Antifungal Therapy: New and Evolving Therapies

Abstract

Invasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug–drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against Candida species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug–drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections.

Keywords

amphotericin B - liposomal amphotericin B - triazoles - echinocandins - olorofim - rezafungin - ibrexafungerp - manogepix - pharmacokinetics - drug-drug interaction

• References

• 1 Nett JE, Andes DR. Antifungal agents: spectrum of activity, pharmacology, and clinical indications. Infect Dis Clin North Am 2016; 30 (01) 51-83
• 2 Andes DR, Safdar N, Baddley JW. , et al; Mycoses Study Group. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 2012; 54 (08) 1110-1122
• 3 Tissot F, Agrawal S, Pagano L. , et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica 2017; 102 (03) 433-444
• 4 Gavaldà J, Meije Y, Fortún J. , et al; ESCMID Study Group for Infections in Compromised Hosts. Invasive fungal infections in solid organ transplant recipients. Clin Microbiol Infect 2014; 20 (Suppl. 07) 27-48
• 5 Eckmanns T, Rüden H, Gastmeier P. The influence of high-efficiency particulate air filtration on mortality and fungal infection among highly immunosuppressed patients: a systematic review. J Infect Dis 2006; 193 (10) 1408-1418
• 6 Partridge-Hinckley K, Liddell GM, Almyroudis NG, Segal BH. Infection control measures to prevent invasive mould diseases in hematopoietic stem cell transplant recipients. Mycopathologia 2009; 168 (06) 329-337
• 7 Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs 2013; 73 (09) 919-934
• 8 Cornely OA, Maertens J, Bresnik M. , et al; AmBiLoad Trial Study Group. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44 (10) 1289-1297
• 9 Diekema DJ, Messer SA, Hollis RJ, Jones RN, Pfaller MA. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2003; 41 (08) 3623-3626
• 10 Sabatelli F, Patel R, Mann PA. , et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother 2006; 50 (06) 2009-2015
• 11 Bern C, Adler-Moore J, Berenguer J. , et al. Liposomal amphotericin B for the treatment of visceral leishmaniasis. Clin Infect Dis 2006; 43 (07) 917-924
• 12 Tiphine M, Letscher-Bru V, Herbrecht R. Amphotericin B and its new formulations: pharmacologic characteristics, clinical efficacy, and tolerability. Transpl Infect Dis 1999; 1 (04) 273-283
• 13 Herbrecht R, Natarajan-Amé S, Nivoix Y, Letscher-Bru V. The lipid formulations of amphotericin B. Expert Opin Pharmacother 2003; 4 (08) 1277-1287
• 14 Patterson TF, Thompson III GR, Denning DW. , et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 63 (04) e1-e60
• 15 Xia D, Sun WK, Tan MM. , et al. Aerosolized amphotericin B as prophylaxis for invasive pulmonary aspergillosis: a meta-analysis. Int J Infect Dis 2015; 30: 78-84
• 16 Rijnders BJ, Cornelissen JJ, Slobbe L. , et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis 2008; 46 (09) 1401-1408
• 17 Drew RH, Dodds Ashley E, Benjamin Jr DK, Duane Davis R, Palmer SM, Perfect JR. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients. Transplantation 2004; 77 (02) 232-237
• 18 Alexander BD, Dodds Ashley ES, Addison RM, Alspaugh JA, Chao NJ, Perfect JR. Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2006; 8 (01) 13-20
• 19 Husain S, Capitano B, Corcoran T. , et al. Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients. Transplantation 2010; 90 (11) 1215-1219
• 20 Bowden R, Chandrasekar P, White MH. , et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2002; 35 (04) 359-366
• 21 Wingard JR, White MH, Anaissie E, Raffalli J, Goodman J, Arrieta A. ; L Amph/ABLC Collaborative Study Group. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis 2000; 31 (05) 1155-1163
• 22 Hoffman HL, Ernst EJ, Klepser ME. Novel triazole antifungal agents. Expert Opin Investig Drugs 2000; 9 (03) 593-605
• 23 Koltin Y, Hitchcock CA. The search for new triazole antifungal agents. Curr Opin Chem Biol 1997; 1 (02) 176-182
• 24 Herbrecht R, Nivoix Y, Fohrer C, Natarajan-Amé S, Letscher-Bru V. Management of systemic fungal infections: alternatives to itraconazole. J Antimicrob Chemother 2005; 56 (Suppl. 01) i39-i48
