Managing Fungal Infections in Cystic Fibrosis Patients: Challenges in Clinical Practice

Figures & data

Table 1 Common Fungal Organisms in Cystic Fibrosis Patients

Aspergillus fumigatus

Aspergillus flavus

Aspergillus niger

Candida albicans

Candida dubliniensis

Candida glabrata

Candida parapsilosis

Candida lusitaniae

Candida krusei

Exophiala spp.

Lomentospora prolificans (formerly Scedosporium prolificans)^Citation23

Penicillium spp.

Rasamsonia argillacea

Scedosporium apiospermum

Scedosporium aurantiacum

Scedosporium boydii (formerly Pseudallescheria boydii)^Citation23

Scedosporium minutisporum

Trichosporon mycotoxinivorans

Trichosporon spp.

Wangiella (Exophiala) dermatitidis

Note: Data from these studies.^22,23

Figure 1 Chronicity and pathogenicity of fungal organisms in cystic fibrosis. Data from Tracy and Moss.⁴

Table 2 Immunologic Classification of Aspergillosis in Adult Cystic Fibrosis

Class		RT-PCR Aspergillus (Sputum)	Total IgE	Specific A. fumigatus IgE	Specific A. fumigatus IgG	GM Index (Sputum)
I	Nondiseased CF patient	±	Normal	Normal	Normal	Negative
II	Serologic ABPA (ABPA-S)	Positive	Increased	Increased	Increased	Positive
III	Aspergillus IgE-sensitization	±	Increased (less than ABPA)	Increased (less than ABPA)	Normal	Negative
IV	Aspergillus infection/bronchitis	Positive	Normal	Normal	Increased	Positive

Note: Data from these studies.^34,35 Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; IgE, immunoglobulin E; IgG, immunoglobulin G; GM, galactomannan; RT-PCR, real-time polymerase chain reaction.

Table 3 Proposed Diagnostic Criteria for Fungal Colonization and Active Infection

Criteria	Colonization	Infection
Major criteria
Microbiology	Minimum of 2 cultures within 12 months
Clinical symptoms	None	New s/sx and/or worsening lung function
Exclude fungal allergy	No evidence of ABPA or Aspergillus sensitization
Bacterial organism	May be present	May be present as comorbidity
Chest imaging	No change	New infiltrate or airway thickening
Response to antibiotics	Clinical improvement	None
Response to antifungal therapy	None	Clinical improvement
Minor criteria
Specific Fungal IgG	Negative or results within normal range	Elevated
GM (sputum or BAL)	Negative	Positive
Bronchoscopy   BAL   Endobronchial biopsy   Transbronchial biopsy	Fungi within alveolar macrophages or airway/alveolar exudates	Fungi within alveolar macrophages or airway/alveolar exudates Mucosal erythema and/or ulceration Invasion of mucosa by fungal hyphae with acute inflammation

Note: Data from Tracy and Moss.⁴ Abbreviations: ABPA, allergic bronchopulmonary aspergillosis; BAL, bronchoalveolar lavage; IgG, immunoglobulin G; GM, galactomannan; s/sx, signs and symptoms.

Table 4 Pharmacokinetics and Pharmacodynamic Properties of Triazole Antifungals

Medication	Bioavailability (%)	Protein Binding (%)	Metabolism	t1/2 (hr)^a	Excretion	Renal Dosing Adjustments
Fluconazole	>90	11–12	Hepatic: CYP2C19 (strong) CYP2C9 (mod) CYP3A4 (mod)	30	80% unchanged in urine	Yes, when CrCl≤50 mL/min
Itraconazole	Variable 55, increasing by 30% under fasted conditions (oral solution)	99.8	Hepatic: CYP3A4 (major)	34–42	<1% active drug excreted in urine; 54% in feces	No
Voriconazole	96	58	Hepatic: CYP2C19 (major) CYP2C9 (minor) CYP3A4 (minor)	Variable, dose-dependent	<2% unchanged in urine	Caution with CrCl<50 mL/min with intravenous product
Posaconazole	Variable	>98	Hepatic: substrate of UGT1A4	26–35	66% unchanged in feces; 13% in urine	Caution with CrCl<50 mL/min with intravenous product
Isavuconazole	98	>99	Hepatic: CYP3A4 (major)	130	<1% unchanged in urine; 33% unchanged in feces	No

Notes: ^at_1/2 listed is for adults with normal renal function. Data from these studies.^63,64,76

Abbreviations: t_1/2, half-life; Mod, moderate; CrCl, creatinine clearance.

