Therapeutic drug monitoring of voriconazole and posaconazole.

Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings.

Voriconazole serum concentrations in prophylactically treated acute myelogenous leukaemia patients.

Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9-21). The mean voriconazole concentration was 486 µg l(-1) and ranged from 136 µg l(-1) to 1257 µg l(-1). Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis.

Association of HSV reactivation and pro-inflammatory cytokine levels with the severity of stomatitis after BEAM chemotherapy and autologous SCT.

BACKGROUND: Stomatitis, including oral mucositis and ulcerations induced by HSV-reactivation are major sources of morbidity after high-dose (HD) chemotherapy and subsequent autologous hematopoietic stem cell transplantation (SCT). While increased synthesis of pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α)-as well as reactivation of viral infections have frequently been observed in this setting, data on their association with the severity of mucositis is limited. MATERIALS AND METHODS: Fifteen patients with Hodgkin's or non-Hodgkin's lymphoma receiving HD conditioning chemotherapy and autologous SCT were assessed with respect to oral pain and severity of stomatitis on day -6, 0, +5 to +7, +13 to +15, and +100. On the same dates, IL-1 and TNF-α were quantified in saliva and screening for a wide range of viral pathogens was carried out by cell culture and PCR and complemented by serological analyses. t Tests were used to assess potential associations between these variables. RESULTS: All but one patient had a positive HSV IgG titer at baseline. Reactivation as confirmed by HSV PCR was observed in seven patients (50%). There was a significant association between the presence of HSV in saliva samples and severity of stomatitis (t test, p = 0.015). The highest concentration of TNF-α and IL-1 coincided with the maximum intensity of stomatitis, but the association was not significant. CONCLUSION: We found a significant association between the presence of HSV in saliva samples and severity of stomatitis in patients receiving HD chemotherapy and subsequent autologous SCT. While acyclovir prophylaxis has become standard for patients undergoing allogeneic SCT, this issue has not been sufficiently explored for other chemotherapy regimens. Based on our findings, conduction of a well-powered controlled randomized trial may be warranted.

Intracellular concentrations of posaconazole in different compartments of peripheral blood.

Therapeutic drug monitoring (TDM) of antifungal plasma concentrations is increasingly recommended. However, data on antifungal concentrations in the other compartments of the peripheral blood are limited. Hence, we collected 23 blood samples from 14 patients receiving posaconazole for prophylaxis of fungal infections. These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. The intracellular posaconazole concentrations of the obtained cells, i.e., the peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs), and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry. The intracellular concentrations of the PBMCs and PMNs were significantly higher than those of surrounding media (P < 0.001). The ratios between the intracellular and extracellular concentrations (C/E) were 22.5 +/- 21.2, 7.66 +/- 6.50, and 0.09 +/- 0.05 for the PBMCs, PMNs, and RBCs, respectively. Posaconazole reaches high concentrations within human PBMCs and PMNs and is, to a lesser extent, present in RBCs. The high intracellular concentrations might contribute to posaconazole efficacy and distribution.

Quantitation of azoles and echinocandins in compartments of peripheral blood by liquid chromatography-tandem mass spectrometry.

A rapid turnaround is a prerequisite of therapeutic drug monitoring (TDM). For antifungals, this need is still unmet, since hardly any method has been established to simultaneously quantitate concentrations of different antifungal classes. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed allowing quantitation of anidulafungin (ANF), caspofungin (CSF), isavuconazole (ISC), micafungin (MCF), posaconazole (PSC), and voriconazole (VRC). Quantitation was successful with diluted plasma samples, peripheral blood mononuclear cells (PBMC), polymorphonuclear leukocytes (PMN), and erythrocytes (RBC). A triple quadrupole mass spectrometer in selected reaction monitoring mode was used with positive electrospray ionization. Cells and calibration standards were extracted with acetonitrile containing internal standard. Internal standards were a CSF derivate for echinocandins and itraconazole for triazoles. Chromatographic separation of the supernatant was achieved by a gradient method facilitating a BetaBasic C4 column. Analytes were quantified in a single 8-min run. Calibration curves were linear and fitted using least squares with a weighting factor of the reciprocal concentration. Limits of detection (ng/ml) were ANF, 8.3; CSF, 31.5; ISC, 1.5; MCF, 97.7; PSC, 3.3; and VRC, 1.4. The lower limits of quantitation (ng/ml) were ANF, 64; CSF, 108; ISC, 4.5; MCF, 160; PSC, 10; and VRC, 4.2. Intraday precisions ranged from 6.3% to 8.8% for azoles and 8.8% to 15.4% for echinocandins. Intraday and interday accuracies (percent bias) of all analytes were within 13.8%. The method was established as standard practice for the quantitation of intracellular antifungal concentrations and optimizes TDM by applying a rapid single method for 6 antifungals.

