Number Of Invasive Fungal Infections Research Articles

Catechin potentiates the antifungal effect of miconazole in Candida glabrata

The rising number of invasive fungal infections caused by drug-resistant Candida strains is one of the greatest challenges for the development of novel antifungal strategies. The scarcity of available antifungals has drawn attention to the potential of natural products as antifungals and in combinational therapies. One of these is catechins—polyphenolic compounds—flavanols, found in a variety of plants. In this work, we evaluated the changes in the susceptibility of Candida glabrata strain characterized at the laboratory level and clinical isolates using the combination of catechin and antifungal azoles. Catechin alone had no antifungal activity within the concentration range tested. Its use in combination with miconazole resulted in complete inhibition of growth in the sensitive C. glabrata isolate and a significant growth reduction in the azole resistant C. glabrata clinical isolate. Simultaneous use of catechin and miconazole leads to increased intracellular ROS generation. The enhanced susceptibility of C. glabrata clinical isolates to miconazole by catechin was accompanied with the intracellular accumulation of ROS and changes in the plasma membrane permeability, as measured using fluorescence anisotropy, affecting the function of plasma membrane proteins.

Antifungal activity and potential mechanism of action of caspofungin in combination with ribavirin against Candida albicans

The number of invasive fungal infections has increased dramatically, resulting in high morbidity and mortality among immunocompromised patients. With increasing use of caspofungin (CAS), resistant strains have emerged frequently and led to limitations in the treatment of patients with severe invasive Candida albicans infections. Combination therapy is an important method to deal with this issue. As such, this study investigated the activity of CAS in combination with ribavirin (RBV) against C. albicans. The results of this in-vitro study showed that the minimum inhibitory concentrations (MICs) of CAS and RBV when they were used as monotherapy were 0.5-1 μg/mL and 2-8 μg/mL, respectively, while the MIC of CAS decreased from 0.5-1 μg/mL to 0.0625-0.25 μg/mL when used in combination with RBV, with a fractional inhibitory concentration index (FICI) ≤0.5. In addition, the RBV+CAS combination group displayed synergistic effects against C. albicans biofilm over 4 h; the sessile MIC (sMIC) of CAS decreased from 0.5-1 µg/mL to 0.0625-0.25µg/mL and the sMIC of RBV decreased from 4-16 µg/mL to 1-2 µg/mL, with FICI <0.5. The survival of C. albicans-infected Galleria mellonella was prolonged, the fungal burden was decreased, and the area of tissue damage was reduced after combination therapy. Further study showed that the mechanisms of action of the synergistic effect were related to the inhibition of biofilm formation, the inhibition of hyphal growth, and the activation of metacaspases, but were not related to the accumulation of reactive oxygen species. It is hoped that these findings will contribute to the understanding of drug resistance in C. albicans, and provide new insights for the application of RBV.

Design of anti-fungal agents by 3D-QSAR

An increase in the number of invasive fungal infections especially in immunocompromised patients is increasing the mortality rate worldwide. Due to the emergence of drug-resistant fungi, the currently available antifungal drugs have become ineffective. Because no alternative treatment is available, some existing drugs are still used. Therefore, there is a need to design and develop novel and effective anti-fungal drugs. Molecular docking and 3-dimensional quantitative structure-activity relationship (3D-QSAR) methods have been useful approaches for the design of novel molecules. A set of 30 molecules reported in the literature containing azoles and non-azoles have been used in this study to derive 3D-QSAR.CoMFA and CoMSIA models for the most active compound and least active compounds have been developed. The structural requirements were obtained by analysing the contour maps. The partial least square analysis for CoMFA and CoMSIA showed a significant cross-validated correlation coefficient of 0.625 and 0.67 and a non-cross validated correlation coefficient of 0.991 and 0.99, respectively. The model was validated by observing the predicted correlation for test molecules with the value of 0.699 and 0.659, respectively.

