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In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts.

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Sabatelli, F., Patel, R., Mann, P. A., Mendrick, C. A., Norris, C. C., Hare, R., Loebenberg, D., Black, T. A., McNicholas, P. M.·2006·Antimicrobial Agents and Chemotherapy

DOI 10.1128/aac.00163-06

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Abstract

The in vitro activity of the novel triazole antifungal agent posaconazole (Noxafil; SCH 56592) was assessed in 45 laboratories against approximately 19,000 clinically important strains of yeasts and molds. The activity of posaconazole was compared with those of itraconazole, fluconazole, voriconazole, and amphotericin B against subsets of the isolates. Strains were tested utilizing Clinical and Laboratory Standards Institute broth microdilution methods using RPMI 1640 medium (except for amphotericin B, which was frequently tested in antibiotic medium 3). MICs were determined at the recommended endpoints and time intervals. Against all fungi in the database (22,850 MICs), the MIC(50) and MIC(90) values for posaconazole were 0.063 microg/ml and 1 mug/ml, respectively. MIC(90) values against all yeasts (18,351 MICs) and molds (4,499 MICs) were both 1 mug/ml. In comparative studies against subsets of the isolates, posaconazole was more active than, or within 1 dilution of, the comparator drugs itraconazole, fluconazole, voriconazole, and amphotericin B against approximately 7,000 isolates of Candida and Cryptococcus spp. Against all molds (1,702 MICs, including 1,423 MICs for Aspergillus isolates), posaconazole was more active than or equal to the comparator drugs in almost every category. Posaconazole was active against isolates of Candida and Aspergillus spp. that exhibit resistance to fluconazole, voriconazole, and amphotericin B and was much more active than the other triazoles against zygomycetes. Posaconazole exhibited potent antifungal activity against a wide variety of clinically important fungal pathogens and was frequently more active than other azoles and amphotericin B.

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Recent advances in the understanding and management of mucormycosis
Pilmis, B., Alanio, A., Lortholary, O., & Lanternier, F. (2018) · F1000Research · doi:10.12688/f1000research.15081.1 · Cited by 91
“Amphotericin B (Amb) and its lipid formulations and posaco-nazole were the only antifungal drugs available with in vitro activity against mucorales 40,41 .”
Background
Two Clinical Isolates of Candida glabrata Exhibiting Reduced Sensitivity to Amphotericin B Both Harbor Mutations in ERG2
Hull, C. M., Bader, O., Parker, J. E., Weig, M., Gross, U., Warrilow, A. G. S., Kelly, D. E., & Kelly, S. L. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01145-12 · Cited by 90
“Aside from solubility and host toxicity issues, the utility of amphotericin B is compromised by the emergence of strains with reduced sensitivity (12, 29) and by species that are intrinsically less susceptible (Aspergillus flavus, Aspergillus terreus [25], Candida lusitaniae [22], Pneumocystis jirovecii [1]).”
Background
Phase 1B Study of the Pharmacokinetics and Safety of Posaconazole Intravenous Solution in Patients at Risk for Invasive Fungal Disease
Maertens, J. A., Cornely, O. A., Ullmann, A. J., Heinz, W., Krishna, G., Patino, H., Caceres, M., Kartsonis, N. A., Waskin, H. A., & Robertson, M. N. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02686-13 · Cited by 90
“In this study, the lower end of the target exposure range (Cavg 500 ng/ml) was based on the exposure-response analysis (4) and was chosen because posaconazole 500 ng/ml is the MIC90 of most clinically important Aspergillus species (24).”
Method
Pharmacokinetics of Oral Posaconazole in Neutropenic Patients Receiving Chemotherapy for Acute Myelogenous Leukemia or Myelodysplastic Syndrome
Krishna, G., Abutarif, M. A., Xuan, F., Martinho, M., Angulo, D. A., & Cornely, O. A. (2008) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.28.10.1223 · Cited by 89
“Posaconazole is highly protein bound (> 98%),(31) and in contrast to total plasma concentrations, unbound posaconazole plasma concentrations fall below the agent’s minimum inhibitory concentration.(7) A similar relationship has been observed for other highly protein-bound lipophilic antifungal agents such as itraconaz…”
Background
In Vitro Activities of Isavuconazole and Other Antifungal Agents against Candida Bloodstream Isolates
Seifert, H., Aurbach, U., Stefanik, D., & Cornely, O. A. (2007) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01217-06 · Cited by 85
“Consistent with previous reports (10), isolates with elevated MICs for one azole were generally less susceptible to all azoles (Table 2).”
