Efficacy Of Antifungal Prophylaxis Research Articles

Genetic Regulation of the Host-Fungus Interaction in the Pathogenesis of Aspergillosis

There is significant interindividual variability in the development and progression of fungal diseases, most notably invasive pulmonary aspergillosis (IPA). The integration of individual traits into clinically valid procedures to predict the risk and progression of infection, and the efficacy of antifungal prophylaxis and therapy, will change the current healthcare landscape regarding the management of patients at risk of IPA and, likely, other fungal infections. Over the last decade, an expanding number of common polymorphisms associated with IPA have been reported, adding to the information available on monogenic defects underlying severe forms of the disease. Predisposition to IPA is therefore nowadays considered to result from a combination of clinical and host factors, with the latter being most likely regulated at the genetic level. In this review, we address the contribution of the genetic profile of the host to the outcome of the host-fungus interaction and discuss the application of this information in potential strategies with the aim of moving towards personalized prognostics, diagnostics, and treatment.

Paving the way for predictive diagnostics and personalized treatment of invasive aspergillosis.

Invasive aspergillosis (IA) is a life-threatening fungal disease commonly diagnosed among individuals with immunological deficits, namely hematological patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation. Vaccines are not available, and despite the improved diagnosis and antifungal therapy, the treatment of IA is associated with a poor outcome. Importantly, the risk of infection and its clinical outcome vary significantly even among patients with similar predisposing clinical factors and microbiological exposure. Recent insights into antifungal immunity have further highlighted the complexity of host-fungus interactions and the multiple pathogen-sensing systems activated to control infection. How to decode this information into clinical practice remains however, a challenging issue in medical mycology. Here, we address recent advances in our understanding of the host-fungus interaction and discuss the application of this knowledge in potential strategies with the aim of moving toward personalized diagnostics and treatment (theranostics) in immunocompromised patients. Ultimately, the integration of individual traits into a clinically applicable process to predict the risk and progression of disease, and the efficacy of antifungal prophylaxis and therapy, holds the promise of a pioneering innovation benefiting patients at risk of IA.

Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia.

Severe infectious complications reflect a continuing problem in patients with acute myeloid leukemia (AML). Based on data from a randomized clinical trial demonstrating a reduction of proven and probable invasive fungal disease (IFD), posaconazole has been approved for prophylaxis of fungal infections in AML patients during induction chemotherapy. Nevertheless, recently published observational studies show contradictory results concerning the efficacy of posaconazole in this clinical setting. Furthermore, oral suspension posaconazole is associated with an unpredictable bioavailability that especially depends on nutritional factors or gastric pH value. We retrospectively analyzed the impact of posaconazole prophylaxis in 70 consecutively evaluable AML patients who underwent induction chemotherapy at a tertiary care hospital. The incidence of IFD classified as proven, probable or possible, antifungal therapy including empiric treatment in high-risk patients and tolerability of posaconazole were determined. In addition, important clinical cofactors such as co-treatment with proton pump inhibitors and risk factors for pneumonia were analyzed in this study. We can demonstrate that posaconazole is well tolerated and had to be stopped in only six patients (8.6%). The overall incidence of IFD was 30% including two patients with proven (2.8%), four patients with probable (5.7%) and 15 patients with possible IFD (21.4%). Importantly, 24 out of 49 patients (49.0%) who did not fulfill the criteria of IFD received empiric antifungal therapy. Including patients classified as possible IFD, 39 of 70 patients (55.7%) underwent at least first-line antifungal treatment. Our "real-life" data obtained from 70 AML patients after induction chemotherapy demonstrate the frequent necessity of systemic antifungal treatment despite prophylaxis with oral suspension posaconazole.

Anti-Fungal Prophylaxis in Lung Transplant Recipients (LTRs): A Meta-Analysis of Cohort Studies

Purpose Majority of lung transplant centers have adopted antifungal prophylaxis directed against Aspergillus (Asp) species based on single center cohort studies. We performed a meta-analysis to determine whether current antifungal prophylaxis strategies decrease the rate of invasive aspergillosis (IA) or Asp. colonization in LTRs. Methods and Materials The search was carried out on MEDLINE (1990-Oct 2012), EMBASE (1990-Oct 2012). For dichotomous outcomes, relative risks (RR) with 95% confidence intervals (CI) were calculated for individual studies and the summary statistics were calculated using a Random effects model (Review Manager [RevMan] Version 5.0, The Nordic Cochrane Centre, The Cochrane Collaboration, 2008). Results Of 323 references retrieved, 16 retrospective cohort studies were identified. Out of these, 8 studies had sufficient information of the comparator for the meta-analysis. These studies included a total of 1,009 LTRs. Antifungal prophylaxis significantly reduced the IA (RR, 0.45; CI, 0.21-0.97) while there was no significant effect on Asp. colonization (RR, 0.82; CI, 0.56-1.20). Antifungal prophylaxis with inhaled-Amphotericin (including lipid preparation) (3 studies), (RR, 0.47; CI, 0.18-1.22) and azoles (6 studies) (RR, 0.42; CI, 0.12-1.52) didn’t show statistically significant risk reduction. Rate of Discontinuation, cough, SOB, nausea and hepatotoxicity was not statistically significant among different antifungals. Conclusions Overall antifungal prophylaxis decreases the rate of IA however, has no effect on the Asp. colonization in LTRs. A randomized controlled trial to assess the efficacy of antifungal prophylaxis is warranted.

