Medication
Targeted Treatment of Chronic Pulmonary Aspergillosis Voriconazole Isavuconazole Itraconazole Liposomal Amphotericin B Posaconazole ECIL-6 (61) ESCMID (60) AII AII BII IDSA (83) Preferred Open in a separate window
Procedures
Antifungal Therapy for Invasive Aspergillosis. Amphotericin B (AmB), a polyene antibiotic that previously was used to treat this condition, has produced variable responses and serious adverse effects. Current treatment options utilize different azole compounds, lipid formulations of AmB, and echinocandins.
What medications are used to treat chronic pulmonary aspergillosis?
The drug is effective in treating invasive candidiasis and aspergillosis. It has emerged as an effective agent in the treatment of invasive pulmonary aspergillosis (25).
What is the best antibiotic for aspergillosis?
For example, voriconazole has emerged as the preferred treatment for invasive pulmonary aspergillosis. This notwithstanding, conventional amphotericin B remains a useful agent for the treatment of paediatric fungal infections.
How effective is amoxicillin for pulmonary aspergillosis?
Is amphotericin B effective in the treatment of pulmonary aspergillosis?
What antifungal medications are used for pulmonary aspergillosis?
Antifungal medications. These drugs are the standard treatment for invasive pulmonary aspergillosis. The most effective treatment is a newer antifungal drug, voriconazole (Vfend). Amphotericin B is another option. All antifungal drugs can have serious side effects, including kidney and liver damage.
What azole antifungal agent is the most appropriate choice for treatment of aspergillosis?
Itraconazole is the only azole at present that may be considered for primary prophylaxis against aspergillosis (147).
Which antifungal drugs are active against Aspergillus organisms?
However, the triazoles' spectrum of activity is somewhat limited. Fluconazole is active mainly against Candida albicans and Cryptococcus neoformans. Itraconazole is most active against Aspergillus spp. and has greater activity than fluconazole against resistant strains of Candida spp.
What new class of antifungals treat Aspergillus?
Two newer agents, voriconazole and posaconazole, are more widely used for these infections, especially in highly immunocompromised patients. Voriconazole has become the first-line antifungal drug for treatment of invasive aspergillosis due to Aspergillus fumigatus.
Is fluconazole effective for aspergillosis?
The newer imidazoles such as itraconazole and fluconazole have fewer side effects than ketoconazole. These drugs may be effective in eliminating aspergillus from the tracheobronchial tree and help in reduction in the dose of corticosteroids needed for control [12, 13].
Can itraconazole treat aspergillosis?
Itraconazole can be used for the treatment of chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis (ABPA) (5).
Which is better fluconazole or itraconazole?
Conclusion: Itraconazole was found to be more effective in the treatment of vulvovaginal candidiasis compared to fluconazole with high cure and low relapse rate.
What are the three types of antifungal drugs?
The three major groups of antifungal agents in clinical use, azoles, polyenes, and allylamine/thiocarbamates, all owe their antifungal activities to inhibition of synthesis of or direct interaction with ergosterol. Ergosterol is the predominant component of the fungal cell membrane (104).
Which is the best antifungal drug?
Amphotericin B, an effective but relatively toxic drug, has long been the mainstay of antifungal therapy for invasive and serious mycoses. However, newer potent and less toxic triazoles and echinocandins are now often recommended as first-line drugs for many invasive fungal infections.
What are the types of antifungal agents?
The four main classes of antifungal drugs are the polyenes, azoles, allylamines and echinocandins.
Which of the following is antifungal agent?
The azole antifungal agents have five-membered organic rings that contain either two or three nitrogen molecules (the imidazoles and the triazoles respectively). The clinically useful imidazoles are clotrimazole, miconazole, and ketoconazole. Two important triazoles are itraconazole and fluconazole.
What antifungal is stronger than fluconazole?
"Itraconazole is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic hematopoietic stem-cell transplantation." the authors write. "Except for gastrointestinal side effects, itraconazole is well tolerated."
What is the name of the drug that is used to treat pulmonary aspergillosis?
