Article Figures & Data
Figures
- Fig. 1.
Efficacy in the transient-suppression model of disseminated aspergillosis. ICR mice were immunosuppressed with a 6-mg/mouse dose of CY administered i.p. 3 days prior to infection with 1.6 × 104 CFU of A. fumigatus MF5668 (i.v.) per mouse. Immunosuppression was maintained by additional doses of CY (2 mg/mouse, i.p.) on days 1, 4, 7, and 10 after infection. Therapy was initiated 24 h after infection, and mice (10/group) were treated i.p., q.d., for 14 days. (A) Caspofungin; (B) AmB.
- Fig. 2.
Efficacy of delayed therapy against disseminatedC. albicans MY1055 infection in CY-treated, transient-suppression model in ICR mice. Mice were challenged i.v. withC. albicans MY1055 at 2.0 × 104 CFU/mouse. Mice (10/group) received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Mice were immunosuppressed with a 6-mg/mouse dose of CY on day −3. Immunosuppression was maintained by additional doses of CY on days 1 and 4 after challenge. (A) Caspofungin; (B) AmB.
- Fig. 3.
Efficacy of delayed therapy against disseminatedC. albicans MY1055 infection in CY-treated, chronically immunosuppressed ICR mice. Mice were challenged i.v. with C. albicans MY1055 at 5.6 × 104 CFU/mouse (study 1) and 1.22 × 105 CFU/mouse (Study 2). Mice received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Survival data were pooled from both studies (20 mice total). Mice were immunosuppressed throughout the experimental period (28 days). (A) Caspofungin; (B) AmB.
- Fig. 4.
Efficacy of delayed therapy with FCZ against disseminated C. albicans MY1055 infection in CY-treated, chronically immunosuppressed ICR mice. Mice were challenged i.v. withC. albicans MY1055 at 5.6 × 104 CFU/mouse (study 1) and 1.22 × 105 CFU/mouse (study 2). Mice (10/group) received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Mice were immunosuppressed throughout the experimental period (28 days).
Tables
- Table 1.
Percent survival and PDs (day 28) for mice in the chronic suppression model of disseminated aspergillosisa
Treatment group % Survival PD50 (95% confidence interval) PD90 (95% confidence interval) Study 1 Study 2 Study 3 Study 1 Study 2 Study 3 Study 1 Study 2 Study 3 Caspofungin 1.0 mg/kg 80.0 50.0 92.0 0.328 (0.199, 0.522) 0.400 (0.194, ∞) 0.173 (0.136, 0.207) >1.0 (NC) >1.0 (NC) 0.486 (0.389, 0.684) 0.5 mg/kg 80.0 100.0 90.0 0.25 mg/kg 40.0 30.0 86.0 AmB 1.0 mg/kg 80.0 50.0 90.0 0.500 (0.314, ∞) 0.600 (0.329, ∞) 0.235 (0.189, 0.282) >1.0 (NC) >1.0 (NC) 0.753 (0.582, ∞) 0.5 mg/kg 40.0 70.0 80.0 0.25 mg/kg 30.0 30.0 56.0 Infected, sham treated 10.0 10.0 22.0 CY controls Sham infected, sham treated 100.0 100.0 95.0 Noninfected, nontreated 90.0 100.0 100.0 ↵a Mice were challenged i.v. with A. fumigatus MF5668 at 1.0 × 104 CFU/mouse (study 1), at 2.4 × 104 CFU/mouse (study 2), and 1.88 × 104 CFU/mouse (study 3). Mice received the first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Mice were immunosuppressed throughout the experimental period (28 days). There were 10 mice per group in studies 1 and 2 and 50 mice per group in study 3, except for the CY control groups, which had 20 mice per group. PD50s and PD90s were calculated based on survival. NC, not calculated; ∞, infinitely large.
- Table 2.
Efficacy of delayed therapy against a disseminatedC. albicans MY1055 infection in the CY-induced, transient-suppression model in ICR micea
Dose (mg/kg) Mean log10 CFU/g of kidneys (% sterilization)b Caspofunginc AmBd 2.0 2.10*f ± 0.01 (100) NTe 1.0 2.14* ± 0.04 (100) 2.89* ± 0.63 (20) 0.5 2.13* ± 0.05 (100) 3.48* ± 0.62 (0) 0.25 2.38* ± 0.58 (80) 4.46* ± 0.99 (0) 0.125 4.62* ± 0.80 (0) 4.78* ± 0.92 (0) 0.063 6.06 ± 0.57 (0) 5.61* ± 0.69 (0) 0 6.47 ± 0.12 (0) 6.47 ± 0.12 (0) ↵a Mice were challenged i.v. with C. albicans MY1055 at 2.0 × 104 CFU/mouse. Mice received first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Kidneys were aseptically collected at day 8 after challenge.
