence microscopy (LSFM) to analyze whole lungs at cellular resolution. Our results will be valuable to optimize and refine animal models to maximize their use in future research.

Download Full-text

Efficacy of Caspofungin in Neutropenic and Corticosteroid-Immunosuppressed Murine Models of Invasive Pulmonary Mucormycosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01812-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3584-3587 ◽

Cited By ~ 5

Author(s):

Russell E. Lewis ◽

Konstantinos Leventakos ◽

Guangling Liao ◽

Dimitrios P. Kontoyiannis

Keyword(s):

Body Weight ◽

Rhizopus Oryzae ◽

Saline Control ◽

Murine Models ◽

Content Type ◽

Fungal Burden ◽

Pulmonary Mucormycosis ◽

Immunosuppressed Mice ◽

Better Than

ABSTRACTCaspofungin (CFG) was tested in neutropenic and corticosteroid-immunosuppressed mice challenged with a lethal sinopulmonary inoculum ofRhizopus oryzae. Compared to untreated controls, CFG administered at 1 mg/kg of body weight/day significantly improved survival (54% versus 19%;P= 0.003) and reduced medianR. oryzaefungal burden by 1.5 log10for conidial equivalent DNA in neutropenic but not corticosteroid-immunosuppressed animals. CFG administered at 16 mg/kg/day was not significantly better than a saline control for treatment of invasive pulmonary mucormycosis (IPM) in either neutropenic or corticosteroid-immunosuppressed animals.

Download Full-text

Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00791-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 36

Author(s):

Alexander J. Lepak ◽

Miao Zhao ◽

Elizabeth L. Berkow ◽

Shawn R. Lockhart ◽

David R. Andes

Keyword(s):

Animal Model ◽

Steady State ◽

Invasive Candidiasis ◽

Maximum Concentration ◽

Multidrug Resistant ◽

Total Drug ◽

Candida Auris ◽

Time Curve ◽

Content Type ◽

Concentration Time

ABSTRACT Candida auris is an emerging multidrug-resistant threat. The pharmacodynamics of three antifungal classes against nine C. auris strains was explored using a murine invasive candidiasis model. The total drug median pharmacodynamic (PD) target associated with net stasis was a fluconazole AUC/MIC (the area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 26, an amphotericin B C max/MIC (maximum concentration of drug in serum divided by the MIC) of 0.9, and a micafungin AUC/MIC of 54. The micafungin PD targets for C. auris were ≥20-fold lower than those of other Candida species in this animal model. Clinically relevant micafungin exposures produced the most killing among the three classes.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02372-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 14

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.

Download Full-text

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01556-08 ◽

2009 ◽

Vol 53 (5) ◽

pp. 2005-2013 ◽

Cited By ~ 34

Author(s):

Wendy W. J. van de Sande ◽

Ron A. A. Mathot ◽

Marian T. ten Kate ◽

Wim van Vianen ◽

Mehri Tavakol ◽

...

Keyword(s):

Therapeutic Efficacy ◽

Invasive Pulmonary Aspergillosis ◽

Immunocompromised Host ◽

Therapeutic Outcome ◽

Pulmonary Aspergillosis ◽

Time Curve ◽

Concentration Time ◽

First Choice ◽

Human Pharmacokinetic ◽

Advanced Stages

ABSTRACT At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02665-15 ◽

2016 ◽

Vol 60 (5) ◽

pp. 2718-2726 ◽

Cited By ~ 26

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.

Download Full-text