Endogenous fungal endophthalmitis, involving only the chorioretinal structures or extending to involve the vitreous (vitritis), is a sight-threatening infection requiring early appropriate therapy. ...Endophthalmitis is a relatively frequent complication of candidemia and less commonly occurs in patients who have invasive aspergillosis. Because the eye is a protected compartment, penetration of systemically administered antifungal agents is highly variable. In the posterior segment of the eye, amphotericin B (AmB) achieves very poor concentrations, but fluconazole concentrations are high. Among newer antifungal agents, voriconazole shows the most promise, because therapeutic concentrations for most Candida and Aspergillus species are achieved in the vitreous, and its antifungal activity is broad. In contrast, neither posaconazole nor the 3 echinocandins achieve adequate therapeutic concentrations in the vitreous. For sight-threatening macular involvement and vitritis, intravitreal injection of either AmB or voriconazole is helpful to achieve high local antifungal activity as quickly as possible. We review the available evidence regarding the most appropriate use of antifungal agents for endogenous fungal endophthalmitis, with the emphasis on treatment of infections due to Candida species.
The pharmacokinetics and antifungal activity of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) were assessed in ascites fluid and plasma of critically ill adults ...treated for suspected or proven invasive candidiasis. Ascites fluid was obtained from ascites drains or during paracentesis. The antifungal activity of the echinocandins in ascites fluid was assessed by incubation of Candida albicans and Candida glabrata at concentrations of 0.03 to 16.00 μg/ml. In addition, ascites fluid samples obtained from our study patients were inoculated with the same isolates and evaluated for fungal growth. These patient samples had to be spiked with echinocandins to restore the original concentrations because echinocandins had been lost during sterile filtration. In ascites fluid specimens of 29 patients, echinocandin concentrations were below the simultaneous plasma levels. Serial sampling in 20 patients revealed a slower rise and decline of echinocandin concentrations in ascites fluid than in plasma. Proliferation of C. albicans in ascites fluid was slower than in culture medium and growth of C. glabrata was lacking, even in the absence of antifungals. In CAS-spiked ascites fluid samples, fungal CFU counts moderately declined, whereas spiking with AFG or MFG had no relevant effect. In ascites fluid of our study patients, echinocandin concentrations achieved by therapeutic doses did not result in a consistent eradication of C. albicans or C. glabrata. Thus, therapeutic doses of AFG, MFG, or CAS may result in ascites fluid concentrations preventing relevant proliferation of C. albicans and C. glabrata, but do not warrant reliable eradication.
Voriconazole: A New Triazole Antifungal Agent Saravolatz, Louis D.; Johnson, Leonard B.; Kauffman, Carol A.
Clinical infectious diseases,
03/2003, Letnik:
36, Številka:
5
Journal Article
Recenzirano
The 1990s witnessed an expansion of the antifungal armamentarium to include 2 new azole agents, fluconazole and itraconazole. These agents changed our approach to treating many fungal infections. ...However, neither was an ideal agent. Itraconazole was plagued by absorption problems; fluconazole had a limited spectrum of antifungal activity, and resistance was soon noted in immunosuppressed hosts who received long-term treatment. Second-generation triazole agents have been in development for the past decade. The first of these new agents to receive approval from the US Food and Drug Administration (FDA) is voriconazole, a synthetic derivative of fluconazole. Replacement of one of the triazole rings with a fluorinated pyrimidine and the addition of an α-methyl group resulted in expanded activity, compared with that of fluconazole. The development of voriconazole proceeded primarily because of this broadened antifungal spectrum.
One of the most common causes of illnesses in humans is from respiratory tract infections caused by bacterial, viral or fungal pathogens. Inhaled anti-infective drugs are crucial for the prophylaxis ...and treatment of respiratory tract infections. The benefit of anti-infective drug delivery via inhalation is that it affords delivery of sufficient therapeutic dosages directly to the primary site of infection, while minimizing the risks of systemic toxicity or avoiding potential suboptimal pharmacokinetics/pharmacodynamics associated with systemic drug exposure. This review provides an up-to-date treatise of approved and novel developmental inhaled anti-infective agents, with particular attention to effective strategies for their use, pulmonary pharmacokinetic properties and safety.
