scholarly journals Combination Therapy in Treatment of Experimental Pulmonary Aspergillosis: In Vitro and In Vivo Correlations of the Concentration- and Dose- Dependent Interactions between Anidulafungin and Voriconazole by Bliss Independence Drug Interaction Analysis

2009 ◽  
Vol 53 (6) ◽  
pp. 2382-2391 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
William W. Hope ◽  
Joseph Meletiadis ◽  
Diana Mickiene ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Interaction Analysis ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Treatment Groups ◽  
Synergistic Interactions ◽  
Significant Difference ◽  
Bliss Independence

ABSTRACT We studied the antifungal activity of anidulafungin (AFG) in combination with voriconazole (VRC) against experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits and further explored the in vitro and in vivo correlations by using Bliss independence drug interaction analysis. Treatment groups consisted of those receiving AFG at 5 (AFG5 group) and 10 (AFG10 group) mg/kg of body weight/day, VRC at 10 mg/kg every 8 h (VRC group), AFG5 plus VRC (AFG5+VRC group), and AFG10 plus VRC (AFG10+VRC group) and untreated controls. Survival throughout the study was 60% for the AFG5+VRC group, 50% for the VRC group, 27% for the AFG10+VRC group, 22% for the AFG5 group, 18% for the AFG10 group, and 0% for control rabbits (P < 0.001). There was a significant reduction of organism-mediated pulmonary injury, measured by infarct scores, lung weights, residual fungal burdens, and galactomannan indexes, in AFG5+VRC-treated rabbits versus those treated with AFG5 and VRC alone (P < 0.05). In comparison, AFG10+VRC significantly lowered only infarct scores and lung weights in comparison to those of AFG10-treated animals (P < 0.05). AFG10+VRC showed no significant difference in other outcome variables. Significant Bliss synergy was found in vivo between AFG5 and VRC, with observed effects being 24 to 30% higher than expected levels if the drugs were acting independently. These synergistic interactions were also found between AFG and VRC in vitro. However, for AFG10+VRC, only independence and antagonism were observed among the outcome variables. We concluded that the combination of AFG with VRC in treatment of experimental IPA in persistently neutropenic rabbits was independent to synergistic at a dosage of 5 mg/kg/day but independent to antagonistic at 10 mg/kg/day, as assessed by Bliss independence analysis, suggesting that higher dosages of an echinocandin may be deleterious to the combination.

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 Antifungal effect of all-trans retinoic acid against Aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model

2020 ◽  
Author(s):  
Elena Campione ◽  
Roberta Gaziano ◽  
Elena Doldo ◽  
Daniele Marino ◽  
Mattia Falconi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Aspergillus Fumigatus ◽  
Rat Model ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Antifungal Drugs ◽  
Pulmonary Aspergillosis ◽  
Fungistatic Activity

AIM: Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. Fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. MATERIALS AND METHODS: A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. RESULTS: ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of sub-inhibitory concentration of Amphotericin B (AmB) and Posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to Posaconazole. CONCLUSION: Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal Hsp90 expression and Hsp90-related genes. ATRA reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as suitable fungistatic agent, also to reduce dosage and adverse reaction of classical antifungal drugs, and new therapeutic strategies against IPA and systemic fungal infections.

Usefulness of ICU criteria for diagnosis of invasive pulmonary aspergillosis in nonhematologic critically ill patients

2019 ◽  
Vol 58 (3) ◽  
pp. 275-281
Author(s):  
Song-I Lee ◽  
Heungsup Sung ◽  
Sang-Bum Hong ◽  
Chae-Man Lim ◽  
Younsuck Koh ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Hematologic Malignancy ◽  
Invasive Pulmonary Aspergillosis ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Pulmonary Aspergillosis ◽  
Treatment Groups ◽  
Significant Difference ◽  
Criteria For Diagnosis

Abstract Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in the intensive care unit (ICU). The ICU criteria were proposed to diagnose IPA in critically ill patients. This study aims to evaluate the usefulness of ICU criteria for diagnosis and treatment of IPA in nonhematologic patients in the ICU. We retrospectively reviewed 103 ICU patients with positive galactomannan test in blood and respiratory tract from January 1, 2016, to May 31, 2017. We excluded patients with hematologic malignancy. We divided the treatment and non-treatment groups according to the IPA treatment. We compared the baseline characteristics and outcomes between two groups and the agreement with ICU criteria. There were 49 patients in treatment groups and 54 patients in non-treatment groups. There were more cases of solid organ transplantation (P = .003), immunosuppressive therapy (P &lt; .001) and bacterial viral coinfection (P = .048) in the treatment group compared to nontreatment group. There was no statistically significant difference in mortality, the use of ventilator, and septic shock between the two groups. The agreement rate between the putative group and treatment was low (59.2%). There was no statistically significant difference in outcome between the putative and colonization groups according to the ICU criteria in each group. The treatment of IPA based on the symptom, radiologic finding and galactomannan test did not showed the better outcome. Also, the treatment based on the ICU criteria didn’t show the difference of outcome. The new criteria for diagnosis of IPA in critically ill patients are needed.

