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Wiesner-Kiełczewska A, Zagrodzki P, Paśko P. The Impact of Dietary Interventions on the Pharmacokinetics of Antifungal Drugs: A Systematic Review with Meta-analyses. Clin Pharmacokinet 2025:10.1007/s40262-025-01511-6. [PMID: 40347349 DOI: 10.1007/s40262-025-01511-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2025] [Indexed: 05/12/2025]
Abstract
BACKGROUND AND OBJECTIVE Managing food-drug interactions may help to optimize the efficacy and safety of antifungal therapy. This systematic review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines to evaluate how food, beverages, antacids, and mineral supplements influence the pharmacokinetic (PK) parameters or pharmacokinetic/pharmacodynamic (PK/PD) indices of 14 orally administered antifungal drugs. METHODS We considered all studies evaluating the effects of food, beverages, antacids, and mineral supplements on PK parameters and PK/PD indices of oral antifungal drugs for inclusion. We excluded in vitro, in silico, animal studies, reviews, and alcohol-related investigations. Searches were conducted in Medline (via PubMed), Embase, and Cochrane Library from database inception to June 2024. We evaluated the risk of bias using the National Institutes of Health (NIH) tool for before-after studies and the Cochrane tool for parallel and cross-over trials. We performed meta-analyses when two or more studies with comparable designs were available; otherwise, results were summarized qualitatively. RESULTS The review included 73 studies from 68 reports. Only studies investigating the effect of dietary interactions on PK parameters were found. Meta-analyses were conducted for seven antifungal drugs, while qualitative synthesis covered the remaining drugs. Open-label, cross-over studies accounted for 58% of trials, aligning with Food and Drug Administration (FDA) recommendations. A high risk of bias appeared in 33% of studies, while only 7% showed low risk. Among 11 antifungals with food-effect data, seven (64%) exhibited clinically important interactions. High positive food effects (area under the concentration-time curve (AUC) or peak serum concentration (Cmax) increased by > 45%) were seen for griseofulvin, itraconazole capsules and tablets (except rice-based meals), and posaconazole immediate-release tablets and suspension. A moderate positive impact of high-fat meals (AUC or Cmax increased in the range of 35-45%) occurred for ibrexafungerp and oteseconazole. A high negative food effect was observed on the absorption of voriconazole and itraconazole oral suspension or super bioavailable (SUBA) capsules (AUC or Cmax decreased by > 40%). Antacids strongly reduced itraconazole and ketoconazole absorption, while nutritional supplements improved posaconazole bioavailability. Acidic beverages such as Coca Cola substantially enhanced the absorption of itraconazole, ketoconazole, and posaconazole, whereas orange juice significantly reduced itraconazole bioavailability. CONCLUSION Interactions were influenced by such factors as drug physicochemical properties, type of dietary intervention, drug formulation, and patient characteristics. Although the review largely filled the existing gaps in recommendations, we judged the overall quality of evidence as low owing to outdated studies, methodological inconsistencies, and uneven data availability. Further research involving PK/PD indices is needed to link the postprandial changes in the bioavailability of antifungal drugs with their clinical efficacy. OTHER The protocol of the systematic review was registered in March 2024 in the Open Science Framework (OSF) Registries ( https://doi.org/10.17605/OSF.IO/HAVK9 ).
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Affiliation(s)
- Agnieszka Wiesner-Kiełczewska
- Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, św. Łazarza 16, 31-530, Kraków, Poland
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Paweł Zagrodzki
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland
| | - Paweł Paśko
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
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Chhatbar M, Borkhataria C, Patel O, Raichura K, Pethani T, Parmar G, Mori D, Manek R. Enhancing the solubility and bioavailability of itraconazole through pharmaceutical cocrystallization: A promising strategy for drug formulation. J Pharm Sci 2025; 114:103770. [PMID: 40139531 DOI: 10.1016/j.xphs.2025.103770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/19/2025] [Accepted: 03/19/2025] [Indexed: 03/29/2025]
Abstract
Itraconazole, a potent antifungal agent, is classified as a Biopharmaceutics Classification System (BCS) Class II drug, exhibiting high permeability but poor aqueous solubility, which significantly limits its bioavailability and therapeutic efficacy. Conventional solubility enhancement techniques such as salt formation, particle size reduction, and encapsulation have shown limited success due to the drug's non-ionizable nature and pH-dependent solubility. Cocrystallization has emerged as a promising pharmaceutical strategy to address these limitations by modifying the crystal lattice structure through non-covalent interactions with pharmaceutically acceptable co-formers. This study explores the formulation of Itraconazole cocrystals with various co-formers to enhance its solubility, dissolution rate, and micromeritic properties, thereby improving its processability in solid dosage forms. The optimized cocrystal formulation (B16) demonstrated a 2.4-fold increase in solubility in 0.1 N HCl (60.47 ± 2.7 µg/mL) and a 25.77-fold increase in phosphate buffer (pH 6.8, 60.57 ± 5.64 µg/mL) compared to pure Itraconazole. The dissolution rate was also significantly improved, with 40.12% drug release in 120 minutes in acidic medium, compared to 32.65% for pure Itraconazole. Furthermore, pharmacokinetic studies in rats revealed a 2.8-fold increase in AUC (3717.58 ng·h/mL) and a Cmax of 206.86 ng/mL, compared to 88.06 ng/mL for the pure drug. The study further examines the industrial feasibility of cocrystallization as an innovative approach for optimizing poorly soluble drugs in commercial formulations. The results highlight the potential of cocrystal technology in overcoming formulation challenges and advancing the development of more effective and patient-friendly antifungal therapies.
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Affiliation(s)
- Meet Chhatbar
- B K Mody Government Pharmacy College, Rajkot 360003, Gujarat, India
| | | | - Om Patel
- GMERS Medical College, Vadnagar 384355, Gujarat, India
| | - Komal Raichura
- Department of English, Government Polytechnic, Jamnagar 361009, Gujarat, India
| | - Trupesh Pethani
- Department of Pharmaceutical Sciences, Saurashtra University, Rajkot 360005, Gujarat, India
| | - Ghanshyam Parmar
- Department of Pharmacy, Sumandeep Vidyapeeth, Pipariya, Vadodara 391760, Gujarat, India
| | - Dhaval Mori
- B K Mody Government Pharmacy College, Rajkot 360003, Gujarat, India
| | - Ravi Manek
- B K Mody Government Pharmacy College, Rajkot 360003, Gujarat, India
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Gadoya A, Dudhat K, Shah S, Borkhataria C, Pethani T, Shah V, Janbukiya N, Jyotishi S, Ansari J, Dhaval M. Amorphous Solid Dispersion/Salt of Efavirenz: Investigating the Role of Molecular Interactions on Recrystallization and In-vitro Dissolution Performance. AAPS PharmSciTech 2025; 26:89. [PMID: 40102289 DOI: 10.1208/s12249-025-03084-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 03/04/2025] [Indexed: 03/20/2025] Open
Abstract
Efavirenz (EFZ), a BCS (Biopharmaceutical classification system) class-II/IV drug, suffers from low oral bioavailability (40-50%) and significant inter/intra-individual variability due to its low solubility and poor dissolution properties. The present investigation aimed to prepare a stable amorphous system of EFZ to improve its dissolution using the slurry method with various polymers and examine the nature of the interaction between them and its impact on the stability (recrystallization) of the formed systems and their in-vitro dissolution performance. Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction (PXRD) studies proved the formation of a complete amorphous system of EFZ with Eudragit® E100, HPMC E5, and HPMCAS-LF up to 50% drug loading. During 90 days accelerated stability studies, amorphous systems prepared using Eudragit® E100 remained stable at 50% drug loading however those prepared with HPMC E5, and HPMCAS-LF only remained stable at 25% drug loading. The ability of Eudragit® E100 based system to stabilize the drug at higher drug loading was attributed to the formation of stronger ionic interaction as revealed by the Fourier-transform infrared spectroscopy (FTIR) study. During in-vitro dissolution study, Eudragit® E100 based amorphous system generated and maintained significantly higher supersaturation compared to those prepared with HPMC E5, and HPMCAS-LF due to the formation of ionic interaction between EFZ and Eudragit® E100 as revealed by solution 1H NMR study.
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Affiliation(s)
- Aastha Gadoya
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India
| | - Kiran Dudhat
- R.K. School of Pharmacy, R.K. University, Rajkot, Gujarat, India
| | - Sunny Shah
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India
| | - Chetan Borkhataria
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India
| | - Trupesh Pethani
- Department of Pharmaceutical Sciences, Saurashtra University, Rajkot, Gujarat, India
| | | | - Nilesh Janbukiya
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India
| | - Saina Jyotishi
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India
| | - Jainabparvin Ansari
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India
| | - Mori Dhaval
- B.K. Mody Government Pharmacy College, Polytechnic Campus, Near Ajidam, Rajkot, Gujarat, 360005, India.
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Wiesner-Kiełczewska A, Zagrodzki P, Gawalska A, Paśko P. Chemometric Methods-A Valuable Tool for Investigating the Interactions Between Antifungal Drugs (Including Antifungal Antibiotics) and Food. Antibiotics (Basel) 2025; 14:70. [PMID: 39858356 PMCID: PMC11761243 DOI: 10.3390/antibiotics14010070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/05/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Developing antifungal drugs with lower potential for interactions with food may help to optimize treatment and reduce the risk of antimicrobial resistance. Chemometrics uses statistical and mathematical methods to analyze multivariate chemical data, enabling the identification of key correlations and simplifying data interpretation. We used the partial least squares (PLS) approach to explore the correlations between various characteristics of oral antifungal drugs (including antifungal antibiotics) and dietary interventions, aiming to identify patterns that could inform the optimization of antifungal therapy. METHODS We analyzed 15 oral antifungal drugs, including azoles (8), antifungal antibiotics (4), antifungal antimetabolites (1), squalene epoxidase inhibitors (1), and glucan synthase inhibitors (1). The input dataset comprised information from published clinical trials, chemical records, and calculations. We constructed PLS models with changes in the pharmacokinetic parameters (∆AUC, area under the curve; ∆Cmax, maximum drug concentration; and ∆Tmax, time to reach maximum drug concentration) after dietary intervention as the response parameters and eight groups of molecular descriptors (M1-M8) as the predictor parameters. We performed separate analyses for the different nutritional interventions. RESULTS In the final PLS model with food as an intervention, we effectively reduced the dimensionality of the dataset while retaining a substantial percentage of the original information (variance), as significant components explained 69.8% and 17.5% of the predictor and response parameter variances, respectively. The PLS model was significant because its components met the cross-validation criteria. We obtained six significant positive and negative correlations between the descriptors related to atoms and the postprandial ∆Tmax. CONCLUSIONS The PLS method is valuable for investigating interactions between antifungal drugs (including antifungal antibiotics) and food. The correlations obtained can be used in drug modeling to predict interactions with dietary interventions based on the antifungal drug's chemical structure. Incorporating chemometric techniques into the early drug development stages could facilitate the design of antifungal antibiotics and other antifungal agents with optimized absorption in the presence of dietary components.
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Affiliation(s)
- Agnieszka Wiesner-Kiełczewska
- Doctoral School of Medical and Health Sciences, Jagiellonian University Medical College, 31-008 Cracow, Poland;
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, 31-008 Cracow, Poland;
| | - Paweł Zagrodzki
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, 31-008 Cracow, Poland;
| | - Alicja Gawalska
- Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 31-008 Cracow, Poland;
| | - Paweł Paśko
- Department of Food Chemistry and Nutrition, Faculty of Pharmacy, Jagiellonian University Medical College, 31-008 Cracow, Poland;
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Wu K, Kwon SH, Zhou X, Fuller C, Wang X, Vadgama J, Wu Y. Overcoming Challenges in Small-Molecule Drug Bioavailability: A Review of Key Factors and Approaches. Int J Mol Sci 2024; 25:13121. [PMID: 39684832 PMCID: PMC11642056 DOI: 10.3390/ijms252313121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/28/2024] [Accepted: 12/04/2024] [Indexed: 12/18/2024] Open
Abstract
The bioavailability of small-molecule drugs remains a critical challenge in pharmaceutical development, significantly impacting therapeutic efficacy and commercial viability. This review synthesizes recent advances in understanding and overcoming bioavailability limitations, focusing on key physicochemical and biological factors influencing drug absorption and distribution. We examine cutting-edge strategies for enhancing bioavailability, including innovative formulation approaches, rational structural modifications, and the application of artificial intelligence in drug design. The integration of nanotechnology, 3D printing, and stimuli-responsive delivery systems are highlighted as promising avenues for improving drug delivery. We discuss the importance of a holistic, multidisciplinary approach to bioavailability optimization, emphasizing early-stage consideration of ADME properties and the need for patient-centric design. This review also explores emerging technologies such as CRISPR-Cas9-mediated personalization and microbiome modulation for tailored bioavailability enhancement. Finally, we outline future research directions, including advanced predictive modeling, overcoming biological barriers, and addressing the challenges of emerging therapeutic modalities. By elucidating the complex interplay of factors affecting bioavailability, this review aims to guide future efforts in developing more effective and accessible small-molecule therapeutics.
