Reduction In Invasive Fungal Infections Research Articles

Comparison of Antifungal Prophylaxis Drugs in Patients With Hematological Disease or Undergoing Hematopoietic Stem Cell Transplantation

Several antifungal drugs are available for antifungal prophylaxis in patients with hematological disease or who are undergoing hematopoietic stem cell transplantation (HSCT). To summarize the evidence on the efficacy and adverse effects of antifungal agents using an integrated comparison. Medline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials were searched to collect all relevant evidence published in randomized clinical trials that assessed antifungal prophylaxis in patients with hematological disease. Sources were search from inception up to October 2019. Studies that compared any antifungal agent with a placebo, no antifungal agent, or another antifungal agent among patients with hematological disease or undergoing HSCT were included. Of 39 709 studies identified, 69 met the criteria for inclusion. The outcome from each study was estimated using the relative risk (RR) with 95% CIs. The Mantel-Haenszel random-effects model was used. The reliability and validity of the networks were estimated by addressing inconsistencies in the evidence from comparative studies of different treatments. Data were analyzed from December 2019 to February 2020. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) guideline. The primary outcomes were invasive fungal infections (IFIs) and mortality. The secondary outcomes were fungal infections, proven IFIs, invasive candidiasis, invasive aspergillosis, fungi-related death, and withdrawal owing to adverse effects of the drug. We identified 69 randomized clinical trials that reported comparisons of 12 treatments with at total of 14 789 patients. Posaconazole was the treatment associated with the best probability of success against IFIs (surface under the cumulative ranking curve, 86.7%; mean rank, 2.5). Posaconazole treatment was associated with a significant reduction in IFIs (RR, 0.57; 95% CI, 0.42-0.79) and invasive aspergillosis (RR, 0.36; 95% CI, 0.15-0.85) compared with placebo. Voriconazole was associated with a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09-0.26) compared with placebo. However, posaconazole was associated with a higher incidence of withdrawal because of the adverse effects of the drug (surface under the cumulative ranking curve, 17.5%; mean rank, 9.2). In subgroup analyses considering efficacy and tolerance, voriconazole might be the best choice for patients undergoing HSCT, especially allogenic HSCT; however, posaconazole was ranked as the best choice for patients with acute myeloid leukemia or myelodysplastic syndrome. These findings suggest that voriconazole may be the best prophylaxis option for patients undergoing HSCT, and posaconazole may be the best prophylaxis option for patients with acute myeloid leukemia or myelodysplastic syndrome.

Breakthrough invasive fungal infections: Who is at risk?

The epidemiology of invasive fungal infections (IFIs) in immunocompromised individuals has changed over the last few decades, partially due to the increased use of antifungal agents to prevent IFIs. Although this strategy has resulted in an overall reduction in IFIs, a subset of patients develop breakthrough IFIs with substantial morbidity and mortality in this population. Here, we review the most significant risk factors for breakthrough IFIs in haematology patients, solid organ transplant recipients, and patients in the intensive care unit, focusing particularly on host factors, and highlight areas that require future investigation.

Reducing invasive fungal infections in patients with acute myeloid leukemia receiving induction and re-induction chemotherapy at the University of Virginia Health System.

120 Background: At the University of Virginia Health System (UVaHS), antifungal prophylaxis was not routinely given to patients undergoing induction and re-induction chemotherapy for acute myeloid leukemia (AML) from 7/2011 to 9/2015. A retrospective chart review of 179 patient encounters identified a 19.7% rate of proven or probable invasive fungal infection (IFI); national averages for IFI are 8-10% in this population. Methods: To target an IFI rate of less than 10%, a multidisciplinary team comprised of oncology and infectious diseases physicians, clinical pharmacists, nurses, and information technology specialists was formed. Through participation in the 2016 ASCO Quality Training Program (QTP), the group developed current and ideal state process maps, a Pareto chart, and a priority matrix to determine an action plan. The group identified the most common problems contributing to IFI: inconsistent definition of IFI, no routine antifungal prophylaxis, and lack of education for the health care team. Results: From 9/2014 to 8/2016, the first PDSA cycle consisted of physicians ordering antifungal prophylaxis on an ad hoc basis, resulting in 11.7% IFI in 77 total patient encounters. During the second PDSA cycle starting in 8/2016, a clinical practice guideline standardized the definition of IFI and appropriate antifungal prophylaxis. Physicians, nurses, and pharmacists were educated on the new standard work. PDSA Cycle #2 is ongoing. As of 11/2016, zero of 8 patient encounters had an IFI. To ensure sustainability of the quality improvement study, monthly electronic medical record reports will capture guideline compliance, specifically the use of antifungal agents, and track future IFI. Future data will be statistically analyzed. Conclusions: Using quality improvement methods learned at ASCO QTP, a multidisciplinary team developed an action plan which to date has shown a clinically significant reduction in IFI; this outcome may lead to decreased hospital length of stay and improved patient quality of life. Further PDSA cycles are scheduled and continuous evaluation of the process is ongoing.

Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients

Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients

Reduction of Invasive Fungal Infections Among Cancer Patients With Chemotherapy-Induced Neutropenia After Protective Environment Implementation May Save Costs in a Developing Country: A Quasi-Experimental Study

Background: Invasive fungal infections (IFI) represent a serious threat for severely immunocompromised patients. Infection control interventions, including protective environment (PE) implementation, are essential to reduce IFI incidence, mortality and burden of hospitalization, among high-risk patients. Information about the impact of these strategies in cancer patients with chemotherapy-induced neutropenia (CIN), in developing countries, is insufficient. Objectives: To assess the impact of PE implementation on IFI incidence, consumption and cost of antifungal treatment, in a general, tertiary teaching hospital, in Southern Brazil. Patients and Methods: We conducted a quasi-experimental study to evaluate an institutional intervention, in a hospital ward, for patients with CIN, which consisted in renovation of the ward and measures involving air-quality technologies installation, the main one being high efficiency particulate air (HEPA) filters. Simultaneously, infection control routines were implemented. Neutropenic patients, admitted to any other hospital ward, prior to the renovation, were included in the historical control group. The IFI incidence was defined, according to the criteria proposed by the European Organization for Research and Treatment of Cancer. Direct costs of antifungal drugs were recorded, for all neutropenic patients. Results: A total of 190 and 181 hospital admissions were included in the intervention and control groups, respectively. Total IFI incidence was reduced in the PE group (7.4% vs. 18.2%; P = 0.002) and the same was observed when considering only proven and probable IFI (1.6% vs. 8.3%; P = 0.003). This benefit persisted even after adjusting for antifungal prophylaxis (OR = 0.17; 95% CI = 0.05 ‒ 0.60). We observed a decreasing trend in molds and yeasts IFI incidence, in the intervention group. Although the final cost of antifungal agents was lower, after intervention (78347.37 USD vs. 154176.60 USD), the median cost per admission did not differ between groups (1.00 USD = 1.9 Brazilian Real, in May 2007). Considering all admissions with IFI, the median cost was significantly higher than recorded in admissions without IFI. Conclusions: This study showed that preventive measures, including PE implementation, reduce IFI incidence in patients with CIN, admitted in a hospital in a developing country. This suggests that those strategies may overcome their costs on the long-term, by saving costs associated with fungal infections.

Newer Antifungal Agents for Fungal Infection Prevention During Hematopoietic Cell Transplantation: A Meta-Analysis

ObjectiveThe efficacy of newer antifungal agents to provide effective prophylaxis during stem cell transplantation has not yet been established. We compared the clinical outcomes using of the newer triazoles and echinocandins for antifungal prophylaxis. MethodsWe electronically searched the databases of Cochrane Central Register of Controlled Trials, Pubmed, EMBASE, and relevant articles from 1987 through 2011. We examined comparative studies for survival, proven fungal infections, mortality, and adverse effects. Our meta-analysis was performed by Review Manager 5.1.6 software with funnel plot regression analysis to assess publication bias. ResultsAmong 1443 records were 17 studies including 5122 patients for analyses. Pooled comparisons of studies showed antifungal prophylaxis with the new agents to reduce the incidence of invasive fungal infections greater than fluconazole or itraconazole. A reduction in invasive fungal infections was achieved using micafungin, voriconazole, and posaconazole for antifungal prophylaxis. Posaconazole and voriconazole prophylaxis decreased transplant mortality compared with fluconazole or itraconazole prophylaxis. Voriconazole and posaconzole showed greater rates of liver dysfunction and lower incidences gastrointestinal side effects than fluconazole. Caspofungin and voriconazole treatment incurred lower rates of nephrotoxic effects than amphotericin B. Only voriconazole displayed significantly decreased adverse events requiring drug discontinuation compared with fluconazole or itraconazole. ConclusionsThis analysis indicated new antifungal agents were well-tolerated with manageable side effects. They were beneficial for prophylaxis of invasive fungal infections.