COVID-19 associated Invasive Fungal Rhinosinusitis: A Retrospective Analysis of 15 Cases

PurposeIndia is witnessing an increasing number of invasive fungal infections, especially mucormycosis, associated with the second wave of the COVID-19 pandemic. The purpose of this study is to describe the epidemiological and clinical features of patients with COVID-19 associated invasive fungal sinusitis (CIFRS) who presented to our centre (KIMSHEALTH, a tertiary hospital in Thiruvananthapuram, Kerala, India).Methods & MaterialsWe included biopsy and/or culture proven invasive fungal rhinosinusitis in patients who had history of COVID-19 infection (confirmed by RT-PCR or an antigen based test). Clinical details were collected by review of the electronic medical records and analysis was done by descriptive statistics.Results15 patients who satisfied the inclusion criteria were included in the analysis. This included 11 cases of rhino orbital mucormycosis, 2 cases of invasive aspergillosis and 2 cases of co-infection with Mucorales and Aspergillus species. Fungal culture showed growth of Mucorales in 4 patients and Aspergillus flavus in one patient. The mean age of the patients was 58.0 ± 9.7 years, and 12 were male. Type 2 diabetes mellitus was a common additional risk factor in all the patients and the mean HbA1c was 9.9 ± 2.1. All patients except two had received corticosteroids as a part of their COVID-19 treatment. All patients except one had used steam inhalation for symptom relief for COVID-19 symptoms. The median duration between the diagnosis of COVID-19 and the diagnosis of CIFRS was 20 days (interquartile range: 16-27). All patients underwent emergency endoscopic sinus debridement surgery followed by antifungal medicines. Antifungals used included liposomal amphotericin B, amphotericin B deoxycholate and isavuconazole for mucormycosis patients while two patients with invasive aspergillosis were treated with isavuconazole. At the time of reporting one patient had expired while the others have shown clinical improvement.ConclusionThe common risk factor for all cases of CIFRS was diabetes mellitus. Majority of patients also had history of steroid use and steam inhalation during their COVID-19 treatment. Their role in pathogenesis need to be ascertained by larger studies.

The effect of Ginkgolide B combined with fluconazole against drug-resistant Candida albicans based on common resistance mechanisms

The number of invasive fungal infections has increased dramatically over recent years, leading to high morbidity and mortality of immunocompromised patients. Candida albicans is the most common cause of life-threatening disseminated candidiasis among invasive fungal infections. Resistance of C. albicans against conventional antifungals is frequently reported. Treatment with a combination of antifungal and non-antifungal agents is often considered in the aim to overcome drug resistance. This study shows for the first time that the combination of ginkgolide B (GB) and fluconazole (FLC) increases the sensitivity of resistant C. albicans to FLC. In vitro studies indicated that the drug combination had a synergistic effect on C. albicans in both planktonic cells and biofilms within 12 h. In vivo efficacy of this drug combination was evaluated using the Galleria mellonella infection model. Survival rate, fungal burden, and histological examination were determined. Studies indicated that the antifungal effects of GB in combination with FLC might be associated with inhibition of hyphal growth, disruption of intracellular calcium, and inhibition of drug efflux pumps. The results indicate a promising solution for overcoming drug resistance of C. albicans and expanding the clinical application of existing drugs.

Gram-negative Late-onset Sepsis in Extremely Low Birth Weight Infants Is Emerging in The Netherlands Despite Quality Improvement Programs and Antibiotic Stewardship!

Late-onset sepsis (LOS) is still an important cause of morbidity and mortality in premature infants. Indwelling devices and lower birth weight (BW) are the most important risk factors. Quality improvement programmes are implemented to reduce incidence of LOS. An increasing number of extremely low BW infants (ELBWs) (≤1000 g) are treated in the Netherlands, including infants with gestational age (GA) 24 weeks since Dutch law changed in 2010. We evaluated the incidence and causative microorganisms of LOS in ELBWs over an 8-year period in 2 Dutch neonatal intensive care units (NICUs). The first LOS episodes of all ELBWs admitted to the NICU of the Wilhelmina Children's Hospital Utrecht and the Isala Hospital Zwolle were included retrospectively from January 2008 to December 2015. LOS was defined as clinical signs of sepsis >72 hours postpartum, combined with a positive blood culture and C-reactive protein of ≥10 mg/L. Two hundred fifty-five out of 923 ELBWs (27.6%) had an episode of LOS, and no decrease in incidence was seen over the years. ELBWs with LOS had lower GA and BW. The percentage of Gram-negative organisms increased from 0% in 2008 to 27% in 2015, mainly in infants with GA <26 weeks. The number of invasive fungal infections decreased to zero. No significant decrease in incidence of LOS in ELBWs was seen, despite the introduction of quality improvement programmes and attention to antibiotic stewardship. Furthermore, an increase in Gram-negative LOS was observed, with an overrepresentation among the growing proportion of the NICU population at the lowest GA and weight. Prevention, including high compliance to hand hygiene policies, may be an impactful intervention.