10. Caillot D, Bassaris H, McGeer A, et al. Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS. Clin Infect Dis. 2001;33:e83-e90.
How to treat invasive aspergillosis?
2 Pending diagnosis, antifungal treatment should be initiated immediately in patients with strongly suspected invasive aspergillosis. IV or oral voriconazole is the primary therapy for most patients with invasive aspergillosis. 2 Parenteral voriconazole should be administered at a dosage of 6 mg/kg IV for day 1, followed by 4 mg/kg IV every 12 hours. 2 Oral voriconazole may be administered at a dosage of 200 mg every 12 hours. For seriously ill patients, the parenteral formulation should be used. Primary alternative therapies including L-AmB should be considered. Salvage therapy options include ABLC, caspofungin, micafungin, posaconazole, and itraconazole (see TABLE 2 for dosages).
How much voriconazole is used for aspergillosis?
Respective dosages for voriconazole and AmB were 4 mg/kg twice daily IV and 1 to 1.5 mg/kg daily IV. Following a minimum 7-day treatment period of parenteral voriconazole, the protocol permitted a switch to oral voriconazole 200 mg twice daily. 7 The median duration of therapy for AmB and voriconazole, respectively, was 10 days and 77 days. Patients unresponsive or intolerant to the study drug were administered other licensed antifungal agents.
What is Amb antibiotic?
Amphotericin B (AmB), a polyene antibiotic that previously was used to treat this condition, has produced variable responses and serious adverse effects. Current treatment options utilize different azole compounds, lipid formulations of AmB, and echinocandins.
What is the name of the polyene antibiotic?
Polyene Antibiotic (Amphotericin B): Amphotericin B (AmB) is a polyene (containing multiple double bonds) macrolide antibiotic originally isolated from a Streptomyces species. 4 It binds to ergosterol, a component of the fungal cell membrane.
How do azoles affect ergosterol synthesis?
Azoles (Voriconazole, Posaconazole, Itraconazole): Chemically, azoles are triazole derivatives. These agents act by inhibiting fungal sterol-14-alpha-demethylase , a cytochrome-dependent enzyme associated with ergosterol synthesis. Inhibition of this enzyme enables the accumulation of methylsterol, thus impairing other cellular functions. 4 Fungal cells acquire resistance to azoles by 1) increasing production of the target enzyme, 2) introducing mutations in the gene encoding sterol-14-alpha-demethylase, and 3) producing drug efflux proteins. As explained below, azoles can interfere with CYP-mediated metabolism of other drugs, resulting in drug-drug interactions and significant AEs. 4
What organs can be affected by invasive aspergillosis?
If left untreated, the disease can spread into other vital organs, including the brain and the heart.
What is amphotericin B used for?
It is used to treat a number of fungal infections, including IA, mucormycosis, cryptococcal meningitis, and invasive candidiasis. Investigation of liposomal amphotericin B (L-AmB) has shown a positive correlation between in-vitro susceptibility testing and positive clinical outcomes in patients with IA. In a study of 29 patients with IA following SCT, all six patients with a mean inhibitory concentration (MIC) of <2 mg/L to L-AmB survived, while 22/23 patients with isolates with an MIC ≥2 mg/L died [53]. Another study using a pharmacokinetic-pharmacodynamic (PK-PD) model simulating free amphotericin B serum concentrations found the estimated breakpoints for susceptibility, intermediate susceptibility, and resistance for A. fumigatusto be ≤0.5, 1, and ≥2, respectively [54]. Overall, L-AmB remains sensitive against most Aspergillusspp., although increasing rates of elevated MICs >2 have recently been reported for Aspergillus fumigatus(>40% of isolates MICs >2), and Apergillus flavus(>80% of isolates) [55]. Aspergillus terreusshows intrinsic resistance [56].
Where is the 3Section of Infectious Diseases and Tropical Medicine and Division of Pulmonology located?
3Section of Infectious Diseases and Tropical Medicine and Division of Pulmonology, Medical University of Graz, Graz 8036, Austria
What are the effects of triazoles on fungi?