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Affiliation(s)
- Ke Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90095, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
| | - Soon Hwan Kwon
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90095, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
| | - Xuhan Zhou
- Department of Pre-Biology, University of California, Santa Barbara (UCSB), Santa Barbara, CA 93106, USA
| | - Claire Fuller
- Department of Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Xianyi Wang
- Department of Chemistry, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Jaydutt Vadgama
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90095, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
| | - Yong Wu
- Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90095, USA
- David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
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Liu J, Vanderwyk KA, Donnelley MA, Thompson III GR. SUBA-itraconazole in the treatment of systemic fungal infections. Future Microbiol 2024; 19:1171-1175. [PMID: 39011995 PMCID: PMC11529195 DOI: 10.1080/17460913.2024.2362128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 05/28/2024] [Indexed: 07/17/2024] Open
Abstract
Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.
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Affiliation(s)
- Jennifer Liu
- Department of Pharmacy, UC-Davis Medical Center, Sacramento, CA95816, USA
| | - Kees A Vanderwyk
- Department of Pharmacy, UC-Davis Medical Center, Sacramento, CA95816, USA
| | - Monica A Donnelley
- Department of Pharmacy, UC-Davis Medical Center, Sacramento, CA95816, USA
| | - George R Thompson III
- Department of Internal Medicine, Division of Infectious Diseases, UC-Davis Medical Center, Sacramento, CA95816, USA
- Department of Medical Microbiology & Immunology, UC-Davis School of Medicine, Davis, CA95616, USA
- UC-Davis Center for Valley Fever, Sacramento, CA95616, USA
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Khurana A, Sharath S, Sardana K, Chowdhary A. Clinico-mycological and therapeutic updates on cutaneous dermatophytic infections in the era of Trichophyton indotineae. J Am Acad Dermatol 2024; 91:315-323. [PMID: 38574764 DOI: 10.1016/j.jaad.2024.03.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 04/06/2024]
Abstract
Trichophyton indotineae has emerged as a novel dermatophyte species resulting in treatment recalcitrant skin infections. While the earliest reports came from India, T. indotineae has now spread to many parts of the world and is rapidly becoming a global health concern. Accurate identification of T. indotineae requires elaborate mycological investigations which is beyond the domain of routine microbiology testing. Extensive, non-inflammatory and atypical presentations are commonly seen with this novel species. T. indotineae shows an alarmingly high rate of mutations in the squalene epoxidase gene leading to lowered in vitro susceptibility to terbinafine. This has also translated into a lowered clinical response and requirement of a higher dose and much longer durations of treatment with the drug. Although the species remains largely susceptible to itraconazole, prolonged treatment durations are required to achieve cure with itraconazole. Fluconazole and griseofulvin do not have satisfactory in vitro or clinical activity. Apart from requirement of prolonged treatment durations, relapse postsuccessful treatment is a distressing and yet unexplained consequence of this "species-shift." Use of third generation azoles and combinations of systemic antifungals is unwarranted as both have not demonstrated clear superiority over itraconazole given alone, and the former is an important class of drugs for invasive mycoses.
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Affiliation(s)
- Ananta Khurana
- Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, New Delhi, India.
| | - Savitha Sharath
- Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, New Delhi, India
| | - Kabir Sardana
- Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, New Delhi, India
| | - Anuradha Chowdhary
- Medical Mycology Unit, Department of Microbiology, National Reference Laboratory for Antimicrobial Resistance in Fungal Pathogens, Vallabhbhai Patel Chest Institute, University of Delhi, New Delhi, India
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Sonego B, Corio A, Mazzoletti V, Zerbato V, Benini A, di Meo N, Zalaudek I, Stinco G, Errichetti E, Zelin E. Trichophyton indotineae, an Emerging Drug-Resistant Dermatophyte: A Review of the Treatment Options. J Clin Med 2024; 13:3558. [PMID: 38930086 PMCID: PMC11204959 DOI: 10.3390/jcm13123558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/11/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Background: Dermatophytosis is a prevalent superficial infection caused by filamentous fungi, primarily affecting the skin and/or its appendages. In recent years, there has been a notable increase in mycotic strains resistant to standard antifungal therapies, including Trichophyton indotineae, a dermatophyte of the Trichophyton mentagrophytes complex. This review aims to provide a comprehensive overview of the treatment options for T. indotineae, elucidating their effectiveness in managing this challenging mycotic infection. Methods: For this review, a search was conducted in the PubMed, Scopus, Web of Science, Embase, and Google Scholar databases, encompassing all published data until March 2024. English-language articles detailing therapy outcomes for patients confirmed to be affected by T. indotineae, identified through molecular analysis, were included. Results: Itraconazole was shown to be a good therapeutic choice, particularly when administered at a dosage of 200 mg/day for 1-12 weeks. Voriconazole was also demonstrated to be effective, while terbinafine exhibited a reduced response rate. Griseofulvin and fluconazole, on the other hand, were found to be ineffective. Although topical treatments were mostly ineffective when used alone, they showed promising results when used in combination with systemic therapy. Mutational status was associated with different profiles of treatment response, suggesting the need for a more tailored approach. Conclusions: When managing T. indotineae infections, it is necessary to optimize therapy to mitigate resistances and relapse. Combining in vitro antifungal susceptibility testing with mutational analysis could be a promising strategy in refining treatment selection.
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Affiliation(s)
- Benedetta Sonego
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (B.S.); (A.C.); (A.B.); (N.d.M.); (I.Z.)
| | - Andrea Corio
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (B.S.); (A.C.); (A.B.); (N.d.M.); (I.Z.)
| | - Vanessa Mazzoletti
- Institute of Dermatology, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy;
| | - Verena Zerbato
- Infectious Diseases Unit, Trieste University Hospital (ASUGI), 34125 Trieste, Italy;
| | - Alessandro Benini
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (B.S.); (A.C.); (A.B.); (N.d.M.); (I.Z.)
| | - Nicola di Meo
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (B.S.); (A.C.); (A.B.); (N.d.M.); (I.Z.)
| | - Iris Zalaudek
- Dermatology Clinic, Maggiore Hospital, University of Trieste, 34125 Trieste, Italy; (B.S.); (A.C.); (A.B.); (N.d.M.); (I.Z.)
| | - Giuseppe Stinco
- Institute of Dermatology, Department of Medicine, University of Udine, 33100 Udine, Italy; (G.S.); (E.E.)
| | - Enzo Errichetti
- Institute of Dermatology, Department of Medicine, University of Udine, 33100 Udine, Italy; (G.S.); (E.E.)
| | - Enrico Zelin
- Institute of Dermatology, Santa Maria della Misericordia University Hospital, 33100 Udine, Italy;
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Hoenigl M, Arastehfar A, Arendrup MC, Brüggemann R, Carvalho A, Chiller T, Chen S, Egger M, Feys S, Gangneux JP, Gold JAW, Groll AH, Heylen J, Jenks JD, Krause R, Lagrou K, Lamoth F, Prattes J, Sedik S, Wauters J, Wiederhold NP, Thompson GR. Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease. Clin Microbiol Rev 2024; 37:e0007423. [PMID: 38602408 PMCID: PMC11237431 DOI: 10.1128/cmr.00074-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2024] Open
Abstract
SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.
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Affiliation(s)
- Martin Hoenigl
- Department of Internal Medicine, Division of Infectious Diseases, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Graz, Austria
- BiotechMed-Graz, Graz, Austria
| | - Amir Arastehfar
- Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Maiken Cavling Arendrup
- Unit of Mycology, Statens Serum Institut, Copenhagen, Denmark
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Roger Brüggemann
- Department of Pharmacy and Radboudumc Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboudumc-CWZ Center of Expertise in Mycology, Nijmegen, The Netherlands
| | - Agostinho Carvalho
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
- ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Tom Chiller
- Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Sharon Chen
- Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, NSW South Wales Health Pathology, Westmead Hospital, Westmead, Australia
- The University of Sydney, Sydney, Australia
| | - Matthias Egger
- Department of Internal Medicine, Division of Infectious Diseases, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Graz, Austria
| | - Simon Feys
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
| | - Jean-Pierre Gangneux
- Centre National de Référence des Mycoses et Antifongiques LA-AspC Aspergilloses chroniques, European Excellence Center for Medical Mycology (ECMM EC), Centre hospitalier Universitaire de Rennes, Rennes, France
- Univ Rennes, CHU Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) UMR_S 1085, Rennes, France
| | - Jeremy A. W. Gold
- Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Andreas H. Groll
- Department of Pediatric Hematology/Oncology and Infectious Disease Research Program, Center for Bone Marrow Transplantation, University Children’s Hospital, Muenster, Germany
| | - Jannes Heylen
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
| | - Jeffrey D. Jenks
- Department of Public Health, Durham County, Durham, North Carolina, USA
- Department of Medicine, Division of Infectious Diseases, Duke University, Durham, North Carolina, USA
| | - Robert Krause
- Department of Internal Medicine, Division of Infectious Diseases, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Graz, Austria
- BiotechMed-Graz, Graz, Austria
| | - Katrien Lagrou
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Laboratory Medicine and National Reference Center for Mycosis, University Hospitals Leuven, Leuven, Belgium
| | - Frédéric Lamoth
- Department of Laboratory Medicine and Pathology, Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- Department of Medicine, Infectious Diseases Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Juergen Prattes
- Department of Internal Medicine, Division of Infectious Diseases, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Graz, Austria
- BiotechMed-Graz, Graz, Austria
| | - Sarah Sedik
- Department of Internal Medicine, Division of Infectious Diseases, ECMM Excellence Center for Medical Mycology, Medical University of Graz, Graz, Austria
| | - Joost Wauters
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
| | - Nathan P. Wiederhold
- Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - George R. Thompson
- Department of Internal Medicine, Division of Infectious Diseases University of California-Davis Medical Center, Sacramento, California, USA
- Department of Medical Microbiology and Immunology, University of California-Davis, Davis, California, USA
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10
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Sousa YV, Santiago MG, de Souza BM, Keller KM, Oliveira CSF, Mendoza L, Vilela RVR, Goulart GAC. Itraconazole in human medicine and veterinary practice. J Mycol Med 2024; 34:101473. [PMID: 38493607 DOI: 10.1016/j.mycmed.2024.101473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 02/03/2024] [Accepted: 03/08/2024] [Indexed: 03/19/2024]
Abstract
Diagnosis and management of fungal infections are challenging in both animals and humans, especially in immunologically weakened hosts. Due to its broad spectrum and safety profile when compared to other antifungals, itraconazole (ITZ) has been widely used in the treatment and prophylaxis of fungal infections, both in human and veterinary medicine. The dose and duration of management depend on factors such as the type of fungal pathogen, the site of infection, sensitivity to ITZ, chronic stages of the disease, the health status of the hosts, pharmacological interactions with other medications and the therapeutic protocol used. In veterinary practice, ITZ doses generally vary between 3 mg/kg and 50 mg/kg, once or twice a day. In humans, doses usually vary between 100 and 400 mg/day. As human and veterinary fungal infections are increasingly associated, and ITZ is one of the main medications used, this review addresses relevant aspects related to the use of this drug in both clinics, including case reports and different clinical aspects available in the literature.
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Affiliation(s)
- Yamara V Sousa
- Department of Pharmaceuticals, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av Antônio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil
| | - Marie G Santiago
- Department of Pharmaceuticals, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av Antônio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil
| | - Bianca M de Souza
- Department of Preventive Veterinary Medicine, Veterinary School, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
| | - Kelly M Keller
- Department of Preventive Veterinary Medicine, Veterinary School, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
| | - Camila S F Oliveira
- Department of Preventive Veterinary Medicine, Veterinary School, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
| | - Leonel Mendoza
- Biomedical Laboratory Diagnostics, Michigan State University, East Lansing, MI 48824, United States
| | - Raquel V R Vilela
- Biomedical Laboratory Diagnostics, Michigan State University, East Lansing, MI 48824, United States; Department of Clinical and Toxicological Analysis, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
| | - Gisele A C Goulart
- Department of Pharmaceuticals, Faculty of Pharmacy, Universidade Federal de Minas Gerais, Av Antônio Carlos, 6627, Belo Horizonte, MG 31270-901, Brazil.
