Management Of Systemic Fungal Infections Research Articles

Management of systemic fungal infections in the presence of a cardiac implantable electronic device: A systematic review.

Evidence to inform the management of systemic fungal infections in the setting of a cardiac implantable electronic devices (CIED), such as a permanent pacemaker or implantable cardioverter-defibrillator, is scant and limited to case reports and series. The available literature suggests high morbidity and mortality. To better characterize the shared experience of these cases and their outcomes, we performed a systematic review. We investigated all published reports of systemic fungal infections-fungemia and fungal vegetative disease-in the context of CIED, drawing from PubMed, EMBASE, and the Cochrane database of systematic reviews, inclusive of patients who received treatment between January 2000 and May 2020. Exclusion criteria included presence of ventricular assist device and concurrent bacteremia, bacterial endocarditis, bacterial vegetative infection, or viremia. Among 6261 screened articles, 48 cases from 41 individual studies were identified. Candida and Aspergillus species were the most commonly isolated fungi. There was significant heterogeneity in antifungal medication selection and duration. CIED extraction-either transvenous or surgical-was associated with increased survival to hospital discharge (92%) and clinical recovery at latest follow-up (81%), compared to cases where CIED extraction was deferred (56% and 40%, respectively). Importantly, there were no prospective data, and the data were limited to individual case reports and one small case series. In summary, CIED extraction is associated with improved fungal clearance and patient survival. Reported antifungal regimens are heterogeneous and nonuniform. Prospective studies are needed to verify these results and define optimal antifungal regimens.

Economic evaluation of the prevention and management of systemic fungal infections in neutropenic patients

Systemic fungal infections in neutropenic patients remain a clinical problem that is associated with morbidity and mortality. Continuing efforts are being made to develop improved (i.e., more effective or safe) drugs, and several new treatments have recently become available. These have increased the therapeutic options available to clinicians to address the problem of systemic fungal infections. Therapeutic choices are difficult when taking into account aspects of efficacy, safety and costs that are associated with the available alternatives. This review summarises the present status of health economic knowledge of the standard therapies that have been available for many years, and also reports on the most recent health economic evidence available for the newly developed treatment alternatives.

Management of systemic fungal infections: alternatives to itraconazole

For many years, amphotericin B and flucytosine have been the only antifungal agents for invasive fungal infections. Amphotericin B was the standard of care for most of these infections. However, its use was often associated with low efficacy and poor tolerance. Fortunately, the antifungal armamentarium has increased during the past two decades with the addition of several new agents. In addition to itraconazole and fluconazole, lipid formulations of amphotericin B, voriconazole, caspofungin and micafungin have arrived on the market. Other agents are expected to be licensed shortly (anidulafungin, posaconazole). These various antifungal agents differ in their spectrum, pharmacokinetic profile, route of administration, efficacy in clinical trials, safety profile, drug-drug interactions and, importantly, their cost. There is no longer a unique standard agent for all or nearly all invasive fungal infections but a real choice among several agents. The characteristics of these new agents are reviewed to help clinicians in their decision to select an antifungal agent for their patients.

The place for itraconazole in treatment

The incidence of systemic fungal infections has risen sharply in the last two decades, reflecting a rise in the number of patients who are predisposed to these diseases because they are immunosuppressed or immunocompromised. The growing use of intensive chemotherapy to treat cancer, highly immunosuppressive drug regimens (not only in transplant recipients), widespread prophylactic or empirical broad-spectrum antibiotics, prolonged parenteral nutrition, long-term indwelling lines, improved survival in neonatal and other intensive care units, together with the AIDS epidemic have led to an upsurge in the number of patients at risk. In addition, there have been changes in the epidemiology of systemic fungal infections, with Aspergillus spp. and Candida spp. other than Candida albicans becoming increasingly common causes. These changes have affected the selection of drugs for first-line or prophylactic use, as not all agents have the critical spectrum of activity required. The management of systemic fungal infections can be divided into four main strategies: prophylaxis, early empirical use, pre-emptive and definite therapy. Antifungal prophylaxis is given based on the patient risk factors, but in the absence of infection. Empirical antifungal therapy is given in patients at risk with signs of infection of unclear aetiology (usually persistent fever) but of possible fungal origin. Therapy is given pre-emptively in patients at risk with additional evidence for the presence of an infective agent in a way predisposing for infection (e.g. Aspergillus colonization; high Candida colonization index). Finally, definite treatment is used in patients with confirmed fungal infection. The distinction between risk-adapted prophylaxis, early empirical therapy, and pre-emptive use of antifungals often becomes unclear and clinical decision making depends largely on local epidemiology and resistance patterns, adequate definition of patient risk categories, early diagnosis and the calculation of cost-benefit ratios. This article addresses the use of itraconazole in the treatment of invasive fungal infections in the haematology patient.