Result
Intrapulmonary Pharmacokinetics and Pharmacodynamics of Posaconazole at Steady State in Healthy Subjects
Conte, J. E., Golden, J. A., Krishna, G., McIver, M., Little, E., & Zurlinden, E. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00663-08 · Cited by 84
Is Azole Resistance in Aspergillus fumigatus a Problem in Spain?
Escribano, P., Peláez, T., Muñóz, P., Bouza, E., & Guinea, J. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02487-12 · Cited by 85
Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids
Sharma, P. K., Balwani, S., Mathur, D., Malhotra, S., Singh, B. K., Prasad, A. K., Len, C., der Eycken, E. V. V., Ghosh, B., Richards, N. G. J., et al. (2016) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.3109/14756366.2016.1151015 · Cited by 83
Intrinsic short-tailed azole resistance in mucormycetes is due to an evolutionary conserved aminoacid substitution of the lanosterol 14α-demethylase
Caramalho, R., Tyndall, J. D. A., Monk, B. C., Larentis, T., Lass‐Flörl, C., & Lackner, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-16123-9 · Cited by 83
Clinical pharmacodynamics and pharmacokinetics of the antifungal extended‐spectrum triazole posaconazole: an overview
Lipp, H. (2010) · British Journal of Clinical Pharmacology · doi:10.1111/j.1365-2125.2010.03680.x · Cited by 82
Fungal infections after lung transplantation
Solé, A., & Salavert, M. (2008) · Transplantation Reviews · doi:10.1016/j.trre.2007.12.007 · Cited by 82
“Of the newer triazoles (voriconazole, posaconazole, and ravuconazole) have demonstrated in vitro activity against S apiospermum [68].”
Background
Impact of Antifungal Prophylaxis on Colonization and Azole Susceptibility of Candida Species
Mann, P. A., McNicholas, P. M., Chau, A. S., Patel, R. J., Mendrick, C. A., Ullmann, A. J., Cornely, O. A., Patino, H., & Black, T. A. (2009) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01031-09 · Cited by 79
“glabrata also did not change; however, the MIC90s (but not the MIC50s) were two- to fourfold higher than those seen previously in a large survey of clinical isolates (14).”
Result
Antifungal Susceptibility Testing of Fusarium: A Practical Approach
Al‐Hatmi, A. M. S., Curfs-Breuker, I., de Hoog, S., Meis, J. F. G. M., & Verweij, P. E. (2017) · Journal of Fungi · doi:10.3390/jof3020019 · Cited by 84
Pharmacokinetics and safety results from the Phase 3 randomized, open-label, study of intravenous posaconazole in patients at risk of invasive fungal disease
Cornely, O. A., Robertson, M. N., Haider, S., Grigg, A., Geddes, M. N., Aoun, M., Heinz, W., RAAD, I. I., Schanz, U., Meyer, R. G., et al. (2017) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkx263 · Cited by 80
Alternaria Keratitis: Clinical Presentation and Resolution With Topical Fluconazole or Intrastromal Voriconazole and Topical Caspofungin
Tu, E. Y. (2008) · Cornea · doi:10.1097/ico.0b013e31818225f8 · Cited by 77
Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications
Autmizguine, J., Guptill, J. T., Cohen‐Wolkowiez, M., Benjamin, D. K., & Capparelli, E. V. (2014) · Drugs · doi:10.1007/s40265-014-0227-3 · Cited by 75
“Despite its broad-spectrum activity against yeast and molds, voriconazole is not active against zygomycetes [12, 84].”
Background
Posaconazole as Salvage Therapy in Patients With Invasive Fungal Infections After Solid Organ Transplant
Alexander, B. D., Perfect, J. R., Daly, J. S., Restrepo, Á., Tobón, Á. M., Patino, H., Hardalo, C. J., & Graybill, J. R. (2008) · Transplantation · doi:10.1097/tp.0b013e3181837585 · Cited by 74
Efficacy, Safety, and Breakthrough Infections Associated with Standard Long-Term Posaconazole Antifungal Prophylaxis in Allogeneic Stem Cell Transplantation Recipients
Winston, D. J., Bartoni, K., Territo, M. C., & Schiller, G. J. (2011) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2010.04.017 · Cited by 73
“Posaconazole is a relatively new oral triazole agent with an enhanced spectrum of in vitro activity against a wide range of medically important fungi, including Candida, Aspergillus, the emerging Zygomycetes, and other filamentous fungi [17].”
