This is one of the first studies to report on therapeutic drug monitoring (TDM) of posaconazole (PCZ) for antifungal prophylaxis in patients with acute myelogenous leukaemia or myelodysplastic ...syndrome outside of the rigours of clinical licencing trials. A number of factors have been identified or proposed as causing poor oral absorption of PCZ. Putative PCZ concentrations have been recommended for TDM (0.5μg/mL or 0.7μg/mL). In this study, 19 (90.5%) of 21 patients failed to reach the higher putative target of 0.7μg/mL, and 16 patients (76.2%) failed to reach the lower target of 0.5μg/mL. Increasing the dose did not help four of six patients reach target concentrations. Three of the patients developed ‘proven’ or ‘possible’ fungal infections, all with PCZ concentrations <0.5μg/mL. Use of acid-suppressing agents appears to explain some of the poor absorption. TDM of PCZ is warranted in patients receiving this orally administered agent.
Fungal echinocandin resistance Walker, Louise A.; Gow, Neil A.R.; Munro, Carol A.
Fungal genetics and biology,
February 2010, 2010-Feb, 2010-02-00, 20100201, Letnik:
47, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The echinocandins are the newest class of antifungal agents in the clinical armory. These secondary metabolites are non-competitive inhibitors of the synthesis of β-(1,3)-glucan, a major structural ...component of the fungal cell wall. Recent work has shown that spontaneous mutations can arise in two hot spot regions of Fks1 the target protein of echinocandins that reduce the enzyme’s sensitivity to the drug. However, other strains have been isolated in which the sequence of FKS1 is unaltered yet the fungus has decreased sensitivity to echinocandins. In addition it has been shown that echinocandin-treatment can induce cell wall salvage mechanisms that result in the compensatory upregulation of chitin synthesis in the cell wall. This salvage mechanism strengthens cell walls damaged by exposure to echinocandins. Therefore, fungal resistance to echinocandins can arise due to the selection of either stable mutational or reversible physiological alterations that decrease susceptibility to these antifungal agents.
Arthropods can produce a wide range of antifungal compounds, including specialist proteins, cuticular products, venoms and haemolymphs. In spite of this, many arthropod taxa, particularly eusocial ...insects, make use of additional antifungal compounds derived from their mutualistic association with microbes. Because multiple taxa have evolved such mutualisms, it must be assumed that, under certain ecological circumstances, natural selection has favoured them over those relying upon endogenous antifungal compound production. Further, such associations have been shown to persist versus specific pathogenic fungal antagonists for more than 50 million years, suggesting that compounds employed have retained efficacy in spite of the pathogens' capacity to develop resistance. We provide a brief overview of antifungal compounds in the arthropods' armoury, proposing a conceptual model to suggest why their use remains so successful. Fundamental concepts embedded within such a model may suggest strategies by which to reduce the rise of antifungal resistance within the clinical milieu.
Recurrent vulvovaginal candidiasis Sobel, Jack D., MD
American journal of obstetrics and gynecology,
2016, January 2016, 2016-Jan, 2016-01-00, 20160101, Letnik:
214, Številka:
1
Journal Article
Recenzirano
Recurrent vulvovaginal candidiasis (RVVC) is a common cause of significant morbidity in women in all strata of society affecting millions of women worldwide. Previously, RVVC occurrence was limited ...by onset of menopause but the widespread use of hormone replacement therapy has extended the at-risk period. Candida albicans remains the dominant species responsible for RVVC, however optimal management of RVVC requires species determination and effective treatment measures are best if species-specific. Considerable progress has been made in understanding risk factors that determine susceptibility to RVVC, particularly genetic factors, as well as new insights into normal vaginal defense immune mechanisms and their aberrations in RVVC. While effective control of RVVC is achievable with the use of fluconazole maintenance suppressive therapy, cure of RVVC remains elusive especially in this era of fluconazole drug resistance. Vaccine development remains a critical challenge and need.
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Over the past decade, topically applied drug products have experienced extraordinary price increases, due to the shortage of multisource generic drug products. This occurrence is ...mainly related to the underlying challenges evolved in topical bioequivalence documentation. Although there has been continuing regulatory efforts to present surrogate in vitro methods to clinical endpoint studies, there is still a continued need for cost- and time-efficient alternatives that account for product specificities. Hence, this work intended to expose bioequivalence assessment issues for complex topical formulations, and more specifically those related with product efficacy guidance. As a model drug and product, a bifonazole 10 mg/g cream formulation was selected and two different batches of the commercially available Reference Product (RP) were used: RP1 that displayed lower viscosity and RP4 which presented high, but not the highest, viscosity. In vitro human skin permeation testing (IVPT) was carried out and the results were evaluated by means of the traditional bioequivalence assessment approach proposed by the EMA, as well as by the Scaled Average Bioequivalence assessment approach proposed by the FDA. Based on previous experience, there was an expectation of a high level of variability in the results, thus alternative methods to evaluate local drug skin availability were developed. More specifically, an infected skin disease model, where ex vivo human skin was infected and ATP levels were used as a biological marker for monitoring antifungal activity after product application. The results showed that permeation equivalence could not be supported between the different RP batches. In contrast, this statistical difference between the formulation batches was not indicated in the disease model. Nevertheless, in pivotal IVPT studies, the lowest permeant formulation (RP4) evidenced a higher antifungal in vitro activity as reported by the lower levels of ATP. A critical appraisal of the results is likewise presented, focusing on an outlook of the real applicability of the regulatory guidances on this subject.
