Combined Therapy of Voriconazole and Anidulafungin in Murine Infections by Aspergillus flavus

Antifungal combination therapy with voriconazole or amphotericin B and an echinocandin is often employed as primary or salvage therapy for management particularly of refractory aspergillosis. The pharmacodynamic interactions of amphotericin Band voriconazole-based combinations with the three echinocandins caspofungin, micafungin, and anidulafungin in the presence of serum were tested against 15 Aspergillus fumigatus complex, A. flavus complex, and A. terreus complex isolates to assess both their growth-inhibitory and fungicidal activities. The in vitro activity of each drug alone and in combination at a 1:1 fixed concentration ratio was tested with a broth microdilution colorimetric method, and interactions were assessed by isobolographic analysis. Synergy was found for all amphotericin B-and voriconazole-based combinations, with amphotericin B-based combinations showing strong inhibitory synergistic interactions (interaction indices of 0.20 to 0.52) and with voriconazole-based combinations demonstrating strong fungicidal synergistic interactions (interaction indices of 0.10 to 0.29) (P < 0.001). Drug-and species-specific differences were found, with caspofungin and the A. fumigatus complex exhibiting the weakest synergistic interactions. In the presence of serum, the synergistic interactions were reduced in the order (from largest to smallest decrease) micafungin > anidulafungin > caspofungin, and A. flavus complex > A. fumigatus complex > A. terreus complex, resulting in additive interactions, particularly for inhibitory activities of amphotericin B-echinocandin combinations and fungicidal activities of voriconazole-echinocandin combinations. Drug-and species-specific differences were found in the presence of serum for inhibitory activities of antifungal drugs, with the lowest interaction indices being observed for amphotericin B-caspofungin (median, 0.77) and for the A. terreus complex (median, 0.56). The present in vitro data showed that serum had a major impact on synergistic interactions of amphotericin B-echinocandin and voriconazole-echinocandin combinations, resulting in additive interactions and explaining the indifferent outcomes usually observed in vivo.

Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 99%

Amphotericin B- and Voriconazole-Echinocandin Combinations against Aspergillus spp.: Effect of Serum on Inhibitory and Fungicidal Interactions

Elefanti

Mouton²,

Verweij³

et al. 2013

“…In the present study, only one dose of voriconazole was evaluated because the use (4) 9.3 (6-30) 7.3 (6)(7)(8)(9)(10)(11)(12)(13)(14) of an additional dose for the same strains would have required more than 40 groups of animals. The dose tested demonstrated efficacy as seen in previous similar studies (9,27), and using this dose, the serum levels of that drug were always greater than the MICs for the strains tested. A possible limitation of the present study is the use of a systemic infection model, which is not the most common clinical presentation of A. fumigatus infection.…”

Section: Discussionsupporting

confidence: 67%

Evaluation of the In Vitro Activity of Voriconazole As Predictive of In Vivo Outcome in a Murine Aspergillus fumigatus Infection Model

Salas

Pastor

Sutton

et al. 2013

Self Cite

bWe have evaluated the in vitro activity of voriconazole against 61 strains of Aspergillus fumigatus by using broth microdilution, disk diffusion, and minimal fungicidal concentration procedures. We observed an excellent correlation between the results obtained with the three methods. Five percent of the strains showed MICs greater than or equal to the epidemiological cutoff value (ECV; 1 g/ml). To assess whether MICs were predictive of in vivo outcome, we tested the efficacy of voriconazole at 25 mg/kg of body weight daily in an immunosuppressed murine model of disseminated infection using 10 strains representing various patterns of susceptibility to the drug as determined by the in vitro study. Voriconazole prolonged survival and reduced fungal load in the kidneys and brain in those mice infected with strains with MICs of <0.25 g/ml, while in mice infected with strains with MICs of 0.5 to 2 g/ml, the efficacy was varied and strain dependent and in mice infected with the strain with a MIC of 4 g/ml, the antifungal did not show efficacy. Voriconazole reduced galactomannan antigenemia against practically all strains with a MIC of <4 g/ml. Our results demonstrate that some relationship exists between voriconazole MICs and in vivo efficacy; however, further studies testing additional strains are needed to better ascertain which MIC values can predict clinical outcome. Invasive aspergillosis is an important cause of morbidity and mortality in the immunocompromised host, Aspergillus fumigatus being the leading cause of invasive aspergillosis worldwide (1). At present, voriconazole is the first choice in the treatment of such infections (2), and although A. fumigatus is generally susceptible to voriconazole, several studies have demonstrated an increasing number of azole-resistant isolates (3-5). This represents an important problem in the clinical management of invasive aspergillosis because therapeutic options are limited.The development of clinical breakpoints of the most usual antifungal drugs might be useful for predicting the outcomes of fungal infections. However, the available antifungal susceptibility data are only based on in vitro and animal studies (6). A recent important step has been the proposal of epidemiological cutoff values (ECVs) for voriconazole against several Aspergillus spp., including A. fumigatus (ECV ϭ 1 g/ml), and theoretically, those isolates showing MICs higher than the ECV will show resistance (7,8).We have evaluated the efficacy of voriconazole at 25 mg/kg of body weight (9) in a murine model of disseminated infection by A. fumigatus, testing isolates with different MICs in order to ascertain the role of the in vitro data as a predictor of infection outcome. MATERIALS AND METHODSSixty-one clinical strains of Aspergillus fumigatus were tested in the in vitro studies. Their susceptibility to voriconazole was evaluated using a broth microdilution method, carried out according to the CLSI guidelines for filamentous fungi (10), and a disk diffusion method that uses nonsupplemented Mueller-Hi...