Primary antifungal prophylaxis in acute myeloblastic leukemia and myelodysplastic syndrome--still an open question?

In this review, we aim to compare different early treatment strategies of invasive fungal diseases in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Three treatment approaches--prophylactic, empiric, and preemptive treatment--are subject to continuous discussion among physicians treating patients at risk. Considering the available clinical basis of evidence, we opt for antifungal prophylaxis with posaconazole 200 mg tid po as our primary prophylactic strategy, while the employment of preemptive treatment should be delayed until more accurate diagnostic tools become available. In addition to antifungal prophylaxis, empiric treatment with caspofungin or L-AmB may be administered to patients with fever resistant to broad-spectrum antibiotic treatment and without radiographic findings typical of invasive fungal disease.

Diagnosis and treatment of fungal infections in allogeneic stem cell and solid organ transplant recipients.

IMPORTANCE OF THE FIELD: Invasive fungal diseases (IFD) are severe complications in patients receiving immunosuppression after solid organ or allogeneic stem cell transplantation. Extensive study has been conducted on therapeutic strategies for IFD in neutropenic patients, mostly those with hematological malignancy. There is an ongoing discussion on whether these studies may be applied to transplant patients as well. AREAS COVERED IN THIS REVIEW: We have reviewed relevant literature on transplantation and clinical mycology of the last 20 years and selected articles relevant for today's treatment decisions. This article reports on the epidemiology of IFD in transplant recipients and current antifungal drugs in the context of tansplantation medicine. For invasive aspergillosis and invasive candidiasis, we give a detailed report of current clinical evidence. WHAT THE READER WILL GAIN: This review is intended as a quick-start for clinicians and other care providers new to transplant care and as an update for experienced transplant physicians. In a field in which evidence is scarce and conflicting, we provide evidence-based strategies for diagnosing and treating the most relevant IFD in transplant recipients. TAKE HOME MESSAGE: Physicians treating transplant patients should maintain a high level of awareness towards IFD. They should know the local epidemiology of IFD to make the optimal decision between current diagnostic and therapeutic strategies. Prophylaxis or early treatment should be considered given the high mortality of IFD.

Efficacy of caspofungin and itraconazole as secondary antifungal prophylaxis: analysis of data from a multinational case registry.

Patients surviving invasive fungal disease (IFD) and needing further antineoplastic chemotherapy are at high risk of recurrent fungal infection. In the absence of randomised controlled trials in this area, secondary prophylactic regimens are diverse. From 448 patients registered with the Multinational Case Registry of Secondary Antifungal Prophylaxis, we performed an analysis of patients receiving caspofungin (CAS) or itraconazole (ITC). All patients had an underlying haematological malignancy and had been diagnosed with an episode of IFD earlier in their course of treatment. Data collected comprised demographics, underlying disease, first episode of IFD, antifungal prophylaxis, incidence and outcome of breakthrough IFD and survival. A total of 75 patients were evaluated, comprising 28 receiving CAS and 47 receiving ITC. Patients in the CAS group were more likely to have had progression of underlying disease (32.1% vs. 8.5%; P=0.028) as well as incomplete response of initial IFD at baseline (85.7% vs. 57.4%; P=0.005). Allogeneic stem cell transplantation was more prevalent in patients receiving CAS (46.4% vs. 14.9%; P=0.010). There was no difference in the occurrence of breakthrough IFD between both groups (32.1% vs. 31.9%). Treatment outcomes for recurrent IFD and overall mortality did not differ between groups. Both ITC and CAS were equally effective in preventing second episodes of IFD. Patients with uncontrolled first IFD, uncontrolled underlying disease or those receiving stem cell transplantation were more likely to have received CAS prophylaxis. Despite antifungal prophylaxis, risk of breakthrough IFD was high in both groups.

Antifungal treatment strategies in high risk patients.

