Influence of Sustained Low-Efficiency Dialysis Treatment on Isavuconazole Plasma Levels in Critically Ill Patients.

Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 µg/ml; P < 0.001). However, even after SLED treatment, isavuconazole concentrations exceeded the in vivo MICs for several relevant Aspergillus species.

Optimization of Voriconazole Therapy for the Treatment of Invasive Fungal Infections in Adults.

Therapeutic concentrations of voriconazole in invasive fungal infections (IFIs) are ensured using a drug monitoring approach, which relies on attainment of steady-state pharmacokinetics. For voriconazole, time to reach steady state can vary from 5-7 days, not optimal for critically ill patients. We developed a population pharmacokinetic/pharmacodynamic model-based approach to predict doses that can maximize the net benefit (probability of efficacy-probability of adverse events) and ensure therapeutic concentrations, early on during treatment. The label-recommended 200 mg voriconazole dose resulted in attainment of targeted concentrations in ≥80% patients in the case of Candida spp. infections, as compared to only 40-50% patients, with net benefit ranging from 5.8-61.8%, in the case of Aspergillus spp. infections. Voriconazole doses of 300-600 mg were found to maximize the net benefit up to 51-66.7%, depending on the clinical phenotype (due to CYP2C19 status and pantoprazole use) of the patient and type of Aspergillus infection.

Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus.

Aspergillus fumigatus is the most prevalent airborne fungal pathogen causing invasive fungal infections in immunosuppressed individuals. The histidine biosynthetic pathway is found in bacteria, archaebacteria, lower eukaryotes, and plants, but is absent in mammals. Here we demonstrate that deletion of the gene encoding imidazoleglycerol-phosphate dehydratase (HisB) in A. fumigatus causes (i) histidine auxotrophy, (ii) decreased resistance to both starvation and excess of various heavy metals, including iron, copper and zinc, which play a pivotal role in antimicrobial host defense, (iii) attenuation of pathogenicity in 4 virulence models: murine pulmonary infection, murine systemic infection, murine corneal infection, and wax moth larvae. In agreement with the in vivo importance of histidine biosynthesis, the HisB inhibitor 3-amino-1,2,4-triazole reduced the virulence of the A. fumigatus wild type and histidine supplementation partially rescued virulence of the histidine-auxotrophic mutant in the wax moth model. Taken together, this study reveals limited histidine availability in diverse A. fumigatus host niches, a crucial role for histidine in metal homeostasis, and the histidine biosynthetic pathway as being an attractive target for development of novel antifungal therapy approaches.

Pharmacodynamics of Voriconazole in Children: Further Steps along the Path to True Individualized Therapy.

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC50) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC50)/15.4 predicted terminal galactomannan (P= 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (P= 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival.

[Molecular markers: an important tool in the diagnosis, treatment and epidemiology of invasive aspergillosis]. / Marcadores moleculares: una herramienta importante en el diagnóstico, tratamiento y epidemiología de la aspergilosis invasora.

Increase in the incidence of invasive aspergillosis has represented a difficult problem for management of patients with this infection due to its high rate of mortality, limited knowledge concerning its diagnosis, and therapeutic practice. The difficulty in management of patients with aspergillosis initiates with detection of the fungus in the specimens of immunosuppressed patients infected with Aspergillus fumigatus; in addition, difficulty exists in terms of the development of resistance to antifungals as a consequence of their indiscriminate use in prophylactic and therapeutic practice and to ignorance concerning the epidemiological data of aspergillosis. With the aim of resolving these problems, molecular markers is employed at present with specific and accurate results. However, in Mexico, the use of molecular markers has not yet been implemented in the routine of intrahospital laboratories; despite the fact that these molecular markers has been widely referred in the literature, it is necessary for it to validated and standardized to ensure that the results obtained in any laboratory would be reliable and comparable. In the present review, we present an update on the usefulness of molecular markers in accurate identification of A. fumigatus, detection of resistance to antifugal triazoles, and epidemiological studies for establishing the necessary measures for prevention and control of aspergillosis.