scholarly journals Heterogeneity among Isolates Reveals that Fitness in Low Oxygen Correlates withAspergillus fumigatusVirulence

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Caitlin H. Kowalski ◽  
Sarah R. Beattie ◽  
Kevin K. Fuller ◽  
Elizabeth A. McGurk ◽  
Yi-Wei Tang ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Experimental Evolution ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Low Oxygen ◽  
Single Strain ◽  
Hypoxia Exposure ◽  
Significant Difference

ABSTRACTPrevious work has shown that environmental and clinical isolates ofAspergillus fumigatusrepresent a diverse population that occupies a variety of niches, has extensive genetic diversity, and exhibits virulence heterogeneity in a number of animal models of invasive pulmonary aspergillosis (IPA). However, mechanisms explaining differences in virulence amongA. fumigatusisolates remain enigmatic. Here, we report a significant difference in virulence of two common lab strains, CEA10 and AF293, in the murine triamcinolone immunosuppression model of IPA, in which we previously identified severe low oxygen microenvironments surrounding fungal lesions. Therefore, we hypothesize that the ability to thrive within these lesions of low oxygen promotes virulence ofA. fumigatusin this model. To test this hypothesis, we performedin vitrofitness andin vivovirulence analyses in the triamcinolone murine model of IPA with 14 environmental and clinical isolates ofA. fumigatus. Among these isolates, we observed a strong correlation between fitness in low oxygenin vitroand virulence. In further support of our hypothesis, experimental evolution of AF293, a strain that exhibits reduced fitness in low oxygen and reduced virulence in the triamcinolone model of IPA, results in a strain (EVOL20) that has increased hypoxia fitness and a corresponding increase in virulence. Thus, the ability to thrive in low oxygen correlates with virulence ofA. fumigatusisolates in the context of steroid-mediated murine immunosuppression.IMPORTANCEAspergillus fumigatusoccupies multiple environmental niches, likely contributing to the genotypic and phenotypic heterogeneity among isolates. Despite reports of virulence heterogeneity, pathogenesis studies often utilize a single strain for the identification and characterization of virulence and immunity factors. Here, we describe significant variation betweenA. fumigatusisolates in hypoxia fitness and virulence, highlighting the advantage of including multiple strains in future studies. We also illustrate that hypoxia fitness correlates strongly with increased virulence exclusively in the nonleukopenic murine triamcinolone immunosuppression model of IPA. Through an experimental evolution experiment, we observe that chronic hypoxia exposure results in increased virulence ofA. fumigatus. We describe here the first observation of a model-specific virulence phenotype correlative within vitrofitness in hypoxia and pave the way for identification of hypoxia-mediated mechanisms of virulence in the fungal pathogenA. fumigatus.

scholarly journals In vitro and in vivo interaction of caspofungin with isavuconazole against Candida auris planktonic cells and biofilms

2021 ◽  
Author(s):  
Fruzsina Nagy ◽  
Zoltán Tóth ◽  
Fanni Nyikos ◽  
Lajos Forgács ◽  
Ágnes Jakab ◽  
...  
Keyword(s):  
Favourable Effect ◽  
Planktonic Cells ◽  
Candida Auris ◽  
Synergistic Interactions ◽  
Immunocompromised Mouse ◽  
Concentration Indices ◽  
Volume Range ◽  
Bliss Independence