Background
Fusarium Infection in Lung Transplant Patients
Carneiro, H. A., Coleman, J. J., Restrepo, A., & Mylonakis, E. E. (2010) · Medicine · doi:10.1097/md.0b013e318207612d · Cited by 74
“Concerning the azoles: fluconazole is not active against molds; itraconazole has good in vitro activity against Aspergillus but not Fusarium or Zygomycetes; voriconazole has good activity against most Aspergillus species but no activity against Zygomycetes; and posaconazole has good in vitro activity against Aspergill…”
BackgroundInfluential
Comparison of the Broth Microdilution (BMD) Method of the European Committee on Antimicrobial Susceptibility Testing with the 24-Hour CLSI BMD Method for Testing Susceptibility of Candida Species to Fluconazole, Posaconazole, and Voriconazole by Use of Epidemiological Cutoff Values
Pfaller, M. A., Espinel‐Ingroff, A., Boyken, L. B., Hollis, R. J., Kroeger, J. S., Messer, S. A., Tendolkar, S., & Diekema, D. J. (2011) · Journal of Clinical Microbiology · doi:10.1128/jcm.02441-10 · Cited by 73
“Despite the broad utilization of these agents in the prevention and treatment of invasive candidiasis (2, 6, 16, 34), longitudinal surveillance studies have documented the sustained potency of all three triazoles since the introduction of fluconazole in 1990 (8, 9, 18, 21, 25, 28, 31).”
Background
Synthesis and Biological Activity of Substituted Urea and Thiourea Derivatives Containing 1,2,4-Triazole Moieties
Koçyiğit‐Kaymakçıoğlu, B., Celen, A., Tabanca, N., Alı, A., Khan, S. I., Khan, I. A., & Wedge, D. E. (2013) · Molecules · doi:10.3390/molecules18033562 · Cited by 73
“Drugs such as fluconazole, itraconazole, and the new generation of triazoles posaconazole, voriconazole, and ravuconazole are the best examples of potent antifungal molecules possessing triazole nuclei [15–17].”
Background
Novel antifungal agents: a patent review (2011 – present)
Castelli, M. V., Butassi, E., Monteiro, M. C., Svetaz, L. A., Vicente, F., & Zacchino, S. A. (2014) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2014.876993 · Cited by 76
“Later, a first generation of triazole-based antifungal drugs such as fluconazole (FCZ) and itraconazole (ITR) appeared in the market [10], which were followed by new generations of triazoles, including voriconazole (VRC) and posaconazole (POS) (Figure 2) [10,20,23].”
Background
Susceptibility of clinical Candida species isolates to antifungal agents by E-test, Southern Iran: A five year study.
Badiee, P., & Alborzi, A. (2011) · Europe PMC (PubMed Central) · Cited by 72
Evaluating prophylaxis of invasive fungal infections in patients with haematologic malignancies
Maertens, J. A. (2006) · European Journal Of Haematology · doi:10.1111/j.1600-0609.2006.00805.x · Cited by 71
“The in vitro activity of posaconazole is generally greater than that of fluconazole and either equal to or greater than that of itraconazole, voriconazole, and amphotericin B (49, 50).”
Background
Effects of oral posaconazole on the pharmacokinetic properties of oral and intravenous midazolam: A phase I, randomized, open-label, crossover study in healthy volunteers
Krishna, G., Moton, A., Ma, L., Savant, I. A., Martinho, M., Seiberling, M., & McLeod, J. F. (2009) · Clinical Therapeutics · doi:10.1016/j.clinthera.2009.02.022 · Cited by 68
Comparativein vitroactivities of posaconazole, voriconazole, itraconazole, and amphotericin B againstAspergillusandRhizopus, and synergy testing forRhizopus
Arıkan, S., Sancak, B., Alp, Ş., Hasçelik, G., & McNicholas, P. M. (2008) · Medical Mycology · doi:10.1080/13693780801975576 · Cited by 68
A Five-Year Survey of Dematiaceous Fungi in a Tropical Hospital Reveals Potential Opportunistic Species
Yew, S. M., Chan, C. L., Lee, K. W., Na, S. L., Tan, R., Hoh, C.-C., Yee, W.-Y., Ngeow, Y. F., & Ng, K. P. (2014) · PLoS ONE · doi:10.1371/journal.pone.0104352 · Cited by 67
“These observations are consistent with previous reports on the enhanced antifungal activity of the later generation triazoles [70,71] and the limited activity of FLC on molds [72].”
