Effect Of Antifungal Prophylaxis Research Articles

Real‐world effectiveness of antifungal prophylaxis with posaconazole as the primary agent in patients with haematological malignancies

Patients undergoing induction/reinduction chemotherapy for haematologic malignancies (HM) are at risk for invasive fungal infections (IFIs). In 2015, Duke University Hospital (DUH) implemented a new standardised fungal prophylaxis protocol for adult patients undergoing induction chemotherapy for acute lymphocytic leukaemia, acute myelocytic leukaemia and myelodysplastic syndrome. This study assessed the impact of protocol implementation on (1) use of antifungal prophylaxis, throughout the at-risk period and (2) patient outcomes such as IFI and mortality. Retrospective, observational study of adult HM patients admitted to DUH for induction/reinduction chemotherapy pre- (7/1/2013-12/31/2014) and post- (1/1/2015-10/31/2016) implementation of standardised antifungal prophylaxis protocol (which recommended posaconazole as the first-line agent). Patients were followed for up to 100 days after initiation of induction chemotherapy to evaluate use of antifungal prophylaxis and patient outcomes. 218 patients with haematologic malignancies were included (90 pre, 128 post). Use of antifungal prophylaxis increased from 81.1% (pre) to 97.7% (post) (p < .0001). Overall, 71% received posaconazole as initial antifungal prophylaxis (64.4% pre, 75.7% post). Approximately one-fourth of patients (25.6%, pre vs 26.6%, post) developed an IFI (proven/probable or possible using modified EORTC definitions) (p=.868); 100-day mortality remained stable (18.9% pre vs 18.8% post, respectively, p=.979). Lack of antifungal prophylaxis and older age (≥60 years) were associated with higher risk of IFI. Implementation of a standardised protocol with posaconazole as the primary agent was associated with increased use of antifungal prophylaxis among patients undergoing induction/reinduction chemotherapy for haematologic malignancies in our hospital. Lack of antifungal prophylaxis was an independent predictor of IFIs, underscoring the importance of prophylaxis in this at-risk population.

Intermittent micafungin for prophylaxis in a rat model of chronic Candida albicans gut colonization.

During antifungal prophylaxis, micafungin is generally infused IV once daily over 1 h. In practice, less-frequent dosing could improve the quality of life in patients requiring long-term treatment or prophylaxis. The feasibility of this approach was assessed using humanized doses of daily or infrequent micafungin regimens. To evaluate the effectiveness of intermittent high-dose micafungin, simulating human exposure, for prophylaxis of invasive candidiasis in a rat model of chronic Candida albicans gastrointestinal colonization and systemic dissemination. Two weeks post-infection with an oral challenge of C. albicans, Sprague-Dawley rats were immunocompromised with a cytotoxic drug and a steroid. Rats received IV infusions of: daily vehicle control; daily subcutaneous micafungin (20 mg/kg SC); high-dose micafungin (20 mg/kg bolus SC + 80 mg/kg infusion/72 h, to simulate intermittent human dosing of 300 mg/72 h); or daily fluconazole by mouth (10 mg/kg PO). The effects of antifungal prophylaxis on faecal fungal burden and systemic C. albicans dissemination were evaluated. A rat model of chronic C. albicans gastrointestinal colonization and systemic dissemination was established, characterized by a sustained microbiological burden over 29 days and fungal recovery from normally sterile tissues. Using this model, intermittent high-dose micafungin (delivered via iPrecio pumps) to simulate humanized doses of 300 mg/72 h was significantly more effective than vehicle control, as effective as once-daily micafungin and similar to daily fluconazole at reducing faecal burden and preventing systemic dissemination. These data indicate that intermittent high-dose micafungin can be as effective as daily therapy, supporting clinical assessment in high-risk patients requiring long-term antifungal prophylaxis.