Azoles in the Management of Systemic Fungal Infections

Azoles are a key element in the antifungal armamentarium. They act by selectively inhibiting the synthesis of ergosterol, a vital component of the fungal cell membrane. The azoles are divided into the older imidazoles (including miconazole and ketoconazole) and the more recently introduced triazoles (fluconazole, itraconazole, and voriconazole). Because of toxicity problems, high relapse rates, and their narrower spectrum, the imidazoles have largely been superseded by the triazoles. Fluconazole is an effective agent for the treatment of oropharyngeal, esophageal, and urinary candidiasis and candidemia, and has played an important role in the prophylaxis of fungal infections in immunocompromised patients. However, it lacks activity against Aspergillus and some non-albicans species of Candida, and resistance to fluconazole, most notably in people with HIV, is well documented. Itraconazole is a broad-spectrum antifungal agent-in addition to being the first azole with activity against Aspergillus, it is effective against Candida species (including non-albicans species), Coccidioides immitis, Blastomyces dermatitidis, Histoplasma species, and other pathogens. The new oral and intravenous formulations of itraconazole have improved bioavailability over the capsules and are suitable for use in a wider range of immunocompromised patients. Itraconazole has been shown to be at least equivalent to the "gold standard" amphotericin B as empirical therapy in patients with hematological malignancies and is promising in the treatment of invasive aspergillosis. Because of its wide spectrum of activity, itraconazole has ideal properties for prophylaxis against fungal infections in neutropenic patients, and the oral solution has proved to be effective in this setting. Voriconazole has demonstrated superiority to amphotericin B deoxycholate against aspergillosis in a randomized trial. Several new triazoles are currently in development, although clinical experience is limited.

Genome-wide Expression Profiling of the Response to Polyene, Pyrimidine, Azole, and Echinocandin Antifungal Agents in Saccharomyces cerevisiae

Antifungal compounds exert their activity through a variety of mechanisms, some of which are poorly understood. Novel approaches to characterize the mechanism of action of antifungal agents will be of great use in the antifungal drug development process. The aim of the present study was to investigate the changes in the gene expression profile of Saccharomyces cerevisiae following exposure to representatives of the four currently available classes of antifungal agents used in the management of systemic fungal infections. Microarray analysis indicated differential expression of 0.8, 4.1, 3.0, and 2.6% of the genes represented on the Affymetrix S98 yeast gene array in response to ketoconazole, amphotericin B, caspofungin, and 5-fluorocytosine (5-FC), respectively. Quantitative real time reverse transcriptase-PCR was used to confirm the microarray analyses. Genes responsive to ketoconazole, caspofungin, and 5-FC were indicative of the drug-specific effects. Ketoconazole exposure primarily affected genes involved in ergosterol biosynthesis and sterol uptake; caspofungin exposure affected genes involved in cell wall integrity; and 5-FC affected genes involved in DNA and protein synthesis, DNA damage repair, and cell cycle control. In contrast, amphotericin B elicited changes in gene expression reflecting cell stress, membrane reconstruction, transport, phosphate uptake, and cell wall integrity. Genes with the greatest specificity for a particular drug were grouped together as drug-specific genes, whereas genes with a lack of drug specificity were also identified. Taken together, these data shed new light on the mechanisms of action of these classes of antifungal agents and demonstrate the potential utility of gene expression profiling in antifungal drug development.

Current management of fungal infections.

The management of superficial fungal infections differs significantly from the management of systemic fungal infections. Most superficial infections are treated with topical antifungal agents, the choice of agent being determined by the site and extent of the infection and by the causative organism, which is usually readily identifiable. One exception is onychomycosis, which usually requires treatment with systemically available antifungals; the accumulation of terbinafine and itraconazole in keratinous tissues makes them ideal agents for the treatment of onychomycosis. Oral candidiasis in immunocompromised patients also requires systemic treatment; oral fluconazole and itraconazole oral solution are highly effective in this setting. Systemic fungal infections are difficult to diagnose and are usually managed with prophylaxis or empirical therapy. Fluconazole and itraconazole are widely used in chemoprophylaxis because of their favourable oral bioavailability and safety profiles. In empirical therapy, lipid-associated formulations of amphotericin-B and intravenous itraconazole are safer than, and at least as effective as, conventional amphotericin-B (the former gold standard). The high acquisition costs of the lipid-associated formulations of amphotericin-B have limited their use.

Central venous catheter-related infections

Central venous catheter-related infections

Antifungal drugs.

