scholarly journals Review of the Novel Investigational Antifungal Olorofim

2020 ◽  
Vol 6 (3) ◽  
pp. 122 ◽  
Author(s):  
Nathan P. Wiederhold
Keyword(s):  
Fungal Infections ◽  
Case Reports ◽  
Fusarium Species ◽  
Pharmacokinetic Profile ◽  
Outcome Data ◽  
Dimorphic Fungi ◽  
Key Enzyme ◽  
Endemic Fungi ◽  
Invasive Mold Infections

The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.

scholarly journals Current status of in vitro and in vivo antifungal activities of posaconazole

2013 ◽  
Vol 1 (1) ◽  
pp. 18-22
Author(s):  
He Sun ◽  
Xin Su ◽  
Yi Shi
Keyword(s):  
Animal Models ◽  
Broad Spectrum ◽  
Fungal Infections ◽  
Current Status ◽  
Dimorphic Fungi ◽  
Antifungal Activities ◽  
Endemic Fungi ◽  
Yeasts And Molds

Abstract Posaconazole (POS) is a new triazole drug with broad-spectrum in vitro activity against most yeasts and molds such as Candida, Cryptococcus neoformans, Aspergillus, Fusarium and Zygomycetes, as well as certain species of dimorphic fungi and endemic fungi. In immunocompetent or immunocompromised animal models with invasive fungal infections, POS has demonstrated highly effective, broad-spectrum antifungal activities. In vitro and in vivo antifungal activities of POS were superior to those of other azoles against Candida glabrata, Candida krusei, Aspergillus terrus, Fusarium and Zygomycetes. In vivo susceptibility studies have shown promising efficacy of POS against life-threatening fungal infections in animal models with different immune status and infection sites.

Oral Terbinafine: A New Antifungal Agent

1997 ◽  
Vol 31 (4) ◽  
pp. 445-456 ◽  
Author(s):  
Susan M Abdel-Rahman ◽  
Milap C Nahata
Keyword(s):  
Adverse Effects ◽  
Drug Interactions ◽  
Fungal Infections ◽  
Case Reports ◽  
Current Standard ◽  
Open Label ◽  
Double Blind ◽  
Pathogenic Yeast

Objective To review the pharmacology, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage guidelines of terbinafine. Available comparative data of terbinafine and other antimycotic agents are described for understanding the potential role of terbinafine in patient care. Data Sources A MEDLINE search restricted to English language during 1966–1996 and extensive review of journals was conducted to prepare this article. MeSH headings included allylamines, terbinafine, SF 86–327, dermatophytosis, dermatomycosis. Data Extraction The data on pharmacokinetics, adverse effects, and drug interactions were obtained from open-label and controlled studies and case reports. Controlled single- or double-blind studies were evaluated to describe the efficacy of terbinafine in the treatment of various fungal infections. Data Synthesis Terbinafine is the first oral antimycotic in the allylamines class: a fungicidal agent that inhibits ergosterol synthesis at the stage of squalene epoxidation. Terbinafine demonstrates excellent in vitro activity against the majority of dermatophyte species including Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum; less activity is seen against Dematiaceae and the filamentous fungi. It is least active against the pathogenic yeast and this correlates with the relatively poor efficacy against these organisms in vivo. High concentrations of terbinafine are achieved in keratinous tissues, the site of superficial infections, and these concentrations are maintained for up to 3 months. The clinical efficacy of terbinafine against a number of dermatophyte infections exceeds that of the current standard of therapy, griseofulvin. The efficacy of terbinafine may be as good or better than that of the azole antifungals. Additional studies are required to confirm these observations. Terbinafine demonstrates a good safety profile, and relatively few drug interactions have been identified. Conclusions Terbinafine is more effective than the gold standard, griseofulvin, in the treatment of tinea pedis and tinea unguinum, with considerably shorter treatment duration in the latter. It has been proven as effective as griseofulvin in the treatment of tinea capitis, tinea corporis, and tinea cruris. Terbinafine does not appear to offer any advantage in the treatment of nondermatophyte infections; its utility in the treatment of systemic infections has yet to be established. Depending on individual institutional costs, terbinafine may be a front-line drug for some superficial infections responding poorly to the current standard of therapy.

