In vivo Efficacy of Posaconazole (POS) against Voriconazole Resistant (VCZ-R) Aspergillus flavus in an Inhalational Neutropenic Murine Model of Invasive Pulmonary Aspergillosis

Main Article Content

Suganthini Krishnan Natesan
Jessica L. Cutright


Invasive aspergillosis (IA) is a life-threatening infection in patients with cancer. Recent studies have reported that non-fumigatus Aspergillus spp., including Aspergillus flavus, are emerging as predominant pathogens in various transplant and cancer centers in the USA and around the world. Clinical and environmental isolates of Aspergillus species showing reduced susceptibility to VCZ have been reported. Mortality, despite therapy, remains high, and drug resistance might partly account for treatment failures. In this in vivo study, the virulence of a VCZ-R cyp51A mutant of A. flavus and the efficacy of POS against this mutant were evaluated using a neutropenic inhalational murine model of invasive pulmonary aspergillosis. VCZ-R A. flavus mutant was virulent in vivo, and had similar infectivity as the VCZ-S parent. Posaconazole had superior activity to that of VCZ in reducing fungal burden (p <0.05) and mortality (p <0.05) in this experimental model of VCZ-R A. flavus murine infection. This study demonstrated that POS may be a viable option for certain strains of VCZ-R A. flavus.

Aspergillus flavus, azole-resistance, posaconazole, voriconazole resistance, pulmonary aspergillosis, Aspergillus fumigates, murine model, neutropenia.

Article Details

How to Cite
Natesan, S. K., & L. Cutright, J. (2019). In vivo Efficacy of Posaconazole (POS) against Voriconazole Resistant (VCZ-R) Aspergillus flavus in an Inhalational Neutropenic Murine Model of Invasive Pulmonary Aspergillosis. Microbiology Research Journal International, 29(3), 1-7.
Original Research Article


McNeil MM, Nash SL, Hajjeh RA, Phelan MA, Conn LA, Plikaytis BD, et al. Trends in mortality due to invasive mycotic diseases in the United States. 1980–1997 Clin Infect Dis. 2001;33:641-647.

Yu J, Cleveland TE, Nierman WC, Bennet JW. Aspergillus flavus genomics: Gateway to human and animal health, food safety, and crop resistance to diseases Rev Iberoam Micol. 2005;22:194-202.

Heo ST, Tatara AM, Jiménez-Ortigosa C, Jiang Y, Lewis RE, Tarrand J, Tverdek F, Albert ND, Verweij PE, Meis JF, Mikos AG, Perlin DS, Kontoyiannis DP. Changes in in vitro susceptibility patterns of Aspergillus to triazoles and correlation with aspergillosis outcome in a Tertiary Care Cancer Center, 1999-2015. Clin Infect Dis. 2017;65(2): 216-225.

Meireles LM, de Araujo ML, Endringer DC, Fronza M, Scherer R. Change in the clinical antifungal sensitivity profile of Aspergillus flavus induced by azole and a benzimidazole fungicide exposure. Diagn Microbiol Infect Dis. 2019;95(2):171-178.

Wiederhold NP, Patterson TF. Emergence of azole resistance in Aspergillus. Semin Respir Crit Care Med. 2015;36(5):673-80.

Paul RA, Rudramurthy SM, Meis JF, Mouton JW, Chakrabarti A. A novel Y319H substitution in CYP51C associated with azole resistance in Aspergillus flavus. Antimicrob Agents Chemother. 2015; 59(10):6615-9.

Paul S, Diekema D, Moye-Rowley WS. Contributions of both ATP-binding cassette transporter and Cyp51A proteins are essential for azole resistance in Aspergillus fumigatus. Antimicrob Agents Chemother. 2017;61(5).

Hagiwara D, Watanabe A, Kamei K, Goldman GH. Epidemiological and genomic landscape of azole resistance mechanisms in Aspergillus fungi. Front Microbiol. 2016;7:1382. eCollection 2016.

Pérez-Cantero A, López-Fernández L, Guarro J, Capilla J. New insights into the Cyp51 contribution to azole resistance in Aspergillus section nigri. Antimicrob Agents Chemother. 2019;63(7).

Parker JE, Warrilow AG, Price CL, Mullins JG, Kelly DE, Kelly SL. Resistance to antifungals that target CYP51. J Chem Biol. 2014;7(4):143-61.

Krishnan-Natesan S, Chandrasekar PH, Alangaden GJ, Manavathu EK. Molecular characterisation of cyp51A and cyp51B genes coding for P450 14alpha-lanosterol demethylases A (CYP51Ap) and B (CYP51Bp) from voriconazole-resistant laboratory isolates of Aspergillus flavus. Int J Antimicrob Agents. 2008;32(6):519-24.