The quinoline bromoquinol exhibits broad-spectrum antifungal activity and induces oxidative stress and apoptosis in Aspergillus fumigatus.

Over the last 30 years, the number of invasive fungal infections among immunosuppressed patients has increased significantly, while the number of effective systemic antifungal drugs remains low. The aim of this study was to identify and characterize antifungal compounds that inhibit fungus-specific metabolic pathways not conserved in humans. We screened a diverse compound library for antifungal activity in the pathogenic mould Aspergillus fumigatus . We determined the in vitro activity of bromoquinol by MIC determination against a panel of fungi, bacteria and cell lines. The mode of action of bromoquinol was determined by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring genes and by RNAseq analysis in A. fumigatus . In vivo efficacy was tested in Galleria mellonella and murine models of A. fumigatus infection. Screening of a diverse chemical library identified three compounds interfering with fungal iron utilization. The most potent, bromoquinol, shows potent wide-spectrum antifungal activity that was blocked in the presence of exogenous iron. Mode-of-action analysis revealed that overexpression of the dba secondary metabolite cluster gene dbaD , encoding a metabolite transporter, confers bromoquinol resistance in A. nidulans , possibly by efflux. RNAseq analysis and subsequent experimental validation revealed that bromoquinol induces oxidative stress and apoptosis in A. fumigatus . Bromoquinol significantly reduced mortality rates of G. mellonella infected with A. fumigatus , but was ineffective in a murine model of infection. Bromoquinol is a promising antifungal candidate with a unique mode of action. Its activity is potentiated by iron starvation, as occurs during in vivo growth.

Risk Factors and Outcomes of Invasive Fungal Infections in Allogeneic Hematopoietic Cell Transplant Recipients.

Allogeneic hematopoietic cell transplant (HCT) recipients are at increased risk of invasive fungal infections (IFI), which are associated with a high mortality rate. We evaluated the impact of IFI in allogeneic HCT patients. In total, 541 consecutive allogeneic HCT recipients were included. The cumulative incidence of any IFI and mold infections at 1-year post-HCT was 10 and 7%, respectively. Median times to IFI and mold infection were 200 and 210days, respectively. There was a trend toward fewer IFI and mold infections in the last several years. Both acute graft-versus-host disease (GVHD) (OR 1.83, p=0.05) and corticosteroid duration (OR 1.0, p=0.026) were significantly associated with increased risk of IFI, acute GVHD (OR 2.3, p=0.027) emerged as the most important association with mold infections. Any IFI [HR 4.1 (2.79-6.07), p<0.0001] and mold infections [HR 3.34 (2.1-5.1), p<0.0001] were independently associated with non-relapse mortality (NRM). This association persisted in the setting of both acute and chronic GVHD. Corticosteroid treatment for >90days was also significantly associated with higher NRM [HR 1.9 (1.3-2.6), p<0.0001]. This study highlights the impact of IFI on NRM among HCT patients. The decrease in number of IFI and mold infections over the last several years may reflect the benefit of prophylaxis with mold-active antifungal agents.

Identification and characterization of haemofungin, a novel antifungal compound that inhibits the final step of haem biosynthesis.

