Pharmacodynamics of Anidulafungin against Clinical Aspergillus fumigatus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

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Invasive aspergillosis (IA) due to Aspergillus flavus is associated with high mortality. Although voriconazole (VRC) is widely recommended as the first-line treatment for IA, emergence of azole resistance in Aspergillus spp. is translating to treatment failure. We evaluated the efficacy of voriconazole in a nonneutropenic murine model of disseminated A. flavus infection using two voriconazole-resistant isolates (one harboring the Y319H substitution in the cyp51C gene) and two wild-type isolates without mutations. All isolates exhibited a dose-response relationship, and voriconazole treatment improved mouse survival in a dose-dependent manner. At 40 mg/kg of body weight, 100% efficacy was observed for 1 susceptible isolate and 1 resistant isolate (with mutation), whereas for another susceptible isolate and resistant isolate (without mutation), survival rates were 81% and 72%, respectively. The Hill equation with a variable slope fitted the relationship between the area under the concentration-time curve (AUC)/MIC ratio and 14-day survival well for each strain. An F test showed the 50% effective doses to be significantly different from each other (P ϭ 0.0023). However, contrary to expectation, there was a significant difference in exposure-response relationships between strains, and it appeared that the susceptible strains required a relatively higher exposure than the resistant ones to result in the same treatment effect, the 50% effective pharmacokinetic/pharmacodynamic (PK/PD) index (EI 50 ) required being negatively and log-linearly related to the MIC (P ϭ 0.04). We conclude that the efficacy of voriconazole depended on drug exposure and the voriconazole MIC of the isolates, but lower exposures are required for strains with higher MICs. These findings may have profound significance in clinical practice with respect to dosing and drug choice.

Section: Fungal Isolates Four Clinicalmentioning

confidence: 99%

Pharmacodynamics of Voriconazole against Wild-Type and Azole-Resistant Aspergillus flavus Isolates in a Nonneutropenic Murine Model of Disseminated Aspergillosis

Rudramurthy

Seyedmousavi

Dhaliwal

et al. 2017

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“…However, the same study showed that although therapy success increased with increasing dosages of the drug, the maximum response was not obtained, even at 20 mg/kg. Furthermore, increasing the dose to 40 mg/kg caused toxic side effects (41). In our study, we did not increase the anidulafungin concentration but slightly reduced the fungal load by maintaining 100% mortality in the control group.…”

Section: Discussionmentioning

confidence: 66%

“…Under therapy with anidulafungin at 10 mg/kg/day, only 18% of animals survived (40). A recent analysis of the pharmacokinetics of anidulafungin in mice revealed a good correlation of serum level with the applied dose, which indicates that an effective concentration in serum can be achieved (41). However, the same study showed that although therapy success increased with increasing dosages of the drug, the maximum response was not obtained, even at 20 mg/kg.…”

Section: Discussionmentioning

confidence: 75%

Assessment of Efficacy of Antifungals against Aspergillus fumigatus: Value of Real-Time Bioluminescence Imaging

Galiger

Brock

Jouvion

et al. 2013

c Aspergillus fumigatus causes life-threatening infections, especially in immunocompromised patients. Common drugs for therapy of aspergillosis are polyenes, azoles, and echinocandins. However, despite in vitro efficacy of these antifungals, treatment failure is frequently observed. In this study, we established bioluminescence imaging to monitor drug efficacy under in vitro and in vivo conditions. In vitro assays confirmed the effectiveness of liposomal amphotericin B, voriconazole, and anidulafungin. Liposomal amphotericin B and voriconazole were fungicidal, whereas anidulafungin allowed initial germination of conidia that stopped elongation but allowed the conidia to remain viable. In vivo studies were performed with a leukopenic murine model. Mice were challenged by intranasal instillation with a bioluminescent reporter strain (5 ؋ 10 5 and 2.5 ؋ 10 5 conidia), and therapy efficacies of liposomal amphotericin B, voriconazole, and anidulafungin were monitored. For monotherapy, the highest treatment efficacy was observed with liposomal amphotericin B, whereas the efficacies of voriconazole and anidulafungin were strongly dependent on the infectious dose. When therapy efficacy was studied with different drug combinations, all combinations improved the rate of treatment success compared to that with monotherapy. One hundred percent survival was obtained for treatment with a combination of liposomal amphotericin B and anidulafungin, which prevented not only pulmonary infections but also infections of the sinus. In conclusion, combination therapy increases treatment success, at least in the murine infection model. In addition, our novel approach based on real-time imaging enables in vivo monitoring of drug efficacy in different organs during therapy of invasive aspergillosis.

