Class of 2013 Abstract / Specific Aims: To describe the characteristics of patients who were switched to or prescribed posaconazole or voriconazole for the treatment of coccidioidomycosis including duration of previous anti-fungal treatment and rationale for changing from the first-line agents to posaconazole or voriconazole. Methods: This was a retrospective medical chart review of all patients admitted to an academic medical center with a diagnosis of coccidioidomycosis and prescribed posaconazole or voriconazole between January 2008 and December 2011. Subjects for the study were identified by ICD-9 codes for coccidioidomycosis (114.0-114.9) and through the pharmacy system for orders for posaconazole or voriconazole. Data collected included demographic information, antifungal prescription data, and outcome of fungal infection, if available. Main Results: A total of 41 subjects were identified as being prescribed either voriconazole or posaconazole for a diagnosis for coccidioidomycosis. The majority of subjects were prescribed voriconazole (93%) rather than posaconazole. While the majority of subjects were diagnosed with only pulmonary disease, 44% of subjects’ coccidioidomycosis diagnoses were classified as disseminated and 46% were admitted to an intensive care unit. The median (range) duration of first-line antifungal therapy was 3 (2-10) days for the posaconazole group and 3 (0-25) days for the voriconazole group. Overall, the reason(s) for switching antifungal therapy was listed as: failure of first-line therapy (26%), adverse drug event (4.3%), other (35%), and unknown (35%). Conclusion: There was no significant difference in baseline or disease characteristics between patients who were prescribed voriconazole or posaconazole for coccidioidomycosis. The main limitation of this retrospective evaluation is that the reason for use of voriconazole or posaconazole rather than first-line agents was often not easily determined based on the documentation in the medical records.

Class of 2012 Abstract / Specific Aims: The primary aim of this study was to determine the incidence of posaconazole and voriconazole concentration monitoring that occurs in transplant patients receiving antifungal prophylaxis therapy. The secondary aim was to determine whether voriconazole and posaconazole serum concentrations were used for dose adjustments. Methods: Patients status post either a liquid or solid organ transplant over the age of 1 year who received invasive fungal infection prophylaxis with either posaconazole or voriconazole between the dates of February 1, 2010 through January 31, 2011 while admitted to academic medical center were included in this descriptive retrospective study. This study has been approved by the Institutional Review Board. Data collected on each subject included demographic information, type of transplant, posaconazole or voriconazole concentrations, and duration and dosage adjustments. Main Results: 54 subjects were identified who received either voriconazole or posaconazole for fungal prophylaxis after transplant. For subjects who were prescribed posaconazole (N = 8), concentration monitoring was performed in 50% of subjects and 0% of posaconazole dose adjustments were based on concentrations. For subjects who were prescribed voriconazole, concentration monitoring and dose adjustments based on voriconazole concentrations were performed in 20% and 78% of subjects respectively. Adverse outcomes associated with the use of antifungal therapy were reported in 0% of the posaconazole therapy group and 17% of the voriconazole therapy group. Conclusions: Both posaconazole and voriconazole concentrations were obtained from patients who were receiving antifungal therapy for invasive fungal infection prophylaxis. Adjustments of prophylactic doses are not well characterized.

Class of 2014 Abstract / Specific Aims: Evaluate serum posaconazole concentrations following dose adjustment in response to subtherapeutic serum concentrations. Determine optimal dose adjustment schema and identify toxicity with doses above 600 mg daily (e.g.: 200 mg per os three times daily). Methods: The health records were reviewed for 29 patients ≥ 18 years with acute myeloid leukemia over a four-year period. Participants initially received posaconazole 200 mg per os three times daily as prophylaxis and required at least one dose adjustment secondary to a subtherapeutic posaconazole serum concentration. Patients were stratified by posaconazole dosing following dose adjustment (A=200mg QID, B=300mg TID, C=400 mg TID, D=400 QID). Main Results: There was a statistically significant increase in posaconazole serum concentration in each group compared to baseline serum concentration, aside from group C (group A and B P<0.001, group C P=0.236, and group D P=0.0076). The majority of participants in 3 of the 4 groups reached therapeutic serum concentration (A=0.87, B=0.76, D=0.80) whereas group C had a serum posaconazole concentration on average below therapeutic range (0.51). There was no significant difference between the four groups in regards to renal function (p=0.35) or hepatic function (AST p=0.676, ALT p=0.877, total bilirubin p=0.097). Conclusion: A dose increase led to an increase in posaconazole serum concentration except for the dosing regimen of 400 mg three times daily. However, the study is limited by a small patient population, an unequal number of patients in each group, and potentially by poor absorption of posaconazole suspension. Further research is required to expand on these findings.