Immediate versus deferred empirical antifungal (IDEA) therapy in high-risk patients with febrile neutropenia: a randomized, double-blind, placebo-controlled, multicenter study

Empirical antifungal therapy is widely used in high-risk neutropenic hematology patients with fever persisting for more than 4 days. This clinical trial assessed whether immediate empirical therapy with voriconazole could lower the rates of invasive fungal infections (IFIs) compared with this approach. In a double-blind, placebo-controlled, multicenter study, patients with acute leukemia undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) recipients were randomized to broad-spectrum antibacterial therapy plus voriconazole (immediate) or placebo (deferred) after the onset of neutropenic fever. If fever persisted for 96 h, patients were switched to open-label intravenous voriconazole; oral treatment was permitted after 96 h. The primary endpoint was the rate of proven/probable IFIs between Days 2 and 28 after fever onset in the modified intent-to-treat (mITT) complete-case population. One hundred and forty-seven patients were randomized to immediate (n = 81) or deferred (n = 66) voriconazole. In the mITT population, six patients in the immediate group and nine in the deferred group developed proven/probable IFI between Days 2 and 28 (p = 0.258). The safety profiles were similar in both groups. While immediate empirical therapy with voriconazole appears to be safe in febrile neutropenic high-risk patients, it was not associated with a significant reduction in IFIs compared with therapy deferred for 96 h after fever onset.

1164 Reduction in Fungal Systemic Infections in Preterm Neonates with Nystatin Prophylaxis

BackgroundInvasive fungal infection is an important cause of mortality and morbidity in the very low birth weight (VLBW) and the extremely low birth weight (ELBW) infants. A policy of oral...

Reduced Incidence of Early Invasive Fungal Infection in Allogeneic Transplant Patients Following Micafungin Prophylaxis

Abstract 4567Reduced incidence of early invasive fungal infection in allogeneic transplant patients following micafungin prophylaxis.D To1, D Warkentin2, R Broady1, J. D. Shepherd1, S.H. Nantel1, T.J. Nevill1,C.M. Toze1, D.E. Hogge1, M.J. Barnett1, K.W. Song1, H.J. Sutherland1, D.L. Forrest1, S. Narayanan1, M. M. Power1 (on behalf of the Leukemia/BMT Program of BC and Department of Pharmacy, Vancouver General Hospital)1Leukemia and Bone Marrow Transplantation Program of BC,2Department of Pharmaceutical Science Vancouver General Hospital and University of British Columbia Introduction:Invasive fungal infection (IFI) is both highly prevalent and highly morbid in the allogeneic transplant (HSCT)patient population. We have previously documented an incidence of IFI in our HSCT patient cohort of 20%(2006–2007). At the time of the initial analysis, low dose amphotercin B (LDAB) (10mg/m2) was the routine prophylaxis given for the neutropenic phase post HSCT. This study was carried out to analyse whether an alteration in prophylaxis strategy for patients during the neutropenic phase post HSCT was effective in reducing the incidence of IFI in this heavily immunocompromised patient group. We also aimed to identify risk factors for IFI which would help to guide prophylactic strategies beyond the neutropenic phase. Methods:A retrospective analysis of all patients undergoing allogeneic stem cell transplant between January 2010 and June 2011 was carried out. 67 patients thus identified were reviewed and the incidence and risk factors for IFI in this group was compared to our historical control group from 2006–2007 (n=69). Patients with a prior history of IFI were excluded. EORTC criteria were used to define possible, probable or proven IFI. Diagnostic criteria guiding treatment of IFI did not change between the two study periods. Micafungin 100mg iv was the prophylaxis given to inpatients undergoing myeloablative or unrelated donor non myeloablative transplantation. For outpatient based non- myeloablative transplants, fluconazole 200 mg orally daily was the prophylaxis of choice. Prophyaxis was started on day +1 and was continued until absolute neutrophil count (ANC) was >0.5× 109/L. Results:The overall incidence of IFI was 10/67 (15%), with 5% proven/probable and 10% possible IFI's. The median time to diagnosis of IFI was 78 days from date of transplant. This represents a decrease in incidence of IFI compared to the earlier cohort (20%). The reduction in IFI seen in our current cohort of patients who received micafungin or fluconazole prophylaxis appears to be largely attributable to a reduction in the rate of early (before day +30) IFI in the group of patients treated with iv micafungin (Table 1). Only one of the 43 patients given micafungin prophylaxis developed an IFI in the first 30 days following transplantion.Table 1Characteristics of IFI and Prophylactic Cohort.HSCT-LDAB N=69HSCT-Mi100 N=43HSCT-fluco N=24IFI %13 (20%)5 (10%)5 (21%)p=0.07Proven/probable IFI4 (6%)2 (4%)1 (4%)nsPossible IFI9 (14%)3 (6%)4 (17%)Median time to IFI from HSCT (days) (range)80 (5-590)139 (56-173)40 (11-184)IFI<30 days38%020%p<0.001IFI 30-100 days17%40%60%IFi>100 days45%60%20%Timing of IFI; median time to diagnosis of IFI was 78 days. Only two patients developed an IFI during the neutropenic phase post chemotherapy (20%), 4 patients developed IFI between days 30 and 100 and 4 patients developed an IFI after day 100. (38%, 17% and 45% in earlier cohort.Risk factors for IFI were assessed(Table 2). Of striking significance is the finding that those patients who developed steroid refractory graft versus host disease (GVHD) had an incidence of IFI of 56% (5 of 9 patients developed an IFI) compared to those patients with GVHD who did not require second line therapy of whom only 7% developed an IFI.50% (5/10) of patients who developed an IFI have died compared to 9% of the patients in the no IFI group (5/57). Mortality attributable to IFI was 30% in the IFI group. Conclusion:We demonstrate a reduction in early IFI in patients prophylaxed with micafungin in this small series of uniformly treated patients. Late IFI remains a problem and we have identified a subgroup of patients for whom further prophylaxis is warranted. Prophylaxis with a mold active azole should be given to all patients who develop steroid refractory GVHD given the unacceptably high incidence of IFI in this patient subset. Disclosures:Sutherland:Centocor Ortho Biotech research & Development: Research Funding.