“…once daily (28), and AFG at 10 mg/kg i.p. once daily (29). Drug level determinations were not performed.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of the Efficacies of Amphotericin B, Posaconazole, Voriconazole, and Anidulafungin in a Murine Disseminated Infection by the Emerging Opportunistic Fungus Sarocladium (Acremonium) kiliense

Fernández-Silva

Capilla²,

Mayayo³

et al. 2013

Self Cite

We evaluated and compared the efficacies of different antifungal drugs against Sarocladium kiliense (formerly Acremonium kiliense), a clinically relevant opportunistic fungus, in a murine model of systemic infection. Three clinical strains of this fungus were tested, and the therapy administered was as follows: posaconazole at 20 mg/kg of body weight (twice daily), voriconazole at 40 mg/kg, anidulafungin at 10 mg/kg, or amphotericin B at 0.8 mg/kg. The efficacy was evaluated by prolonged animal survival, tissue burden reduction, and (1¡3)-␤-D-glucan serum levels. In general, the four antifungal drugs showed high MICs and poor in vitro activity. The efficacy of the different treatments was only modest, since survival rates were never higher than 40% and no drug was able to reduce fungal load in all the organs for the three strains tested. Posaconazole, in spite of its high MICs (>16 g/ ml), showed the highest efficacy. The (1¡3)-␤-D-glucan serum levels were equally reduced by all drugs evaluated.A cremonium kiliense is a saprobic fungus with a worldwide distribution which has been reported in recent years as an emerging opportunistic pathogen able to cause a wide range of human infections (1-4). Localized infections, such as mycetoma, keratitis, or onychomycosis, are acquired mainly by immunocompetent patients through trauma (5-11). Invasive infections generally affect immunosuppressed hosts such as those undergoing transplantation or those with AIDS, resulting in a high degree of fatality (12-16). More rarely, though, invasive infections have also been reported in immunocompetent individuals (17,18). Recently, based on molecular studies, this fungus has been transferred to the genus Sarocladium as Sarocladium kiliense (1). This species is the most clinically relevant of the genus and apparently also the most virulent (4,19,20). Considering that the morphological identification of these fungi is difficult, it is likely that some clinical isolates of this species have been misidentified as Acremonium strictum, another clinically important species of Acremonium (19). Infections by Acremonium spp. are difficult to treat due to the intrinsic resistance to the current antifungal agents, and an effective treatment has not yet been determined (19,(21)(22)(23). Amphotericin B (AMB) is the drug most commonly used to treat severe fungal infections caused by opportunistic molds (4). Despite its poor in vitro activity and variable clinical results, this drug still remains the first therapeutic choice against invasive Acremonium infections (2, 4, 19). Clinical experience with other drugs, such as posaconazole (PSC), voriconazole (VRC), and the echinocandins, is very poor.To evaluate possible therapeutic strategies, we tested the efficacies of PSC, VRC, and anidulafungin (AFG) compared to that of AMB against S. kiliense in a recently developed murine model of disseminated infection (20). MATERIALS AND METHODSThree clinical strains of Sarocladium kiliense, UTHSC 01-2238, UTHSC 03-3197, and UTHSC 07-550, previously identified by...