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Seminars in Respiratory and Critical... Feb 2020Invasive pulmonary aspergillosis (IPA) remains difficult to diagnose and to treat. Most common risk factors are prolonged neutropenia, hematopoietic stem cell or solid... (Review)
Review
Invasive pulmonary aspergillosis (IPA) remains difficult to diagnose and to treat. Most common risk factors are prolonged neutropenia, hematopoietic stem cell or solid organ transplantation, inherited or acquired immunodeficiency, administration of steroids or other immunosuppressive agents including monoclonal antibodies and new small molecules used for cancer therapy. Critically ill patients are also at high risk of IPA. Clinical signs are unspecific. Early computed tomography (CT)-scan identifies the two main aspects, angioinvasive and airway invasive aspergillosis. Although CT-scan findings are not fully specific they usually allow early initiation of therapy before mycological confirmation of the diagnosis. Role of F-fludeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) is discussed. Confirmation is based on microscopy and culture of respiratory samples, histopathology in case of biopsy, and importantly by detection of galactomannan using an immunoassay in serum and bronchoalveolar lavage fluid. Deoxyribonucleic acid detection by polymerase chain reaction is now standardized and increases the diagnosis yield. Two point of care tests detecting an glycoprotein using a lateral flow assay are also available. Mycological results allow classification into proven (irrespective of underlying condition), probable or possible (for cancer and severely immunosuppressed patients) or putative (for critically ill patients) IPA. New antifungal agents have been developed over the last 2 decades: new azoles (voriconazole, posaconazole, isavuconazole), lipid formulations of amphotericin B (liposomal amphotericin B, amphotericin B lipid complex), echinocandins (caspofungin, micafungin, anidulafungin). Results of main trials assessing these agents in monotherapy or in combination are presented as well as the recommendations for their use according to international guidelines. New agents are under development.
Topics: Amphotericin B; Antifungal Agents; Aspergillus; Bronchoalveolar Lavage Fluid; Galactose; Humans; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Mannans; Microbial Sensitivity Tests; Positron Emission Tomography Computed Tomography; Practice Guidelines as Topic; Radiography, Thoracic; Triazoles
PubMed: 32000286
DOI: 10.1055/s-0039-3401990 -
Infection Dec 2017Because of the high mortality of invasive fungal infections (IFIs), appropriate exposure to antifungals appears to be crucial for therapeutic efficacy and safety. (Review)
Review
INTRODUCTION
Because of the high mortality of invasive fungal infections (IFIs), appropriate exposure to antifungals appears to be crucial for therapeutic efficacy and safety.
MATERIALS AND METHODS
This review summarises published pharmacokinetic data on systemically administered antifungals focusing on co-morbidities, target-site penetration, and combination antifungal therapy.
CONCLUSIONS AND DISCUSSION
Amphotericin B is eliminated unchanged via urine and faeces. Flucytosine and fluconazole display low protein binding and are eliminated by the kidney. Itraconazole, voriconazole, posaconazole and isavuconazole are metabolised in the liver. Azoles are substrates and inhibitors of cytochrome P450 (CYP) isoenzymes and are therefore involved in numerous drug-drug interactions. Anidulafungin is spontaneously degraded in the plasma. Caspofungin and micafungin undergo enzymatic metabolism in the liver, which is independent of CYP. Although several drug-drug interactions occur during caspofungin and micafungin treatment, echinocandins display a lower potential for drug-drug interactions. Flucytosine and azoles penetrate into most of relevant tissues. Amphotericin B accumulates in the liver and in the spleen. Its concentrations in lung and kidney are intermediate and relatively low myocardium and brain. Tissue distribution of echinocandins is similar to that of amphotericin. Combination antifungal therapy is established for cryptococcosis but controversial in other IFIs such as invasive aspergillosis and mucormycosis.
Topics: Antifungal Agents; Drug Interactions; Drug Therapy, Combination; Humans; Mycoses; Tissue Distribution
PubMed: 28702763
DOI: 10.1007/s15010-017-1042-z -
Annals of Internal Medicine Jan 2015Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy.
OBJECTIVE
To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA.
DESIGN
Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479).
SETTING
93 international sites.
PATIENTS
454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed.
MEASUREMENTS
The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures.
RESULTS
Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different.
LIMITATIONS
Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability.
CONCLUSION
Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority.
PRIMARY FUNDING SOURCE
Pfizer.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anidulafungin; Antifungal Agents; Aspergillosis; Double-Blind Method; Drug Therapy, Combination; Echinocandins; Female; Galactose; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Karnofsky Performance Status; Male; Mannans; Middle Aged; Platelet Count; Treatment Outcome; Voriconazole; Young Adult
PubMed: 25599346
DOI: 10.7326/M13-2508 -
Journal of Enzyme Inhibition and... Dec 2022With increasing number of immunocompromised patients as well as drug resistance in fungi, the risk of fatal fungal infections in humans increases as well. The action of... (Review)
Review
With increasing number of immunocompromised patients as well as drug resistance in fungi, the risk of fatal fungal infections in humans increases as well. The action of echinocandins is based on the inhibition of β-(1,3)-d-glucan synthesis that builds the fungal cell wall. Caspofungin, micafungin, anidulafungin and rezafungin are semi-synthetic cyclic lipopeptides. Their specific chemical structure possess a potential to obtain novel derivatives with better pharmacological properties resulting in more effective treatment, especially in infections caused by and species. In this review we summarise information about echinocandins with closer look on their chemical structure, mechanism of action, drug resistance and usage in clinical practice. We also introduce actual trends in modification of this antifungals as well as new methods of their administration, and additional use in viral and bacterial infections.
