Efficacy of Caspofungin against Aspergillus terreus

This study investigated the possible mechanisms underlying the paradoxical caspofungin activity in vivo in preclinical aspergillosis. We evaluated the activity of escalating doses of caspofungin in vivo in different preclinical models of invasive aspergillosis, including mice deficient for selected innate immune receptors. The therapeutic efficacy of caspofungin in experimental invasive aspergillosis was strictly dose dependent, being observed at doses of 0.1 and 1 mg/kg of body weight depending on the experimental models. Paradoxical increase in pulmonary fungal burden as well as inflammatory pathology was observed at the highest dose of caspofungin (5 mg/kg), occurred independently of the so-called Eagle effect and susceptibility to caspofungin in vitro, and was contingent upon the presence of TLR2, Dectin-1, and TLR9. Increased expression of Dectin-1 and TLR9 were observed upon exposure to caspofungin in vitro and in vivo. Together, these findings suggest that the net activity of caspofungin in vivo is orchestrated by the activation, directly or indirectly, of multiple innate immune receptors. Invasive mold infections are major causes of morbidity and mortality among severely immunocompromised individuals (24,34). Aspergillus fumigatus is currently the most important airborne fungal pathogen and causes different kinds of disease, ranging from allergies to life-threatening infections depending on the immune status of the host (35). The risk of invasive Aspergillus infection is particularly high for patients with persistent neutropenia, graft-versus-host disease (especially with concomitant steroid therapy), and certain types of hematopoietic transplantation (24,26,34).The echinocandins are the newest addition to the arsenal against fungal infections. They demonstrate similar in vitro and in vivo activity against Aspergillus spp., but only caspofungin (CAS) is approved for treatment of patients who are intolerant of or refractory to other therapies (27,38). CAS has been evaluated in the salvage and primary therapy of invasive aspergillosis, and combination regimens incorporating an echinocandin were promising in the treatment of aspergillosis (11). Echinocandins exhibit a unique, fungus-specific mechanism of action by targeting 1,3-␤-D-glucan synthase (14,17,19), thereby inhibiting the biosynthesis of 1,3-␤-D-glucan, an important component of the fungal cell wall. In addition to having a structural role, ␤-glucan, as a fungal pathogen-associated molecular pattern (PAMP), exhibits potent immunostimulatory properties mediated by pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), which are expressed on host cells. Dectin-1 is the main PRR that recognizes ␤-glucans. Following binding, it induces the activation of phagocytic and proinflammatory responses (13).Studies with Candida albicans and Saccharomyces cerevisiae have revealed an echinocandin-susceptible genetic network that conceals ␤-glucan from the immune system, thus limiting an effective host respons...

Section: Discussionsupporting

confidence: 70%

Role of Innate Immune Receptors in Paradoxical Caspofungin ActivityIn Vivoin Preclinical Aspergillosis

Moretti

Bozza

D’Angelo

et al. 2012

“…In recent studies of caspofungin activity in mouse models of invasive aspergillosis, survival was different among groups infected with Aspergillus isolates with the same or comparable MEC values, suggesting that the MEC was not a good predictor of in vivo response to caspofungin and that other factors may play a role (4,7). Furthermore, in a study by Cacciapuoti et al (7) (28).…”

Section: Discussionmentioning

confidence: 99%

Concentration-Dependent Effects of Caspofungin on the Metabolic Activity of Aspergillus Species

Antachopoulos

Meletiadis

Sein

et al. 2007

The minimum effective concentration (MEC) used to assess the in vitro antifungal activity of caspofungin against Aspergillus spp. is a qualitative endpoint requiring microscopic examination of hyphae. We therefore developed a tool for the quantitative assessment of caspofungin activity against Aspergillus spp. at clinically applicable concentrations. Susceptibility to caspofungin (0.008 to 8 g/ml) was studied for 9 A. fumigatus, 8 A. flavus, and 12 A. terreus isolates based on the Clinical and Laboratory Standards Institute M38-A protocol. After 48 h of incubation, the MEC was defined microscopically, and metabolic activity assessed with a modified XTT assay, using 100 g of the tetrazolium salt XTT/ml and 6.25 M menadione. A significant reduction in metabolic activity was demonstrated at the MEC (0.25 to 0.5 g/ml) for all Aspergillus spp. and was more pronounced for A. flavus (median metabolic activity, 25% of control) compared to A. fumigatus and A. terreus (median metabolism, 42 and 53%, respectively), allowing determination of MEC with the XTT assay (93 to 100% agreement with microscopic MEC). Fungal metabolism tended to reach the lowest levels (median, 17 to 38% of control) one to two dilutions higher than the MEC, at the minimum metabolic activity concentration (MMC). For 5 of 9 A. fumigatus isolates, 6 of 12 A. terreus isolates, and 1 of 8 A. flavus isolates, a paradoxical increase in metabolism was observed at concentrations greater than the MMC. Sigmoid (E max ) or bell-shaped models described accurately (median R 2 ‫؍‬ 0.97) the concentration-dependent metabolic changes in the absence or presence, respectively, of paradoxical response. Assessment of metabolic activity may provide useful quantitative endpoints for in vitro studies of caspofungin against Aspergillus spp.Echinocandins are lipopeptide antifungal compounds that inhibit the (1,3)-␤-D-glucan synthase activity of Candida spp. and Aspergillus spp. Caspofungin has shown efficacy in the treatment of invasive candidiasis and aspergillosis in vivo and in clinical trials and is currently the most widely used echinocandin (1,11,13,16,21).Assessment of in vitro activity of caspofungin against Aspergillus spp. is complicated by the fact that the MIC often exceeds safely achievable plasma concentrations, which range approximately between 1 and 11 g/ml in adults receiving 50 mg/day and between 1 and 20 g/ml in children receiving 50 mg/m 2 /day (11,12,25,27). The minimum effective concentration (MEC), defined as the lowest drug concentration at which short, stubby, and highly branched hyphae are observed on microscopic examination has been shown to generate more consistent susceptibility results than the MIC and is currently the suggested endpoint for determining the in vitro activity of caspofungin against Aspergillus spp. (3, 11, 12, 20).The MEC endpoint, however, still represents a subjective assessment of the appearance of growth and cannot be automated. Its determination requires laborious microscopic examination of the hyphal structures or sufficient...

“…Barchiesi et al (4) observed that CAS therapy provided protection in neutropenic mice infected with either of two A. terreus strains, with a significant fungal burden reduction in the kidneys achieved with 1 and 5 mg/kg CAS and a significant fungal burden reduction in the brain achieved with 5 mg/kg CAS. Of note, the peak kidney CFU reduction was comparable to the kidney CE reduction (ϳ1 log 10 ) shown here.…”

mentioning

confidence: 99%

“…Although Aspergillus fumigatus accounts for the majority of cases of human aspergillosis, the number of infections caused by other Aspergillus species has increased (4,28). The emerging threat posed by these species is especially important to understand because of their inherent reduced susceptibilities to many antifungal agents (8,13,30).…”

mentioning

confidence: 99%

“…CAS has been demonstrated to have activity against A. terreus in animal models (4,12), and case reports have described the efficacy of CAS in patients infected with A. flavus (15) Clinical isolates of A. flavus (CLF9089), A. terreus (CLF9062), and A. nidulans (CLF14) were used in these studies. Spores were harvested from cultures incubated for 5 to 7 days at 35°C on Sabouraud dextrose agar (SDA).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Efficacy of Caspofungin against Aspergillus flavus , Aspergillus terreus , and Aspergillus nidulans

Bowman¹,

Abruzzo²,

Flattery³

et al. 2006