“…A total of 604 outbred CD-1 (Charles River, the Netherlands) female mice, 4 to 5 weeks old, weighing 20 to 25 g, were randomized into groups of 11 mice for L-AmB monotherapy. Animals were infected using the procedure described before (11,13,15,25). Before performing the experiment, the isolates were cultured once on SAD for 5 days at 35 to 37°C and subcultured twice on 15-cm Takashio slants for 5 days at 35 to 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, it is important to explore alternative treatment regimens. Lipid formulations of the amphotericin B and echinocandin antifungals or combination therapy may be important alternative options, in patients with azole-resistant Aspergillus diseases.We previously investigated the pharmacodynamics of anidulafungin monotherapy and the combination of voriconazole and anidulafungin (13)(14)(15). Although anidulafungin treatment improved the survival of mice in a dose-dependent manner, a maximal response was not achieved when mice were infected with an azole-susceptible or azole-resistant isolate, even in those treated with the highest anidulafungin dose.…”

mentioning

confidence: 99%

Pharmacodynamics and Dose-Response Relationships of Liposomal Amphotericin B against Different Azole-Resistant Aspergillus fumigatus Isolates in a Murine Model of Disseminated Aspergillosis

Seyedmousavi

Melchers

Mouton

et al. 2013

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bThe management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus, which is associated with treatment failure and a mortality rate of 88%. Treatment with liposomal amphotericin B (L-AmB) may be a useful alternative to improve therapeutic outcome in azole-resistant IA. Four clinical A. fumigatus isolates obtained from patients with proven IA were studied in a nonneutropenic murine model of infection: a wildtype isolate without mutations in the cyp51A gene and three azole-resistant isolates harboring a single mutation at codon 220 (M220I) and tandem repeat mutations (a 34-bp tandem repeat mutation in the promoter region of the cyp51A gene in combina Voriconazole is the recommended first-choice therapy for invasive infections caused by Aspergillus species (1, 2). However, the management of invasive aspergillosis (IA) has become more complicated due to the emergence of acquired azole resistance in Aspergillus fumigatus (3), and azole resistance has been reported on different continents (4-8). There is increasing evidence that azole resistance is associated with treatment failure (5, 9, 10), and a mortality rate of 88% has been reported (5). These clinical observations are also supported by animal models of IA, where the MIC was shown to have major implications for the efficacy of voriconazole and posaconazole (11,12). Therefore, it is important to explore alternative treatment regimens. Lipid formulations of the amphotericin B and echinocandin antifungals or combination therapy may be important alternative options, in patients with azole-resistant Aspergillus diseases.We previously investigated the pharmacodynamics of anidulafungin monotherapy and the combination of voriconazole and anidulafungin (13)(14)(15). Although anidulafungin treatment improved the survival of mice in a dose-dependent manner, a maximal response was not achieved when mice were infected with an azole-susceptible or azole-resistant isolate, even in those treated with the highest anidulafungin dose. The results of combination therapy suggested that voriconazole and anidulafungin have a synergistic interaction in mice infected with a voriconazole-susceptible isolate. However, the synergistic interaction was lost in the azole-resistant isolate (voriconazole MIC, 4 mg/liter), as only an additive interaction was observed (13). A relation between the voriconazole MIC and the fractional inhibitory concentration (FIC) index was observed in vitro, which indicated that further increase of the voriconazole MIC was associated with less favorable drug interaction (14). In infection due to isolates which are highly resistant to voriconazole, the efficacy of the combination might rely only on that of anidulafungin, which is suboptimal. In clinical practice, this is a major drawback, as isolates that are highly resistant to voriconazole are increasingly common (4), and in culture-negative patients we will be unable to determine voriconazole susceptibility.Treatment with a lipos...