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.

A prospective, randomised study on the use of well-fitting masks for prevention of invasive aspergillosis in high-risk patients

The problem of inhalation of Aspergillus spores outside rooms with high-efficiency particulate air (HEPA) filtration has not been resolved as yet. Well-fitting masks are used in industrial and health care settings to protect from inhaling particles of 0.3–0.5μm size. To investigate the efficacy and tolerability of well-fitting masks in high-risk patients, we conducted a prospective, randomised, multicentre study comparing standard hospital hygiene procedures with or without wearing masks in adults undergoing chemotherapy for acute leukaemia or allogeneic haematopoietic stem-cell transplantation (aHSCT). Forty-one patients were randomly assigned to wearing masks and 39 to the control group. In all, 76% of patients were treated in laminar airflow or HEPA-filtered rooms, 84% received oral polyenes, and three aHSCT recipients were given fluconazole. Duration of neutropenia was similar in both treatment groups. Invasive fungal infections were diagnosed in eight patients in either study arm. One patient in each arm died from proven invasive aspergillosis. There was no difference in the use of systemic antifungals. Of patients in the mask group, 65% described the comfort as acceptable, 26% as unpleasant, and 9% as intolerable. This first randomised study on the use of well-fitting masks failed to show a reduction of invasive fungal infections.

Antifungal agents for preventing fungal infections in solid organ transplant recipients.

Invasive fungal infections (IFIs) are important causes of morbidity and mortality in solid organ transplant recipients. This study aims to systematically identify and summarise the effects of antifungal prophylaxis in solid organ transplant recipients. The Cochrane Central Register of Controlled Trials (Issue 3, 2003), MEDLINE (1966-June 2003), and EMBASE (1980-June 2003) were searched. Reference lists, abstracts of conference proceedings and scientific meetings (1998-2003) were handsearched. Authors of included studies and pharmaceutical manufacturers were contacted. Randomised controlled trials (RCTs) in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal, or another antifungal agent or regimen. Two reviewers independently applied selection criteria, performed quality assessment, and extracted data using an intention-to-treat approach. Differences were resolved by discussion. Data were synthesised using the random effects model and expressed as relative risk (RR) with 95% confidence intervals (95% CI). Fourteen unique trials with 1497 randomised participants were included. Antifungal prophylaxis did not reduce mortality (RR 0.90, 95% CI 0.57 to 1.44). In liver transplant recipients, a significant reduction in IFIs was demonstrated for fluconazole (RR 0.28, 95% CI 0.13 to 0.57). Although less data were available for itraconazole and liposomal amphotericin B, indirect comparisons and one direct comparative trial suggested similar efficacy. Fluconazole prophylaxis did not significantly increase invasive infections or colonisation with fluconazole-resistant fungi. In renal and cardiac transplant recipients, neither ketoconazole nor clotrimazole significantly reduced invasive infections. Overall, the strength and precision of comparisons however were limited by a paucity of data. For liver transplant recipients, antifungal prophylaxis with fluconazole significantly reduces the incidence of IFIs with no definite mortality benefit. Given a 10% incidence of IFI, 14 liver transplant recipients would require fluconazole prophylaxis to prevent one infection. In transplant centres where the incidence of IFIs is high, or in situations where the individual risk is great, antifungal prophylaxis should be considered.