Breakthrough Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

We sought to determine the occurrence, risk factors, effect of antifungal prophylaxis, and outcomes of invasive fungal infections (IFIs) in patients with acute myeloid leukemia (AML). We performed a retrospective analysis of all adult patients admitted to the University of Michigan Health System for AML over a 3-year period from 2010 to 2013. We determined comorbidities, hematopoietic cell transplant (HCT) status, antifungal prophylaxis, proven and probable IFI, and outcomes at 12weeks after initiation of appropriate antifungal therapy. Of 333 patients in our cohort, 116 of whom had received a HCT, 98 (29%) developed an IFI. Of the 30 (9%) patients who had a proven or probable IFI, 18 had breakthrough infection while on micafungin (n = 5), voriconazole (n = 4), posaconazole (n = 5), or fluconazole (n = 4). Breakthrough IFIs were due to Aspergillus species (n = 11), other molds (n = 4), and Candida species (n = 3). Factors associated with breakthrough IFI were prolonged severe neutropenia (p = .05) and having received tacrolimus (p = .04). Antifungal therapy was successful in 7 of the 18 (39%) patients with breakthrough IFI and 8 of the 12 (67%) patients with non-breakthrough IFI, p = .13. Mortality at 12weeks was 27%, 5 with breakthrough IFI and 3 with non-breakthrough IFI and was associated with prolonged severe neutropenia, p = .04. Patients with AML remain at risk for IFI despite the use of several different antifungal agents for prophylaxis. Mortality remains high in patients with AML who develop IFI.

Retrospective study evaluating the performance of risk factors for invasive mold infections in liver transplantation

Mold infections in liver transplant are associated with high mortality. Guidelines recommend prophylaxis targeted against mold based upon risk factors of fulminant hepatic failure, retransplantation, reoperation, and renal replacement therapy post-transplant. It is not known if these factors identify risk of mold infection at every center. A retrospective study was conducted of adult liver transplant recipients at a single center from 2010 to 2014. The association between risk factors and invasive mold infection and effect of antifungal prophylaxis were determined. Five hundred thirty-four liver transplant recipients were identified. The overall incidence of invasive mold infection was 0.9% (N=5). The incidence in patients with (N=128) and without (N=406) risk factors was 0.78% and 0.98%, respectively. Antifungal prophylaxis with mold activity was administered to 23/128 (18%) with risk factors, and none developed infection. No mold-active prophylaxis was given to 105/128 (82%) with risk factors, and incidence of mold infection was 0.95% (N=1). Number needed to treat was 105. Traditional risk factors for mold infection in liver transplant performed poorly. These results underscore the importance of transplant center-specific data to inform adoption of an antifungal prophylactic strategy. Studies are needed to determine alternative risk factors to facilitate appropriate targeting of antifungals.

Safety and effectiveness of antifungal prophylaxis in preventing fungal infection after liver transplantation: a meta-analysis of randomized clinical trials

Fungal infections are widely recognized as a complication of liver transplantation, and their prevention and treatment are a challenge for clinicians. This was a randomized clinical trial (RCT)-based meta-analysis investigating the safety and effectiveness of antifungal prophylaxis in preventing fungal infection after liver transplantation. Studies published before December 2013 were searched for in several databases. Patients who underwent antifungal prophylaxis were included in the treatment group. Studies that met the inclusion criteria were included in this meta-analysis. Quality assessment, data extraction, and statistical analysis were performed. A total of 342 articles was identified, and 7 eligible articles were included in the present study. The pooled estimate of the OR for all-cause mortality was 0.82 (95% confidence interval (CI): 0.51-1.30, p=0.39). The pooled estimate of the OR of fungal infection-related mortality was 0.29 (95% CI: 0.11-0.75, p=0.01), which was significantly different between the treatment and control groups. The pooled estimate of the OR of defined invasive fungal infection was 0.41 (95% CI: 0.26-0.63, p < 0.001). The OR of adverse events was 1.20 (95% CI: 0.68-2.12, p=0.53). This meta-analysis suggests that antifungal prophylaxis could effectively reduce the risk of invasive fungal infections in patients who underwent liver transplantation. Overall mortality rate was not different with prophylaxis, according to current evidence. This needs to be further investigated.

Effect of Prophylactic Antifungal Protocols on the Prognosis of Liver Transplantation: A Propensity Score Matching and Multistate Model Approach.

Background. Whether routine antifungal prophylaxis decreases posttransplantation fungal infections in patients receiving orthotopic liver transplantation (OLT) remains unclear. This study aimed to determine the effectiveness of antifungal prophylaxis for patients receiving OLT. Patients and Methods. This is a retrospective analysis of a database at Chang Gung Memorial Hospital. We have been administering routine antibiotic and prophylactic antifungal regimens to recipients with high model for end-stage liver disease scores (>20) since 2009. After propensity score matching, 402 patients were enrolled. We conducted a multistate model to analyze the cumulative hazards, probability of fungal infections, and risk factors. Results. The cumulative hazards and transition probability of “transplantation to fungal infection” were lower in the prophylaxis group. The incidence rate of fungal infection after OLT decreased from 18.9% to 11.4% (p = 0.052); overall mortality improved from 40.8% to 23.4% (p < 0.001). In the “transplantation to fungal infection” transition, prophylaxis was significantly associated with reduced hazards for fungal infection (hazard ratio: 0.57, 95% confidence interval: 0.34–0.96, p = 0.033). Massive ascites, cadaver transplantation, and older age were significantly associated with higher risks for mortality. Conclusion. Prophylactic antifungal regimens in high-risk recipients might decrease the incidence of posttransplant fungal infections.