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Nepenthes spp. are carnivorous plants that have developed insect capturing traps, evolved by specific modification of the leaf tips, and are able to utilize insect degradation products as nutritional ...precursors. A chitin-induced antifungal ability, based on the production and secretion to the trap liquid of droserone and 5-O-methyldroserone, is described here. Such specific secretion uniquely occurred when chitin injection was used as the eliciting agent and probably reflects a certain kind of defence mechanism that has been evolved for protecting the carnivory-based provision of nutritional precursors. The pitcher liquid containing droserone and 5-O-methyldroserone at 3:1 or 4:1 molar ratio, as well as the purified naphthoquinones, exerted an antifungal effect on a wide range of plant and human fungal pathogens. When tested against Candida and Aspergillus spp., the concentrations required for achieving inhibitory and fungicidal effects were significantly lower than those causing cytotoxicity in cells of the human embryonic kidney cell line, 293T. These naturally secreted 1,4-naphthoquinone derivatives, that are assumed to act via semiquinone enhancement of free radical production, may offer a new lead to develop alternative antifungal drugs with reduced selectable pressure for potentially evolved resistance.
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Combatting the ever-increasing threat from invasive fungal pathogens faces numerous fundamental challenges, including constant human exposure to large reservoirs of species in the ...environment, the increasing population of immunocompromised or immunosuppressed individuals, the unsatisfactory efficacy of current antifungal drugs and their associated toxicity, and the scientific and economic barriers limiting a new antifungal pipeline. DectiSomes represent a new drug delivery platform that enhances antifungal efficacy for diverse fungal pathogens and reduces host toxicity for current and future antifungals. DectiSomes employ pathogen receptor proteins − C-type lectins − to target drug-loaded liposomes to conserved fungal cognate ligands and away from host cells. DectiSomes represent one leap forward for urgently needed effective pan-antifungal therapy. Herein, we discuss the problems of battling fungal diseases and the state of DectiSome development.
Background. Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Recent ...diagnostic improvements may ensure the early diagnosis of potentially invasive fungal disease. Reserving antifungals for this stage may achieve similar survival rates and reduce treatment toxicity and costs. Methods. In this multicenter, open-label, randomized noninferiority trial, we compared an empirical antifungal strategy with a preemptive one. Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Preemptive treatment was defined as treatment of patients who have clinical, imaging, or galactomannan-antigen-assay evidence suggesting fungal disease. First-line antifungal treatment was amphotericin B deoxycholate (1 mg/kg/day) or liposomal amphotericin (3 mg/kg/day), depending on daily renal function. The primary efficacy outcome was the proportion of patients alive at 14 days after recovery from neutropenia. Results. The median duration of neutropenia (neutrophil count, <500 cells/mm3) for the 293 patients enrolled was 18 days (range, 5–69 days). By intention-to-treat analysis, survival was 97.3% with empirical treatment and 95.1% with preemptive treatment. The lower 95% confidence limit for the difference in mortality was −5.9%, which was within the noninferiority margin of −8%. Probable or proven invasive fungal infections were more common among patients who received preemptive treatment than among patients who received empirical treatment (13 of 143 vs. 4 of 150; P<.05 ), and most infections occurred during induction therapy (12 of 73 patients in the preemptive treatment group vs. 3 of 78 patients in the empirical treatment group were infected during induction therapy; P<.01 ). Preemptive treatment did not decrease nephrotoxicity but decreased costs of antifungal therapy by 35%. Conclusions. Preemptive treatment increased the incidence of invasive fungal disease, without increasing mortality, and decreased the costs of antifungal drugs. Empirical treatment may provide better survival rates for patients receiving induction chemotherapy.
