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. 2017 Aug 24;61(9):e00305-17.
doi: 10.1128/AAC.00305-17. Print 2017 Sep.

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

Vidmantas Petraitis  1   2 , Ruta Petraitiene  3   2 , Matthew W McCarthy  3 , Laura L Kovanda  4 , Myo H Zaw  3 , Kaiser Hussain  3 , Naima Shaikh  3 , Bo Bo W Maung  3 , Navjot K Sekhon  3 , William W Hope  5 , Thomas J Walsh  1   6
Affiliations

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

Vidmantas Petraitis et al. Antimicrob Agents Chemother. .

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.

Keywords: (1→3)-β-d-glucan; Aspergillus fumigatus; aspergillosis; combination therapy; galactomannan; isavuconazole; micafungin; neutropenia; pharmacokinetics; rabbit.

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Figures

FIG 1
FIG 1
Response of primary pulmonary aspergillosis to antifungal therapy in persistently neutropenic untreated control (UC) rabbits and rabbits receiving oral isavuconazole (BAL4815), measured by mean lung weight (A) and mean pulmonary infarct score (B). Values are given as means ± SEMs. P values are indicated as follows: *, P < 0.05; †, P < 0.01. P values are for decreased lung weights and pulmonary infarct scores in ISA40-MFG2-treated rabbits in comparison to those in rabbits treated with ISA40 or MFG2 alone.
FIG 2
FIG 2
Response of primary pulmonary aspergillosis to antifungal therapy in persistently neutropenic untreated control (UC) rabbits and persistently neutropenic rabbits receiving oral isavuconazole (BAL4815), measured by survival (A) and mean pulmonary tissue residual fungal burden (log number of CFU per gram) (B). Values are given as means ± SEMs. For the measure of survival, the values on the y axis are the probability of survival. Survival was plotted by Kaplan-Meier analysis. Differences in the rates of survival between the treatment groups and the untreated controls were analyzed by the log-rank test. P values are indicated as follows: †, P < 0.01 for decreased residual fungal burden in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits versus MFG2-treated or UC rabbits; ¶, P < 0.01 for prolonged survival of ISA40-MFG2-treated rabbits versus rabbits treated with ISA40 or MFG2 alone; £, P < 0.01 for prolonged survival of rabbits treated with ISA20-MFG2, ISA40-MFG2, and ISA60-MFG2 versus UC rabbits.
FIG 3
FIG 3
Serum (1→3)-β-d-glucan levels in persistently neutropenic untreated control (UC) rabbits and persistently neutropenic rabbits receiving oral doses of isavuconazole (BAL4815) in the model of experimental pulmonary aspergillosis. Values are given as (1→3)-β-d-glucan concentrations. P values are indicated as follows: *, P < 0.05 for the decrease in plasma (1→3)-β-d-glucan concentrations in ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits versus MFG2-treated or UC rabbits. d, days.
FIG 4
FIG 4
Expression of galactomannan antigenemia in persistently neutropenic untreated control (UC) rabbits with pulmonary aspergillosis and persistently neutropenic rabbits with pulmonary aspergillosis receiving an oral dose of isavuconazole (BAL4815). Values are given as the mean GMI ± SEM. P values are indicated as follows: *, P < 0.05 for a lower GMI in ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits versus MFG2-treated or UC rabbits; †, P < 0.01 for a lower GMI in ISA20-MFG2-treated rabbits than MFG2-treated rabbits.
FIG 5
FIG 5
Strong correlation between GMI and outcome variables. (A) Total lung weights (r = 0.764; P < 0.001); (B) infarct scores (r = 0.911; P < 0.001).
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