Effect of Anti-Fungal Prophylaxis on the Fungal Mycobiome after Allogeneic Bone Marrow Transplantation

Background: Intestinal bacteria shape the immune system and have been shown to contribute to GI tract inflammation. Modification of the lower GI tract bacterial microbiota has been correlated with decreased acute graft-versus-host disease (aGvHD) [1]. Additionally, decreased intestinal bacterial diversity has been associated with increased nonrelapse mortality following allogeneic stem cell transplantation (alloSCT), largely due to an association with severe aGvHD[2]. However, the role of the fungal mycobiome during aGvHD has been largely ignored. Antifungal prophylaxis with fluconazole has been found to decrease long-term transplant mortality following alloSCT. We wanted to determine (1) effect of anti-fungal prophylaxis on the fungal mycobiome and (2) whether enteric fungi contributes to aGvHD by promoting a pro-inflammatory environment in the GI tract, similar to certain bacteria.Methods: B6D2 recipient mice were lethally irradiated, and the following day, recipient mice received 3 x106 T cell depleted bone marrow cells and 4 x 106 naïve T cells from B6 donor mice. Recipient mice were followed for survival and scored for clinical GvHD using a standard scoring system. Mice were treated daily with the antifungal agent fluconazole at 5mg/kg/day. Stool samples were collected on days 0, 7, and 14 post-transplant, and DNA was isolated from stool. The fungal ribosomal internal transcribed spacer region (specifically ITS-1) was amplified by PCR and sequencing libraries generated using Illumina chemistry and evaluated on a MiSeq sequencer. Additionally, real-time PCR was performed on DNA from stool samples to quantitate fungi in the colon. Colons were harvested, immune cells isolated and evaluated for flow cytometric analysis after bone marrow transplantation. Intestinal permeability was assessed by oral administration of FITC-labeled dextran 4000, followed by peripheral blood collection to assess plasma FITC-dextran levels.Results: In B6D2 mice, the most common fungal species found in the colon before and after bone marrow transplantation was Candida tropicalis. We found a 50-75% decrease in the quantity of fungi present in the colon in fluconazole treated mice. However there was no alteration in the percentages of fungi found in the GI tract indicating that anti-fungal therapy alter the quantity and not the quality of the fungal microbiome. Specifically, we did not find that the administration of fluzonazole was associated with an increase in fluconazole-resistant Candida species such as C kruseii or with fungi intrinsically resistant to fluconazole such as Aspergillus organisms. While there was no difference in clinical scoring of GVHD or weight loss in fluconazole treated mice, there was a modest improvement in overall survival in the treated group. We found no differences in IFN-γ or IL-17 production by colonic T cells from mice treated with fluconazole as compared to control mice evaluated 14 days after transplant. Additionally, the percentage of Foxp3+ T cells was also similar between treated and control mice. We also found no change in aGvHD mediated intestinal permeability suggesting that fluconazole treatment has no effect on epithelial barrier function.Conclusion: These studies demonstrate that fluconazole decreases total colonic fungi without altering the relative frequency of fungal organisms and is not associated in mice with an increase in the presence of fluconazole-resistant fungi. Fluconazole treatment was associated with a modest improvement in overall survival. However, no differences were found in the percentage/number of donor TH1, TH17 or Treg cells in the colon. These data suggest that, in the B6->B6D2 model, decreasing fungal burden in the colon is associated with a modest improvement in overall survival without substantially altering the generation of pro-inflammatory T cells or Tregs.1. Jenq RR et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J Exp Med. 2012 May 7;209(5):903-11. doi: 10.1084/jem.20112408. Epub 2012 Apr 30.2. Taur Y, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014 Aug 14;124(7):1174-82. doi: 10.1182/blood -2014-02-554725. Epub 2014 Jun 17. DisclosuresNo relevant conflicts of interest to declare.