During recent decades, the number of invasive fungal infections among immunosuppressed patients has increased significantly, whereas the number of effective systemic antifungal drugs remains low and unsatisfactory. The aim of this study was to characterize a novel antifungal compound, CW-8/haemofungin, which we previously identified in a screen for compounds affecting fungal cell wall integrity. The in vitro characteristics of haemofungin were investigated by MIC evaluation against a panel of pathogenic and non-pathogenic fungi, bacteria and mammalian cells in culture. Haemofungin mode-of-action studies were performed by screening an Aspergillus nidulans overexpression genomic library for resistance-conferring plasmids and biochemical validation of the target. In vivo efficacy was tested in the Galleria mellonella and Drosophila melanogaster insect models of infection. We demonstrate that haemofungin causes swelling and lysis of growing fungal cells. It inhibits the growth of pathogenic Aspergillus, Candida, Fusarium and Rhizopus isolates at micromolar concentrations, while only weakly affecting the growth of mammalian cell lines. Genetic and biochemical analyses in A. nidulans and Aspergillus fumigatus indicate that haemofungin primarily inhibits ferrochelatase (HemH), the last enzyme in the haem biosynthetic pathway. Haemofungin was non-toxic and significantly reduced mortality rates of G. mellonella and D. melanogaster infected with A. fumigatus and Rhizopus oryzae, respectively. Further development and in vivo validation of haemofungin is warranted.

New insights on the development of fungal vaccines: from immunity to recent challenges

Fungal infections are emerging as a major problem in part due to high mortality associated with systemic infections, especially in the case of immunocompromised patients. With the development of new treatments for diseases such as cancer and the acquired immune deficiency syndrome pandemic, the number of immunosuppressed patients has increased and, as a consequence, also the number of invasive fungal infections has increased. Several studies have proposed new strategies for the development of effective fungal vaccines. In addition, better understanding of how the immune system works against fungal pathogens has improved the further development of these new vaccination strategies. As a result, some fungal vaccines have advanced through clinical trials. However, there are still many challenges that prevent the clinical development of fungal vaccines that can efficiently immunise subjects at risk of developing invasive fungal infections. In this review, we will discuss these new vaccination strategies and the challenges that they present. In the future with proper investments, fungal vaccines may soon become a reality.

Reduction in incidence of invasive fungal infection in patients receiving allogeneic stem cell transplantation using combined diagnostic-driven approach and itraconazole oral solution.

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic-driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non-significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic-driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non-statistically significant, number of IFI in our medical centre.

Safety of posaconazole

Introduction: The increasing number of invasive fungal infections (IFI) among immunocompromised hosts is a significant clinical issue. Diagnosis of IFI, choosing among the available antifungal drugs, and the high morbidity/mortality associated with IFI pose clinical challenges for healthcare providers. Besides efficacy, a thorough knowledge of the pharmacokinetics, drug–drug interactions and safety profile of the antifungal drugs is critical for appropriate drug selection. Among the commonly used triazoles, the recently released posaconazole is relatively less well investigated in terms of its safety. With expanding clinical use of posaconazole, the present review examines the safety of the drug and its propensity for drug–drug interaction.Areas covered: This paper mainly discusses the safety profile of posaconazole, its adverse effects and drug–drug interaction.Expert opinion: Posaconazole is generally safe and well tolerated. Lack of an intravenous formulation and unpredictable bioavailability of the suspension form are significant factors limiting the widespread use of posaconazole.

Epidemiology of invasive fungal infections in kidney transplant patients

Epidemiology of invasive fungal infections in kidney transplant patients Behzad EinollahiNephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IranI recently read with great interest the review article "Epidemiology and treatment approaches in management of invasive fungal infections" by Kriengkauykiat et al1 that was published in your journal. This review drew attention to the steadily growing number of invasive fungal infections (IFIs) that are due to the increasing number of severely immunocompromised patients. Despite advances in antifungal regimens in terms of prophylaxis and treatment, IFIs may lead to high mortality rates in solid organ recipients.

Epidemiology and treatment approaches in management of invasive fungal infections

