1. TA M A R A B Y S T R A K
P H A R M D C A N D I D AT E
2 0 1 7
Fungemia in the Setting of Acute
Lymphocytic Leukemia (ALL)

2. Objectives
 Evaluate a patient case
 Understand the transition from empiric to organism
specific antifungal therapy
 Learn about the increasing incidence of trichosporon
infection in immunocompromised patients
 Review the mechanism of action, drug interactions,
pharmacokinetics, and adverse events related to treatment
with voriconazole
 Apply voriconazole trough-based dosing to the patient
case

3. Initial
Presentation
 A 6 y.o male patient with ALL on
protocol AALL1231 (Day 43 of
Delayed Intensification) admitted for
febrile neutropenia after receiving
vincristine
 Wt: 20.5 kg
 Induction chemotherapy:
 Bortezomib1
 Vincristine
 Doxorubicin
 IT methotrexate
Li J, Li Y, Huang B, Zheng D, Chen M, Zhou Z. Drug-induced modulation of T lymphocytes as a potential mechanism of susceptibility to infections in patients with
multiple myeloma during bortezomib therapy. Cell Biochem Biophys. 2015; 71(1):457-64.

4. JD
Initial
Presentation
 Subjective
 CC: “Sickly appearance”
 Chills
 Decreased appetite lately
 Fatigue
 Abdominal pain
 Headache
 N/V/D
 Muscle pain

5. JD
Initial
Presentation
 Objective
 Fever 38.1ºC (100.6ºF)
 Neutropenia: ANC 66 and dropping
 Hgb 7.8, Hct 22%
 Platelets 63K
 CRP 2.24
 Chem-7: WNL
 BP 100/60 bpm
 RR 22 breathes/min
 Tachycardia at 129-178 bpm
 Oral lesions
 Decreased bowel sounds
 Blood culture (+) strep

6. JD
Initial
Presentation
 Assessment
 Streptococcal viridans bacteremia
 Neutropenic enterocolitis (typhlitis)
 Plan
 Ceftazidime 150mg/kg/day split q 8hr x 10 days
 s. viridans bacteremia
 Flagyl 30mg/kg/day split q 6hr x 10 days
 enterocolitis
 Vancomycin 30mg/kg q 6hr
 recurrent high fever, neutropenia

7. 1 Week Later…
 New onset abdominal pain
 Tachypnea at 42 breathes/min
 Micropapullar rash over upper & lower extremities and trunk
(including face, palms and soles) w/ pus, ulcerations and crusting
 Persistent fever > 5 days up to 41.9ºC
 CRP = 8.92 and rising
 Severe neutropenia ANC = 0
 Suspect fungal infection pending cultures
 Continue vancomycin and Flagyl
 D/C ceftazidime, start meropenem

8. http://www.slideshare.net/lhenparungao/opportunistic-mycoses-11082636

9. Available Systemic Antifungal Agents for Common Invasive Fungal Infections in Leukemia
Patients on Azole Prophylaxis
Konstantinos Leventakos et al. Clin Infect Dis. 2010;50:405-415 © 2010 by the Infectious Diseases Society of America

10. In Vitro Activity of Currently Used Antifungal Agents
Konstantinos Leventakos et al. Clin Infect Dis. 2010;50:405-415
© 2010 by the Infectious Diseases Society of America

11. Empiric Antifungal Treatment Plan
 Amphotericin B (Liposomal)
 6mg/kg/day IV
 Non-aspergillus, non-candida fungal coverage
 Micafungin
 3mg/kg/day IV
 Broad candida coverage
 Cannot use an azole yet – worsens vincristine neurotoxicity via
inhibiting CYP3A4 metabolism1
van Schie RM, Brüggemann RJ, Hoogerbrugge PM, te Loo DM. Effect of azole antifungal therapy on vincristine toxicity in childhood acute
lymphoblastic leukaemia. J Antimicrob Chemother. 2011;66(8):1853-6.

12. Confirmed Fungemia
 Cultures + for trichosporon spp.
 Basidiomycetous yeast-like anamorphic organisms
 Inhabit soil and colonize human skin/GI/resp tract
 Can cause opportunistic infections, endocarditis, fungemia, or
hypersensitivity pneumonitis
 38 species identified
 Localized systemic as well as disseminated infections are frequently
T.asahii or T.mucoides
 Second most common disseminating yeast in humans
 Imaging shows cutaneous lesions in liver, kidney, and spleen
 Disseminated trichosporon infection
 Primary RF: Hematologic malignancy (63% of reported cases)
 Additional risk factors: corticosteroid use, hemochromatosis, other
deficiencies of granulocyte function, HIV/AIDS, and ESRD
Maves RC. Medscape. Trichosporon infections. URL: http://emedicine.medscape.com/article/230705-overview [accessed 2016 Nov 16]

13. http://thunderhouse4-yuri.blogspot.com/2014/08/trichosporon-species.html
T. Asahii