La kératite à Acanthamoeba (KA) est une kératite infectieuse rare et grave,potentiellement cécitante. L'infection est causée par Acanthamoeba spp., unprotozoaire ubiquitaire présent dans le sol, l'air et l'eau. Jusqu'à 85% des cas de KAsont associés au port de lentilles cornéennes, et plus rarement suite à untraumatisme.Actuellement, aucune molécule n’a d’autorisation de mise sur le marché danscette indication dans l'Union européenne et aux États-Unis. Ces dernières années,des combinaisons d'agents anti-amibiens tels que les biguanides et les diamidinesont été utilisées comme traitement de référence. Cependant, les schémasthérapeutiques et les concentrations d'agents actifs reposent sur des donnéesempiriques. Récemment, le voriconazole, antifongique triazolé, a été utilisé avecsuccès pour traiter des KA humaines. Malgré cela, la communauté ophtalmologiquese heurte le plus souvent dans les formes sévères à de grandes difficultés de prise encharge et se retrouve parfois en situation d’impasse thérapeutique. La pertefonctionnelle et anatomique de l’oeil est encore possible.A partir d’un modèle de KA chez le rat, plusieurs molécules et voiesd’administration ont été testées. Dans une première partie, en lien avec projeteuropéen ODAK (Orphan drug for Acanthamoeba Keratitis), nos travaux ont suggéréqu’une concentration de collyre PHMB supérieure ou égale à 0,04% devait êtrepréférée. Dans une deuxième partie, nous avons pu montrer la supériorité duvoriconazole en collyre par rapport à la voie orale. Enfin, l’étude de lapharmacocinétique du voriconazole et du posaconazole après injections directesintracornéennes, démontre leur faible utilité en clinique humaine du fait de lafréquence nécessaire de réinjection, bien que des analyses complémentairesconcernant le posaconazole en collyre pour confirmer son intérêt soient nécessaires.L'ensemble de ces travaux pourrait permettre d’adapter les protocolesthérapeutiques de la KA. / Acanthamoeba keratitis (AK) is a rare and severe form of infectious keratitis,which is potentially sight-threatening. The infection is caused by Acanthamoeba spp.a common protozoan present in soil, air and water. Up to 85% of AK cases areassociated with contact lens wearing, more rarely after corneal injury.Currently, there are no agents approved for the treatment of AK in theEuropean Union or in the United States of America. In recent years, combinations ofunlicensed anti-amoebic agents such as biguanides and diamidines have been usedas the reference treatment. Treatment regimens and concentrations of active agentsare based on empirical data. Recently, voriconazole, a mono-triazole, wassuccessfully used to treat cases of human AK. Despite this, the ophthalmologicalcommunity is most often faced with severe forms of the disease with severemanagement difficulties and sometimes with a situation of therapeutic impasse. Thefunctional and anatomical loss of an eye can occur.Several agents and routes of administration have been tested in a rat model ofAK. First, as part of the European ODAK project (Orphan drug for AcanthamoebaKeratitis), our work suggested that a concentration of PHMB eye drops greater thanor equal to 0.04% should be preferred. Second, we were able to show the superiorityof voriconazole in eye drops compared to the oral route. Finally, our study on thepharmacokinetics of voriconazole and posaconazole after intrastromal injections,demonstrates their low utility in human because of the need for frequent reinjection.Nevertheless, additional analyses are necessary to confirm the interest ofposaconazole eye drops. All of this work could make it possible to adapt thetherapeutic protocols of AK.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I) is exceptionally common in Finland. Most patients have chronic oral candidiasis since childhood. Thus, most patients receive repeated courses of antifungals throughout their life. Eleven of our patients (31.4%) have become colonized with Candida albicans with decreased sensitivity to fluconazole. A total of 43 isolates of C. albicans from 23 APECED patients isolated during the years 1994 to 2004 were divided into 2 groups: fluconazole-susceptible dose-dependent (MIC, 16-32 μg/mL, 18 isolates) and fluconazole-susceptible (MIC ≤8 μg/mL, 25 isolates) groups. Antifungal activity of amphotericin B, echinocandins, and azoles was determined by the Clinical and Laboratory Standards Institute M27-A2 methodology. All isolates were highly susceptible to amphotericin B and echinocandins. Posaconazole and voriconazole were active against all isolates. Our data suggest that topical amphotericin B could continue to be a safe and active drug for daily administration for APECED patients. Posaconazole, voriconazole, and echinocandins may be useful in some complicated cases.

Pharmacodynamic studies are important for the optimal use of antimicrobial agents. Combination antifungal therapy may be one method to improve outcome in invasive Candida infections. An in vitro kinetic model to study the pharmacodynamic effects of a combination of two antifungal agents with different elimination rates was developed and the pharmacodynamics of amphotericin B (AMB), voriconazole (VRC) or the combination was evaluated. Exposure to VRC inhibited the fungicidal activity of sequential doses of AMB against VRC-susceptible strains of C. albicans. The interaction was VRC dose-dependent. AMB activity was regained once VRC was removed or it increased gradually when the concentration of VRC had fallen below the minimum inhibitory concentration (MIC). The VRC-AMB interaction, however, was also present against strains of C. albicans, C. glabrata and C. krusei despite reduced VRC susceptibility. Against these strains the interaction was not predicted by the MIC value, suggesting that mechanisms of resistance may be of importance. Until more data are available, a reasonable recommendation is probably to avoid the sequential use of VRC followed by AMB and to use the combination of VRC and AMB for the treatment of Candida infections with caution. Only the unbound fraction of a drug is generally accepted as pharmacologically active. The activity of posaconazole (POS) with a protein binding of 98-99% was tested in serum against Candida species and compared with the calculated unbound serum concentration in protein-free media. Significant differences emerged at clinically relevant POS serum concentrations of 1.0 and 0.10 mg/l compared with the serum control regimen against one strain of C. lusitaniae. In RPMI 1640 the corresponding calculated unbound concentrations resulted in no effect for the low dose regimen compared with the RPMI 1640 control regimen. Further, against seven additional Candida strains tested, the effect of POS was greater in serum than in RPMI 1640. A flux from serum protein bound to fungal lanosterol 14α-demethylase bound POS may be the explanatory mechanism.