Efficacy and safety of antifungal prophylaxis with oral itraconazole solution among patients receiving corticosteroids: who should be given prophylaxis?

The incidence of systemic fungal infections has risen, as shown by increases in the numbers of immunosuppressed or immunocompromised patients. The consequences of these fungal infections are occasionally serious. However, the efficacy of antifungal prophylaxis in patients receiving corticosteroid treatment has not been well investigated, even though they are susceptible to severe fungal infections. Therefore, we retrospectively evaluated the prophylactic efficacy of an antifungal agent-oral itraconazole solution (ITCZ-OS)-for immunosuppressed patients receiving corticosteroids in a single institution. Of 39 patients, 18 received prophylaxis with ITCZ-OS at a dose of 200mg/day, and 21 did not. As a result, no fungal infections developed in the prophylactic group, but 7 of the 21 patients (33%) in the non-prophylactic group suffered from fungal infections consisting of 3 non-invasive candidiases, 2 invasive candidiases, and 2 invasive pulmonary aspergilloses. Among the non-prophylactic group, aging and hypoalbuminemia were statistically significantly associated with incidence of invasive fungal infections. Of the four patients with invasive fungal infections, three had concomitant chronic illness such as diabetes. Toxicity among the prophylactic group was not statistically significantly different from that of the non-prophylactic group. In addition, none needed discontinuation of the drug. These results indicate the potential antifungal prophylactic effect of ITCZ-OS for a subset of patients treated with moderate or high doses of corticosteroids.

Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies

There is still no consensus on the efficacy of antifungal prophylaxis in neutropenic patients after more than 50 clinical trials. This review evaluates the current evidence from all available meta-analyses of the use of intravenous amphotericin B, fluconazole and itraconazole for this indication. Four systematic reviews with meta-analysis and one evidence-based review without meta-analysis were evaluated. Efficacy of fluconazole has been shown on short-term follow-up after allogeneic stem cell transplantation but only itraconazole was effective in neutropenic patients with haematological malignancies for prolonged prophylaxis after allogeneic stem cell transplantation. Direct comparison between fluconazole and itraconazole for this indication shows the superiority of itraconazole which was the only drug able to prevent invasive Aspergillus infections in our previously published meta-analysis of 13 trials and 3597 patients. Efficacy of itraconazole correlates closely with its dose; an effect was seen only in clinical trials using at least 400 mg/day oral solution or 200 mg/day intravenous solution. With this dose, invasive fungal infections were reduced by 53% and mortality from invasive fungal infections was reduced by 47% (P<0.05). Toxicity of itraconazole is rare and usually not severe and drug interactions are easily manageable. Itraconazole is recommended for antifungal prophylaxis in high-risk neutropenic patients with haematological malignancies or for prolonged prophylaxis after allogeneic stem cell transplantation based on unambiguous evidence of efficacy and low toxicity from clinical trials and systematic reviews.

Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients.

Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% +/- 13%; P =.002), the incidence of invasive yeast infections (mean, 53% +/- 19%; P =.004) and the mortality from invasive fungal infections (mean, 35% +/- 17%; P =.04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% +/- 21%; P =.02) and not itraconazole capsules (mean, 75% +/- 73% increase; P =.3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and-shown for the first time for antifungal prophylaxis-reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or i.v. formulations (200 mg/d) of itraconazole are necessary for these effects.

Intensive Intravenous Amphotericin B for Prophylaxis of Systemic Fungal Infections

Background: Invasive fungal infections are an increasing cause of morbidity in acute leukemia (AL) patients. Methods: In a prospective pilot trial, the safety and efficacy of antifungal prophylaxis with intravenous (i.v.) amphotericin B (AMB; 1 mg/kg every 48 h) was studied in 46 consecutive cycles. Prophylaxis with i.v. AMB was carried out in patients treated with intensive chemotherapy for AL and compared with a control of 49 cycles without prophylaxis. Results: Pulmonary infiltrates (5 vs. 23; p < 0.001) and fungal microabscesses in the liver or spleen (0 vs. 6; p = 0.014) occurred significantly less frequently in the prophylaxis group. While there were 3 deaths related to systemic fungal infections in the control group, there were none in the prophylaxis group. Escalation to conventional AMB (1.0 mg/kg/day) was significantly less frequent in the prophylaxis group (9 out of 46 cycles) compared with the control arm (29 out of 49 cycles; p = 0.001). A total of 695 mg of AMB per cycle was administered in the prophylaxis arm, compared with 634 mg/cycle for empirical treatment in the control group (p = 0.6). Infusion-related toxicity was documented in 29% of the cycles of prophylaxis compared with 55% of the cycles of empirical treatment with i.v. AMB in the control group. The nephrotoxicity of AMB prophylaxis was moderate, with ≥ WHO degree II reported in 1 out of 46 cycles only. Conclusion: Intensive i.v. AMB prophylaxis reduced invasive fungal infections and led to a reduction in fungal microabscesses in the liver or spleen, as well as pulmonary infiltrates, in patients treated for AL. The need for escalation to empirical i.v. AMB treatment was significantly reduced. Intensive AMB prophylaxis was feasible, with moderate adverse effects.