Result
In Vitro Activity of the New Azole Isavuconazole (BAL4815) Compared with Six Other Antifungal Agents against 162 Cryptococcus neoformans Isolates from Cuba
Zaragozí, M. T. I., Martínez, G., Curfs-Breuker, I., Fernández, C. M., Boekhout, T., & Meis, J. F. G. M. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01384-07 · Cited by 67
“These agents possess potent broad-spectrum activity and favorable pharmacokinetic profiles (14, 18, 23).”
Background
In Vitro Activities of Amphotericin B, Caspofungin, Itraconazole, Posaconazole, and Voriconazole against 45 Clinical Isolates of Zygomycetes: Comparison of CLSI M38-A, Sensititre YeastOne, and the Etest
Torres-Narbona, M., Guinea, J., Martínez-Alarcón, J., Peláez, T., & Bouza, E. (2006) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01539-06 · Cited by 66
“proved to be quite resistant in vitro, and this correlates well with previous reports on the clinical inefficacy of both drugs in the treatment of zygomycosis (6, 7, 10, 27, 29).”
Result
How Does Antifungal Pharmacology Differ for Mucormycosis Versus Aspergillosis?
Lewis, R. E., Lortholary, O., Spellberg, B. J., Roilides, E., Kontoyiannis, D. P., & Walsh, T. J. (2012) · Clinical Infectious Diseases · doi:10.1093/cid/cir884 · Cited by 66
“a MIC data are adapted from from references [15, 16].”
Method
Approaches to the Management of Invasive Fungal Infections in Hematologic Malignancy and Hematopoietic Cell Transplantation
Michallet, M., & Ito, J. I. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.20.1178 · Cited by 64
Chromoblastomycosis
Torres‐Guerrero, E., Isa‐Isa, R., Isa, M., & Arenas, R. (2012) · Clinics in Dermatology · doi:10.1016/j.clindermatol.2011.09.011 · Cited by 65
Fungal infections after lung transplantation
Solé, A., & Salavert, M. (2009) · Current Opinion in Pulmonary Medicine · doi:10.1097/mcp.0b013e328326f410 · Cited by 64
Chronic mucocutaneous candidiasis, from bench to bedside
Eyerich, K., Eyerich, S., Hiller, J., Behrendt, H., & Traidl‐Hoffmann, C. (2010) · European Journal of Dermatology · doi:10.1684/ejd.2010.0910 · Cited by 68
In VitroAntifungal Activity of Isavuconazole against 345 Mucorales Isolates Collected at Study Centers in Eight Countries
Verweij, P. E., González, G. M., Wiederhold, N. P., Lass‐Flörl, C., Warn, P. A., Heep, M., Ghannoum, M. A., & Guinea, J. (2009) · Journal of Chemotherapy · doi:10.1179/joc.2009.21.3.272 · Cited by 63
Is there a serious risk of resistance development to azoles among fungi due to the widespread use and long-term application of azole antifungals in medicine?
Hof, H. (2008) · Drug Resistance Updates · doi:10.1016/j.drup.2008.01.001 · Cited by 60
“The latter agents are moreover able to bind to an additional domain of the enzyme by means of their long side chain (Fig. 2 )( Li et al., 2004; Marichal et al., 1999; Xiao et al., 2004), so that these agents can still inhibit the target, even when fluconazole and voriconazole are no more reactive (Chau et al., 2004; S…”
BackgroundInfluential
Posaconazole inhibits dengue virus replication by targeting oxysterol-binding protein
Meutiawati, F., Bezemer, B., Strating, J. R. P. M., Overheul, G. J., Žusinaite, E., van Kuppeveld, F. J. M., van Cleef, K. W. R., & van Rij, R. P. (2018) · Antiviral Research · doi:10.1016/j.antiviral.2018.06.017 · Cited by 58
Review of the New Delayed‐Release Oral Tablet and Intravenous Dosage Forms of Posaconazole
Guarascio, A. J., & Slain, D. (2015) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1002/phar.1533 · Cited by 57
“2 Compared with other triazole antifungals, posaconazole most notably exhibits enhanced activity against Candida sp (including fluconazole-resistant strains), Aspergillus sp, and the class of Mucormycetes.(2) Posaconazole currently holds U.”
