Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp.

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Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1¡3)-␤-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and ( Infections caused by Aspergillus fumigatus are a persistent public health problem. Diagnosis is slow and inaccurate, and there are still relatively few antifungal agents. The use of available compounds is difficult and requires specialist knowledge. The antiAspergillus triazoles (itraconazole, voriconazole, and posaconazole) and the polyenes have relatively narrow therapeutic indices (1). Suboptimal and toxic drug exposures are both potentially lethal. Both intrinsic and acquired forms of drug resistance to the triazoles are an ever-present concern (2) and are associated with a high mortality rate; in some centers, this has influenced local prescribing practices. There is an urgent requirement for the development of new antifungal compounds and a better understanding of the use of existing agents (1). Amphotericin B was first developed in 1957 (1). Despite this, there is still a relatively limited understanding of its pharmacokinetics (PK) and pharmacodynamics (PD) against A. fumigatus, and uncertainty surrounds the use of each of the formulations for the treatment of invasive pulmonary aspergillosis (IPA).Here, we provide further insight into the PD of three clinically licensed formulations of amphotericin B against A. fumigatus. Using a well-validated persistently-neutropenic-rabbit model of IPA (3), we linked concentrations of amphotericin B with levels of circulating galactomannan and (1¡3)-␤-D-glucan, both of which are licensed for the diagnosis of IPA and widely available in routine clinical microbiology laboratories. We linked the kinetics of these biomarkers with more basic measures of organism-mediated pulmonary injury (OPMI), such as lung weight and pulmonary infarct score. We describe the resultant exposure-response relationships and reflect on the adequacy of currently recommended antifungal regimens, as well as the potential limitations of fixed regimens.(This work was presented at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 5 t...

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

Al-Nakeeb

Petraitis

Goodwin

et al. 2015

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“…The MIC was defined as the lowest concentration that completely inhibited growth in comparison to that seen in the drug-free well (control) as assessed by visual inspection (51). The EUCAST breakpoints were used to classify azole-susceptible and azole-resistant isolates (52). Antifungal agents.…”

Section: Fungal Strains the Following Two Clinical A Fumigatus Isolmentioning

confidence: 99%

In Vivo Efficacy of Liposomal Amphotericin B against Wild-Type and Azole-Resistant Aspergillus fumigatus Isolates in Two Different Immunosuppression Models of Invasive Aspergillosis

Seyedmousavi

Mouton

Melchers

et al. 2017

Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866 -1871, 2013, https://doi.org/10.1128/AAC.02226 -12). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR 34 /L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR 34 /L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR 34 /L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED 50 ) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR 34 /L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR 34 /L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P Ͼ 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.

“…Susceptibility interpretation was performed by applying the defined EUCAST breakpoints (21,22; http://www.eucast.org/clinical_breakpoints/).…”

Section: Methodsmentioning

confidence: 99%

Posttreatment Antifungal Resistance among Colonizing Candida Isolates in Candidemia Patients: Results from a Systematic Multicenter Study

Jensen

Johansen

Søes

et al. 2016

The prevalence of intrinsic and acquired resistance among colonizing Candida isolates from patients after candidemia was investigated systematically in a 1-year nationwide study. Patients were treated at the discretion of the treating physician. Oral swabs were obtained after treatment. Species distributions and MIC data were investigated for blood and posttreatment oral isolates from patients exposed to either azoles or echinocandins for <7 or >7 days. Species identification was confirmed using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and internal transcribed spacer (ITS) sequencing, susceptibility was examined by EUCAST EDef 7.2 methodology, echinocandin resistance was examined by FKS sequencing, and genetic relatedness was examined by multilocus sequence typing (MLST). One hundred ninety-three episodes provided 205 blood and 220 oral isolates. MLST analysis demonstrated a genetic relationship for 90% of all paired blood and oral isolates. Patients exposed to azoles for >7 days (n ‫؍‬ 93) had a significantly larger proportion of species intrinsically less susceptible to azoles (particularly Candida glabrata) among oral isolates than among initial blood isolates (36.6% versus 12.9%; P < 0.001). A similar shift toward species less susceptible to echinocandins among 85 patients exposed to echinocandins for >7 days was not observed (4.8% of oral isolates versus 3.2% of blood isolates; P > 0.5). Acquired resistance in Candida albicans was rare (<5%). However, acquired resistance to fluconazole (29.4%; P < 0.05) and anidulafungin (21.6%; P < 0.05) was common in C. glabrata isolates from patients exposed to either azoles or echinocandins. Our findings suggest that the colonizing mucosal microbiota may be an unrecognized reservoir of resistant Candida species, especially C. glabrata, following treatment for candidemia. The resistance rates were high, raising concern in general for patients exposed to antifungal drugs.