Anidulafungin: A Novel Echinocandin Vazquez, Jose A.; Sobel, Jack D.
Clinical infectious diseases,
07/2006, Letnik:
43, Številka:
2
Journal Article
Recenzirano
Until recently, the treatment available for serious fungal infections was composed of amphotericin B and azoles, and each class demonstrated significant limitations. Echinocandins are a new class of ...drugs that have shown promising results in treating a variety of fungal infections. of these, anidulafungin is a novel echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It has potent in vitro activity against Aspergillus and Candida species, including those resistant to fluconazole or amphotericin B. Results of several clinical trials indicate that anidulafungin is effective in treating esophageal candidiasis, including azole-refractory disease. The results of a recent study comparing fluconazole versus anidulafungin demonstrated the superiority of anidulafungin in the treatment of candidemia and invasive candidiasis (IC). Studies evaluating the concomitant use of anidulafungin and either amphotericin B, voriconazole, or cyclosporine did not demonstrate significant drug-drug interactions or adverse events. To date, anidulafungin appears to have an excellent safety profile. On the basis of early clinical experience, it appears that anidulafungin will be a valuable asset in the management of serious and difficult-to-treat fungal infections.
Voriconazole, a broad-spectrum antifungal drug used to prevent and treat invasive fungal infections, shows complex pharmacokinetics and is primarily metabolised by various CYP enzymes. An adequate ...unbound antibiotic concentration-time profile at the target-site of an infection is crucial for effective prophylaxis or therapy success. Therefore, the aim was to evaluate the pharmacokinetics of voriconazole after the approved sequence dosing in healthy volunteers in interstitial space fluid, assessed by microdialysis, and in plasma. Moreover, potential pharmacogenetic influences of CYP2C19 polymorphisms on pharmacokinetics were investigated. The prospective, open-labelled, uncontrolled long-term microdialysis study included 9 healthy male individuals receiving the approved sequence dosing regimen for voriconazole. Unbound voriconazole concentrations were sampled over 84 h in interstitial space fluid of subcutaneous adipose tissue and in plasma and subsequently quantified via high-performance liquid chromatography. For pharmacokinetic data analysis, non-compartmental analysis was used. High interindividual variability in voriconazole concentration-time profiles was detected although dosing was adapted to body weight for the first intravenous administrations. Due to nonlinear pharmacokinetics, target-site exposure of voriconazole in healthy volunteers was found to be highly comparable to plasma exposure, particularly after multiple dosing. Regarding the CYP2C19 genotype-predicted phenotype, the individuals revealed a broad spectrum, ranging from poor to rapid metaboliser status. A strong relation between CYP2C19 genotype-predicted phenotype and voriconazole clearance was identified.
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Abstract Purpose Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary bypass device that is used to temporarily support the most critically ill of patients with respiratory and/or cardiac ...failure. Infection and its sequelae may be an indication for ECMO or infections may be acquired while on ECMO and are associated with a mortality >50%. Effective therapy requires optimal dosing. However, optimal dosing can be different in patients on ECMO because the ECMO circuit can alter drug pharmacokinetics. This review assessed the current literature for pharmacokinetic data and subsequent dosing recommendations for anti-infective drugs in patients on ECMO. Methods We searched the PubMed and Embase databases (1965 to February 2016) and included case reports, case series, or studies that provided pharmacokinetic data for anti-infective drugs including antibiotics, antifungals, and antivirals being used to treat patients of all age groups on ECMO. Pharmacokinetic parameters and dosing recommendations based on these data are presented. Findings The majority of data on this topic comes from neonatal studies of antibiotics from the 1980s and 1990s. These studies generally demonstrate a larger volume of distribution due to ECMO and therefore higher doses are needed initially. More adult data are now emerging, but with a predominance of case reports and case series without comparison with critically ill controls. The available pharmacokinetic analyses do suggest that volume of distribution and clearance are unchanged in the adult population, and therefore dosing recommendations largely remain unchanged. There is a lack of data on children older than 1 year of age. The data support the importance of therapeutic drug monitoring when available in this population of patients. Implications This review found reasonably robust dosing recommendations for some drugs and scant or no data for other important anti-infectives. In order to better determine optimal dosing for patients on ECMO, a systematic approach is needed. Approaches that combine ex vivo ECMO experiments, animal studies, specialized pharmacokinetic modeling, and human clinical trials are being developed.
Blastomycosis Mazi, Patrick B; Rauseo, Adriana M; Spec, Andrej
Infectious disease clinics of North America,
06/2021, Letnik:
35, Številka:
2
Journal Article
Recenzirano
Blastomycosis is the fungal disease caused by thermally dimorphic fungi in the genus Blastomyces, with B dermatitidis complex causing most cases. It is considered hyperendemic in areas adjacent to ...the Great Lakes and along the St. Lawrence, Mississippi, and Ohio rivers, but definitive geographic distribution of blastomycoses remains obscure. Clinical presentation is variable. Disseminated blastomycosis with extrapulmonary manifestations is more common in immunosuppressed individuals. Culture positivity is required for definitive diagnosis, but compatible histology is often sufficient for presumptive diagnosis and initiation of treatment. Treatment should be provided to all symptomatic cases to prevent progression or recurrence.
Highlights • Subtherapeutic voriconazole (VCZ) concentrations are common in clinical practice. • The CYP2C19*17 allele is associated with increased VCZ metabolism. • VCZ doses to achieve target ...levels are higher in CYP2C19*17 carriers. • CYP2C19 genotyping can predict VCZ exposure/dose to achieve effective levels.
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