AbstractThe in vitro and in vivo efficacy of caspofungin was determined in combination with isavuconazole against Candida auris. Drug–drug interactions were assessed utilising the fractional inhibitory concentration indices (FICIs), the Bliss independence model and an immunocompromised mouse model. Median planktonic minimum inhibitory concentrations (pMICs) of 23 C. auris isolates were between 0.5 and 2 mg/L and between 0.015 and 4 mg/L for caspofungin and isavuconazole, respectively. Median pMICs for caspofungin and isavuconazole in combination showed 2–128-fold and 2–256-fold decreases, respectively. Caspofungin and isavuconazole showed synergism in 14 out of 23 planktonic isolates (FICI range 0.03–0.5; Bliss cumulative synergy volume range 0–4.83). Median sessile MICs (sMIC) of 14 biofilm-forming isolates were between 32 and >32 mg/L and between 0.5 and >2 mg/L for caspofungin and isavuconazole, respectively. Median sMICs for caspofungin and isavuconazole in combination showed 0–128-fold and 0-512-fold decreases, respectively. Caspofungin and isavuconazole showed synergistic interaction in 12 out of 14 sessile isolates (FICI range 0.023–0.5; Bliss cumulative synergy volume range 0.13–234.32). In line with the in vitro findings, synergistic interactions were confirmed by in vivo experiments. The fungal kidney burden decreases were more than 3 log volumes in mice treated with combination of 1 mg/kg caspofungin and 20 mg/kg isavuconazole daily; this difference was statistically significant compared with control mice (p<0.001). Despite the favourable effect of isavuconazole in combination with caspofungin, further studies are needed to confirm the therapeutic advantage of this combination when treating an infection caused by C. auris.

scholarly journals Triazole‐Polyene Antagonism in Experimental Invasive Pulmonary Aspergillosis: In Vitro and In Vivo Correlation

2006 ◽  
Vol 194 (7) ◽  
pp. 1008-1018 ◽  
Author(s):  
Joseph Meletiadis ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Pengxin Lin ◽  
Theodouli Stergiopoulou ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis

scholarly journals Itraconazole Preexposure Attenuates the Efficacy of Subsequent Amphotericin B Therapy in a Murine Model of Acute Invasive Pulmonary Aspergillosis

2002 ◽  
Vol 46 (10) ◽  
pp. 3208-3214 ◽  
Author(s):  
Russell E. Lewis ◽  
Randall A. Prince ◽  
Jingduan Chi ◽  
Dimitrios P. Kontoyiannis
Keyword(s):  
Amphotericin B ◽  
Murine Model ◽  
High Performance ◽  
Invasive Pulmonary Aspergillosis ◽  
Conidial Suspension ◽  
Pulmonary Aspergillosis ◽  
Drug Pharmacokinetics ◽  
Higher Doses

ABSTRACT Antagonism has been described in vitro and in vivo for azole-polyene combinations against Aspergillus species. Using an established murine model of invasive pulmonary aspergillosis, we evaluated the efficacy of several amphotericin B (AMB) dosages given alone or following preexposure to itraconazole (ITC). Mice were immunosuppressed with cortisone acetate and cyclophosphamide. During immunosuppression, animals were administered either ITC solution (50 mg/kg of body weight) or saline by oral gavage twice daily for 3 days prior to infection. Infection was induced by intranasally inoculating mice with a standardized conidial suspension (1 × 108 CFU/ml) of Aspergillus fumigatus strain AF 293. AMB was then administered by daily intraperitoneal injections (0.25, 0.5, 1.0, and 3.0 mg/kg) starting 24 h after inoculation and continuing for a total of 72 h. Drug pharmacokinetics of AMB and ITC in plasma were determined by high-performance liquid chromatography. Four different endpoints were used to examine the efficacy of antifungal therapy: (i) viable counts from harvested lung tissue (in CFU per milliliter), (ii) the whole-lung chitin assay, (iii) mortality at 96 h, and (iv) histopathology of representative lung sections. At AMB doses of >0.5 mg/kg/day, fewer ITC-preexposed mice versus non-ITC-preexposed mice were alive at 96 h (0 to 20 versus 60%, respectively). At all time points, the fungal lung burden was consistently and significantly higher in animals preexposed to ITC, as measured by the CFU counts (P = 0.001) and the chitin assay (P = 0.03). Higher doses of AMB did not overcome this antagonism. ITC preexposure was associated with poorer mycological efficacy and survival in mice treated subsequently with AMB for invasive pulmonary aspergillosis.

scholarly journals Comparative Antifungal Activities and Plasma Pharmacokinetics of Micafungin (FK463) against Disseminated Candidiasis and Invasive Pulmonary Aspergillosis in Persistently Neutropenic Rabbits

2002 ◽  
Vol 46 (6) ◽  
pp. 1857-1869 ◽  
Author(s):  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Andreas H. Groll ◽  
Kristin Roussillon ◽  
Melissa Hemmings ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Invasive Pulmonary Aspergillosis ◽  
Vena Cava ◽  
Pulmonary Aspergillosis ◽  
Pulmonary Infarction ◽  
Pulmonary Tissue ◽  
Disseminated Candidiasis ◽  
Antifungal Activities