Paul RA, Rudramurthy SM, Dhaliwal M, Singh P, Ghosh AK, Kaur H, Varma S, Agarwal R, Chakrabarti A. Magnitude of voriconazole resistance in clinical and environmental isolates of Aspergillus flavus and investigation into the role of multidrug efflux pumps. Antimicrob Agents Chemother. 2018;62(11).

Sharma C, Kumar R, Kumar N, Masih A, Gupta D, Chowdhary A. Investigation of multiple resistance mechanisms in voriconazole-resistant Aspergillus flavus clinical isolates from a Chest Hospital Surveillance in Delhi, India. Antimicrob Agents Chemother. 2018;62(3).

Natesan SK, Lamichchane AK, Swaminathan S, Wu W. Differential expression of ATP-binding cassette and/or major facilitator superfamily class efflux pumps to voriconazole resistance in Aspergillus flavus. Diagn Microbiol Infect Dis. 2013;76(4):458-63.

Bedin Denardi L, Hoch Dalla-Lana B, Pantella Kunz de Jesus F, Bittencourt Severo C, Morais Santurio J, Zanette RA, Hartz Alves S. In vitro antifungal susceptibility of clinical and environmental isolates of Aspergillus fumigatus and Aspergillus flavus in Brazil. Braz J Infect Dis. 2018;22(1):30-36.

Meis JF, Chowdhary A, Rhodes JL, Fisher MC, Verweij PE. Clinical implications of globally emerging azole resistance in Aspergillus fumigatus. Philos Trans R Soc Lond B Biol Sci. 2016;371(1709).

Liu M, Zheng N, Li D, Zheng H, Zhang L, Ge H, Liu W. cyp51A-based mechanism of azole resistance in Aspergillus fumigatus: Illustration by a new 3D Structural Model of Aspergillus fumigatus CYP51A protein. Med Mycol. 2016;54(4):400-8.

Verweij PE, Chowdhary A, Melchers WJ, Meis JF. Azole Resistance in Aspergillus fumigatus: Can We Retain the Clinical Use of Mold-Active Antifungal Azoles? Clin Infect Dis. 2016;62(3):362-8.

Krishnan Natesan S, Wu W, Cutright JL, Chandrasekar PH. In vitro-in vivo correlation of voriconazole resistance due to G448S mutation (cyp51A gene) in Aspergillus fumigatus. Diagn Microbiol Infect Dis. 2012;74(3):272-7.

Perea S, Pennick GJ, Modak A, Fothergill AW, Sutton DA, Sheehan DJ, Rinaldi MG. Comparison of high-performance liquid chromatographic and microbiological methods for determination of voriconazole levels in plasma. Antimicrob Agents Chemother. 2000;44(5):1209-13.

Vermeulen E, Maertens J, De Bel A, Nulens E, Boelens J, Surmont I, Mertens A, Boel A, Lagrou K. Nationwide Surveillance of Azole Resistance in Aspergillus Diseases. Antimicrob Agents Chemother. 2015;59(8):4569-76.

Dudakova A, Spiess B, Tangwattanachuleeporn M, Sasse C, Buchheidt D, Weig M, Groß U, Bader O. Molecular tools for the detection and deduction of azole antifungal drug resistance phenotypes in Aspergillus Species. Clin Microbiol Rev. 2017;30(4): 1065-1091.

White PL, Posso RB, Barnes RA. Analytical and clinical evaluation of the patho nostics asper genius assay for detection of invasive aspergillosis and resistance to azole antifungal drugs directly from plasma samples. J Clin Microbiol. 2017;55(8):2356-2366.

Chong GM, van der Beek MT, von dem Borne PA, Boelens J, Steel E, Kampinga GA, Span LF, Lagrou K, Maertens JA, Dingemans GJ, Gaajetaan GR, van Tegelen DW, Cornelissen JJ, Vonk AG, Rijnders BJ. PCR-based detection of Aspergillus fumigatus Cyp51A mutations on bronchoalveolar lavage: A multicentre validation of the Asper Genius assay® in 201 patients with haematological disease suspected for invasive aspergillosis. J Antimicrob Chemother. 2016;71(12):3528-35.

Dudakova A, Spiess B, Tangwattanachuleeporn M, Sasse C, Buchheidt D, Weig M, Groß U, Bader O. Molecular tools for the detection and deduction of azole antifungal drug resistance phenotypes in Aspergillus Species. Clin Microbiol Rev. 2017;30(4): 1065-91.

Al-Wathiqi F, Ahmad S, Khan Z. Molecular identification and antifungal susceptibility profile of Aspergillus flavus isolates recovered from clinical specimens in Kuwait. BMC Infect Dis. 2013;13:126.