Broad-spectrum triazoles inhibit ergosterol synthesis in the membrane sterol of fungi leading to cell death. Several of the newer-generation triazoles, particularly voriconazole and isavuconazole, are appealing alternatives to the use of L-AmB. While azole resistant clinical Aspergillusisolates have been reported from many parts of the world, resistance rates remain low in most settings, not influencing primary choice of antifungal therapy [62]. Pharmacokinetics of a broad spectrum differ significantly, and intra- and interpatient variability of plasma levels, but also variability in intracellular concentrations remains an issue [63]. Therapeutic drug monitoring (TDM) may be required to achieve efficacy and also to avoid toxicity in particular for voriconazole in treatment and prophylactic settings [64,65,66], but also for posaconazole oral suspension (efficacy only) [67,68,69], which is associated with significantly lower posaconazole plasma concentrations when compared to tablet or IV formulations [70], while there are currently no recommendations of TDM for isavuconazole [63,71].
How many patients were randomly assigned to voriconazole?
In a large randomized, double-blind, placebo-controlled multicenter trial, 454 patients with hematological malignancies and suspected or documented IA were randomly assigned to primary treatment with voriconazole and anidulafungin or voriconazole and placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed. Mortality rates at 6 weeks were 19.3% for combination therapy and 27.5% for monotherapy (difference, −8.2 percentage points [95% CI, −19.0 to 1.5]; p= 0.087). In a post hoc analysis of 218 patients who had IA diagnosis established by radiographic findings and galactomannan positivity, 6-week mortality was lower in combination therapy than monotherapy (15.7% vs. 27.3%; difference, −11.5 percentage points [CI, −22.7 to −0.4]; p= 0.037) [83]. While the study was insufficiently powered to detect a difference in the main analysis, results indicate that combination therapy may be associated with better survival [83].
What is CPA in lung?
CPA is characterized by slowly progressive destruction of lung parenchyma, in the form of single of multiple cavities, nodules, infiltrates, or fibrosis, with or without an aspergilloma [2]. Due to the nonspecific and indolent presentation, diagnosis may be delayed or missed, resulting in severe morbidity. Diagnostic criteria include presence of respiratory and/or constitutional symptoms for at least 3 months, suggestive abnormalities on imaging, and serological or microbiological evidence of Aspergillus[44]. For mycological evidence, Aspergillusspecific IgG has a central role, while biomarkers and tests for invasive growth, including GM, are mostly negative [44,45].
Is voriconazole approved for IA?
Voriconazole, available in tablet, IV, and suspension formulation, is approved for the treatment of IA, Candidainfections, scedosporiosis, and furasiosis. A prospective randomized trial in patients with underlying hematologic disease and IA investigated 144 patients randomized to receive IV voriconazole and 133 patients randomized to receive IV amphotericin B deoxycholate. The primary outcome was partial or complete response to therapy. At twelve weeks, 52.8% of patients met the primary outcome in the voriconazole group (a complete response of 20.8% and a partial response of 31.9%) versus 31.6% in the amphotericin group (a complete response of 16.5% and a partial response of 15.0%), a statistically significant difference. At 12 weeks, the survival rate was 70.8% in the voriconazole group versus 57.9% in the amphotericin group, which again was statistically significant. In addition, there were fewer drug-related adverse events in the voriconazole group, although side effects to treatment, such as blurry vision and photophobia, were common [72]
Is Posaconazole a refractory drug?
A number of studies have suggest ed that posaconazole, available in delayed-release tablets, oral suspension, and IV formulation, may be an option to treat refractory IA [77]. An open-labeled trial investigated the use of posaconazole as a salvage therapy for the treatment of IA in patients that were refractory or intolerant to other treatment, of which 80% of patients had underlying hematologic malignancy. Of 107 patients who received posaconazole oral suspension, 42% had a treatment response compared to 26% of the 86 external control patients (p= 0.006) [78]. In another prospective trial of patients with refractory IA, 53 patients received posaconazole given orally or via an enteral feeding tube, 52 received lipid formulation of amphotericin B (LPD/AMB), and 38 patients received a combination of caspofungin plus LPD/AMB. The primary outcome was clinical improvement or resolution at 12 weeks and over 90% of patients had underlying hematologic malignancy. The primary outcome was met in 40% of patients in the posaconazole group, 8% in the LPD/AMB group, and 11% in the combination group (p< 0.002). At 12 months, 40% of patients died in the posaconazole group compared to 65% in the LPD/AMB group and 68% in the combination group (p< 0.008) [79].