Several fungi act as parasites for crops causing huge annual crop losses at both pre- and post-harvest stages. For years, chemical fungicides were the solution; however, their wide use has caused ...environmental contamination and human health problems. For this reason, the use of biofungicides has been in practice as a green solution against fungal phytopathogens. In the context of a more sustainable agriculture, microbial biofungicides have the largest share among the commercial biocontrol products that are available in the market. Precisely, the genus
Bacillus
has been largely studied for the management of plant pathogenic fungi because they offer a chemically diverse arsenal of antifungal secondary metabolites, which have spawned a heightened industrial engrossment of it as a biopesticide. In this sense, it is indispensable to know the wide arsenal that
Bacillus
genus has to apply these products for sustainable agriculture. Having this idea in our minds, in this review, secondary metabolites from
Bacillus
having antifungal activity are chemically and structurally described giving details of their action against several phytopathogens. Knowing the current status of
Bacillus
secreted antifungals is the base for the goal to apply these in agriculture and it is addressed in depth in the second part of this review.
There is a continuous search for more reliable and effective alternatives to control phytopathogens through different strategies. In this context, indole-containing phytoalexins are stimuli-induced ...compounds implicated in plant defense against plant pathogens. However, phytoalexins' efficacy have been limited by fungal detoxifying mechanisms, thus, the research on bioisosteres-based analogs can be a friendly alternative regarding the control of
phytopathogens, but there are currently few studies on it. Thus, as part of our research on antifungal agents, a set of 21 synthetic indole-containing phytoalexin analogs were evaluated as inhibitors against the phyopathogen
. Results indicated that analogs of the
,
-dialkylthiourea,
-dialkyldithiocarbamate and substituted-1,3-thiazolidin-5-one groups exhibited the best docking scores and interaction profiles within the active site of
spp. enzymes. Vina scores exhibited correlation with experimental mycelial growth inhibition using supervised statistics, and this antifungal dataset correlated with molecular interaction fields after CoMFA. Compound
(
-butyl (((3-oxo-1,3-diphenylpropyl)thio)carbonothioyl)-l-tryptophanate), a very active analog against
, exhibited the best interaction with lanosterol 14α-demethylase according to molecular docking, molecular dynamics and molecular mechanic/poisson-boltzmann surface area (MM/PBSA) binding energy performance. After data analyses, information on mycelial growth inhibitors, structural requirements and putative enzyme targets may be used in further antifungal development based on phytoalexin analogs for controlling phytopathogens.
Background. We describe antifungal therapy and management of complications due to Cryptococcus gattii infection in 86 Australian patients followed for at least 12 months. Methods. Patient data from ...culture-confirmed cases (2000–2007) were recorded at diagnosis, 6 weeks, 6 months, and 12 months. Clinical, laboratory, and treatment variables associated with raised intracranial pressure (ICP) and immune reconstitution inflammatory syndrome (IRIS) were determined. Results. Seven of 10 patients with lung infection received amphotericin B (AMB) induction therapy (6 with 5-flucytosine 5-FC for a median of 2 weeks); median duration of therapy including azole eradication therapy was 41 weeks, with a complete/partial clinical response in 78%. For neurologic disease, 88% of patients received AMB, 78% with 5-FC, for a median of 6 weeks. The median total course was 18 months. Nine patients receiving fluconazole induction therapy were reinduced with AMB plus 5-FC for clinical failure. Raised ICP (31 patients) was associated with initial abnormal neurology, and neurologic sequelae and/or death at 12 months (both P = .02); cerebrospinal fluid drains/shunts were placed in 58% of patients and in 64% of 22 patients with hydrocephalus. IRIS developed 2–12 months after starting antifungals in 8 patients, who presented with new/enlarging brain lesions. Risk factors included female sex, brain involvement at presentation, and higher median CD4 counts (all P < .05); corticosteroids reduced cryptococcoma-associated edema. Conclusions. Induction AMB plus 5-FC is indicated for C. gattii neurologic cryptococcosis (6 weeks) and when localized to lung (2 weeks). Shunting was often required to control raised ICP. IRIS presents with cerebral manifestations.
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