Endemic Fungi Presenting as Community-Acquired Pneumonia: A Review

2020 ◽  
Vol 41 (04) ◽  
pp. 522-537
Author(s):  
Marwan M. Azar ◽  
Joshua Malo ◽  
Chadi A. Hage
Keyword(s):  
Histoplasma Capsulatum ◽  
Fungal Infections ◽  
Treatment Strategies ◽  
Community Acquired Pneumonia ◽  
Land Utilization ◽  
Coccidioides Posadasii ◽  
Dimorphic Fungi ◽  
Pulmonary Histoplasmosis ◽  
Diagnostic Modalities ◽  
Endemic Fungi

AbstractIn endemic areas, dimorphic fungal infections due to Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides posadasii/immitis account for up to 30% of cases of community-acquired pneumonia. Because respiratory manifestations are often indistinguishable from common bacterial causes of pneumonia, the diagnosis of pulmonary histoplasmosis, blastomycosis, and coccidioidomycosis is often delayed and associated with antibiotics overuse. In addition to being highly endemic to certain regions of North America, dimorphic fungi have global significance due to established areas of endemicity in all six inhabited continents, an increasingly interconnected world of travelers and transported goods, and a changing epidemiology as a result of global heating and anthropomorphic land utilization. In this review, we discuss the epidemiology, pathogenesis, clinical presentation, diagnostic modalities, and treatment strategies for histoplasmosis, blastomycosis, and coccidioidomycosis.

scholarly journals In Vitro Activity of Novel Antifungal Olorofim against Filamentous Fungi and Comparison to Eight Other Antifungal Agents

2021 ◽  
Vol 7 (5) ◽  
pp. 378
Author(s):  
Ourania Georgacopoulos ◽  
Natalie S. Nunnally ◽  
Eric M. Ransom ◽  
Derek Law ◽  
Mike Birch ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Fusarium Species ◽  
Geometric Mean ◽  
Treatment Options ◽  
Antifungal Susceptibility ◽  
Dihydroorotate Dehydrogenase ◽  
Drug Classes

Olorofim is a novel antifungal drug that belongs to the orotomide drug class which inhibits fungal dihydroorotate dehydrogenase (DHODH), thus halting pyrimidine biosynthesis and ultimately DNA synthesis, cell growth and division. It is being developed at a time when many invasive fungal infections exhibit antifungal resistance or have limited treatment options. The goal of this study was to evaluate the in vitro effectiveness of olorofim against a large collection of recently isolated, clinically relevant American mold isolates. In vitro antifungal activity was determined for 246 azole-susceptible Aspergillus fumigatus isolates, five A. fumigatus with TR34/L98H-mediated resistance, 19 Rhizopus species isolates, 21 Fusarium species isolates, and one isolate each of six other species of molds. Olorofim minimum inhibitory concentrations (MICs) were compared to antifungal susceptibility testing profiles for amphotericin B, anidulafungin, caspofungin, isavuconazole, itraconazole, micafungin, posaconazole, and voriconazole. Olorofim MICs were significantly lower than those of the echinocandin and azole drug classes and amphotericin B. A. fumigatus wild type and resistant isolates shared the same MIC50 = 0.008 μg/mL. In non-Aspergillus susceptible isolates (MIC ≤ 2 μg/mL), the geometric mean (GM) MIC to olorofim was 0.54 μg/mL with a range of 0.015–2 μg/mL. Olorofim had no antifungal activity (MIC ≥ 2 μg/mL) against 10% of the collection (31 in 297), including some isolates from Rhizopus spp. and Fusarium spp. Olorofim showed promising activity against A. fumigatus and other molds regardless of acquired azole resistance.

scholarly journals Antifungal Combinations in Dermatophytes

2021 ◽  
Author(s):  
Lucia Brescini ◽  
Simona Fioriti ◽  
Gianluca Morroni ◽  
Francesco Barchiesi
Keyword(s):  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Case Reports ◽  
Antifungal Susceptibility ◽  
Calcineurin Inhibitors ◽  
Clinical Results ◽  
In Vitro Studies ◽  
Superficial Infection

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations in dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies, and 31 articles referring to case reports/clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts/essential oils, calcineurin inhibitors, peptides, disinfectant agents and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e.: azole [mainly itraconazole], terbinafine or griseofulvin) plus a topical medication (i.e.: azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful in accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available as far, it is desirable to continue the research in this field.