Table 5 Food and Acid-Suppressing Medication Interactions with Triazole Antifungals

Medication	Effect of Food on Medication	Effect of PPI/H2RA on Medication
Fluconazole	No effect on absorption	No effect on absorption
Itraconazole	Food decreases absorption of oral solution	No effect on absorption of oral solution
	Capsule/tablet best taken with food	Decreased absorption of capsule/tablet when gastric acidity is reduced
Voriconazole	Food decrease absorption	No effect on absorption
Posaconazole	Oral suspension best taken with food	Decreased absorption of oral suspension when gastric acidity is reduced
	Delayed release tablets best taken with food	No effect on absorption of delayed release tablets
Isavuconazole	No effect on absorption	No effect on absorption

Note: Data from these studies.^63,64Abbreviations: PPI, proton pump inhibitor: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; H₂RA, histamine H₂ receptor antagonist: cimetidine, famotidine, ranitidine.

Table 6 Therapeutic Drug Monitoring of Triazole Antifungals

Medication	Timing	Recommended Trough Range
Itraconazole	4–7 days after initiation or dose adjustment	>0.5 −1 mcg/mL
Voriconazole	4–7 days after initiation, dose adjustment, or change interacting medications	>1 mcg/mL; >5 mcg/mL associated with toxicity
Posaconazole	6–10 days after initiation, dose adjustment, or change interacting medications	>0.7 mcg/mL, increase to >1/25 mcg/mL if response is poor
Fluconazole and isavuconazole	No recommendations for therapeutic drug monitoring	No recommendations for therapeutic drug monitoring

Note: Data from these studies.^63,64

Table 7 Dose Adjustments Required for Drug–Drug Interactions Between Moderate^a and Strong^b CYP3A Inhibitors and Elexacaftor/Tezacaftor/Ivacaftor and Ivacaftor

Moderate^a CYP3A Inhibitors
	Day 1	Day 2	Day 3	Day 4
Morning dose	Two elexacaftor/tezacaftor/ivacaftor tablets	One ivacaftor tablet	Two elexacaftor/tezacaftor/ivacaftor tablets	One ivacaftor tablet
Evening dose	The evening dose of ivacaftor should not be taken.
Strong^b CYP3A Inhibitors
	Day 1	Day 2	Day 3	Day 4
Morning dose	Two elexacaftor/tezacaftor/ivacaftor tablets	No dose	No dose	Two elexacaftor/tezacaftor/ivacaftor tablets
Evening dose	The evening dose of ivacaftor should not be taken.

Notes: ^aModerate CYP3A4 inhibitor: fluconazole. ^bStrong CYP3A4 inhibitor: itraconazole, posaconazole, voriconazole. Data from Trikafta [Package Insert].⁷¹

Lackner M, de Hoog GS, Yang L, et al. Proposed nomenclature for Pseudallescheria, Scedosporium and related genera. Fungal Divers. 2014;67:1–10. doi:10.1007/s13225-014-0295-4

 Web of Science ®Google Scholar

Ziesing S, Suerbaum S, Sedlacek L. Fungal epidemiology and diversity in cystic fibrosis patients over a 5-year period in a national reference center. Med Mycol. 2016;54:781–786. doi:10.1093/mmy/myw03527364649

 PubMed Web of Science ®Google Scholar

Tracy MC, Moss RB. The myriad challenges of respiratory fungal infection in cystic fibrosis. Pediatr Pulmonol. 2018;53(S3):S75–S85. doi:10.1002/ppul.2412629992775

 PubMed Web of Science ®Google Scholar

Delfino E, Del Puente F, Briano F, Sepulcri C, Roberto Giacobbe D. Respiratory fungal diseases in adult patients with cystic fibrosis. Clin Med Insights Circ Respir Pulm Med. 2019;13:1–6.

 Web of Science ®Google Scholar

Baxter CG, Dunn G, Jones AM, et al. Novel immunologic classification of aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol. 2013;132:560–566.e10. doi:10.1016/j.jaci.2013.04.00723726262

 PubMed Web of Science ®Google Scholar

Rivosecchi RM, Samanta P, Demehin M, et al. Pharmacokinetics of azole antifungals in cystic fibrosis. Mycopathologia. 2018;183(1):139–150. doi:10.1007/s11046-017-0189-628795298

 PubMed Web of Science ®Google Scholar

Fluconazole, Itraconazole, Voriconazole, Posaconazole, and Isavuconazole. Lexi-drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available from: http://online.lexi.com. Accessed 1215, 2020.

 Google Scholar

Dodds Ashley ES, Lewis R, Lewis JS, Martin C, Andes D. Pharmacology of systemic antifungal agents. Clin Infect Dis. 2006;43:S28–S39. doi:10.1086/504492

 Web of Science ®Google Scholar

Trikafta [Package Insert]. Boston, MA: Vertex Pharmaceutical Inc.; 2019.

 Google Scholar