Prevention of invasive fungal infections in liver transplant recipients: the role of prophylaxis with lipid formulations of amphotericin B in high-risk patients.

Invasive fungal infections (IFI) are associated with high mortality in liver transplant recipients. Prevention remains an elusive goal, especially for IFI caused by moulds. From January 1998, patients who fulfilled four or more variables identified as risk factors for IFI received a cumulative dose of 1-1.5 g of lipid formulations of amphotericin B (L-AmpB; AmBisome or Abelcet). The development of IFI in these patients was compared with historical patients. Two hundred and eighty liver transplant recipients were analysed over a period of 8 years. In the historical group, IFI were observed in 22 of 131 patients (17%) and invasive aspergillosis in 13 of them (10%). After January 1998, IFI were observed in nine of 149 (6%) (P < 0.01) and invasive aspergillosis in six patients (4%) (P = 0.08). In patients with four or more risk factors (high risk) for IFI, the administration of L-AmpB reduced the risk from 36% to 14% (P = 0.07), and the risk of aspergillosis from 23% to 5% (P = 0.08). Notably, prophylaxis reduced the risk of aspergillosis from 32% to 0% in dialysed patients (P = 0.03). Variables independently associated with IFI in high-risk patients were dialysis [odds ratio (OR) 3.9; 95% confidence interval (CI) 1-16.7] and surgical reintervention (OR 5.4; 95% CI 1.2-24.6), while L-AmpB was a protective factor in this multivariate analysis (OR 0.1; 95% CI 0.02-0.8). The analysis in these high-risk patients was not able to demonstrate an association between the administration of L-AmpB and higher survival. Selected risk factors are good predictors of IFI in liver transplant recipients. The administration of L-AmpB in high-risk patients is independently associated with a reduction of IFI.

Preemptive prophylaxis with a lipid preparation of amphotericin B for invasive fungal infections in liver transplant recipients requiring renal replacement therapy.

Posttransplant renal replacement therapy has been shown to be an independently significant risk factor for invasive fungal infections after liver transplantation. We assessed the efficacy of a lipid preparation of amphotericin B as prophylaxis for invasive fungal infections, directed toward liver transplant recipients requiring renal replacement therapy. A total of 148 patients transplanted between 1990 and 1997 received no antifungal prophylaxis. Since 1997, 38 patients underwent liver transplantation; antifungal prophylaxis with a lipid preparation of amphotericin B was used in patients requiring renal replacement therapy. Fifteen percent (22 of 148) of the patients transplanted before 1997 required renal replacement therapy. In this cohort, the incidence of invasive fungal infections (36% vs. 7%, P=0.0007) and invasive aspergillosis (14% vs. 2%, P=0.02) was significantly higher in patients who required renal replacement therapy compared with those who did not. Since 1997, 29% (11 of 38) of the patients required renal replacement therapy and received antifungal prophylaxis. Invasive fungal infections occurred in 36% (8 of 22) of the patients who received no prophylaxis (patients before 1997), and 0% (0 of 11, P=0.03) in those who received antifungal prophylaxis (since 1997). Antifungal prophylaxis was independently associated with protection from fungal infection (P=0.017). No reduction in mortality with antifungal prophylaxis was documented. Prophylaxis with a lipid preparation of amphotericin B was associated with a significant reduction in invasive fungal infections in high-risk liver transplant recipients, i.e., those requiring renal replacement therapy. However, no beneficial effect on survival could be documented.