Update on Drug Interactions with Azole Antifungal Agents

1998 ◽  
Vol 32 (9) ◽  
pp. 915-928 ◽  
Author(s):  
Ben M Lomaestro ◽  
Michelle Ann Piatek
Keyword(s):  
Drug Interactions ◽  
Clinical Relevance ◽  
Antimicrobial Agents ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Case Reports ◽  
Improve Patient Care ◽  
Double Blind ◽  
Medline Search

OBJECTIVE: T o review and update the incidence, mechanism, and clinical relevance of drug interactions with itraconazole, ketoconazole, and fluconazole. DATA SOURCES: Literature was identified by MEDLINE search (from January 1990 to May 1997) using the name of each antifungal and the term “interaction” as MeSH headings. Abstracts were identified by literature citation and by review of Interscience Conference on Antimicrobial Agents and Chemotherapy from 1995 to 1996. STUDY SELECTION: Randomized, controlled, double-blind studies were emphasized; however, uncontrolled studies and case reports were also included. In vitro data were selected from literature review and citations. DATA EXTRACTION: Data were evaluated with respect to study design, clinical relevance, magnitude of interaction, and recommendations provided. DATA SYNTHESIS: The incidence of fungal infections and consequent azole antifungal usage continues to increase. By virtue of their antifungal mechanism (i.e., inhibition of cytochrome P450 fungal enzyme systems), azoles have been investigated and implicated in several drug interactions. The magnitude of interactions can vary from trivial to potentially fatal, and also vary with specific azole and interactant. CONCLUSIONS: The azole antifungal agents represent a commonly used class of agents with a broad range of potential interactions. Recent data have increased our understanding of drug-drug interactions with azoles. Pharmacists are in a unique position to identify these interactions and to intervene to decrease their morbidity and improve patient care.

Voriconazole: A Novel Antifungal

2003 ◽  
Vol 19 (2) ◽  
pp. 97-108
Author(s):  
Shana M Gunderson ◽  
Rupali Jain ◽  
Larry H Danziger
Keyword(s):  
Clinical Trials ◽  
Case Reports ◽  
Package Insert ◽  
Published Data ◽  
Candida Spp ◽  
Dimorphic Fungi ◽  
In Vitro Susceptibility ◽  
Aspergillus Infection

Objective: To review the published in vitro, in vivo, and clinical data and FDA background documents that led to the approval of voriconazole. Data Sources: Articles were identified by the referenced package insert and by a MEDLINE search (1966–October 2002) using the terms voriconazole, azole antifungal, aspergillosis, and UK-109, 496. Additionally, journal Web sites and abstracts from major infectious disease meetings were researched to obtain newly published data. Study Selection: All animal and human data published in journals, abstracts, and FDA background documentation were used. The only in vitro susceptibility testing studies used were those that incorporated a large number of fungal isolates. Data Synthesis: Voriconazole is a novel monotriazole antifungal agent that inhibits the fungal cytochrome P450–mediated 14 α-lanosterol demethylation. In vitro susceptibility studies, in vivo clinical trials, and case reports have shown potent activity against various Aspergillus spp., Scedosporium, and Fusarium. Additionally, voriconazole has shown in vitro activity against dimorphic fungi and yeast, including Candida spp. and Cryptococcus neoformans. The efficacy of voriconazole has been evaluated in 4 clinical trials. The clinical studies indicate that it is at least as effective as amphotericin B for the treatment of acute invasive aspergillus infection. The most common adverse effects in clinical trials included visual disturbances, rash, and elevated liver function tests. Voriconazole is metabolized by CYP2C19, CYP2C9, and CYP3A4 and thus causes multiple serious drug–drug interactions. Conclusions: Voriconazole provides an advance in therapy for the treatment of acute invasive aspergillus infection.

Itraconazole in Antifungal Therapy

1992 ◽  
Vol 26 (4) ◽  
pp. 502-509 ◽  
Author(s):  
John D. Cleary ◽  
Jerry W. Taylor ◽  
Stanley W. Chapman
Keyword(s):  
English Language ◽  
Rating Scale ◽  
Fungal Infections ◽  
Case Reports ◽  
Data Extraction ◽  
Pharmacokinetic Profile ◽  
Study Selection ◽  
Primary Literature ◽  
Primary Focus ◽  
Immunocompromised Hosts