Over the past 20 years, the number of invasive fungal infections has continued to persist, due primarily to the increased numbers of patients subjected to severe immunosuppression. Despite the development of more active, less toxic antifungal agents and the standard use of antifungal prophylaxis, invasive fungal infections (especially invasive mold infections) continue to be a significant factor in hematopoietic cell and solid organ transplantation outcomes, resulting in high mortality rates. Since the use of fluconazole as standard prophylaxis in the hematopoietic cell transplantation setting, invasive candidiasis has come under control, but no mold-active antifungal agent (except for posaconazole in the setting of acute myelogenous leukemia and myelodysplastic syndrome) has been shown to improve the survival rate over fluconazole. With the advent of new azole and echinocandin agents, we have seen the emergence of more azole-resistant and echinocandin-resistant fungi. The recent increase in zygomycosis seen in the hematopoietic cell transplantation setting may be due to the increased use of voriconazole. This has implications for the empiric approach to pulmonary invasive mold infections when zygomycosis cannot be ruled out. It is imperative that an amphotericin B product, an antifungal that has never developed resistance in over 50 years, be initiated. The clinical presentations of invasive mold infections and invasive candidiasis can be nonspecific and the diagnostic tests insensitive, so a high index of suspicion and immediate initiation of empiric therapy is required. Unfortunately, our currently available serologic tests do not predict infection ahead of disease, and, therefore cannot be used to initiate “preemptive” therapy. Also, the Aspergillus galactomannan test gives a false negative result in patients receiving antimold prophylaxis, ie, virtually all of our patients with hematologic malignancy and hematopoietic cell transplant recipients. We may eventually be able to select patients at highest risk for invasive fungal infections for prophylaxis by genetic testing. However, with our current armamentarium of antifungal agents and widespread use of prophylaxis in high-risk groups (hematologic malignancy, hematopoietic cell transplantation), we continue to see high incidence and mortality rates, and our future hope lies in reversing the immunosuppression or augmenting the immune system of these severely immunocompromised hosts by developing and utilizing immunotherapy, immunoprophylaxis, and vaccines.

The value of amphotericin B in the treatment of invasive fungal infections

Over the last 20 years, there has been an increase in the total number of invasive fungal infections (IFIs) and in infections caused by rare and emerging pathogens. This is due in part to the growing population of immunocompromised patients at risk of developing fungal infections. Three classes of antifungal agents are widely used for the treatment of systemic fungal infections: polyenes, azoles, and echinocandins. Polyenes were the first antifungal agents developed and have a long-standing history in the treatment of IFIs. The use of conventional amphotericin B has been limited because of toxic side effects, which have been reduced by the lipid formulations of amphotericin B. Treatment options for invasive mycoses have expanded with the recent introduction of the second-generation triazoles (voriconazole and posaconazole) and the echinocandins (caspofungin, micafungin, anidulafungin). Despite the increased number of antifungal drugs, resistance issues present a problem in the treatment of IFIs. Although some fungal pathogens display innate resistance, others have developed resistance secondary to selective pressure. This article briefly reviews the changing epidemiology of fungal infections and associated risk factors, resistance issues with commonly administered antifungal agents, and treatment options for IFIs, with a focus on polyenes.

Design of Clinical Trials of Empiric Antifungal Therapy in Patients with Persistent Febrile Neutropenia: Considerations and Critiques

Febrile neutropenic patients who receive antibiotics are at risk for fungal infections. This risk increases greatly with the length and severity of neutropenia. Because diagnostic tests for fungal infections lack sensitivity and specificity and because established fungal infections are associated with poor outcomes, empiric antifungal therapy is frequently given to patients with fever that persists despite antibacterial therapy. Early trials of empiric amphotericin B showed reductions in the number of invasive fungal infections and in related morbidity and mortality. However, as a result of infusion-related and renal adverse effects of amphotericin B, newer agents, such as lipid formulations of amphotericin B, extended-spectrum azoles, and echinocandins, have been developed. Although these alternatives have been associated with decreased toxicity, improved efficacy has not been clearly demonstrated. Although empiric antifungal therapy can prevent undetected breakthrough infections and morbidity associated with many fungal infections, its shortcomings include overtreatment, toxicity, and increased costs of unnecessary treatment. Recent studies have highlighted several questions in trial design and data interpretation. For example, what is the appropriate study design? Who should be enrolled in studies of empiric antifungal therapy? How should successful therapy be defined? These issues are reviewed to determine whether new antifungal agents should be evaluated for empiric use in patients with fever and neutropenia.

Voriconazole in Primary Prophylaxis Reduces the Incidence of IFI in High Risk Hematologic Patients.