ABSTRACT Micafungin (FK463) is an echinocandin that demonstrates potent in vitro antifungal activities against Candida and Aspergillus species. However, little is known about its comparative antifungal activities in persistently neutropenic hosts. We therefore investigated the plasma micafungin pharmacokinetics and antifungal activities of micafungin against experimental disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. The groups with disseminated candidiasis studied consisted of untreated controls (UCs); rabbits treated with desoxycholate amphotericin B (DAMB) at 1 mg/kg of body weight/day; or rabbits treated with micafungin at 0.25, 0.5, 1, and 2 mg/kg/day intravenously. Compared with the UCs, rabbits treated with micafungin or DAMB showed significant dosage-dependent clearance of Candida albicans from the liver, spleen, kidney, brain, eye, lung, and vena cava. These in vivo findings correlated with the results of in vitro time-kill assays that demonstrated that micafungin has concentration-dependent fungicidal activity. The groups with invasive pulmonary aspergillosis studied consisted of UCs; rabbits treated with DAMB; rabbits treated with liposomal amphotericin B (LAMB) at 5 mg/kg/day; and rabbits treated with micafungin at 0.5, 1, and 2 mg/kg/day. In comparison to the significant micafungin dosage-dependent reduction of the residual burden (in log CFU per gram) of C. albicans in tissue, micafungin-treated rabbits with invasive pulmonary aspergillosis had no reduction in the concentration of Aspergillus fumigatus in tissue. DAMB and LAMB significantly reduced the burdens of C. albicans and A. fumigatus in tissues (P < 0.01). Persistent galactomannan antigenemia in micafungin-treated rabbits correlated with the presence of an elevated burden of A. fumigatus in pulmonary tissue. By comparison, DAMB- and LAMB-treated animals had significantly reduced circulating galactomannan antigen levels. Despite a lack of clearance of A. fumigatus from the lungs, there was a significant improvement in the rate of survival (P < 0.001) and a reduction in the level of pulmonary infarction (P < 0.05) in micafungin-treated rabbits. In summary, micafungin demonstrated concentration-dependent and dosage-dependent clearance of C. albicans from persistently neutropenic rabbits with disseminated candidiasis but not of A. fumigatus from persistently neutropenic rabbits with invasive pulmonary aspergillosis.

scholarly journals In Vitro and In Vivo Activities of NS-718, a New Lipid Nanosphere Incorporating Amphotericin B, againstAspergillus fumigatus

1999 ◽  
Vol 43 (3) ◽  
pp. 471-475 ◽  
Author(s):  
Takakazu Otsubo ◽  
Shigefumi Maesaki ◽  
Mohammad Ashraf Hossain ◽  
Yoshihiro Yamamoto ◽  
Kazunori Tomono ◽  
...  
Keyword(s):  
Survival Rate ◽  
Amphotericin B ◽  
Low Dose ◽  
Invasive Pulmonary Aspergillosis ◽  
Pharmacokinetic Studies ◽  
In Vitro Activity ◽  
Pulmonary Aspergillosis ◽  
In Vivo Efficacy

ABSTRACT We evaluated the in vitro and in vivo potencies of a new lipid nanosphere that incorporates amphotericin B (AmB), NS-718, againstAspergillus fumigatus. The in vitro activity of NS-718 (the MIC at which 90% of strains are inhibited [MIC90], 0.25 μg/ml) against 18 isolates of A. fumigatus was similar to that of deoxycholate AmB (D-AmB; Fungizone; MIC90, 0.25 μg/ml), but NS-718 was more potent than liposomal AmB (L-AmB; AmBisome; MIC90, 1.0 μg/ml). The in vivo efficacy of NS-718 in a rat model of invasive pulmonary aspergillosis was compared with those of D-AmB and L-AmB. A low dose (1 mg/kg of body weight) of L-AmB was ineffective (survival rate, 0%), although equivalent doses of D-AmB and NS-718 were more effective (survival rate, 17%). However, a higher dose of NS-718 (3 mg/kg) was more effective (survival rate, 100%) than equivalent doses of D-AmB and L-AmB (survival rate, 0%). To explain these differences, pharmacokinetic studies showed higher concentrations of AmB in the plasma of rats treated with NS-718 than in the plasma of those treated with D-AmB. Our results suggest that NS-718, a new preparation of AmB, is a promising antifungal agent with activity against pulmonary aspergillosis.

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.

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