↵b Mean log10 CFU/gram ± standard deviation at 8 days after challenge for paired kidneys. There were five mice per group except for the groups receiving no drug (three mice per group). Percent sterilization indicates the number of mice with no detectable yeast, where the limit of detection was 50 yeast cells per pair of kidneys.
↵c ED90s and ED99s (95% confidence intervals) were calculated based on reduction in CFU/gram of kidneys of treated groups compared to sham-treated control animals and were 0.049 (0.014, 0.180) and 0.119 (0.038, 0.374), respectively.
↵d See footnote c. Corresponding values were 0.071 (0.020, 0.254) and 0.198 (0.069, 0.571), respectively.
↵e NT, not tested.
↵f *, significantly different from result for sham-treated control (P < 0.05; Excel ttest).
- Table 3.
Efficacy of delayed therapy against disseminated C. albicans MY1055 infection in ICR mice with CY-induced, chronic immunosuppressiona
Compound Dose (mg/kg) Log10CFU/g kidneys (% sterilizationb [% reduction from control]c) at time point after challenge Day 4 Day 8 Day 14 Day 21 Day 28 Caspofungin 1.00 3.64* ± 0.18 (0 [99.85]) 2.30* ± 0.83 (90 [99.98]) 2.07* ± 0.07 (70 [99.99]) 2.07* ± 0.07 (100 [99.99]) 2.09* ± 0.08 (100 [99.99]) 0.50 3.94* ± 0.28 (0 [99.70]) 2.10* ± 0.04 (100 [99.99]) 2.06* ± 0.06 (100 [99.99]) 2.08* ± 0.08 (100 [99.99]) 2.10* ± 0.05 (90 [99.99]) 0.25 4.34* ± 0.34 (0 [99.26]) 2.10* ± 0.15 (90 [99.99]) 2.78* ± 0.96 (60 [99.97]) 3.44* ± 1.66 (50 [99.68]) 3.80* ± 1.74 (40 [99.93]) AmB 1.00 5.09* ± 0.80 (0 [95.82]) 2.07* ± 0.07 (80 [99.99]) 2.46* ± 0.79 (60 [99.98]) 2.37* ± 0.82 (80 [99.97]) 3.41* ± 2.11 (80 [99.97]) 0.50 5.63* ± 0.92 (0 [85.49]) 2.91* ± 0.49 (60 [99.93]) 2.93* ± 1.00 (50 [99.95]) 3.47* ± 1.40 (20 [99.66]) 4.14* ± 2.11 (40 [99.84]) 0.25 6.20 ± 0.39 (0 [46.79]) 3.58* ± 0.51 (10 [99.67]) 4.08* ± 0.93 (10 [99.33]) 4.56 ± 1.30 (10 [95.78]) 4.44* ± 2.57 (50 [99.68]) FCZ 80.00 5.57* ± 0.51 (0 [90.53]) 3.51* ± 1.35 (20 [99.87]) 4.37* ± 0.38 (0 [99.69]) 6.75 ± 0.91 (0 [NC]d) 6.01 ± 2.26 (20 [NC]) 40.00 5.91* ± 0.18 (0 [79.26]) 3.45* ± 0.30 (0 [99.89]) 5.35 ± 0.48 (0 [97.11]) 6.97 ± 0.41 (0 [NC]) 6.17 ± 2.36 (20 [NC]) 20.00 5.70* ± 0.36 (0 [87.12]) 2.87 ± 0.59 (20 [99.97]) 5.22 ± 1.01 (0 [97.85]) 4.15 ± 2.01 (40 [NC]) 7.68 (0 [NC]) Sham treated 6.47 ± 0.30 (0) 6.06 ± 0.30 (0) 6.26 ± 1.28 (0) 5.94 ± 2.24 (0) 6.93 ± 0.41 (0) ↵a Mice were challenged i.v. with C. albicans MY1055 at 5.6 × 104 CFU/mouse (study 1) and 1.22 × 105 CFU/mouse (study 2). Mice received the first treatment 24 h after challenge (delayed therapy) and were treated i.p., q.d., for 7 days. Mice were immunosuppressed throughout the experimental period (28 days). Kidneys were aseptically collected at days 4, 8, 14, 21, and 28 after challenge.
↵b Mean log10 CFU/gram ± standard deviation at time points after challenge for paired kidneys. There were 10 mice per group except as follows. For FCZ-treated mice, there were five mice per group, except for the 20-mg/kg dose at day 28 (one mouse). Groups of sham-treated mice contained eight, five, and two mice on days 14, 21, and 28, respectively. Percent sterilization indicates the number of mice with no detectable yeast, where the limit of detection was 50 yeast cells per pair of kidneys. Data for caspofungin are pooled from studies 1 and 2.
↵c Percent reduction calculated based on reduction in CFU/g of kidneys of treated groups compared to sham-treated control animals.
↵d NC, not calculated.
e *, significantly different from result for sham-treated control (P < 0.05; Excel ttest).