OBJETIVE: To analyse the eficacy and safety of voriconazole as primary prophylaxis in hematologic patients with high risk of invasive fungal infections (IFI) due to severe neutropenia after induction/intensification chemotherapy for acute myeloid leukemia (AML) and allogeneic hematopoietic cell transplantation (allo-HCT).PATIENTS AND METHODS: between June-04 and May-05 we prospectively included 31 episodes of severe neutropenia (<0,5x109/l, >10 days) after chemotherapy for AML and 24 patients submitted to an allo-HCT in a primary prophylaxis treatment with voriconazole (200 mg po/12 h) from the starting of chemotherapy until the neutrophils recovery (>0,5x109/l) in AML and from the starting of the conditioning regimen until the withdrawal of immunossupression in allo-HCT (by three months after transplantation) and we compared both groups with historic controls (63 episodes of neutropenia after AML and 31 allo-HCT) treated between January-03 and May-04 with fluconazole as primary prophylaxis (400 mg po/24 h) in the same way. Drugs were adjusted to weight in children. In case of severe mucositis voriconazole or fluconazole were temporarily used intravenously. EORTC/MSG criteria for IFI definitions were used and galactomanane antigen determinations were done twice a week. In case of neutropenic fever, empiric antifungal treatment was started in the fith day with lyposomal amfotericin B the primary prophylaxis was stopped.RESULTS: AML GROUP: We didn't find statistical differences among groups of VORI (n=31) and FLUCO (n=63) when we analyse age (VORI mean 49y, 18–64;FLUCO mean53y,21–72), sex, FAB classification, disease status, number of broad spectrum antibiotics, bacterial infections, days of neutropenia (19 vs 18) and days of fever (5.8 vs 7.2). The number of detected IFI was superior in the fluconazole group in spite of no statistical differences (VORI 3 vs FLUCO 11; 9,6% vs 17,4%, p=NS) with a sum of proven+probable 2 vs 5 (6,4% vs 8%, p=NS). Interestingly, the number of fatal IFI was statistical superior in the fluconazole group (VORI 0 vs FLUCO 4, p<0,05) and the need for empiric antifungal treatment was superior in the fluconazole group (VORI 19,3% vs FLUCO 50,8%, p=0,004). None patient had to interrupt voriconazole due to toxicity.ALLO-HCT GROUP: we didn't find statistical differences among groups of VORI (n=24) and FLUCO (n=31) when we analyse age (VORI mean 37y, 2–64 and FLUCO mean 30y, 5–56), sex, diagnosis and status at transplantation. In spite of differences in the conditioning regimen with more reduced-intensity conditioning regimen in the voriconazole group, both groups were similar when we analyse incidence of aGVHD II–IV grades, steroids use, VOD, number of bacterial infections, CMV infections and cGVHD. The days of fever were superior in the fluconazole group (VORI 4 vs FLUCO 7, p=0,04) and so the need for empiric antifungal treatment (VORI 6 vs FLUCO 16, p=0,042). The number of IFI was superior in the fluconazole group (VORI 2 vs FLUCO 10, p=0,04) and the number of fatal events due to IFI was superior in the fluconazole group (VORI 1 vs FLUCO 5, p<0,05). Voriconazole was temporarily stopped in two patients with hepatic aGVHD and one patient with VOD. Three patients developped hepatic colestasis by day +75 wich was reversible after discontinuating voriconazole one week.CONCLUSSIONS: voriconazole as primary prophylaxis of IFI is a safety and well tolerated efective drug wich reduces the need for empiric antifungal treatment and the fatal events due to IFI in AML and allo-HCT.