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11
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Saraswat A, Dogra S, Shenoy M, Verma S, K S, Ghate S, Ganjoo A, Aurangabadkar S, Tiwari A, Poojary S, Inamdar A, Majid I, Girdhar M, Shah B, Varma S, Ramamoorthy R, Dhoot D, Barkate H. Clinical Use of Super-Bioavailable Itraconazole for the Management of Dermatophytosis: Consensus Statement by Dermatologists from India via the Modified Delphi Technique. Dermatology 2024; 240:671-683. [PMID: 38697027 DOI: 10.1159/000538080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 02/26/2024] [Indexed: 05/04/2024] Open
Abstract
Super-bioavailable itraconazole (SB ITZ) overcomes the limitations of conventional itraconazole (CITZ) such as interindividual variability and reduced bioavailability. It has been approved for systemic mycoses in Australia and Europe as 50 mg and the USA as 65 mg and in India as 50 mg, 65 mg, 100 mg, and 130 mg. However, data on the ideal dose and duration of SB ITZ treatment in managing dermatophytosis are insufficient. This consensus discusses the suitability, dosage, duration of treatment, and relevance of using SB ITZ in managing dermatophytosis in different clinical scenarios. Sixteen dermatologists (>15 years of experience in the field and ≥2 years clinical experience with SB ITZ), formed the expert panel. A modified Delphi technique was employed, and a consensus was reached if the concordance in response was >75%. A total of 26 consensus statements were developed. The preferred dose of SB ITZ is 130 mg once daily and if not tolerated, 65 mg twice daily. The preferred duration for treating naïve dermatophytosis is 4-6 weeks and that for recalcitrant dermatophytosis is 6-8 weeks. Moreover, cure rates for dermatophytosis are a little better with SB ITZ than with CITZ with a similar safety profile as of CITZ. Better patient compliance and efficacy are associated with SB ITZ than with CITZ, even in patients with comorbidities and special needs such as patients with diabetes, extensive lesions, corticosteroid abuse, adolescents, and those on multiple drugs. Expert clinicians reported that the overall clinical experience with SB ITZ was better than that with CITZ.
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Affiliation(s)
- Abir Saraswat
- Department of Dermatology, Indushree Skin Clinic, Lucknow, India
| | - Sunil Dogra
- Department of Dermatology, Venereology and Leprology Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Manjunath Shenoy
- Department of Dermatology, Yenepoya Medical College, Mangalore, India
| | - Shyam Verma
- Department of Dermatology, Nirvan Skin Clinic, Vadodara, India
| | - Seetharam K
- Department of Dermatology, GSL Medical College, Rajamundry, India
| | - Sunil Ghate
- Department of Dermatology, Dr Ghate's Skin, Hair and LASER Centre, Mumbai, India
| | - Anil Ganjoo
- Department of Dermatology, Skinnovation Clinics, New Delhi, India
| | - Sanjeev Aurangabadkar
- Department of Dermatology, Dr. Aurangabadkar's Skin and Laser Clinics, Hyderabad, India
| | - Anurag Tiwari
- Department of Dermatology, Center for Skin Diseases and Laser Treatment, Bhopal, India
| | - Shital Poojary
- Department of Dermatology, K J Somaiya Medical College, Mumbai, India
| | - Arun Inamdar
- Department of Dermatology, Sri B M Patil Medical College, BLDE Deemed University, Vijayapur, India
| | - Imran Majid
- Department of Dermatology, Cutis Institute of Dermatology, Srinagar, India
| | - Mukesh Girdhar
- Department of Dermatology, Max Super Specialty Hospital, Ppg, Delhi, India
| | - Bela Shah
- Department of Dermatology, BJ Medical College and Civil Hospital, Ahmedabad, India
| | - Sachin Varma
- Department of Dermatology, Skinvita Clinic, Kolkata, India
| | | | - Dhiraj Dhoot
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd., Mumbai, India
| | - Hanmant Barkate
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd., Mumbai, India
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12
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Cabañero-Resta GJ, Sánchez-Dengra B, Ruiz-Picazo A, Bermejo M, Merino V, Gonzalez-Alvarez I, Gonzalez-Alvarez M. Pharmaceutical Compounding in Veterinary Medicine: Suspension of Itraconazole. Pharmaceutics 2024; 16:576. [PMID: 38794238 PMCID: PMC11125331 DOI: 10.3390/pharmaceutics16050576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/09/2024] [Accepted: 04/19/2024] [Indexed: 05/26/2024] Open
Abstract
Itraconazole is a drug used in veterinary medicine for the treatment of different varieties of dermatophytosis at doses between 3-5 mg/kg/day in cats. Nevertheless, in Spain, it is only available in the market as a 52 mL suspension at 10 mg/mL. The lack of alternative formulations, which provide sufficient formulation to cover the treatment of large animals or allow the treatment of a group of them, can be overcome with compounding. For this purpose, it has to be considered that itraconazole is a weak base, class II compound, according to the Biopharmaceutics Classification System, that can precipitate when reaching the duodenum. The aim of this work is to develop alternative oral formulations of itraconazole for the treatment of dermatophytosis. Several oral compounds of itraconazole were prepared and compared, in terms of dissolution rate, permeability, and stability, in order to provide alternatives to the medicine commercialized. The most promising formulation contained hydroxypropyl methylcellulose and β-cyclodextrin. This combination of excipients was capable of dissolving the same concentration as the reference product and delaying the precipitation of itraconazole upon leaving the stomach. Moreover, the intestinal permeability of itraconazole was increased more than two-fold.
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Affiliation(s)
- Gema J. Cabañero-Resta
- Departamento de Farmacia y Tecnología Farmacéutica y Parasitología, Universitat de València, Vicente Andrés Estelles s/n, Burjassot, 46100 Valencia, Spain; (G.J.C.-R.); (V.M.)
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, 46100 Valencia, Spain
| | - Bárbara Sánchez-Dengra
- Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 San Juan de Alicante, Spain; (B.S.-D.); (A.R.-P.); (M.B.); (M.G.-A.)
| | - Alejandro Ruiz-Picazo
- Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 San Juan de Alicante, Spain; (B.S.-D.); (A.R.-P.); (M.B.); (M.G.-A.)
| | - Marival Bermejo
- Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 San Juan de Alicante, Spain; (B.S.-D.); (A.R.-P.); (M.B.); (M.G.-A.)
| | - Virginia Merino
- Departamento de Farmacia y Tecnología Farmacéutica y Parasitología, Universitat de València, Vicente Andrés Estelles s/n, Burjassot, 46100 Valencia, Spain; (G.J.C.-R.); (V.M.)
- Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, 46100 Valencia, Spain
| | - Isabel Gonzalez-Alvarez
- Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 San Juan de Alicante, Spain; (B.S.-D.); (A.R.-P.); (M.B.); (M.G.-A.)
| | - Marta Gonzalez-Alvarez
- Engineering: Pharmacokinetics and Pharmaceutical Technology Area, Miguel Hernandez University, 03550 San Juan de Alicante, Spain; (B.S.-D.); (A.R.-P.); (M.B.); (M.G.-A.)
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13
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Şuta LM, Ridichie A, Ledeţi A, Temereancă C, Ledeţi I, Muntean D, Rădulescu M, Văruţ RM, Watz C, Crăineanu F, Ivan D, Vlase G, Stelea L. Host-Guest Complexation of Itraconazole with Cyclodextrins for Bioavailability Enhancement. Pharmaceutics 2024; 16:560. [PMID: 38675221 PMCID: PMC11054515 DOI: 10.3390/pharmaceutics16040560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/09/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Itraconazole is an antifungal agent included in the triazole pharmacological classification that belongs to the BCS class II, characterized by a low solubility in an aqueous medium (of 1 ng/mL, at neutral pH), which is frequently translated in a low oral bioavailability but with a high permeability. In this sense, it is necessary to find solutions to increase/improve the solubility of itraconazole in the aqueous environment. The main purpose of this study is the preparation and analysis of five different guest-host inclusion complexes containing intraconazole. Initially, a blind docking process was carried out to determine the interactions between itraconazole and the selected cyclodextrins. The second step of the study was to find out if the active pharmaceutical ingredient was entrapped in the cavity of the cyclodextrin, by using spectroscopic and thermal techniques. Also, the antifungal activity of the inclusion complexes was studied to examine if the entrapment of itraconazole influences the therapeutic effect. The results showed that the active substance was entrapped in the cavity of the cyclodextrins, with a molar ratio of 1:3 (itraconazole-cyclodextrin), and that the therapeutic effect was not influenced by the entrapment.
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Affiliation(s)
- Lenuţa-Maria Şuta
- Advanced Instrumental Screening Center, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (L.-M.Ş.); (A.L.); (I.L.); (D.I.)
- Department II—Pharmaceutical Technology, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania
| | - Amalia Ridichie
- Advanced Instrumental Screening Center, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (L.-M.Ş.); (A.L.); (I.L.); (D.I.)
- Faculty of Industrial Chemistry and Environmental Engineering, University Politehnica Timisoara, 2 Victoriei Square, 300006 Timisoara, Romania
| | - Adriana Ledeţi
- Advanced Instrumental Screening Center, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (L.-M.Ş.); (A.L.); (I.L.); (D.I.)
| | - Claudia Temereancă
- Faculty of Industrial Chemistry and Environmental Engineering, University Politehnica Timisoara, 2 Victoriei Square, 300006 Timisoara, Romania
| | - Ionuţ Ledeţi
- Advanced Instrumental Screening Center, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (L.-M.Ş.); (A.L.); (I.L.); (D.I.)
- Faculty of Industrial Chemistry and Environmental Engineering, University Politehnica Timisoara, 2 Victoriei Square, 300006 Timisoara, Romania
| | - Delia Muntean
- Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (D.M.); (M.R.); (F.C.); (L.S.)
| | - Matilda Rădulescu
- Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (D.M.); (M.R.); (F.C.); (L.S.)
| | - Renata-Maria Văruţ
- Faculty of Pharmacy, University of Medicine and Pharmacy Craiova, 2-4 Petru Rares Str., 200349 Craiova, Romania;
| | - Claudia Watz
- Department I—Pharmaceutical Physics, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania;
| | - Florentin Crăineanu
- Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (D.M.); (M.R.); (F.C.); (L.S.)
| | - Denisa Ivan
- Advanced Instrumental Screening Center, Faculty of Pharmacy, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (L.-M.Ş.); (A.L.); (I.L.); (D.I.)
| | - Gabriela Vlase
- Research Centre for Thermal Analysis in Environmental Problems, West University of Timisoara, Pestalozzi Street 16, 300115 Timisoara, Romania;
| | - Lavinia Stelea
- Faculty of Medicine, Victor Babeş University of Medicine and Pharmacy, 2 Eftimie Murgu Square, 300041 Timisoara, Romania; (D.M.); (M.R.); (F.C.); (L.S.)
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14
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Spec A, Thompson GR, Miceli MH, Hayes J, Proia L, McKinsey D, Arauz AB, Mullane K, Young JA, McGwin G, McMullen R, Plumley T, Moore MK, McDowell LA, Jones C, Pappas PG. MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial. Open Forum Infect Dis 2024; 11:ofae010. [PMID: 38440302 PMCID: PMC10911225 DOI: 10.1093/ofid/ofae010] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 01/08/2024] [Indexed: 03/06/2024] Open
Abstract
Background Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). Methods This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180. Results Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 (P = .03) and 14 (P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications (P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001). Conclusions SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra. Clinical Trials Registration NCT03572049.