OBJECTIVE: This overview compares and contrasts the pharmacotherapy of itraconazole with that of other antifungal agents. DATA SOURCES: Primary literature on itraconazole was identified through a medical literature search from 1976 through 1991. This search included journal articles, abstracts, conference proceedings, and reports of animal and human research published in the English language. STUDY SELECTION: All primary literature was reviewed regardless of the study design or outcome. Literature evaluations of efficacy were ranked using a literature rating scale (Dalen JE, Hirsh J. Arch Intern Med 1986;146:462–72), which was slightly modified to include case reports and observations. DATA EXTRACTION: All data were collected and represented with a primary focus on itraconazole's mechanism of action, pharmacokinetics, clinical efficacy in systemic mycotic infections, drug interactions, and adverse reactions. All articles were referenced in the final data presentation unless grouped data had been accurately reviewed and published. DATA SYNTHESIS: Despite the paucity of controlled comparative trials with itraconazole in patients with deep mycoses, results on efficacy are encouraging. It is still unclear what role itraconazole will have in the prophylaxis of fungal infections in immunocompromised hosts. The favorable pharmacokinetic profile permits once- or twice-daily administration and itraconazole appears to be safe and well tolerated. CONCLUSIONS: Itraconazole should prove to be a useful replacement for ketoconazole on hospital formularies. This recommendation is based on itraconazole's greater apparent safety and efficacy. Reevaluation of this agent will be necessary upon the release of newer imidazoles and triazoles.

scholarly journals Antifungal Combinations in Dermatophytes

2021 ◽  
Vol 7 (9) ◽  
pp. 727
Author(s):  
Lucia Brescini ◽  
Simona Fioriti ◽  
Gianluca Morroni ◽  
Francesco Barchiesi
Keyword(s):  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Case Reports ◽  
Antifungal Susceptibility ◽  
Calcineurin Inhibitors ◽  
Clinical Results ◽  
In Vitro Studies ◽  
Superficial Infection

Dermatophytes are the most common cause of fungal infections worldwide, affecting millions of people annually. The emergence of resistance among dermatophytes along with the availability of antifungal susceptibility procedures suitable for testing antifungal agents against this group of fungi make the combinatorial approach particularly interesting to be investigated. Therefore, we reviewed the scientific literature concerning the antifungal combinations against dermatophytes. A literature search on the subject performed in PubMed yielded 68 publications: 37 articles referring to in vitro studies and 31 articles referring to case reports or clinical studies. In vitro studies involved over 400 clinical isolates of dermatophytes (69% Trichophyton spp., 29% Microsporum spp., and 2% Epidermophyton floccosum). Combinations included two antifungal agents or an antifungal agent plus another chemical compound including plant extracts or essential oils, calcineurin inhibitors, peptides, disinfectant agents, and others. In general, drug combinations yielded variable results spanning from synergism to indifference. Antagonism was rarely seen. In over 700 patients with documented dermatophyte infections, an antifungal combination approach could be evaluated. The most frequent combination included a systemic antifungal agent administered orally (i.e., terbinafine, griseofulvin, or azole—mainly itraconazole) plus a topical medication (i.e., azole, terbinafine, ciclopirox, amorolfine) for several weeks. Clinical results indicate that association of antifungal agents is effective, and it might be useful to accelerate the clinical and microbiological healing of a superficial infection. Antifungal combinations in dermatophytes have gained considerable scientific interest over the years and, in consideration of the interesting results available so far, it is desirable to continue the research in this field.

Significance of In-Vitro and In-Vivo Correlation in Drug Delivery System

2018 ◽  
Vol 4 (4) ◽  
pp. 523-531
Author(s):  
Hina Mumtaz ◽  
Muhammad Asim Farooq ◽  
Zainab Batool ◽  
Anam Ahsan ◽  
Ashikujaman Syed
Keyword(s):  
Dosage Form ◽  
Pharmaceutical Preparations ◽  
Pharmacokinetic Profile ◽  
In Vitro Dissolution ◽  
Time Saving ◽  
Pharmaceutical Dosage Form ◽  
Short Period ◽  
Form Development

The main purpose of development pharmaceutical dosage form is to find out the in vivo and in vitro behavior of dosage form. This challenge is overcome by implementation of in-vivo and in-vitro correlation. Application of this technique is economical and time saving in dosage form development. It shortens the period of development dosage form as well as improves product quality. IVIVC reduce the experimental study on human because IVIVC involves the in vivo relevant media utilization in vitro specifications. The key goal of IVIVC is to serve as alternate for in vivo bioavailability studies and serve as justification for bio waivers. IVIVC follows the specifications and relevant quality control parameters that lead to improvement in pharmaceutical dosage form development in short period of time. Recently in-vivo in-vitro correlation (IVIVC) has found application to predict the pharmacokinetic behaviour of pharmaceutical preparations. It has emerged as a reliable tool to find the mode of absorption of several dosage forms. It is used to correlate the in-vitro dissolution with in vivo pharmacokinetic profile. IVIVC made use to predict the bioavailability of the drug of particular dosage form. IVIVC is satisfactory for the therapeutic release profile specifications of the formulation. IVIVC model has capability to predict plasma drug concentration from in vitro dissolution media.

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