New strategy for fungal infections

An alarming increase in the number of invasive fungal infections has been observed. This is due to more aggres-sive bone marrow ablative regimens as well as to intensive use of corticosteroids and other immunosuppressants in numerous disorders. Principally amongst seriously ill non-cancer patientsCandida has become a very prominent isolate. The attributable mortality from candidemia ranges from about 40% in patients with candidemia alone to over 90% for those who have acute tissue invasion with or without fungemia. Secondary bloodstream infections, which evolve from infectious foci such as wounds, carry a higher mortality than do primary, catheter-related infections. Many patients die within the first 48 hours after establishing the diagnosis. If applicable, a return of the granulocytes is an important prognostic feature, just as timely commencement of antifungal agents. Until recently fluconazole and amphotericin B were seen as a first line options for the treatment of disseminated candidosis. However, whereas more than 15 years ago, 80% infections by yeasts were due toC. albicans, in the 1990’s non-albicans species have now become responsible for at least half of them, presumably related to the intensive prophylactic use of fluconazole. Development of the lipid formulations, with their improved therapeutic index raised hope for the future, but evidence on their general efficacy is still rather limited. Moreover, the results published on the treatment of non-albicans species have been rather disappointing up until now. On the other hand, the high expectations on the activity of the new candins againstCandida species, including those resistant to the azoles and polyenes, appear justified. These compounds have a mechanism of action totally different from the traditional antifungals. Data on an improved outcome of candidemia if a central venous catheter is removed promptly are conflicting. To avoid untimely death, most specialists nowadays prescribe systemic empirical antifungal therapy to immunocompromised patients who fail to respond to adequate broad spectrum antibacterial treatment or show any sign of an invasive fungal infection. Given its broad spectrum of activity, amphotericin B at a dose of 1 mg/kg per day is still the drug of choice for such purposes; the lipid preparation should be reserved for patients who can not tolerate the conventional formulation. Fluconazole can be an option for cases with a low risk of invasive mould infections but its lack of activity againstAspergillus species is a major drawback. The other traditional antifungal agent registered for used for the treatment of invasive aspergillosis is itraconazole. A randomized study in neutropenic patients comparing itraconazole with amphotericin B hinted at equivalence but did not reach a statistical endpoint. Unfavorable drug interactions has led to failure in many a patient. The new azoles, voriconazole and posaconazole possess an expanded spectrum of activity. Voriconazole, which now has been filed for approval in many countries, was shown to be clearly superior to amphotericin B in the first-line treatment of invasive pulmonary aspergillosis. It also offers promise for the treatment of some hitherto notoriously difficult-to-treat infections by rare organisms such asScedosporium andFusarium species. A phase II trial assessing the activity of caspofungin in the treatment of refractory invasive aspergillosis provided results that warrant a further evaluation of its potency for rescue purposes and in an empirical setting, where both moulds and yeasts can be encountered.

The use of itraconazole as prophylaxis against invasive fungal infection in blood and marrow transplant recipients.

Invasive fungal infections play a key role in contributing to morbidity and mortality in patients undergoing treatment for haematological malignancies and related diseases. Risk factors for development of invasive fungal infections after blood or bone marrow transplantation include the use of broad-spectrum antibiotics, steroids, mismatched or unrelated donor transplant, right atrial catheters, and prolonged or profound neutropenia. Previous attempts at use of oral itraconazole as antifungal prophylaxis in the setting of chemotherapy-induced neutropenia were unsuccessful because of its poor absorption in capsule form. Itraconazole-cyclodextrin is well absorbed even in the presence of chemotherapy-induced neutropenia. Plasma levels of 250-500 ng/ml are required for prophylaxis. Studies to date show a favourable outcome in patients receiving itraconazole as prophylaxis against invasive fungal infections, although many studies looked at small numbers of patients and the incidence of invasive fungal infection in the control groups was low, prohibiting meaningful statistical evaluation. Fungi differ in their sensitivity to antifungal agents, and itraconazole is not the agent of choice in all patients. With the widespread use of antifungal prophylaxis, the possibility of resistance to antifungal agents and an increase in the number of invasive fungal infections caused by ubiquitous fungi previously considered nonpathogenic must be considered as potential problems.

Treatment of Fungal Infections in Surgical Patients Using Conventional Antifungals

In surgical and intensive care units an alarming increase in the number of invasive fungal infections has been observed. This is partly due to temporal transferral of patients from hemato-oncological units or transplant units and partly to the enhanced use of corticosteroids and other immunosuppressants. Candida species have now become a common isolate in ill patients. Amphotericin B with or without flucytosine constituted the standard therapy for candidosis but similar response rates with less toxicity may be obtained with lipid and with fluconazole. Data on an improved outcome of candidemia if a central venous catheter is removed promptly are conflicting. Amphotericin B remains the standard therapy for other invasive mycoses; it is seldom possible to administer adequate doses and therefore the options and limitations of the triazoles and liposomal preparations should be explored.