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Affiliation(s)
- Andrej Spec
- Division of Infectious Disease, Washington University in St Louis School of Medicine, St Louis, Missouri, USA
| | - George R Thompson
- Department of Internal Medicine, Division of Infectious Diseases and Department of Medical Microbiology and Immunology, University of California Davis Medical Center, Sacramento, California, USA
| | - Marisa H Miceli
- Department of Internal Medicine, Division of Infectious Disease, University of Michigan, Ann Arbor, Michigan, USA
| | - Justin Hayes
- Division of Infectious Diseases, University of Arizona College of Medicine, Tucson, Arizona, USA
| | - Laurie Proia
- Department of Medicine, Rochester Regional Health, Rochester, New York, USA
| | - David McKinsey
- Metro Infectious Disease Consultants, Kansas City, Missouri, USA
| | - Ana Belen Arauz
- Department of Medicine, University of Panama and Hospital Santo Tomas, Panama City, Panama
| | - Kathleen Mullane
- Department of Medicine/Section of Infectious Diseases and Global Health, University of Chicago, Chicago, Illinois, USA
| | - Jo-Ann Young
- Department of Medicine, Division of Infectious Disease and International Medicine, Program in Adult Transplant Infectious Disease, University of Minnesota, Minneapolis, Minnesota, USA
| | - Gerald McGwin
- Department of Internal Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rachel McMullen
- Department of Internal Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Mycoses Study Group Education and Research Consortium, Birmingham, Alabama, USA
| | - Tyler Plumley
- Department of Internal Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Mary K Moore
- Department of Internal Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Carolynn Jones
- College of Nursing, The Ohio State University College of Nursing, Columbus, Ohio, USA
- Mycoses Study Group Education and Research Consortium, Birmingham, Alabama, USA
| | - Peter G Pappas
- Department of Internal Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Mycoses Study Group Education and Research Consortium, Birmingham, Alabama, USA
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15
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Patel NH, Sardana K, Shenoy MM, Rengasamy M, Khurana A, Ghate S, Venkata CK, Marfatiya Y, Bhunia D, Jayaraman J, Das A, Jain AK. IADVL SIG Recalcitrant Dermatophytosis Position Statement on Super Bioavailable Itraconazole. Indian Dermatol Online J 2024; 15:1-7. [PMID: 38283009 PMCID: PMC10810390 DOI: 10.4103/idoj.idoj_668_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 04/18/2023] [Accepted: 05/19/2023] [Indexed: 01/30/2024] Open
Abstract
Itraconazole (ITZ) has been the mainstay of oral antifungal treatment for the current epidemic of recalcitrant dermatophytosis (RD) in India. Recently, a newer formulation of ITZ, super bioavailable itraconazole (SUBA-ITZ), is made available in the market by many pharmaceutical companies. It is important for dermatologists to understand the pharmacokinetic properties of SUBA-ITZ vis-a-vis conventional pellet formulation to use it effectively and safely. Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) has established a special interest group for recalcitrant dermatophytosis (SIG-RD) to strengthen research, continuing medical education, and industry collaboration on the subject. This position statement on SUBA-ITZ by SIG-RD is an attempt to address current pieces of evidence and the position of this new formulation in the management of RD.
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Affiliation(s)
- Nayankumar H. Patel
- Department of DVL, GCS Medical College Hospital and Research Centre, Ahmedabad, Gujarat, India
| | - Kabir Sardana
- Department of Dermatology, Dr. Ram Manohar Lohia Hospital and Atal Bihari Vajpayee Institute of Medical Sciences, New Delhi, India
| | | | - Madhu Rengasamy
- Department of DVL, Madras Medical College, Chennai, Tamil Nadu, India
| | - Ananta Khurana
- Department of Dermatology, Dr. Ram Manohar Lohia Hospital and Atal Bihari Vajpayee Institute of Medical Sciences, New Delhi, India
| | - Sunil Ghate
- Dr. Ghate’s Skin, Hair and LASER Centre, Mumbai, Maharashtra, India
| | | | | | | | - Jyothi Jayaraman
- Department of Dermatology, Father Muller Medical College, Manglore, Karnataka, India
| | - Anupam Das
- Department of DVL, KPC Medical College and Hospital, Kolkata, West Bengal, India
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16
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Kluwe F, Michelet R, Huisinga W, Zeitlinger M, Mikus G, Kloft C. Towards Model-Informed Precision Dosing of Voriconazole: Challenging Published Voriconazole Nonlinear Mixed-Effects Models with Real-World Clinical Data. Clin Pharmacokinet 2023; 62:1461-1477. [PMID: 37603216 PMCID: PMC10520167 DOI: 10.1007/s40262-023-01274-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/18/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND AND OBJECTIVES Model-informed precision dosing (MIPD) frequently uses nonlinear mixed-effects (NLME) models to predict and optimize therapy outcomes based on patient characteristics and therapeutic drug monitoring data. MIPD is indicated for compounds with narrow therapeutic range and complex pharmacokinetics (PK), such as voriconazole, a broad-spectrum antifungal drug for prevention and treatment of invasive fungal infections. To provide guidance and recommendations for evidence-based application of MIPD for voriconazole, this work aimed to (i) externally evaluate and compare the predictive performance of a published so-called 'hybrid' model for MIPD (an aggregate model comprising features and prior information from six previously published NLME models) versus two 'standard' NLME models of voriconazole, and (ii) investigate strategies and illustrate the clinical impact of Bayesian forecasting for voriconazole. METHODS A workflow for external evaluation and application of MIPD for voriconazole was implemented. Published voriconazole NLME models were externally evaluated using a comprehensive in-house clinical database comprising nine voriconazole studies and prediction-/simulation-based diagnostics. The NLME models were applied using different Bayesian forecasting strategies to assess the influence of prior observations on model predictivity. RESULTS The overall best predictive performance was obtained using the aggregate model. However, all NLME models showed only modest predictive performance, suggesting that (i) important PK processes were not sufficiently implemented in the structural submodels, (ii) sources of interindividual variability were not entirely captured, and (iii) interoccasion variability was not adequately accounted for. Predictive performance substantially improved by including the most recent voriconazole observations in MIPD. CONCLUSION Our results highlight the potential clinical impact of MIPD for voriconazole and indicate the need for a comprehensive (pre-)clinical database as basis for model development and careful external model evaluation for compounds with complex PK before their successful use in MIPD.
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Affiliation(s)
- Franziska Kluwe
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany
- Graduate Research Training Program PharMetrX, Berlin/Potsdam, Germany
| | - Robin Michelet
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany
| | - Wilhelm Huisinga
- Institute of Mathematics, University of Potsdam, Karl-Liebknecht-Str. 24/25, 14476 Potsdam, Germany
| | - Markus Zeitlinger
- Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Gerd Mikus
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany
- Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 419, 69120 Heidelberg, Germany
| | - Charlotte Kloft
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany
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Shenoy MM, De A, Shah B, Das A, Saraswat A, Lahiri K, Yadav S, Sarda A, Chakraborty D, J D, Kamat S, Doshi Y, Gonsalves N, Choudhary A, Dhoot D, Mahadkar N, Bhushan S, Gadkari R, Barkate H. Efficacy of Super-Bioavailable Itraconazole and Conventional Itraconazole at Different Dosing Regimens in Glabrous Tinea Infection - A Randomized Clinical Trial. Drug Des Devel Ther 2023; 17:2899-2908. [PMID: 37766823 PMCID: PMC10520254 DOI: 10.2147/dddt.s421583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
Introduction Itraconazole follows non-linear pharmacokinetics and hence is recommended once daily, but in real-world practice, is commonly prescribed as twice daily. Hence, this study aimed to evaluate the efficacy and safety of super-bioavailable-itraconazole-130 mg (SB-130) and conventional-itraconazole-200 mg (CITZ-200) once daily compared with conventional-itraconazole-100 mg (CITZ-100) twice daily in glabrous tinea. Methods A total of 261 eligible patients were enrolled in this prospective, randomized, clinical study from December-2021 to August-2022 at seven centers in India. Efficacy and safety assessments were done at week-3 and 6, with follow-up at week-10 for relapse. The primary objective was to assess the proportion of patients who achieved complete cure at week-6 following treatment in all itraconazole groups. The secondary outcomes were safety and clinical and mycological cure rates. Results Of 261 patients, 240 were included in the analysis. At week-6, 140 patients were completely cured; thus, overall cure rate was 58.33%. Fifty-five patients (69%) in SB-130 while 47/77 (61%) and 38/83 (46%) patients were completely cured in CITZ-200 and CITZ-100 groups respectively (p<0.05; SB-130: CITZ-100, p=0.32; SB-130: CITZ-200, p=0.058; CITZ-200: CITZ-100). There was no statistical difference in the mycological cure rate and area clearance rate between any of the groups (p=0.14); however, a statistically significant difference was noted for OD dosing over BD dosing in achieving clinical cure rates (p<0.05). A total of 13/140 patients (9%) relapsed following complete cure, with no statistically significant difference between any of the groups (p=0.50). All treatments were safe and well-tolerated, with no discontinuation. Conclusion In this clinical study, moderate efficacy with all doses of ITZ was reported but was better with OD dosing. Although there was no statistical difference between SB-130 and CITZ-200, SB-130 may be preferred over CITZ-200 owing to the advantage of SB over the conventional ITZ.
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Affiliation(s)
| | - Abhishek De
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Bela Shah
- Department of Dermatology, BJ Medical College and Civil Hospital, Ahmedabad, Gujarat, India
| | - Anupam Das
- Department of Dermatology, Iris Multispecialty Hospital, Kolkata, West Bengal, India
| | - Abir Saraswat
- Department of Dermatology, Indushree Skin Clinic, Lucknow, Uttar Pradesh, India
| | - Koushik Lahiri
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Sheetal Yadav
- Department of Dermatology, ABVIMS and Dr. RML Hospital, New Delhi, India
| | - Aarti Sarda
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Disha Chakraborty
- Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
| | - Dharmender J
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Shruti Kamat
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Yashika Doshi
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Nelry Gonsalves
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Ankita Choudhary
- Department of Dermatology, Wizderm Specialty Skin and Hair Clinic, Kolkata, West Bengal, India
| | - Dhiraj Dhoot
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Namrata Mahadkar
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Sumit Bhushan
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Rujuta Gadkari
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Hanmant Barkate
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
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Khurana A, Sharath S, Sardana K, Chowdhary A, Panesar S. Therapeutic Updates on the Management of Tinea Corporis or Cruris in the Era of Trichophyton Indotineae: Separating Evidence from Hype-A Narrative Review. Indian J Dermatol 2023; 68:525-540. [PMID: 38099117 PMCID: PMC10718250 DOI: 10.4103/ijd.ijd_832_23] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2023] Open
Abstract
The emergence and spread of Trichophyton indotineae (T. indotineae) has led to a sea change in the prescription practices of clinicians regarding the management of dermatophytic skin infections. An infection easily managed with a few weeks of antifungals, tinea corporis or cruris, is now often chronic and recurrent and requires prolonged treatment. Rising resistance to terbinafine, with documented squalene epoxidase (SQLE) gene mutations, and slow clinical response to itraconazole leave clinicians with limited treatment choices. However, in these testing times, it is essential that the tenets of antifungal stewardship be followed in making therapeutic decisions, and that the existing armamentarium of antifungals be used in rationale ways to counter this extremely common cutaneous infection, while keeping the growing drug resistance among dermatophytes in check. This review provides updated evidence on the use of various systemic antifungals for dermatophytic infection of the glabrous skin, especially with respect to the emerging T. indotineae species, which is gradually becoming a worldwide concern.
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Affiliation(s)
- Ananta Khurana
- From the Department of Dermatology, Venereology and Leprosy, ABVIMS and Dr. RML Hospital, New Delhi, India
| | - Savitha Sharath
- From the Department of Dermatology, Venereology and Leprosy, ABVIMS and Dr. RML Hospital, New Delhi, India
| | - Kabir Sardana
- From the Department of Dermatology, Venereology and Leprosy, ABVIMS and Dr. RML Hospital, New Delhi, India
| | - Anuradha Chowdhary
- Medical Mycology Unit, Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
| | - Sanjeet Panesar
- Department of Community Medicine, ABVIMS and Dr. RML Hospital, New Delhi, India
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Saha SK, Joshi A, Singh R, Dubey K. Review of industrially recognized polymers and manufacturing processes for amorphous solid dispersion based formulations. Pharm Dev Technol 2023; 28:678-696. [PMID: 37427544 DOI: 10.1080/10837450.2023.2233595] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/27/2023] [Accepted: 07/02/2023] [Indexed: 07/11/2023]
Abstract
Evolving therapeutic landscape through combinatorial chemistry and high throughput screening have resulted in an increased number of poorly soluble drugs. Drug delivery strategies quickly adapted to convert these drugs into successful therapies. Amorphous solid dispersion (ASD) technology is widely employed as a drug delivery strategy by pharmaceutical industries to overcome the challenges associated with these poorly soluble drugs. The development of ASD formulation requires an understanding of polymers and manufacturing techniques. A review of US FDA-approved ASD-based products revealed that only a limited number of polymers and manufacturing technologies are employed by pharmaceutical industries. This review provides a comprehensive guide for the selection and overview of polymers and manufacturing technologies adopted by pharmaceutical industries for ASD formulation. The various employed polymers with their underlying mechanisms for solution-state and solid-state stability are discussed. ASD manufacturing techniques, primarily implemented by pharmaceutical industries for commercialization, are presented in Quality by Design (QbD) format. An overview of novel excipients and progress in manufacturing technologies are also discussed. This review provides insights to the researchers on the industrially accepted polymers and manufacturing technology for ASD formulation that has translated these challenging drugs into successful therapies.