BackgroundInfluential
Genetic Analysis Using an Isogenic Mating Pair of Aspergillus fumigatus Identifies Azole Resistance Genes and Lack of MAT Locus’s Role in Virulence
Losada, L. C., Sugui, J. A., Eckhaus, M., Chang, Y. C., Mounaud, S. H., Abigail, F., Joardar, V., Pakala, S., Pakala, S. M., Venepally, P., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004834 · Cited by 61
Posaconazole/hydroxypropyl-β-cyclodextrin host–guest system: Improving dissolution while maintaining antifungal activity
Tang, P., Ma, X., Wu, D., Li, S., Xu, K., Tang, B., & Li, H. (2016) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2016.01.042 · Cited by 58
Design, synthesis and evaluation of aromatic heterocyclic derivatives as potent antifungal agents
Zhao, S., Zhang, X., Peng, W. J., Su, X., Zhao, L., Wu, M., Hao, C., Liu, C., Zhao, D., & Cheng, M. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.05.043 · Cited by 58
Traditional and Emerging Antifungal Therapies
Arnold, T. M., Dotson, E. K., Sarosi, G. A., & Hage, C. A. (2010) · Proceedings of the American Thoracic Society · doi:10.1513/pats.200906-048al · Cited by 57
Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men
Krishna, G., Sansone‐Parsons, A., & Kantesaria, B. S. (2007) · Current Medical Research and Opinion · doi:10.1185/030079907x187937 · Cited by 57
Species and susceptibility distribution of 1062 clinical yeast isolates to azoles, echinocandins, flucytosine and amphotericin B from a multi‐centre study
Schmalreck, A., Willinger, B., Haase, G., Blum, G., Lass‐Flörl, C., Fegeler, W., Becker, K., & for the Antifungal Susceptibility Testing (AFST) Study Group (2012) · Mycoses · doi:10.1111/j.1439-0507.2011.02165.x · Cited by 57
The clinical spectrum of Exophiala jeanselmei, with a case report and in vitro antifungal susceptibility of the species
Badali, H., Najafzadeh, M. J., Esbroeck, M. V., den Enden, E. V., Tarazooie, B., Meis, J. F. G. M., & de Hoog, S. (2009) · Medical Mycology · doi:10.1080/13693780903148353 · Cited by 56

Authors: Sabatelli, F., Patel, R., Mann, P. A., Mendrick, C. A., Norris, C. C., Hare, R., Loebenberg, D., Black, T. A., & McNicholas, P. M.
Affiliations: Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
ORCID: Mann, P. A.
Venue: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
Published: 2006-06
Volume: 50
Issue: 6
Pages: 2009-2015
ISSN: 0066-4804 (ISSN-L)
1098-6596
DOI: 10.1128/aac.00163-06
OpenAlex: W2139126851
Cited by: 491
References: 38
Citations by year: 2026: 8 · 2025: 13 · 2024: 8 · 2023: 8 · 2022: 13 · 2021: 16 · 2020: 17 · 2019: 16 · 2018: 37 · 2017: 20 · 2016: 21 · 2015: 26 · 2014: 33 · 2013: 23 · 2012: 27
FWCI: 28.15
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Antimicrobial Agents and Chemotherapy (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
Life Sciences › Agricultural and Biological Sciences › Plant Science › Fungal Plant Pathogen Control
Keywords: posaconazole, fluconazole, itraconazole, voriconazole, amphotericin B, antifungal susceptibility, minimum inhibitory concentration, molds, yeast, Candida, Cryptococcus, Aspergillus, Zygomycetes, triazole antifungals, antifungal resistance, in vitro antifungal activity
MeSH terms: Amphotericin B, Antifungal Agents, Aspergillosis, Aspergillus, Candida, Candidiasis, Cryptococcosis, Cryptococcus, Fungi, Humans, Microbial Sensitivity Tests, Mycoses, Pyrimidines, Triazoles, Fluconazole, Itraconazole, Drug Resistance, Fungal, Voriconazole, In Vitro Techniques

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In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts.

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