• 25 Herbrecht R, Patterson TF, Slavin MA. , et al. Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versus amphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization for Research and Treatment of Cancer Infectious Diseases Group. Clin Infect Dis 2015; 60 (05) 713-720
• 26 Kontoyiannis DP, Lionakis MS, Lewis RE. , et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis 2005; 191 (08) 1350-1360
• 27 Siwek GT, Dodgson KJ, de Magalhaes-Silverman M. , et al. Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis 2004; 39 (04) 584-587
• 28 Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39 (05) 743-746
• 29 Guinea J, Peláez T, Recio S, Torres-Narbona M, Bouza E. In vitro antifungal activities of isavuconazole (BAL4815), voriconazole, and fluconazole against 1,007 isolates of zygomycete, Candida, Aspergillus, Fusarium, and Scedosporium species. Antimicrob Agents Chemother 2008; 52 (04) 1396-1400
• 30 Jørgensen KM, Astvad KMT, Hare RK, Arendrup MC. EUCAST susceptibility testing of isavuconazole: MIC data for contemporary clinical mold and yeast isolates. Antimicrob Agents Chemother 2019; 63 (06) 63
• 31 Poirier JM, Cheymol G. Optimisation of itraconazole therapy using target drug concentrations. Clin Pharmacokinet 1998; 35 (06) 461-473
• 32 Krieter P, Flannery B, Musick T, Gohdes M, Martinho M, Courtney R. Disposition of posaconazole following single-dose oral administration in healthy subjects. Antimicrob Agents Chemother 2004; 48 (09) 3543-3551
• 33 Roffey SJ, Cole S, Comby P. , et al. The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human. Drug Metab Dispos 2003; 31 (06) 731-741
• 34 Debruyne D, Ryckelynck JP. Clinical pharmacokinetics of fluconazole. Clin Pharmacokinet 1993; 24 (01) 10-27
• 35 McCarthy MW, Moriyama B, Petraitiene R, Walsh TJ, Petraitis V. Clinical pharmacokinetics and pharmacodynamics of isavuconazole. Clin Pharmacokinet 2018; 57 (12) 1483-1491
• 36 Black DJ, Kunze KL, Wienkers LC. , et al. Warfarin-fluconazole. II. A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996; 24 (04) 422-428
• 37 Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull 2005; 28 (09) 1805-1808
• 38 Sakaeda T, Iwaki K, Kakumoto M. , et al. Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs. J Pharm Pharmacol 2005; 57 (06) 759-764
• 39 Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995; 13 (03) 129-134
• 40 Eytan GD, Regev R, Assaraf YG. Functional reconstitution of P-glycoprotein reveals an apparent near stoichiometric drug transport to ATP hydrolysis. J Biol Chem 1996; 271 (06) 3172-3178
• 41 Ferté J. Analysis of the tangled relationships between P-glycoprotein-mediated multidrug resistance and the lipid phase of the cell membrane. Eur J Biochem 2000; 267 (02) 277-294
• 42 Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW. Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother 2002; 46 (01) 160-165
• 43 Gupta A, Unadkat JD, Mao Q. Interactions of azole antifungal agents with the human breast cancer resistance protein (BCRP). J Pharm Sci 2007; 96 (12) 3226-3235
• 44 Debruyne D. Clinical pharmacokinetics of fluconazole in superficial and systemic mycoses. Clin Pharmacokinet 1997; 33 (01) 52-77
• 45 Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH. The disposition and metabolism of [14C]fluconazole in humans. Drug Metab Dispos 1991; 19 (04) 764-767
• 46 Van de Velde VJ, Van Peer AP, Heykants JJ. , et al. Effect of food on the pharmacokinetics of a new hydroxypropyl-beta-cyclodextrin formulation of itraconazole. Pharmacotherapy 1996; 16 (03) 424-428
• 47 Heykants J, Van Peer A, Van de Velde V. , et al. The clinical pharmacokinetics of itraconazole: an overview. Mycoses 1989; 32 (Suppl. 01) 67-87
• 48 Lindsay J, Sandaradura I, Wong K. , et al. Serum levels, safety and tolerability of new formulation SUBA-itraconazole prophylaxis in patients with haematological malignancy or undergoing allogeneic stem cell transplantation. J Antimicrob Chemother 2017; 72 (12) 3414-3419
• 49 Abuhelwa AY, Foster DJ, Mudge S, Hayes D, Upton RN. Population pharmacokinetic modeling of itraconazole and hydroxyitraconazole for oral SUBA-itraconazole and sporanox capsule formulations in healthy subjects in fed and fasted states. Antimicrob Agents Chemother 2015; 59 (09) 5681-5696