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Affiliation(s)
- Sumit Kumar Saha
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India
- Formulation Research and Development - Orals, Sun Pharmaceuticals Industries Limited, Gurugram, India
| | | | - Romi Singh
- Formulation Research and Development - Orals, Sun Pharmaceuticals Industries Limited, Gurugram, India
| | - Kiran Dubey
- Department of Pharmacology, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, India
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Tietz HJ. [Dermatomycoses - diagnostics and therapy]. MMW Fortschr Med 2023; 165:54-59. [PMID: 37537465 DOI: 10.1007/s15006-023-2800-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Affiliation(s)
- Hans-Jürgen Tietz
- Institut für Pilzkrankheiten, mycoclinic Berlin, Luisenstr. 50, 10117, Berlin, Deutschland.
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Mahajan K, Grover C, Relhan V, Tahiliani S, Singal A, Shenoy MM, Jakhar D. Nail Society of India (NSI) Recommendations for Pharmacologic Therapy of Onychomycosis. Indian Dermatol Online J 2023; 14:330-341. [PMID: 37266092 PMCID: PMC10231711 DOI: 10.4103/idoj.idoj_355_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 10/30/2022] [Accepted: 12/11/2022] [Indexed: 06/03/2023] Open
Abstract
Onychomycosis (OM) is the commonest cause of dystrophic nails, responsible for upto 50% of cases. Apart from significantly damaging the nails, quality of life, and self-image of the sufferer, it also acts as a reservoir of fungal infections carrying important implications for emerging recalcitrant dermatophytoses. Treatment of OM is based on guidelines released almost a decade back, in addition to published literature and personal preferences. Hence, an expert group of nail society of India (NSI) worked towards drafting these guidelines aimed at compiling recommendations for pharmacologic treatment of OM, based on scientific evidence, along with practical experience. The group did an extensive analysis of available English language literature on OM published during the period 2014-2022. The evidence compiled was graded and discussed to derive consensus recommendations for practice. Special focus was placed on combination therapies and adjunct therapies, including experience of members, to improve treatment outcomes.
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Affiliation(s)
- Khushbu Mahajan
- Consultant Dermatologist, Mahajan Skin Centre and Kubba Skin Clinic, Delhi, India
| | - Chander Grover
- Department of Dermatology and STD, University College of Medical Sciences and GTB Hospital, Delhi, India
| | - Vineet Relhan
- Department of Dermatology and STD, Maulana Azad Medical College and LN Hospital, Delhi, India
| | - Sushil Tahiliani
- Consultant Dermatologist, Hinduja Hospital and MRC, Dr Tahiliani’s Skin Clinic, Mumbai, Maharashtra, India
| | - Archana Singal
- Department of Dermatology and STD, University College of Medical Sciences and GTB Hospital, Delhi, India
| | - M Manjunath Shenoy
- Department of Dermatology, Venereology and Leprosy, Yenepoya Medical College, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Deepak Jakhar
- Consultant Dermatologist, Dermosphere Skin Clinic, Delhi, India
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Seah V, Sreeharan T, Kocic D, Reuter SE, Girgis L, Marriott DJE, Stocker SL. Effect of Therapeutic Plasma Exchange on Itraconazole Pharmacokinetics: A Case Study. Ther Drug Monit 2023; 45:129-132. [PMID: 36730858 DOI: 10.1097/ftd.0000000000001057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/08/2022] [Indexed: 02/04/2023]
Abstract
ABSTRACT The authors present the case of a 34-year-old male patient who underwent therapeutic plasma exchange (TPE) for amyopathic dermatomyositis. Immunosuppression resulted in Aspergillus lentulus pulmonary infection , requiring treatment with super bioavailable-itraconazole. Therapeutic itraconazole concentrations were attained after 2 weeks of treatment after dose adjustments. Interestingly, a substantial reduction in plasma itraconazole concentration was observed during TPE, which was attributed to an insufficient delay between the dosing of itraconazole and TPE initiation. Furthermore, there was an increase in plasma concentration post-TPE, which presumably reflects the redistribution of itraconazole from peripheral compartments back into plasma. This was confirmed by sampling of the TPE plasmapheresate, which revealed that changes in plasma concentration overestimated itraconazole clearance. These findings highlight that the pharmacokinetics of itraconazole are altered during TPE, which should be considered when timing drug administration and obtaining plasma concentrations.
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Affiliation(s)
- Vincent Seah
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney
- Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Sydney
- Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney
| | - Thulashigan Sreeharan
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney
- Sydney School of Pharmacy, The University of Sydney, Sydney
| | - Danijela Kocic
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney
- Department of Chemical Pathology and Clinical Pharmacology, SydPath, St Vincent's Hospital, Sydney
| | - Stephanie E Reuter
- UniSA Clinical and Health Sciences, University of South Australia, Adelaide; and
| | - Laila Girgis
- Department of Rheumatology, St Vincent's Hospital, Sydney, Australia
| | - Deborah J E Marriott
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney
- Department of Clinical Microbiology and Infectious Diseases, St Vincent's Hospital, Sydney
| | - Sophie L Stocker
- St Vincent's Clinical School, Faculty of Medicine, The University of New South Wales, Sydney
- Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital, Sydney
- Sydney School of Pharmacy, The University of Sydney, Sydney
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Naqvi SMH, Gala MYN, Muchhala S, Arumugam A, Panigrahi D, Patil D, Rathod R, Mane A. Pharmacokinetics/Pharmacodynamics study of Fixtral SB as compared to supra bioavailable itraconazole and conventional itraconazole. World J Pharmacol 2023; 12:1-11. [DOI: 10.5497/wjp.v12.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/11/2022] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Itraconazole is a broad-spectrum triazole antifungal inhibiting fungal growth by inhibiting ergosterol synthesis and exhibits a nonlinear pharmacokinetic profile. Erratic absorption pattern with wide fluctuations in blood levels causes inconsistent and unpredictable clinical behaviour of this drug despite its low minimum inhibitory concentration (MIC) as compared to other antifungal agents.
AIM To compare the oral bioavailability and bioequivalence of Fixtral SB (supra bioavailable itraconazole) with reference product R2 (supra bioavailable 2 × 50 mg itraconazole).
METHODS The study population consisted of 54 healthy volunteers, aged between 18-45 years and randomized to receive a single oral dose of either test [T; Fixtral SB (supra bioavailable itraconazole) 100 mg] or reference product (R1; Sporanox 100 mg × 2 capsules and R2; Lozanoc capsules 50 mg × 2 capsules). Blood samples were taken pre-dose and post-dose up to 96 h. The study evaluated bioequivalence by comparing the oral bioavailability of the test product with reference product R2. The pharmacodynamic characteristics of the drug were evaluated by comparing the test product with reference product R1. Pharmacokinetics (PK)-PD comparative analysis [area under the concentration-time curve (AUC)/ minimum inhibitory concentration (MIC) > 25] was performed for conventional itraconazole 100 mg and supra bioavailable itraconazole 50 mg. Adverse events (AEs) assessments were performed in each study period and post-study evaluation.
RESULTS Statistical analysis of primary PK variables revealed bioequivalence, with confidence intervals being completely inside the acceptance criteria of 80%-125%. The peak concentration levels of itraconazole were achieved at 10 h (T) and 8.5 h (R2), respectively. Pharmacodynamic parameter assessment showed that AUC/MIC for R1 are comparable to Fixtral SB 100mg for MIC levels up to 16mcg/mL (P > 0.05 and observed P = 0.3196). Six AEs were observed that were mild to moderate in severity and resolved. No severe AE was reported.
CONCLUSION Test product itraconazole Capsule 100 mg is bioequivalent with the reference product (R2) at 100 mg dose (2 capsules of Lozanoc® 50 mg) under fed conditions. Pharmacodynamics activity in terms of AUC/MIC is comparable between the test product at 100 mg dose and marketed itraconazole 200 mg. Fixtral SB is expected to have therapeutically similar efficacy at half the equivalent dose. Tested formulations were found to be safe and well tolerated.
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Affiliation(s)
| | | | - Snehal Muchhala
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Anand Arumugam
- Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | | | - Dipak Patil
- Global Clinical Management, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Rahul Rathod
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
| | - Amey Mane
- Medical Affairs, Dr Reddy’s Laboratories, Hyderabad 500016, India
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Chen C, Zhou X, Lavezzi SM, Arshad U, Sharma R. Concept and application of the probability of pharmacological success (PoPS) as a decision tool in drug development: a position paper. J Transl Med 2023; 21:17. [PMID: 36631827 PMCID: PMC9832631 DOI: 10.1186/s12967-022-03849-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/23/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND In drug development, few molecules from a large pool of early candidates become successful medicines after demonstrating a favourable benefit-risk ratio. Many decisions are made along the way to continue or stop the development of a molecule. The probability of pharmacological success, or PoPS, is a tool for informing early-stage decisions based on benefit and risk data available at the time. RESULTS The PoPS is the probability that most patients can achieve adequate pharmacology for the intended indication while minimising the number of subjects exposed to safety risk. This probability is usually a function of dose; hence its computation typically requires exposure-response models for pharmacology and safety. The levels of adequate pharmacology and acceptable risk must be specified. The uncertainties in these levels, in the exposure-response relationships, and in relevant translation all need to be identified. Several examples of different indications are used to illustrate how this approach can facilitate molecule progression decisions for preclinical and early clinical development. The examples show that PoPS assessment is an effective mechanism for integrating multi-source data, identifying knowledge gaps, and forcing transparency of assumptions. With its application, translational modelling becomes more meaningful and dose prediction more rigorous. Its successful implementation calls for early planning, sound understanding of the disease-drug system, and cross-discipline collaboration. Furthermore, the PoPS evolves as relevant knowledge grows. CONCLUSION The PoPS is a powerful evidence-based framework to formally capture multiple uncertainties into a single probability term for assessing benefit-risk ratio. In GSK, it is now expected for governance review at all early-phase decision gates.
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Affiliation(s)
- Chao Chen
- grid.418236.a0000 0001 2162 0389Clinical Pharmacology Modelling and Simulation, GSK, London, UK
| | - Xuan Zhou
- grid.418236.a0000 0001 2162 0389Clinical Pharmacology Modelling and Simulation, GSK, London, UK
| | - Silvia Maria Lavezzi
- Clinical Pharmacology, Modelling and Simulation, Parexel International, Dublin, Ireland
| | - Usman Arshad
- grid.418236.a0000 0001 2162 0389Clinical Pharmacology Modelling and Simulation, GSK, London, UK
| | - Raman Sharma
- grid.418236.a0000 0001 2162 0389Clinical Pharmacology Modelling and Simulation, GSK, London, UK
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Dhoot D, Jain GK, Manjhi M, Kesharwani P, Mahadkar N, Barkate H. Pharmacokinetic and clinical comparison of super-bioavailable itraconazole and conventional itraconazole at different dosing in dermatophytosis. Drugs Context 2023; 12:dic-2022-8-1. [PMID: 36660014 PMCID: PMC9835899 DOI: 10.7573/dic.2022-8-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 12/02/2022] [Indexed: 01/07/2023] Open
Abstract
Background Due to changing face of dermatophytosis in India, many dermatologists practice different dosing patterns of itraconazole (ITZ). Recently, a new form of ITZ, super-bioavailable ITZ (SBITZ), has been commercialized to overcome the pharmacokinetic challenges of conventional ITZ (CITZ). Serum and sebum concentration of ITZ plays an important role in the management of dermatophytosis. Hence, the current study compares the rate and extent of serum and sebum concentration of SBITZ and CITZ at different dosing to determine their efficacy and safety in patients with dermatophytosis. Methods This was an open-label, randomized, four-arm study including 40 adult patients diagnosed with glabrous tinea who were randomized equally into four groups to receive either CITZ-100-BD or CITZ-200-OD (2×100 mg capsules) or SBITZ-130-OD or SBITZ-100-OD (2×SBITZ-50 mg capsules) for 4 weeks. Serum and sebum samples were analysed at different time intervals along with clinical efficacy and safety. Results For serum concentration, on day 28, the arithmetic mean and standard deviation (SD) for CITZ-100-BD, CITZ-200-OD, SB-130-OD and SB100-OD were 1262±233.5 ng/mL, 1704±261.6 ng/mL, 1770±268.9 ng/mL and 1520±231.7 ng/mL, respectively, which was statistically significant for OD dosing of ITZ/SBITZ over CITZ-100-BD. Similarly, for sebum concentration, the arithmetic mean and SD for CITZ-100-BD, CITZ-200-OD, SB-130-OD and SB-100-OD were 1042±163.45 ng/mg, 1423±192.46 ng/mg, 1534±227.55 ng/mg and 1107±182.35 ng/mg, respectively, which was statistically significant for SB-130-OD and CITZ-200-OD over CITZ-100-BD and SBITZ-100-OD dosing. No significant difference was noted between SBITZ-130 and CITZ-200 (p=0.25). Only two patients achieved complete cure in the SBITZ-130 group, whereas no patients achieved the same in other groups (p=0.47). All the dosages were very well tolerated with only 12 adverse events reported by ten patients in all groups. Conclusion All formulations achieved desired serum and sebum concentrations required for efficacy in dermatophytosis, but SB 130 mg OD and CITZ 200 mg OD were statistically significant than other ITZ doses in achieving sebum concentration. Additionally, SBITZ 130 mg OD was bioequivalent to CITZ 200 mg OD and achieved similar results to those of CITZ 200 mg OD but at 35% lower drug concentrations.