El incremento en la incidencia de la aspergilosis invasora representa un grave problema para el tratamiento de pacientes con esta micosis, debido a su elevada tasa de mortalidad por deficiencias diagnósticas y terapéuticas. Éstas se han atribuido a la dificultad para detectar Aspergillus fumigatus, principal agente etiológico de esta micosis, en las muestras biológicas de pacientes inmunosuprimidos, que son los principales afectados por el hongo; además por la resistencia a los antifúngicos como consecuencia del uso incontrolado de éstos, a nivel profiláctico y terapéutico, y el desconocimiento de aspectos epidemiológicos de la aspergilosis. En la actualidad, para superar estas limitaciones se han empleado marcadores moleculares. En México su uso aún no está implementado en la rutina de los laboratorios intrahospitalarios, porque a pesar de que se han reportado ampliamente en la bibliografía, hace falta validarlos y estandarizarlos para asegurar que los resultados que se obtengan en cualquier laboratorio sean confiables y comparables. En este trabajo se presenta una revisión actualizada de la utilidad de los marcadores moleculares en la identificación certera de A. fumigatus en la detección de resistencia a los antifúngicos triazólicos y en estudios epidemiológicos para establecer las medidas necesarias en la prevención y control de la aspergilosis.

The role of azoles in the management of azole-resistant aspergillosis: from the bench to the bedside.

Azole resistance is an emerging problem in Aspergillus fumigatus and is associated with a high probability of treatment failure. An azole resistance mechanism typically decreases the activity of multiple azole compounds, depending on the mutation. As alternative treatment options are limited and in some isolates the minimum inhibitory concentration (MIC) increases by only a few two-fold dilutions steps, we investigated if voriconazole and posaconazole have a role in treating azole-resistant Aspergillus disease. The relation between resistance genotype and phenotype, pharmacokinetic and pharmacodynamic properties, and (pre)clinical treatment efficacy were reviewed. The results were used to estimate the exposure needed to achieve the pharmacodynamic target for each MIC. For posaconazole adequate exposure can be achieved only for wild type isolates as dose escalation does not allow PD target attainment. However, the new intravenous formulation might result in sufficient exposure to treat isolates with a MIC of 0.5 mg/L. For voriconazole our analysis indicated that the exposure needed to treat infection due to isolates with a MIC of 2 mg/L is feasible and maybe isolates with a MIC of 4 mg/L. However, extreme caution and strict monitoring of drug levels would be required, as the probability of toxicity will also increase.

EDTA as an adjunct antifungal agent for invasive pulmonary aspergillosis in a rodent model.

Rats immunosuppressed by the administration of cyclophosphamide and cortisone acetate and then infected with Aspergillus fumigatus were treated with an antifungal drug, EDTA, or a combination of one of the antifungal agents, amphotericin B lipid complex (ABLC; 5 mg/kg of body weight/day for 7 days), and EDTA (30 mg/kg/day for 7 days). The mortality rate was reduced, the duration of survival was increased, fewer A. fumigatus organisms were recovered from the lungs, and less-severe lung lesions were seen histopathologically in the rats receiving the combination treatment than in the rats receiving either an antifungal agent or EDTA alone. Further studies regarding the mechanisms of EDTA and its interactions with ABLC are warranted, and further studies are needed to more fully examine the safety, tolerance, and optimal dosing of EDTA in the treatment of this and other fungal infections.

Efficacy of unilamellar liposomal amphotericin B in treatment of pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of bronchoalveolar D-mannitol and serum galactomannan as markers of infection.

A model of primary pulmonary aspergillosis in rabbits was developed to reproduce the persistent levels of profound granulocytopenia and the histopathologic features of bronchopneumonia, vascular invasion, and hemorrhagic infarction encountered in humans. D-mannitol was detectable in bronchoalveolar lavage fluid by gas-liquid chromatography/mass spectroscopy, and galactomannan was measurable in serum by latex agglutination immunoassay. A pharmacokinetically distinctive unilamellar vesicle formulation of liposomal amphotericin B, 5 mg/kg/day intravenously, compared with high-dose conventional desoxycholate amphotericin B, 1 mg/kg/day intravenously, was more effective in preventing nephrotoxicity, increasing survival, reducing the number of viable organisms, and decreasing tissue injury due to Aspergillus organisms. Thus, D-mannitol in lavage fluid and galactomannan in serum may be useful markers of pulmonary aspergillosis, and liposomal amphotericin B was significantly more effective and safer than desoxycholate amphotericin B for treatment of pulmonary aspergillosis in profoundly granulocytopenic rabbits.