A Review of Candida Prophylaxis in the Neonatal Intensive Care Population

To review the efficacy and safety of antifungal prophylaxis in the neonatal intensive care setting. English-language literature was accessed using MEDLINE (January 1988- December 2010). The following Medical Subject Heading (MeSH) search terms were used: "amphotericin B," "fluconazole," "nystatin," "itraconazole," "caspofungin," "voriconazole," "Candida," "prevention and control," and "critically ill." Literature was further limited to studies focusing on patient birth to 6 months of age. Abstracts and original research articles were included. Preference was given to published controlled trials. Articles providing descriptions of the safety and effectiveness of antifungal prophylaxis in neonatal intensive care patients were also used in this review. Twenty-two studies have evaluated the impact of antifungal prophylaxis on Candida colonization or invasive infections in the Neonatal Intensive Care Unit (NICU). The two antifungal agents most commonly studied were nystatin and fluconazole. All of the nystatin studies demonstrated that nystatin is effective at reducing fungal colonization and invasive fungal infections. All of the studies designed to evaluate the impact of fluconazole prophylaxis on fungal colonization demonstrated a reduction in the incidence of fungal colonization with fluconazole prophylaxis. A total of 12 of 16 studies that evaluated the impact of fluconazole prophylaxis on the incidence of invasive fungal infections demonstrated a reduction in invasive fungal infections with fluconazole prophylaxis. Two studies found no difference between fluconazole and nystatin when used for prophylaxis. Antifungal prophylaxis appears to be effective in reducing the incidence of Candida colonization and invasive Candida infections in the NICU. Antifungal prophylaxis also appears to be safe in the NICU population. The impact of antifungal prophylaxis on resistance patterns could be significant and needs to be evaluated long term before widespread prophylaxis can be recommended.

Antifungal Prophylaxis in Neutropenic Patients with Hematologic Malignancies: Is There a Real Benefit?

Invasive fungal infections have been reported with an increasing incidence over the last 20 years. Fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. Therefore, in neutropenic patients different regimens of antifungal prophylaxis have been performed for more than 20 years, but the effect of antifungal prophylaxis is controversial. A long duration of neutropenia, impaired cell-mediated immunity as well as continuous corticosteroid therapy and sustained immunosuppression for graft-versus-host disease in patients treated with allogeneic bone marrow transplantation are known risk factors for invasive mycosis. Since early diagnosis of invasive fungal infection is difficult, strategies to prevent fungal infections seem to be attractive. The introduction of triazoles have provided us with a better armamentarium to prevent fungal infections. In this review, the current strategies of antifungal prophylaxis are discussed. Antifungal prophylaxis has been effective in reducing candida infection, however, there has been no proven successful prevention of invasive aspergillosis. In addition, there is no clearly proven benefit of antifungal prophylaxis regarding the reduction in the overall mortality. Thus the best way to reduce invasive fungal-related mortality will be early diagnosis and preemptive therapeutic approaches.

Antifungal prophylaxis to prevent invasive mycoses among bone marrow transplantation recipients.

We reviewed the effect of systemic, intranasal, and lipid formulations of amphotericin B, fluconazole, itraconazole for antifungal prophylaxis. Specifically we reviewed the effect of antifungal prophylaxis on the development of fungal colonization, frequency of superficial and invasive mycosis, and overall mortality and that due to invasive mycoses in bone marrow transplantation recipients. A MEDLINE search was conducted to identify literature describing the risk factors, epidemiology, and chemoprophylaxis of invasive mycosis in these patients. Preliminary data published as abstracts at national infectious diseases and hematology conferences within the last 5 years were included. Antifungal prophylaxis reduces fungal colonization and superficial infection. The ability of antifungal prophylaxis to prevent systemic infection or reduce the need for empiric amphotericin B depends on specific variables. Ultimately, antifungal prophylaxis has no affect on overall mortality, and very little impact on mortality attributed to fungi.

The incidence of pathogenic yeasts among open-heart surgery patients–the value of prophylaxis

The normal levels of commensal yeasts in patients undergoing open-heart surgery are established and the effect of antifungal prophylaxis is assessed. Mouth swabs and feces were taken for culture from patients on admission to hospital and 1,2, and 3 weeks postoperatively. Eighty-seven patients who received normal treatment and 50 patients who were given oral and topical antifungal prophylaxis commencing 12 days before hospitalization were studied. Yeast pathogens, mainly Candida albicans, were isolated from 42 (48.3 per cent) of the normal group on admission. There was a marked increase in the incidence and quantities of yeasts isolated from patients in the immediate postoperative period. The incidence and levels of yeasts in patients receiving antifungal prophylaxis was considerably reduced both on admission and postoperatively. The risk of Candida sepsis in open-heart surgery patients with high levels of commensal yeasts is discussed and the possibility of routine antifungal prophylaxis raised.