IntroductionFungi have been recognized as pathogens for many years. However, the incidence of fungal infections in the pediatric population has increased substantially due to the increased use of broad-spectrum antibiotics, immunosuppressive agents, hyperalimentation products, and central venous catheters in addition to the acquired immunodeficiency syndrome (AIDS) epidemic. The physician involved with the care of children should know the agents effective against these pathogens (Table 1). Amphotericin B has a long history of both efficacy and toxicity because it was the only available systemic agent for many years. With the introduction of ketoconazole, fluconazole, and itraconazole over the past decade, the decision of which agent to use has become much more difficult. Clinical trials are underway to help answer these questions, but until these are completed, the clinician must weigh the risks and benefits of therapy for each patient individually.Amphotericin BBACKGROUNDAmphotericin B is entering its fourth decade as an antifungal agent. Since its introduction in the mid-1950s, it has been the cornerstone of management of systemic fungal infections. Even with the introduction of the azoles, it continues to be the treatment of choice for many conditions.CHEMISTRY, MECHANISM OF ACTIONStreptomyces nodosus, a soil actinomycete, is the source of the amphotericins A and B. Amphotericin B is the commercially available product, and it may contain a small amount (<5%) of amphotericin A.

Antifungal Drugs

Introduction Fungi have been recognized as pathogens for many years. However, the incidence of fungal infections in the pediatric population has increased substantially due to the increased use of broad-spectrum antibiotics, immunosuppressive agents, hyperalimentation products, and central venous catheters in addition to the acquired immunodeficiency syndrome (AIDS) epidemic. The physician involved with the care of children should know the agents effective against these pathogens (Table 1). Amphotericin B has a long history of both efficacy and toxicity because it was the only available systemic agent for many years. With the introduction of ketoconazole, fluconazole, and itraconazole over the past decade, the decision of which agent to use has become much more difficult. Clinical trials are underway to help answer these questions, but until these are completed, the clinician must weigh the risks and benefits of therapy for each patient individually. Amphotericin B BACKGROUND Amphotericin B is entering its fourth decade as an antifungal agent. Since its introduction in the mid-1950s, it has been the cornerstone of management of systemic fungal infections. Even with the introduction of the azoles, it continues to be the treatment of choice for many conditions. CHEMISTRY, MECHANISM OF ACTION Streptomyces nodosus, a soil actinomycete, is the source of the amphotericins A and B. Amphotericin B is the commercially available product, and it may contain a small amount (&amp;lt;5%) of amphotericin A.

Treating systemic fungal infections in AIDS patients

Fungal infections have become one of the major causes of death among immunocompromised patients, particularly patients with AIDS. Accurate and quick diagnosis is difficult; therefore, empirical therapy is often necessary. This scenario is complicated by the fact that most antifungal agents are toxic at the doses used or relatively ineffective against deep-seated mycoses. Because the population of AIDS patients is increasing, physicians will be faced more often with the management of systemic fungal infections. Despite the current bleak prognosis for these patients, several new antigen detection tests are being developed and triazole agents are proving to be effective and less toxic than their predecessors. Many cases of systemic mycoses do result in mortality, but appropriate treatment can both prolong life and improve its quality.

Fluconazole: A New Triazole Antifungal Agent

Fluconazole is a fluorine-substituted, bis-triazole antifungal agent. Its mechanism of action, like that of other azoles, involves interruption of the conversion of lanosterol to ergosterol via binding to fungal cytochrome P-450 and subsequent disruption of fungal membranes. Activity against Aspergillus spp., Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, and Paracoccidioides brasiliensis has been demonstrated in several animal models. Fluconazole can be administered both orally and intravenously. Mean peak serum concentrations achieved in human volunteers after 50 and 100 mg (oral) are 3.1 and 7.0 mumols/L respectively. Protein binding is low (11 percent) and cerebrospinal fluid to serum ratio is 0.58 to 0.89. Serum half-life is long (22-32 hours) and elimination is via renal clearance of unchanged drug. Clinical trials and reports support the use of fluconazole in treatment of candidiasis, particularly oropharyngeal and esophageal infections in immunocompromised hosts. Fluconazole is also approved for initial and suppressive therapy of cryptococcal meningitis. Its role in management of systemic fungal infections will be further defined once results of other comparative trials become available. Fluconazole is well tolerated and its effects on steroidogenesis are markedly less than those of ketoconazole. Antipyrine clearance is not altered at low doses (50 mg) of fluconazole; however, drug interactions with the use of larger doses can be anticipated with agents such as cyclosporin, phenytoin, oral hypoglycemics, and warfarin. Rifampin appears to decrease metabolic clearance of fluconazole. Fluconazole is available as oral and parenteral formulations. Once-daily doses of 100-400 mg are recommended. Dosage reduction is advised for patients with impaired renal function.