Background
Oral itraconazole and voriconazole are currently recommended in the initial management of chronic pulmonary aspergillosis (CPA). However, only a few studies have compared outcomes with different anti-fungal agents (AFAs) in treating CPA. Herein, we perform a network meta-analysis comparing the efficacy of different AFAs in CPA.
Methods
We searched the PubMed and EmBase databases to identify studies (either randomised-controlled trials [RCTs] or observational) reporting treatment outcomes with AFAs in patients of CPA. The study quality was assessed using the Newcastle-Ottawa scale (NOS).
Results
We found ten studies (718 patients) investigating different AFAs (oral AFAs [n = 5], intravenous AFAs [n = 5]) in the treatment of CPA. There were four RCTs and six observational studies. The studies using oral agents reported long-term outcomes (>12 weeks), while those with intravenous agents provided only short-term outcomes (<6 weeks).
Conclusion
Oral itraconazole may be preferred over other azoles as the initial therapy for CPA. Amongst the intravenous agents, echinocandins and voriconazole may be preferred over amphotericin B. Randomised-controlled trials comparing different AFAs, especially the newer AFAs, are urgently needed.
What is the mainstay of systemic antifungal therapy?
Traditionally, the mainstay of systemic antifungal therapy has been amphotericin B deoxycholate (conventional amphotericin B). Newer agents have been developed to fulfill special niches and to compete with conventional amphotericin B by virtue of having more favourable toxicity profiles. Some agents have displaced conventional amphotericin B for the treatment of specific fungal diseases. For example, voriconazole has emerged as the preferred treatment for invasive pulmonary aspergillosis. This notwithstanding, conventional amphotericin B remains a useful agent for the treatment of paediatric fungal infections. Knowledge of the characteristics of the newer agents is important, given the increasing numbers of patients who are being treated with these drugs. Efforts need to be directed at research aimed at generating paediatric data where these are lacking. The antifungal agents herein described are most often used as monotherapy regimens because there is no uniform consensus on the value of combination therapy, except for specific scenarios.
What is the treatment for systemic fungal infections in children?
Antifungal agents for the treatment of systemic fungal infections in children
Is there a major increase in the number of antifungal agents?
Over the past 15 years, there has been a major increase in the number of available antifungal agents. The newer agents have been evaluated to a lesser degree in children compared with adults (1). The present overview offers a perspective on amphotericin B deoxycholate and the newer antifungal agents, as well as their roles in paediatric antifungal therapy.
Is amphotericin B a parenteral agent?
Amphotericin B products are available as parenteral agents. Newer and more costly (lipid-based) formulations of amphotericin B are increasingly being used in clinical practice (2–7). The major toxicities associated with amphotericin B are nephrotoxicity and infusion-related events (fevers, chills and rigors) (8). The lipid-based products are less nephrotoxic, with comparable efficacy relative to conventional amphotericin B (amphotericin B deoxycholate). The dosing of these agents, indications and body fluid concentrations are shown in Table 1.
Abstract
Introduction: Aspergillus may cause different types of lung infections: invasive, chronic pulmonary or allergic bronchopulmonary aspergillosis. Pharmacological management with antifungals poses as a challenge. Patients diagnosed with pulmonary aspergillosis are complex, as well as the problems associated with antifungal agents.
References (173)
Pneumonia is the commonest nosocomial infection complicating hospital stay, with both non-ventilated hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) occurring frequently amongst patients in intensive care.
Therapeutically Important Antifungal Agents
Treatment Recommendations
Important Clinical Trials
Conclusion