• 50 Templeton IE, Thummel KE, Kharasch ED. , et al. Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo. Clin Pharmacol Ther 2008; 83 (01) 77-85
• 51 Barone JA, Koh JG, Bierman RH. , et al. Food interaction and steady-state pharmacokinetics of itraconazole capsules in healthy male volunteers. Antimicrob Agents Chemother 1993; 37 (04) 778-784
• 52 Isoherranen N, Kunze KL, Allen KE, Nelson WL, Thummel KE. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos 2004; 32 (10) 1121-1131
• 53 Purkins L, Wood N, Ghahramani P, Greenhalgh K, Allen MJ, Kleinermans D. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob Agents Chemother 2002; 46 (08) 2546-2553
• 54 Levêque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics of voriconazole. Int J Antimicrob Agents 2006; 27 (04) 274-284
• 55 Pearson MM, Rogers PD, Cleary JD, Chapman SW. Voriconazole: a new triazole antifungal agent. Ann Pharmacother 2003; 37 (03) 420-432
• 56 Schwartz S, Thiel E. CNS-aspergillosis: are there new treatment options?. Mycoses 2003; 46 (Suppl. 02) 8-14
• 57 Black KE, Baden LR. Fungal infections of the CNS: treatment strategies for the immunocompromised patient. CNS Drugs 2007; 21 (04) 293-318
• 58 Hyland R, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab Dispos 2003; 31 (05) 540-547
• 59 Ikeda Y, Umemura K, Kondo K, Sekiguchi K, Miyoshi S, Nakashima M. Pharmacokinetics of voriconazole and cytochrome P450 2C19 genetic status. Clin Pharmacol Ther 2004; 75 (06) 587-588
• 60 Courtney R, Radwanski E, Lim J, Laughlin M. Pharmacokinetics of posaconazole coadministered with antacid in fasting or nonfasting healthy men. Antimicrob Agents Chemother 2004; 48 (03) 804-808
• 61 Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol 2004; 57 (02) 218-222
• 62 Wiederhold NP. Pharmacokinetics and safety of posaconazole delayed-release tablets for invasive fungal infections. Clin Pharmacol 2015; 8: 1-8
• 63 Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother 2003; 47 (09) 2788-2795
• 64 Wexler D, Courtney R, Richards W, Banfield C, Lim J, Laughlin M. Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study. Eur J Pharm Sci 2004; 21 (05) 645-653
• 65 Schmitt-Hoffmann A, Desai A, Kowalski D, Pearlman H, Yamazaki T, Townsend R. Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH. Int J Clin Pharmacol Ther 2016; 54 (08) 572-580
• 66 Schmitt-Hoffmann A, Roos B, Heep M. , et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 2006; 50 (01) 279-285
• 67 Schmitt-Hoffmann A, Roos B, Maares J. , et al. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 2006; 50 (01) 286-293
• 68 Schmitt-Hoffmann AH, Kato K, Townsend R. , et al. Tissue distribution and elimination of isavuconazole following single and repeat oral-dose administration of isavuconazonium sulfate to rats. Antimicrob Agents Chemother 2017; 61 (12) e01292-17
• 69 Desai A, Kovanda L, Kowalski D, Lu Q, Townsend R, Bonate PL. Population pharmacokinetics of isavuconazole from phase 1 and phase 3 (SECURE) trials in adults and target attainment in patients with invasive infections due to Aspergillus and other filamentous fungi. Antimicrob Agents Chemother 2016; 60 (09) 5483-5491
• 70 Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46 (02) 201-211
• 71 Lebeaux D, Lanternier F, Elie C. , et al. Therapeutic drug monitoring of posaconazole: a monocentric study with 54 adults. Antimicrob Agents Chemother 2009; 53 (12) 5224-5229
• 72 Gautier-Veyret E, Bolcato L, Roustit M. , et al. Treatment by posaconazole tablets did not reduced variability of posaconazole trough concentrations compared to posaconazole suspension. Antimicrob Agents Chemother 2019; 63 (10) e00484-19
• 73 Pappas PG, Kauffman CA, Andes DR. , et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016; 62 (04) e1-e50
• 74 Douglas CM, D'Ippolito JA, Shei GJ. , et al. Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors. Antimicrob Agents Chemother 1997; 41 (11) 2471-2479
• 75 Bowman JC, Hicks PS, Kurtz MB. , et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother 2002; 46 (09) 3001-3012