Topics: Antifungal Agents; Aspergillus; Candida; Cell Wall; Drug Design; Echinocandins; Glucans; Microbial Sensitivity Tests; Molecular Structure
PubMed: 35296203
DOI: 10.1080/14756366.2022.2050224 -
Expert Opinion on Drug Safety Feb 2017Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological... (Review)
Review
Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents. Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure. Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.
Topics: Amphotericin B; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Echinocandins; Humans; Invasive Fungal Infections; Liver Function Tests; Triazoles
PubMed: 27927037
DOI: 10.1080/14740338.2017.1270264 -
Expert Opinion on Drug Safety Sep 2021Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades... (Comparative Study)
Comparative Study Review
INTRODUCTION
Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades have seen a considerable expansion in antifungal drug research, resulting in the clinical development of different classes of antifungal agents with different pharmacologic properties. Among drug-specific characteristics of antifungal agents, renal disposition and nephrotoxicity are important clinical considerations as many patients requiring antifungal therapy have compromised organ functions or are receiving other potentially nephrotoxic medications.
AREAS COVERED
The present article reviews incidence, severity and mechanisms of nephrotoxicity associated with antifungal agents used for prevention and treatment of invasive fungal diseases by discussing distribution, metabolism, elimination and drug-related adverse events in the context of safety data from phase II and III clinical studies.
EXPERT OPINION
Based on the available data amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.
Topics: Animals; Antifungal Agents; Drug Development; Drug Interactions; Humans; Immunocompromised Host; Incidence; Invasive Fungal Infections; Kidney; Renal Insufficiency; Severity of Illness Index
PubMed: 33896310
DOI: 10.1080/14740338.2021.1922667 -
Virulence Dec 2022Antifungal resistance to pathogens increases morbidity and mortality of immunosuppressive patients, an emerging crisis worldwide. Understanding the prevalence and... (Review)
Review
Antifungal resistance to pathogens increases morbidity and mortality of immunosuppressive patients, an emerging crisis worldwide. Understanding the prevalence and antifungal susceptibility pattern is necessary to control and treat candidiasis. We aimed to systematically analyse the susceptibility profiles of species published in the last ten years (December 2011 to December 2021) from mainland China. The studies were collected from PubMed, Google Scholar, and Science Direct search engines. Out of 89 included studies, a total of 44,716 isolates were collected, mainly comprising (49.36%), (21.89%), (13.92%), and (11.37%). The lowest susceptibility was detected for azole group; fluconazole susceptibilities against , and were 93.25%, 91.6%, 79.4%, 77.95%, 76%, 50%, and 0% respectively. Amphotericin B and anidulafungin were the most susceptible drugs for all species. Resistance to azole was mainly linked with mutations in , and genes. Mutation in and in and causing resistance to echinocandins was stated in two studies. Gaps in the studies' characteristics were detected, such as 79.77%, 47.19 %, 26.97%, 7.86%, and 4.49% studies did not mention the mortality rates, age, gender, breakpoint reference guidelines, and fungal identification method, respectively. The current study demonstrates the overall antifungal susceptibility pattern of species, gaps in surveillance studies and risk-reduction strategies that could be supportive in candidiasis therapy and for the researchers in their future studies.
Topics: Humans; Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Candida; Candida albicans; Candida glabrata; Candida parapsilosis; Candida tropicalis; Candidiasis; Echinocandins; Fluconazole; Microbial Sensitivity Tests
PubMed: 36120738
DOI: 10.1080/21505594.2022.2123325 -
Medicina Oral, Patologia Oral Y Cirugia... Mar 2019Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and... (Review)
Review
BACKGROUND
Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation.
MATERIAL AND METHODS
Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library.
RESULTS
Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides.
CONCLUSIONS
Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.
Topics: Administration, Intravenous; Administration, Oral; Administration, Topical; Amphotericin B; Anidulafungin; Antifungal Agents; Azoles; Candidiasis, Oral; Caspofungin; Clotrimazole; Databases, Factual; Drug Interactions; Echinocandins; Fluconazole; Humans; Miconazole; Nitriles; Nystatin; Pyridines; Triazoles
PubMed: 30818309
DOI: 10.4317/medoral.22978 -
Haematologica Mar 2017The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies...
The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies for various types of infection in patients with hematologic malignancies or hematopoietic stem cell transplantation recipients. Meetings are held every two years since 2005 and evidence-based recommendations are elaborated after evaluation of the literature and discussion among specialists of nearly all European countries. In this manuscript, the ECIL group presents the 2015-update of the recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis. Current data now allow a very strong recommendation in favor of echinocandins for first-line therapy of candidemia irrespective of the underlying predisposing factors. Anidulafungin has been given the same grading as the other echinocandins for hemato-oncological patients. The beneficial role of catheter removal in candidemia is strengthened. guidelines now recommend the use of either voriconazole or isavuconazole for first-line treatment of invasive aspergillosis, while first-line combination antifungal therapy is not routinely recommended. As only few new data were published since the last ECIL guidelines, no major changes were made to mucormycosis recommendations.
Topics: Antifungal Agents; Aspergillosis; Candidiasis, Invasive; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Europe; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Mucormycosis; Treatment Outcome
PubMed: 28011902
DOI: 10.3324/haematol.2016.152900