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Affiliation(s)
- Dhiraj Dhoot
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, India
| | - Gaurav Kumar Jain
- Center of Advanced Formulation Technology, Delhi Pharmaceutical Science and Research University, New Delhi, India
| | - Mukesh Manjhi
- Department of Dermatology, Hamdard Institute of Medical Sciences and Research, New Delhi, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Namrata Mahadkar
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, India
| | - Hanmant Barkate
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, India
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Panda S, Ghosh A. Evidence-based management of dermatophytosis in India today. APOLLO MEDICINE 2023. [DOI: 10.4103/am.am_171_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Shah B, Mistry D, Jairam D, Kansara K, Pandya R, Vasani P, Dhoot D, Mahadkar N, Bhushan S, Barkate H. Comparative Efficacy of Super Bioavailable Itraconazole Capsules 50 mg vs 65 mg Twice Daily in the Management of Glabrous Tinea. Infect Drug Resist 2023; 16:2409-2416. [PMID: 37125212 PMCID: PMC10146068 DOI: 10.2147/idr.s407946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 04/15/2023] [Indexed: 05/02/2023] Open
Abstract
Introduction Owing to pharmacokinetic challenges of itraconazole, super-bioavailable itraconazole (SB) was developed and recently approved in strengths of 50mg and 65mg. But comparative study was lacking between these two strengths in glabrous tinea (dermatophytosis) management. Hence, this study was planned to compare the efficacy of both these strengths in dermatophytosis. Methods One hundred eligible patients were enrolled in this prospective, randomized, clinical study during May-2022 to September-2022 at tertiary hospital in Ahmedabad in adults. Efficacy and safety assessments were done at week-3 and 6 with follow up at week-10 for relapse. Primary objective was to assess the proportion of patients achieving complete cure at week-6 following treatment in both the groups. Secondary outcomes compared safety, clinical and mycological cure rates. Results Of the 100 patients enrolled, 98 patients (50 in SB-50mg and 48 in SB-65mg group) included in the final analysis. At week 6, 20 patients (40%) and 30 patients (62.5%) achieved complete cure (p < 0.05) in SB-50mg and SB-65mg groups, respectively. In completely cured patients, relapse was reported in 3 (15%) and 5 (17%) patients of SB-50mg and SB-65mg groups, respectively (p = 1). A significant difference was noted in clearance of symptoms and lesions in SB-65mg group (p < 0.05). Moreover, similar results were also obtained in sub-group analysis of recalcitrant dermatophytosis. Both the treatments were found to be safe and well tolerated with no discontinuation. Conclusion Study result concluded the superiority of SB-65mg over SB-50mg in terms of cure rate and resolution of symptoms in dermatophytosis management.
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Affiliation(s)
- Bela Shah
- Department of Dermatology, B J Medical College, Civil Hospital, Ahmedabad, Gujarat, India
| | | | - Dharmender Jairam
- Department of Dermatology, B J Medical College, Civil Hospital, Ahmedabad, Gujarat, India
| | - Kajal Kansara
- Department of Dermatology, B J Medical College, Civil Hospital, Ahmedabad, Gujarat, India
| | - Rutvi Pandya
- Department of Dermatology, B J Medical College, Civil Hospital, Ahmedabad, Gujarat, India
| | - Presha Vasani
- Department of Dermatology, B J Medical College, Civil Hospital, Ahmedabad, Gujarat, India
| | - Dhiraj Dhoot
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
- Correspondence: Dhiraj Dhoot, Glenmark Pharmaceuticals Ltd., B D Sawant Marg, Near Bisleri Plant, Chakala, Andheri (E), Mumbai, 400099, India, Tel +919619811219, Email
| | - Namrata Mahadkar
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Sumit Bhushan
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Hanmant Barkate
- Department of Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
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Praphawatvet T, Cui Z, Williams RO. Pharmaceutical dry powders of small molecules prepared by thin-film freezing and their applications – A focus on the physical and aerosol properties of the powders. Int J Pharm 2022; 629:122357. [DOI: 10.1016/j.ijpharm.2022.122357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/25/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022]
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Teixeira MM, Carvalho DT, Sousa E, Pinto E. New Antifungal Agents with Azole Moieties. Pharmaceuticals (Basel) 2022; 15:1427. [PMID: 36422557 PMCID: PMC9698508 DOI: 10.3390/ph15111427] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 09/22/2023] Open
Abstract
Fungal conditions affect a multitude of people worldwide, leading to increased hospitalization and mortality rates, and the need for novel antifungals is emerging with the rise of resistance and immunocompromised patients. Continuous use of azole drugs, which act by inhibiting the fungal CYP51, involved in the synthesis of ergosterol, essential to the fungal cell membrane, has enhanced the resistance and tolerance of some fungal strains to treatment, thereby limiting the arsenal of available drugs. The goal of this review is to gather literature information on new promising azole developments in clinical trials, with in vitro and in vivo results against fungal strains, and complementary assays, such as toxicity, susceptibility assays, docking studies, among others. Several molecules are reviewed as novel azole structures in clinical trials and with recent/imminent approvals, as well as other innovative molecules with promising antifungal activity. Structure-activity relationship (SAR) studies are displayed whenever possible. The azole moiety is brought over as a privileged structure, with multiple different compounds emerging with distinct pharmacophores and SAR. Particularly, 1,2,3-triazole natural product conjugates emerged in the last years, presenting promising antifungal activity and a broad spectrum against various fungi.
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Affiliation(s)
- Melissa Martins Teixeira
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, 4450-208 Matosinhos, Portugal
| | - Diogo Teixeira Carvalho
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Laboratory of Research in Pharmaceutical Chemistry, Department of Food and Drugs, Faculty of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas 37137-001, Brazil
| | - Emília Sousa
- Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, 4450-208 Matosinhos, Portugal
| | - Eugénia Pinto
- Laboratory of Microbiology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
- Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), University of Porto, 4450-208 Matosinhos, Portugal
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Abstract
Purpose of Review Recent Findings Summary
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Model-Informed Precision Dosing of Linezolid in Patients with Drug-Resistant Tuberculosis. Pharmaceutics 2022; 14:pharmaceutics14040753. [PMID: 35456587 PMCID: PMC9032906 DOI: 10.3390/pharmaceutics14040753] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/21/2022] [Accepted: 03/28/2022] [Indexed: 11/23/2022] Open
Abstract
Linezolid is an efficacious medication for the treatment of drug-resistant tuberculosis but has been associated with serious safety issues that can result in treatment interruption. The objectives of this study were thus to build a population pharmacokinetic model and to use the developed model to establish a model-informed precision dosing (MIPD) algorithm enabling safe and efficacious dosing in patients with multidrug- and extensively drug-resistant tuberculosis. Routine hospital therapeutic drug monitoring data, collected from 70 tuberculosis patients receiving linezolid, was used for model development. Efficacy and safety targets for MIPD were the ratio of unbound area under the concentration versus time curve between 0 and 24 h over minimal inhibitory concentration (fAUC0–24h/MIC) above 119 and unbound plasma trough concentration (fCmin) below 1.38 mg/L, respectively. Model building was performed in NONMEM 7.4.3. The final population pharmacokinetic model consisted of a one-compartment model with transit absorption and concentration- and time-dependent auto-inhibition of elimination. A flat dose of 600 mg once daily was appropriate in 67.2% of the simulated patients from an efficacy and safety perspective. Using the here developed MIPD algorithm, the proportion of patients reaching the efficacy and safety target increased to 81.5% and 88.2% using information from two and three pharmacokinetic sampling occasions, respectively. This work proposes an MIPD approach for linezolid and suggests using three sampling occasions to derive an individualized dose that results in adequate efficacy and fewer safety concerns compared to flat dosing.
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Ashok A, Mangalore RP, Morrissey CO. Azole Therapeutic Drug Monitoring and its Use in the Management of Invasive Fungal Disease. CURRENT FUNGAL INFECTION REPORTS 2022. [DOI: 10.1007/s12281-022-00430-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Kably B, Launay M, Derobertmasure A, Lefeuvre S, Dannaoui E, Billaud EM. Antifungal Drugs TDM: Trends and Update. Ther Drug Monit 2022; 44:166-197. [PMID: 34923544 DOI: 10.1097/ftd.0000000000000952] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 12/09/2021] [Indexed: 11/25/2022]
Abstract
PURPOSE The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. METHODS We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure. RESULTS More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available. CONCLUSIONS TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.
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Affiliation(s)
- Benjamin Kably
- Laboratoire de Pharmacologie-Toxicologie, Hôpital Européen Georges Pompidou, AP-HP Centre
- Faculté de Médecine, Université de Paris, Paris, France
| | - Manon Launay
- Laboratoire de Pharmacologie-Toxicologie-Gaz du sang, Hôpital Nord-CHU Saint Etienne, Saint-Etienne
| | - Audrey Derobertmasure
- Laboratoire de Pharmacologie-Toxicologie, Hôpital Européen Georges Pompidou, AP-HP Centre
| | - Sandrine Lefeuvre
- Laboratoire de Toxicologie et Pharmacocinétique, CHU de Poitiers, Poitiers; and
| | - Eric Dannaoui
- Faculté de Médecine, Université de Paris, Paris, France
- Unité de Parasitologie-Mycologie, Laboratoire de Microbiologie, Hôpital Européen Georges Pompidou, Paris, France
| | - Eliane M Billaud
- Laboratoire de Pharmacologie-Toxicologie, Hôpital Européen Georges Pompidou, AP-HP Centre
- Faculté de Médecine, Université de Paris, Paris, France
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Mohod B, Jain D, Kumar P, Chowdhuri S, Doshi H, Jain U, Beergouder S, Maganti K, Rani R, Jaiswal A. A retrospective analysis of real-world data to evaluate the safety and effectiveness of topical amorolfine in tinea infection. INDIAN JOURNAL OF DRUGS IN DERMATOLOGY 2022. [DOI: 10.4103/ijdd.ijdd_8_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Dhoot D, Mahajan H, Jain G, Deshmukh G, Barkate H. Serum and sebum pharmacokinetics evaluation of a novel formulation of itraconazole in healthy volunteers. INDIAN JOURNAL OF DRUGS IN DERMATOLOGY 2022. [DOI: 10.4103/ijdd.ijdd_23_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Teh BW, Yeoh DK, Haeusler GM, Yannakou CK, Fleming S, Lindsay J, Slavin MA. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021. Intern Med J 2021; 51 Suppl 7:67-88. [PMID: 34937140 DOI: 10.1111/imj.15588] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Antifungal prophylaxis can reduce morbidity and mortality from invasive fungal disease (IFD). However, its use needs to be optimised and appropriately targeted to patients at highest risk to derive the most benefit. In addition to established risks for IFD, considerable recent progress in the treatment of malignancies has resulted in the development of new 'at-risk' groups. The changing epidemiology of IFD and emergence of drug resistance continue to impact choice of prophylaxis, highlighting the importance of active surveillance and knowledge of local epidemiology. These guidelines aim to highlight emerging risk groups and review the evidence and limitations around new formulations of established agents and new antifungal drugs. It provides recommendations around use and choice of antifungal prophylaxis, discusses the potential impact of the changing epidemiology of IFD and emergence of drug resistance, and future directions for risk stratification to assist optimal management of highly vulnerable patients.
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Affiliation(s)
- Benjamin W Teh
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Daniel K Yeoh
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Infectious Diseases, Perth Children's Hospital, Perth, Western Australia, Australia
| | - Gabrielle M Haeusler
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Infectious Diseases, Royal Children's Hospital, Melbourne, Victoria, Australia.,Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Costas K Yannakou
- Department of Molecular Oncology and Cancer Immunology, Epworth Freemasons Hospital, Epworth HealthCare, Melbourne, Victoria, Australia
| | - Shaun Fleming
- Malignant Haematology and Stem Cell Transplantation Service, Alfred Health, Melbourne, Victoria, Australia
| | - Julian Lindsay
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Department of Haematology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Monica A Slavin
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.,National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.,Immunocompromised Host Infection Service, Royal Melbourne Hospital, Melbourne, Victoria, Australia
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Bouz G, Doležal M. Advances in Antifungal Drug Development: An Up-To-Date Mini Review. Pharmaceuticals (Basel) 2021; 14:1312. [PMID: 34959712 PMCID: PMC8706862 DOI: 10.3390/ph14121312] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 12/20/2022] Open
Abstract
The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry.