• 76 Barchiesi F, Spreghini E, Tomassetti S. , et al. Effects of caspofungin against Candida guilliermondii and Candida parapsilosis . Antimicrob Agents Chemother 2006; 50 (08) 2719-2727
• 77 Wiederhold NP, Kontoyiannis DP, Chi J, Prince RA, Tam VH, Lewis RE. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis 2004; 190 (08) 1464-1471
• 78 Song JC, Stevens DA. Caspofungin: pharmacodynamics, pharmacokinetics, clinical uses and treatment outcomes. Crit Rev Microbiol 2016; 42 (05) 813-846
• 79 Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother 2002; 46 (01) 245-247
• 80 Vazquez JA, Sobel JD. Anidulafungin: a novel echinocandin. Clin Infect Dis 2006; 43 (02) 215-222
• 81 Chandrasekar PH, Sobel JD. Micafungin: a new echinocandin. Clin Infect Dis 2006; 42 (08) 1171-1178
• 82 Eschenauer G, Depestel DD, Carver PL. Comparison of echinocandin antifungals. Ther Clin Risk Manag 2007; 3 (01) 71-97
• 83 Wagner C, Graninger W, Presterl E, Joukhadar C. The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications. Pharmacology 2006; 78 (04) 161-177
• 84 Stone JA, Holland SD, Wickersham PJ. , et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother 2002; 46 (03) 739-745
• 85 Hebert MF, Smith HE, Marbury TC. , et al. Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction. J Clin Pharmacol 2005; 45 (10) 1145-1152
• 86 Kauffman CA, Carver PL. Update on echinocandin antifungals. Semin Respir Crit Care Med 2008; 29 (02) 211-219
• 87 Saner F, Gensicke J, Rath P. , et al. Safety profile of concomitant use of caspofungin and cyclosporine or tacrolimus in liver transplant patients. Infection 2006; 34 (06) 328-332
• 88 Chowdhary A, Meis JF, Guarro J. , et al; European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. Clin Microbiol Infect 2014; 20 (Suppl. 03) 47-75
• 89 Waldorf AR, Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother 1983; 23 (01) 79-85
• 90 Pfaller MA, Bale MJ, Buschelman B, Rhomberg P. Antifungal activity of a new triazole, D0870, compared with four other antifungal agents tested against clinical isolates of Candida and Torulopsis glabrata . Diagn Microbiol Infect Dis 1994; 19 (02) 75-80
• 91 Perfect JR, Durack DT. Treatment of experimental cryptococcal meningitis with amphotericin B, 5-fluorocytosine, and ketoconazole. J Infect Dis 1982; 146 (03) 429-435
• 92 Queiroz-Telles F, de Hoog S, Santos DW. , et al. Chromoblastomycosis. Clin Microbiol Rev 2017; 30 (01) 233-276
• 93 Sanglard D, Odds FC. Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2002; 2 (02) 73-85
• 94 Schönebeck J, Polak A, Fernex M, Scholer HJ. Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy 1973; 18 (06) 321-336
• 95 Vermes A, Guchelaar HJ, Dankert J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 2000; 46 (02) 171-179
• 96 Kauffman CA, Frame PT. Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob Agents Chemother 1977; 11 (02) 244-247
• 97 Sofjan AK, Mitchell A, Shah DN. , et al. Rezafungin (CD101), a next-generation echinocandin: a systematic literature review and assessment of possible place in therapy. J Glob Antimicrob Resist 2018; 14: 58-64
• 98 Hager CL, Larkin EL, Long LA, Ghannoum MA. Evaluation of the efficacy of rezafungin, a novel echinocandin, in the treatment of disseminated Candida auris infection using an immunocompromised mouse model. J Antimicrob Chemother 2018; 73 (08) 2085-2088
• 99 Davis MR, Donnelley MA, Thompson GR. Ibrexafungerp: a novel oral glucan synthase inhibitor. Med Mycol 2019; (e-pub ahead of print)
• 100 Spec A, Pullman J, Thompson GR. , et al; Mycoses Study Group. MSG-10: a phase 2 study of oral ibrexafungerp (SCY-078) following initial echinocandin therapy in non-neutropenic patients with invasive candidiasis. J Antimicrob Chemother 2019; 74 (10) 3056-3062
• 101 Colley T, Sehra G, Daly L. , et al. Antifungal synergy of a topical triazole, PC945, with a systemic triazole against respiratory Aspergillus fumigatus infection. Sci Rep 2019; 9 (01) 9482
• 102 Oliver JD, Sibley GEM, Beckmann N. , et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci U S A 2016; 113 (45) 12809-12814
• 103 Buil JB, Rijs AJMM, Meis JF. , et al. In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates. J Antimicrob Chemother 2017; 72 (09) 2548-2552
