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Aerosolization of Second-generation Triazoles

In Vitro Evaluation and Application in Therapy of Invasive Airway Aspergillosis

Thanukrishnan, Harisudhan MPharm1; Corcoran, Timothy E. PhD2,3,4; Iasella, Carlo J. PharmD, BCPS5; Moore, Cody A. PharmD, BCPS5; Nero, Joseph A. MS2; Morrell, Matthew R. MD3; McDyer, John F. MD3; Hussain, Shahid MD6; Nguyen, M. Hong MD7; Venkataramanan, Raman PhD1,8; Ensor, Christopher R. PharmD, BCPS3,5

doi: 10.1097/TP.0000000000002697
Original Clinical Science—General
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Background. A lung transplant patient with invasive aspergillosis (IA) manifested symptoms of voriconazole-induced transaminitis with systemic voriconazole and progression of IA after switching to oral posaconazole. With limited options for standard triazole therapy, aerosolized delivery with one of the second-generation triazoles was considered.

Methods. Feasibility for aerosolized delivery was evaluated using cascade impactor and analysis of physicochemical characteristics of voriconazole (10 mg/mL) and posaconazole (6, 12 mg/mL) solutions.

Results. Both triazoles showed favorable characteristics for aerosol delivery with mass median aerodynamic diameter, geometric standard deviation, respirable fraction (<5.4 µm) of 2.8 µm, 2.0, 86%; 3.4 µm, 2.4, 78%; and 3.0 µm, 2.3, 79% for voriconazole and 6, 12 mg/mL of posaconazole, respectively. Aspergillus fumigatus isolate from the patient was more susceptible to voriconazole, and hence aerosolized voriconazole was introduced around the third month posttransplant at 40 mg TID for 1 week, 40 mg BID for 1 week, followed by 40 mg daily thereafter, along with IV caspofungin (50 mg/d) and liposomal amphotericin B (300 mg/d). The aerosol regimen was well tolerated by the patient with undetectable trough plasma levels of voriconazole. Bronchoscopy at the fourth month revealed improvement in anastomotic plaques with reduction in bronchoalveolar lavage galactomannan values (7.48–2.15 ng/mL). This consolidated aerosolized and intravenous regimen was maintained until 2.97 years posttransplant.

Conclusions. The intravenous solutions of both second-generation triazoles showed characteristics that were suitable for aerosol delivery. Our report further adds to the therapeutic experience with the use of aerosolized voriconazole for IA in a lung transplant patient.

1 Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA.

2 Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, PA.

3 Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.

4 Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA.

5 Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA.

6 Multi-Organ Transplant Program, Division of Infectious Diseases, Transplant Infectious Diseases, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON.

7 Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, PA.

8 Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA.

Received 21 August 2018. Revision received 11 February 2019.

Accepted 13 February 2019.

The authors declare no funding or conflicts of interest.

H.T. performed the experiments and prepared the manuscript. T.E.C. contributed with design and planning for the evaluation of aerosol delivery systems and critically revised the manuscript. C.J.I. and C.A.M. were involved in clinical execution. J.A.N. was involved with size distribution, pulmonary dose prediction of voriconazole, and analysis of samples. M.R.M., J.F.M., S.H., and M.H.N. contributed with clinical evaluation, interpretations, and critical revision of manuscript. R.V. critically revised the manuscript and provided final approval. C.R.E. was involved in primary concept, informed consent, clinical execution, and revision of manuscript.

Correspondence: Raman Venkataramanan, PhD, Department of Pharmaceutical Sciences, Room 4103, University of Pittsburgh, 700 Technology Dr, Pittsburgh Technology Center, Pittsburgh, PA 15219. (rv@pitt.edu).

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