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Affiliation(s)
- Ghada Bouz
- Faculty of Pharmacy in Hradec Králové, Charles University, 50005 Hradec Králové, Czech Republic
| | - Martin Doležal
- Faculty of Pharmacy in Hradec Králové, Charles University, 50005 Hradec Králové, Czech Republic
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Lindsay J, Othman J, Kong Y, Yip A, Van Hal S, Larsen S, Bryant C, Gibson J, Kerridge I, Fay K, Stevenson W, Arthur C, Chen SCA, Kong DCM, Greenwood M, Pergam SA, Liu C, Slavin MA. SUBA-Itraconazole for Primary Antifungal Prophylaxis After Allogeneic Hematopoietic Cell Transplantation. Open Forum Infect Dis 2021; 8:ofab502. [PMID: 35559121 PMCID: PMC9088511 DOI: 10.1093/ofid/ofab502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/29/2021] [Indexed: 11/08/2022] Open
Abstract
Background Itraconazole (ITZ) is an effective agent when used as primary invasive fungal disease (IFD) prophylaxis, but is limited by drug tolerability and variability in serum concentrations. A new formulation, SUBA-itraconazole (for "super bioavailability"; S-ITZ), addresses the limitations of conventional ITZ formulations. Methods We conducted a retrospective cohort study at 2 Australian centers to evaluate the safety, tolerability, and effectiveness of S-ITZ as primary antifungal prophylaxis in hematopoietic cell transplant (HCT) recipients without grade II-IV acute graft-vs-host disease, from day 1 until approximately day 100 (cohort A) or day 1 until neutrophil engraftment (cohort B). A total of 204 patients and 1410 trough plasma ITZ concentrations were assessed. Results The incidence of breakthrough proven/probable IFD at day 180 was 1.0% (95% confidence interval [CI], .2%-3.2%), with 1.6% in cohort A and 0% in cohort B, and overall fungal-free survival of proven/probable IFD was 82.9% (95% CI, 76.8%-87.4%). Preengraftment early permanent S-ITZ discontinuation was 3.4% overall, with no significant difference between cohorts. No patients required cessation due to gastrointestinal intolerance attributed to S-ITZ. The geometric mean trough plasma ITZ concentration was 1130ng/mL (interquartile range, 566-1801ng/mL; coefficient of variation, 56.57%) and the median time to achieve therapeutic levels was 10 days. Conclusions S-ITZ is a safe and well-tolerated oral formulation and is a novel alternative for primary IFD prophylaxis after HCT.
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Affiliation(s)
- Julian Lindsay
- National Centre for Infection in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
- Vaccine and Infectious Disease and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jad Othman
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
| | - Yvonne Kong
- Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Annie Yip
- Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Sebastiaan Van Hal
- Infectious Diseases Department, Royal Prince Alfred Hospital, Sydney, Australia
| | - Stephen Larsen
- Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Christian Bryant
- Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia
| | - John Gibson
- Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Ian Kerridge
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
- Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Keith Fay
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
| | - William Stevenson
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
- Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Chris Arthur
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
| | - Sharon C A Chen
- National Centre for Infection in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- Centre for Infectious Diseases and Microbiology Laboratory Services, Institute of Clinical Pathology and Medical Research, New South Wales Health Pathology, Westmead Hospital, and Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia
| | - David C M Kong
- National Health and Medical Research Council National Centre for Antimicrobial Stewardship at the Peter Doherty Institute for Infections and Immunity, Parkville, Victoria, Australia
- Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Pharmacy Department, Ballarat Health Services, Ballarat, Victoria, Australia
| | - Matthew Greenwood
- Haematology Department, Royal North Shore Hospital, Sydney, Australia
- Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia
| | - Steven A Pergam
- Vaccine and Infectious Disease and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Catherine Liu
- Vaccine and Infectious Disease and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, USA
| | - Monica A Slavin
- National Centre for Infection in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
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Shenoy M, Dhoot D, Mahajan H, Barkate H. An Open-Label, Randomized, Double-Arm Clinical Trial to Compare the Effectiveness and Safety of Super Bioavailable Itraconazole Capsules and Itraconazole Capsules in the Management of Dermatophytosis in India. Clin Cosmet Investig Dermatol 2021; 14:1367-1376. [PMID: 34611418 PMCID: PMC8485852 DOI: 10.2147/ccid.s326642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 08/05/2021] [Indexed: 11/23/2022]
Abstract
Purpose A new oral formulation of itraconazole, called super bioavailable itraconazole (SBITZ), has been launched in India, exhibiting greater bioavailability than conventional itraconazole (CITZ). No clinical studies on its effectiveness and safety in dermatophytosis in comparison with CITZ have been conducted in India. Hence, the aim of this clinical study was to compare the effectiveness and safety of SBITZ capsules and CITZ capsules in dermatophytosis. Patients and Methods This was an open-label, randomized, double-arm clinical study in which 70 patients (≥18 years of age) of either gender and diagnosed with tinea cruris, tinea corporis, and/or tinea faciei were included. The study was divided into two parts, the first part comprising a treatment period of 4 weeks and the second part an observation period for recurrence, comprised of another 4 weeks, thus making an entire study duration of 8 weeks. Results Of the 70 patients enrolled in this study, 59 (33 patients in the CITZ group and 26 patients in the SBITZ group) were included in the final analysis. In both groups, most patients were diagnosed with tinea cruris et corporis, with five or more lesions. At week 4, 11 patients (33.33%) and 17 patients (65.38%) had achieved complete cure (p<0.05), whereas 22 patients (66.67%) and 22 patients (84.61%) had achieved mycological cure (p=0.14), in the CITZ and SBITZ groups, respectively. During the observation period, recurrence was seen in 1/11 and 4/17 completely cured patients in the CITZ and SBITZ groups, respectively (p=0.15). A significant difference was noted in resolution of symptoms as well as lesions of dermatophytosis in the SBITZ group (p<0.05). Both treatments were found to be safe and well tolerated. Conclusion In the light of real-world evidence on effectiveness and safety, SBITZ should be considered as a potent therapeutic choice to effectively control the current menace of dermatophytosis in India.
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Affiliation(s)
- Manjunath Shenoy
- Department of Dermatology, Yenepoya Medical College, Deralakatte, Mangalore, India.,Omega Hospital, Mangalore, Karnataka, India
| | - Dhiraj Dhoot
- Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Harshal Mahajan
- Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
| | - Hanmant Barkate
- Global Medical Affairs, Glenmark Pharmaceuticals Ltd, Mumbai, Maharashtra, India
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Han AN, Han BR, Zhang T, Heimbach T. Hepatic Impairment Physiologically Based Pharmacokinetic Model Development: Current Challenges. CURRENT PHARMACOLOGY REPORTS 2021; 7:213-226. [DOI: 10.1007/s40495-021-00266-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/09/2021] [Indexed: 01/03/2025]
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Bioavailability of Single-Dose SUBA-Itraconazole Compared to Conventional Itraconazole under Fasted and Fed Conditions. Antimicrob Agents Chemother 2021; 65:e0013421. [PMID: 34031053 DOI: 10.1128/aac.00134-21] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Conventional itraconazole (C-ITZ) suffers from absorption variability. SUBA-itraconazole (S-ITZ) is more bioavailable than C-ITZ at steady state in a fed condition, but there are no data comparing the two under a fasted state. An open-label, single-dose, randomized, bioequivalence study was performed comparing S-ITZ to C-ITZ capsules under fasted and fed conditions in healthy adults measuring itraconazole and hydroxyitraconazole plasma levels. This study demonstrated less variability of S-ITZ compared to C-ITZ capsules under fasted conditions.
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Abbotsford J, Foley DA, Goff Z, Bowen AC, Blyth CC, Yeoh DK. Clinical experience with SUBA-itraconazole at a tertiary paediatric hospital. J Antimicrob Chemother 2021; 76:249-252. [PMID: 32929460 DOI: 10.1093/jac/dkaa382] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 08/04/2020] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Itraconazole remains a first-line antifungal agent for certain fungal infections in children, including allergic bronchopulmonary aspergillosis (ABPA) and sporotrichosis, but poor attainment of therapeutic drug levels is frequently observed with available oral formulations. A formulation of 'SUper BioAvailability itraconazole' (SUBA-itraconazole; Lozanoc®) has been developed, with adult studies demonstrating rapid and reliable attainment of therapeutic levels, yet paediatric data are lacking. OBJECTIVES To assess the safety, efficacy and attainment of therapeutic drug levels of the SUBA-itraconazole formulation in children. METHODS A single-centre retrospective cohort study was conducted, including all patients prescribed SUBA-itraconazole from May 2018 to February 2020. The recommended initial treatment dose was 5 mg/kg twice daily (to a maximum of 400 mg/day) rounded to the nearest capsule size and 2.5 mg/kg/day for prophylaxis. RESULTS Nineteen patients received SUBA-itraconazole and the median age was 12 years. The median dose was 8.5 mg/kg/day and the median duration was 6 weeks. Indications included ABPA (16 patients), sporotrichosis (1), cutaneous fungal infection (1) and prophylaxis (1). Of patients with serum levels measured, almost 60% (10/17) achieved a therapeutic level, 3 with one dose adjustment and 7 following the initial dose. Adherence to dose-adjustment recommendations amongst the seven patients not achieving therapeutic levels was poor. Of patients with ABPA, 13/16 (81%) demonstrated a therapeutic response in IgE level. SUBA-itraconazole was well tolerated with no cessations related to adverse effects. CONCLUSIONS SUBA-itraconazole is well tolerated in children, with rapid attainment of therapeutic levels in the majority of patients, and may represent a superior formulation for children in whom itraconazole is indicated for treatment or prevention of fungal infection.
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Affiliation(s)
- Joanne Abbotsford
- Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia
| | - David A Foley
- Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia
| | - Zoy Goff
- Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia
| | - Asha C Bowen
- Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia.,Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia.,University of Western Australia, School of Medicine, Perth, Western Australia, Australia
| | - Christopher C Blyth
- Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia.,Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia.,University of Western Australia, School of Medicine, Perth, Western Australia, Australia.,Department of Microbiology, PathWest Laboratory Medicine, QEII Medical Centre, Royal Perth Hospital and Fiona Stanley Hospital, Western Australia, Australia
| | - Daniel K Yeoh
- Department of Infectious Diseases, Perth Children's Hospital, Nedlands, Western Australia, Australia
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Abstract
Over the past 15 years, there has been an increase in the development and utilization of newer antifungal agents. The ideal antifungal, however, in regard to spectrum of activity, pharmacokinetic/pharmacodynamic properties, development of resistance, safety, and drug interaction profile remains elusive. This article reviews pharmacologic aspects of Food and Drug Administration-approved polyenes, flucytosine, azoles, and echinocandins as well as promising pipeline antifungal agents. Unique properties of these newer agents are highlighted. The clinical role of established and investigational antifungal agents as treatment and/or prevention of invasive fungal infections is discussed.
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Affiliation(s)
- Melissa D Johnson
- Duke University Medical Center, Box 102359 DUMC, Durham NC 27710, USA.
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McKinsey DS. Treatment and Prevention of Histoplasmosis in Adults Living with HIV. J Fungi (Basel) 2021; 7:jof7060429. [PMID: 34071599 PMCID: PMC8229061 DOI: 10.3390/jof7060429] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 11/16/2022] Open
Abstract
Histoplasmosis causes life-threatening disseminated infection in adult patients living with untreated HIV. Although disease incidence has declined dramatically in countries with access to antiretroviral therapy, histoplasmosis remains prevalent in many resource-limited regions. A high index of suspicion for histoplasmosis should be maintained in the setting of a febrile multisystem illness in severely immunosuppressed patients, particularly in persons with hemophagocytic lymphohistiocytosis. Preferred treatment regimens for initial therapy include liposomal amphotericin B for severe disease, or itraconazole for mild to moderate disease. Subsequently, itraconazole maintenance therapy should be administered for at least one year and then discontinued if CD4 count increases to ≥150 cells/µL. Antiretroviral therapy, which improves outcome when administered together with an antifungal agent, should be instituted immediately, as the risk of triggering Immune Reconstitution Syndrome is low. The major risk factor for relapsed infection is nonadherence. Itraconazole prophylaxis reduces risk for histoplasmosis in patients with CD4 counts <100/µL but is not associated with survival benefit and is primarily reserved for use in outbreaks. Although most patients with histoplasmosis have not had recognized high-risk exposures, avoidance of contact with bird or bat guano or inhalation of aerosolized soil in endemic regions may reduce risk. Adherence to effective antiretroviral therapy is the most important strategy for reducing the incidence of life-threatening histoplasmosis.