• 104 Rivero-Menendez O, Cuenca-Estrella M, Alastruey-Izquierdo A. In vitro activity of olorofim (F901318) against clinical isolates of cryptic species of Aspergillus by EUCAST and CLSI methodologies. J Antimicrob Chemother 2019; 74 (06) 1586-1590
• 105 Biswas C, Law D, Birch M. , et al. In vitro activity of the novel antifungal compound F901318 against Australian Scedosporium and Lomentospora fungi . Med Mycol 2018; 56 (08) 1050-1054
• 106 Mammen MP, Armas D, Hughes FH. , et al. A First-in-human phase 1 study to assess safety, tolerability and pharmacokinetics of a novel antifungal drug VL-2397 in healthy adults. Antimicrob Agents Chemother 2019; (e-pub ahead of print)
• 107 Dietl AM, Misslinger M, Aguiar MM. , et al. The siderophore transporter Sit1 determines susceptibility to the antifungal VL-2397. Antimicrob Agents Chemother 2019; AAC.00807-19
• 108 Arendrup MC, Jensen RH, Cuenca-Estrella M. In vitro activity of ASP2397 against Aspergillus isolates with or without acquired azole resistance mechanisms. Antimicrob Agents Chemother 2015; 60 (01) 532-536
• 109 Miyazaki M, Horii T, Hata K. , et al. In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. Antimicrob Agents Chemother 2011; 55 (10) 4652-4658
• 110 Pfaller MA, Huband MD, Flamm RK, Bien PA, Castanheira M. In vitro activity of APX001A (manogepix) and comparator agents against 1,706 fungal isolates collected during an international surveillance program in 2017. Antimicrob Agents Chemother 2019 63
• 111 Wiederhold NP, Najvar LK, Fothergill AW. , et al. The investigational agent E1210 is effective in treatment of experimental invasive candidiasis caused by resistant Candida albicans . Antimicrob Agents Chemother 2015; 59 (01) 690-692
• 112 Pfaller MA, Hata K, Jones RN, Messer SA, Moet GJ, Castanheira M. In vitro activity of a novel broad-spectrum antifungal, E1210, tested against Candida spp. as determined by CLSI broth microdilution method. Diagn Microbiol Infect Dis 2011; 71 (02) 167-170
• 113 Vazquez L. Antifungal prophylaxis in immunocompromised patients. Mediterr J Hematol Infect Dis 2016; 8 (01) e2016040
• 114 Le J, Schiller DS. Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep 2010; 4 (02) 96-102
• 115 Maertens JA, Raad II, Marr KA. , et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016; 387 (10020): 760-769
• 116 Sandherr M, Maschmeyer G. Pharmacology and metabolism of voriconazole and posaconazole in the treatment of invasive aspergillosis: review of the literature. Eur J Med Res 2011; 16 (04) 139-144
• 117 Nivoix Y, Levêque D, Herbrecht R, Koffel JC, Beretz L, Ubeaud-Sequier G. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet 2008; 47 (12) 779-792
• 118 Rengelshausen J, Banfield M, Riedel KD. , et al. Opposite effects of short-term and long-term St John's wort intake on voriconazole pharmacokinetics. Clin Pharmacol Ther 2005; 78 (01) 25-33
• 119 Townsend R, Dietz A, Hale C. , et al. Pharmacokinetic evaluation of CYP3A4-mediated drug-drug interactions of isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin Pharmacol Drug Dev 2017; 6 (01) 44-53
• 120 Surowiec D, DePestel DD, Carver PL. Concurrent administration of sirolimus and voriconazole: a pilot study assessing safety and approaches to appropriate management. Pharmacotherapy 2008; 28 (06) 719-729
• 121 Groll AH, Desai A, Han D. , et al. Pharmacokinetic assessment of drug-drug interactions of isavuconazole with the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Clin Pharmacol Drug Dev 2017; 6 (01) 76-85
• 122 Desai A, Yamazaki T, Dietz AJ. , et al. Pharmacokinetic and pharmacodynamic evaluation of the drug-drug interaction between isavuconazole and warfarin in healthy subjects. Clin Pharmacol Drug Dev 2017; 6 (01) 86-92
• 123 Rivosecchi RM, Clancy CJ, Shields RK. , et al. Effects of isavuconazole on the plasma concentrations of tacrolimus among solid-organ transplant patients. Antimicrob Agents Chemother 2017; 61 (09) 61
• 124 Nivoix Y, Ubeaud-Sequier G, Engel P, Levêque D, Herbrecht R. Drug-drug interactions of triazole antifungal agents in multimorbid patients and implications for patient care. Curr Drug Metab 2009; 10 (04) 395-409