We discuss different strategies for the treatment of invasive fungal infections (IFI) in high risk patients with a focus on patients experiencing profound and prolonged neutropenia, comprising those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy and on patients undergoing allogeneic haematopoietic stem cell transplantation (SCT). Among these patients, invasive aspergillosis (IA) is the most frequently observed form of IFI, as opposed to high risk intensive care unit (ICU) patients in whom an increased incidence of invasive candidiasis (IC) can be observed. In both groups, initiation of early treatment has a profound impact on mortality rates, but adequate diagnostic tools are lacking. These circumstances have led to the parallel use of different treatment strategies, e.g. prophylaxis, empiric, pre-emptive and targeted treatment of IFI. The optimum treatment strategies for these severe infections are a matter of extensive research and discussion. A review of major clinical trials on the issue reveals that comparisons between different treatment strategies cannot be made. Considering the complexity of the issue, we advocate an eclectic treatment approach that reduces morbidity and mortality from IFI without compromising tolerability. In allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS and those under immunosuppressive medication for graft vs. host disease after allogeneic HSCT, we recommend prophylaxis with posaconazole. For empiric treatment of persistently febrile neutropenic patients, we opt for caspofungin as first and liposomal amphotericin B deoxycholate (L-AmB) as second line choice. If the diagnosis of IA can be established, voriconazole should be favoured over the alternative, liposomal amphotericin B (L-AmB). While high risk ICU patients benefit from fluconazole prophylaxis for IC, the choice of an optimal agent for targeted therapy depends largely on the neutrophil count. In non-neutropenic patients, we recommend an echinocandin as the first line treatment option. Patients with susceptible Candida spp. may be switched to fluconazole. Caspofungin or micafungin might be preferred to anidulafungin in the neutropenic patient. L-AmB is a valuable second line treatment option for both groups of patients.

Patients at high risk of invasive fungal infections: when and how to treat.

When and how to treat invasive fungal infections (IFIs) is discussed in this review, with a focus on the two most prevalent non-endemic IFIs, namely invasive aspergillosis and invasive candidiasis. Early treatment initiation in patients with IFIs has a profound impact on mortality rates, but reliable diagnostic measures are lacking. This situation has led to the parallel use of different treatment strategies, e.g. prophylaxis, empirical and pre-emptive treatment, as well as targeted treatment in response to a definite diagnosis of IFI. Identifying high-risk patients is the first step in reducing IFI-related mortality. Patients at risk of invasive aspergillosis comprise (i) those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy; (ii) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT); (iii) recipients of solid organ transplants; and (iv) those with other conditions of severe and prolonged immunosuppression. Patients at high risk of invasive candidiasis are less well defined. Risk factors are diverse and include haematological malignancy, neutropenia, age <1 month or >65 years, and recent abdominal surgery. The individual risk further depends on the presence of a variety of other risk factors, including central venous catheters, use of broad spectrum antibacterials, prolonged intensive care unit (ICU) stay, total parenteral nutrition, mucosal Candida spp. colonization and renal failure.Extensive research has been conducted to facilitate the best possible treatment strategies for these severe infections. Optimal timing and choice of antifungal agents largely remain a matter of controversy. After having reviewed the major clinical trials, we conclude that comparisons between different treatment strategies cannot be made, neither at present nor in the near future. The complexity of the clinical problem leads to an eclectic treatment approach to reduce morbidity and mortality from IFIs without compromising tolerability. We recommend prophylaxis with posaconazole for allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS, and those undergoing immunosuppressive therapy for graft-versus-host disease after allogeneic HSCT. For the empirical treatment of persistently febrile neutropenia, caspofungin is our first- and liposomal amphotericin B deoxycholate (LAmB) our second-line choice. Once a diagnosis of invasive aspergillosis has been established, voriconazole should be the preferred treatment option, with LAmB being an alternative. Fluconazole prophylaxis for invasive candidiasis should remain restricted to high-risk ICU patients. Once a diagnosis has been established, the drug of choice for adequate treatment depends largely on neutrophil count and haemodynamic stability. In non-neutropenic patients, an echinocandin should be considered the first-line treatment option, while patients with susceptible Candida spp. may be switched to fluconazole. In neutropenic patients, caspofungin or micafungin might be preferred to anidulafungin as first-line treatment. LAmB is a second-line treatment option in both settings.Early diagnosis of IFIs is imperative to facilitate treatment success. In all patients at risk for IFIs, blood cultures, galactomannan antigen and diagnostic imaging should be rigorously enforced.