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Affiliation(s)
- David S McKinsey
- Metro Infectious Disease Consultants, Kansas City, MO 64132, USA
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Samaddar A, Sharma A. Emergomycosis, an Emerging Systemic Mycosis in Immunocompromised Patients: Current Trends and Future Prospects. Front Med (Lausanne) 2021; 8:670731. [PMID: 33968970 PMCID: PMC8104006 DOI: 10.3389/fmed.2021.670731] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Recently, the global emergence of emergomycosis, a systemic fungal infection caused by a novel dimorphic fungus Emergomyces species has been observed among immunocompromised individuals. Though initially classified under the genus Emmonsia, a taxonomic revision in 2017 based on DNA sequence analyses placed five Emmonsia-like fungi under a separate genus Emergomyces. These include Emergomyces pasteurianus, Emergomyces africanus, Emergomyces canadensis, Emergomyces orientalis, and Emergomyces europaeus. Emmonsia parva was renamed as Blastomyces parvus, while Emmonsia crescens and Emmonsia sola remained within the genus Emmonsia until a taxonomic revision in 2020 placed both the species under the genus Emergomyces. However, unlike other members of the genus, Emergomyces crescens and Emergomyces sola do not cause disseminated disease. The former causes adiaspiromycosis, a granulomatous pulmonary disease, while the latter has not been associated with human disease. So far, emergomycosis has been mapped across four continents: Asia, Europe, Africa and North America. However, considering the increasing prevalence of HIV/AIDS, it is presumed that the disease must have a worldwide distribution with many cases going undetected. Diagnosis of emergomycosis remains challenging. It should be considered in the differential diagnosis of histoplasmosis as there is considerable clinical and histopathological overlap between the two entities. Sequencing the internal transcribed spacer region of ribosomal DNA is considered as the gold standard for identification, but its application is compromised in resource limited settings. Serological tests are non-specific and demonstrate cross-reactivity with Histoplasma galactomannan antigen. Therefore, an affordable, accessible, and reliable diagnostic test is the need of the hour to enable its diagnosis in endemic regions and also for epidemiological surveillance. Currently, there are no consensus guidelines for the treatment of emergomycosis. The recommended regimen consists of amphotericin B (deoxycholate or liposomal formulation) for 1–2 weeks, followed by oral itraconazole for at least 12 months. This review elaborates the taxonomic, clinical, diagnostic, and therapeutic aspects of emergomycosis. It also enumerates several novel antifungal drugs which might hold promise in the treatment of this condition and therefore, can be potential areas of future studies.
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Affiliation(s)
- Arghadip Samaddar
- Department of Microbiology, All India Institute of Medical Sciences, Jodhpur, India
| | - Anuradha Sharma
- Department of Microbiology, All India Institute of Medical Sciences, Jodhpur, India
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Sardana K, Mathachan SR. Super Bioavailable Itraconazole and Its Place and Relevance in Recalcitrant Dermatophytosis: Revisiting Skin Levels of Itraconazole and Minimum Inhibitory Concentration Data. Indian Dermatol Online J 2021; 12:1-5. [PMID: 33768016 PMCID: PMC7982045 DOI: 10.4103/idoj.idoj_618_20] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/04/2020] [Accepted: 10/05/2020] [Indexed: 11/29/2022] Open
Abstract
Itraconazole, is the most commonly prescribed oral antifungal agent in India, and has a low minimum inhibitory concentration as compared to other oral antifungals, and in conjunction with the markedly high skin levels, the drug should have a predictably good clinical response which is not the consistent experience of clinicians. Probably the variation in pelletization parameters might affect the bioavailability of the drug and consequently affect the serum levels. The maximum bioavailability of conventional itraconazole is 55 percent, which is neither consistent nor predictable. However, the novel itraconazole (Super bioavailable Itraconazole) with targeted drug release in the small intestine has predictable serum levels with minimum interindividual variability, which could make it a potentially useful drug in recalcitrant dermatophytosis.
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Affiliation(s)
- Kabir Sardana
- Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. RML Hospital, New Delhi, India
| | - Sinu Rose Mathachan
- Department of Dermatology, Venereology and Leprosy, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. RML Hospital, New Delhi, India
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Beck KR, Odermatt A. Antifungal therapy with azoles and the syndrome of acquired mineralocorticoid excess. Mol Cell Endocrinol 2021; 524:111168. [PMID: 33484741 DOI: 10.1016/j.mce.2021.111168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 12/31/2020] [Accepted: 01/06/2021] [Indexed: 10/22/2022]
Abstract
The syndromes of mineralocorticoid excess describe a heterogeneous group of clinical manifestations leading to endocrine hypertension, typically either through direct activation of mineralocorticoid receptors or indirectly by impaired pre-receptor enzymatic regulation or through disturbed renal sodium homeostasis. The phenotypes of these disorders can be caused by inherited gene variants and somatic mutations or may be acquired upon exposures to exogenous substances. Regarding the latter, the symptoms of an acquired mineralocorticoid excess have been reported during treatment with azole antifungal drugs. The current review describes the occurrence of mineralocorticoid excess particularly during the therapy with posaconazole and itraconazole, addresses the underlying mechanisms as well as inter- and intra-individual differences, and proposes a therapeutic drug monitoring strategy for these two azole antifungals. Moreover, other therapeutically used azole antifungals and ongoing efforts to avoid adverse mineralocorticoid effects of azole compounds are shortly discussed.
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Affiliation(s)
- Katharina R Beck
- Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Alex Odermatt
- Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
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Whitmore TJ, Yaw M, Lavender M, Musk M, Boan P, Wrobel J. A novel highly bio-available itraconazole formulation (SUBA®-Itraconazole) for anti-fungal prophylaxis in lung transplant recipients. Transpl Infect Dis 2021; 23:e13587. [PMID: 33590676 DOI: 10.1111/tid.13587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/28/2021] [Accepted: 02/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Antifungal prophylaxis remains a mainstay of lung transplantation, given invasive fungal infection is a common and serious complication after lung transplantation. Choice of systemic agent to prevent invasive fungal infection varies between centers and funding of agents remains challenging. Our center has recently changed from posaconazole to a highly bioavailable formulation of itraconazole (SUBA®-itraconazole) at substantially reduced cost, but safety and toxicity require further assessment. A retrospective study of lung transplant patients receiving systemic antifungal prophylaxis from December 2016 through December 2019 following change from posaconazole to itraconazole as standard practice. 150 patients with lung transplants were managed in this time period, with 88 (59%) receiving at least 1 mold-active triazole during the study period. 48 (58%) of these patients received SUBA®-itraconazole; 68 (82%) received posaconazole and 10 (12%) received voriconazole. The average cost per patient during the study period was significantly lower on SUBA®-itraconazole (mean $1548/patient/6 month course) than posaconazole (mean $16 921.35/patient/6 month course). Target trough concentrations for prophylaxis of itraconazole > 0.5 mg/L and posaconazole > 0.7 mg/L were achieved on empiric dosing in 49% and 68% respectively. Overall trough itraconazole (0.50 vs 1.12 mg/L, P < .001) and posaconazole (1.37 vs 2.10 mg/L P < .001) concentrations were significantly lower in patients with cystic fibrosis. Calcineurin inhibitor dose changes on introduction or cessation were similar for SUBA®-itraconazole and posaconazole. Breakthrough invasive fungal infection and toxicity were rare. SUBA®-itraconazole is well-tolerated, associated with rare breakthrough invasive fungal infection, and lower cost. Prospective studies following general introduction are required to determine long-term safety, tolerability, and efficacy.
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Affiliation(s)
- Timothy James Whitmore
- Department of Infectious Diseases, Fiona Stanley Hospital, Perth, WA, Australia.,Department of Microbiology, PathWest Laboratory Medicine WA, Perth, WA, Australia.,Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia
| | - Meow Yaw
- Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia
| | - Melanie Lavender
- Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia
| | - Michael Musk
- Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia
| | - Peter Boan
- Department of Infectious Diseases, Fiona Stanley Hospital, Perth, WA, Australia.,Department of Microbiology, PathWest Laboratory Medicine WA, Perth, WA, Australia
| | - Jeremy Wrobel
- Department of Respiratory Medicine, Fiona Stanley Hospital, Perth, WA, Australia.,School of Medicine, University of Notre Dame Australia, Fremantle, WA, Australia
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Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy Adults. Antimicrob Agents Chemother 2020; 64:AAC.00400-20. [PMID: 32457106 PMCID: PMC7526808 DOI: 10.1128/aac.00400-20] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 05/14/2020] [Indexed: 01/07/2023] Open
Abstract
Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered three times daily for 3 days and once on day 4 (n = 15). For the steady-state administration study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered twice daily for 14 days and a last dose was administered 30 min after a meal on day 15 (n = 16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares geometric means were used to compare the maximum peak concentration of drug after administration at steady state prior to administration of the subsequent dose (C max_ss), the minimum drug level after administration prior to the subsequent dose (C trough), and the area under the curve over the dosing interval (AUCtau) of each formulation. The ratios of itraconazole (ITZ) and OH-ITZ for S-ITZ to C-ITZ were between 107% and 118% in both studies for C max_ss, C trough, and AUCtau, which were within the U.S. FDA-required bioequivalence range of 80% to 125%. At the end of the steady-state administration study, 13 of 16 volunteers obtained higher mean ITZ blood C trough levels of >1,000 ng/ml when they were administered S-ITZ (81%) than when they were administered C-ITZ (44%). The study drugs were well tolerated in both studies, with similar adverse events (AEs). All treatment-emergent AEs resolved after study completion. One volunteer receiving C-ITZ discontinued due to a treatment-unrelated AE in the steady-state administration study. No serious AEs were reported. Total, trough, and peak ITZ and OH-ITZ exposures were similar between the two formulations. Therefore, SUBA-ITZ, which has 35% less drug than C-ITZ, was bioequivalent to C-ITZ in healthy adult volunteers and exhibited a safety profile similar to that of C-ITZ.
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Larkin PMK, Multani A, Beaird OE, Dayo AJ, Fishbein GA, Yang S. A Collaborative Tale of Diagnosing and Treating Chronic Pulmonary Aspergillosis, from the Perspectives of Clinical Microbiologists, Surgical Pathologists, and Infectious Disease Clinicians. J Fungi (Basel) 2020; 6:E106. [PMID: 32664547 PMCID: PMC7558816 DOI: 10.3390/jof6030106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic pulmonary aspergillosis (CPA) refers to a spectrum of Aspergillus-mediated disease that is associated with high morbidity and mortality, with its true prevalence vastly underestimated. The diagnosis of CPA includes characteristic radiographical findings in conjunction with persistent and systemic symptoms present for at least three months, and evidence of Aspergillus infection. Traditionally, Aspergillus infection has been confirmed through histopathology and microbiological studies, including fungal culture and serology, but these methodologies have limitations that are discussed in this review. The treatment of CPA requires an individualized approach and consideration of both medical and surgical options. Most Aspergillus species are considered susceptible to mold-active triazoles, echinocandins, and amphotericin B; however, antifungal resistance is emerging and well documented, demonstrating the need for novel therapies and antifungal susceptibility testing that correlates with clinical response. Here, we describe the clinical presentation, diagnosis, and treatment of CPA, with an emphasis on the strengths and pitfalls of diagnostic and treatment approaches, as well as future directions, including whole genome sequencing and metagenomic sequencing. The advancement of molecular technology enables rapid and precise species level identification, and the determination of molecular mechanisms of resistance, bridging the clinical infectious disease, anatomical pathology, microbiology, and molecular biology disciplines.
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Affiliation(s)
- Paige M. K. Larkin
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.M.K.L.); (A.J.D.); (G.A.F.)
- Department of Pathology, NorthShore University HealthSystem, Evanston, IL 60201, USA
| | - Ashrit Multani
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.M.); (O.E.B.)
| | - Omer E. Beaird
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, CA 90095, USA; (A.M.); (O.E.B.)
| | - Ayrton J. Dayo
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.M.K.L.); (A.J.D.); (G.A.F.)
| | - Gregory A. Fishbein
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.M.K.L.); (A.J.D.); (G.A.F.)
| | - Shangxin Yang
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA; (P.M.K.L.); (A.J.D.); (G.A.F.)
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