14. http://slideplayer.com/slide/7760162/

15. Iturrieta-González IA, Padovan AC, Bizerra FC, Hahn RC, Colombo AL. Multiple species of Trichosporon produce biofilms highly resistant to triazoles and amphotericin B. PLoS One.
2014;9(10):e109553.
Multiple Species of Trichosporon Produce Biofilms
Highly Resistant to Triazoles and Amphotericin B
 Invasive infections caused by Trichosporon spp. have increased
considerably in recent years, especially in neutropenic and critically
ill patients using catheters and antibiotics
 Trial tested n=54 clinical isolates of Trichosporon spp. obtained
from different patients between 2001 and 2010
 T. asahii was the most frequent species identified (66.7%)
 All species exhibited high adhesion and biofilm formation
capabilities, equal or greater to that of candida spp.
 Limited sensitivity to antifungals due to incredibly resistant biofilm
producing cells
 Triazoles are first line (voriconazole, fluconazole, itraconazole)
 Voriconazole exhibited the best in vitro activity against all species
tested

16. Mitchell KF, Zarnowski R, Andes DR (2016) Fungal Super Glue: The Biofilm Matrix and Its Composition, Assembly, and Functions. PLoS Pathog 12(9): e1005828.

17. Head-to-Head Comparison of Inhibitory and Fungicidal Activities
of five triazoles against Trichosporon asahii
 N=90 clinical isolates tested
 Results suggest that azoles display
fungistatic activity (based on
MIC) but lack fungicidal effect
(based on MFC) against T. asahii
 Killing activity is dose dependent
and occurred at concentrations not
reached in serum
Hazirolan G, Canton E, Sahin S, Arikan-Akdagli S. Head-to-head comparison of inhibitory and fungicidal activities of fluconazole, itraconazole, voriconazole, posaconazole, and
isavuconazole against clinical isolates of Trichosporon asahii. Antimicrob Agents Chemother. 2013;57(10):4841-7.
By rank order, the most active triazoles:
Voriconazole
Itraconazole,
Posaconazole,
Isavuconazole
Fluconazole

18. Trichosporin Specific Treatment
 Start voriconazole
 Literature supports efficacy of triazoles in Trichosporon spp.
 Can give an azole now that vincristine is on hold
 Patient cultures also show susceptibility
 Weekly ultrasounds of liver/spleen to assess progression
 D/C amphotericin and micafungin
 Amphotericin B frequently displays inadequate fungicidal
activity and there have been cases of resistance reported
 Echinocandins have no meaningful antifungal effect against
this genus

19. Voriconazole
A Triazole Antifungal
http://www.pharmacy4world.com/voriconazole-200mg-2369610.html
http://www.life-worldwide.org/fungal-diseases/voriconazole

20. Azole
Antifungals
Mechanism of
Action (MOA)
• Competitively inhibits fungal cytochrome P-450
enzymes (14-sterol demethylase)
• Accumulation of 14-methylsterols
• Prevents ergosterol synthesis. Ergosterol is needed
in fungal cell membranes
https://www.studyblue.com/notes/note/n/anti-fungal/deck/5772604
DRUGDEX® System (electronic version). Voriconazole. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited:
11/11/2016).

21. Voriconazole Dosing
1 mo. – 12 yr.
Patient = age 6
12+ yr
(NO phenytoin or
efavirenz)
12+ yr, phenytoin, or
efavirenz
Loading Dose 7-8 mg/kg/dose
q 12hr
6 mg/kg/dose q 12hr
for 2 doses
6 mg/kg/dose q 12hr
for 2 doses
Maintenance
Dose
7-8 mg/kg/dose
q 12hr
4 mg/kg/dose q 12hr 5 mg/kg/dose q 12hr
Connecticut Childrens Medical Center. Voriconazole dosing and monitoring in pediatric patients requiring treatment doses. BeST statement. June 2013.

22. (VFEND) Voriconazole Prescribing Information
 Available IV, PO tablets, and oral suspension
 Safety & efficacy not established in age < 12
 Max: 350 mg/dose
 The pharmacokinetics of voriconazole are non-linear
(dose dependent) due to saturation of its metabolism
• Increasing the oral dose from 200 mg BID to 300 mg BID leads to a
2.5-fold increase in exposure (AUC)
• Increasing the intravenous dose from 3 mg/kg BID to 4 mg/kg BID
produces a 2.3-fold increase in exposure
VFEND (voriconazole)[package insert]. Pfizer Inc. New York (NY) 2015.

23. ADME
 Absorption
 Tmax: 1-2 hrs (immunocompromised children: 1.3 - 2.8 hr)
 Oral bioavailability, pediatrics: 65% to 66%
 High-fat meals reduce the mean Cmax and AUC by 34% and 24%
(tablet) and by 58% and 37% (oral suspension)
 Advise to take at least 1hr before/after meal
 Distribution
 Vd, Children: 1.852 L/kg
 Protein binding: 58% PO
VFEND (voriconazole)[package insert]. Pfizer Inc. New York (NY) 2015.

24. ADME
 Metabolism
 Hepatic via CYP2C19 (CYP2C9 and CYP3A4)
 CYP2C19 exhibits genetic polymorphism
 It is recommended that the standard loading dose regimens be used, but
maintenance dose be halved in patients with mild to moderate hepatic
cirrhosis
 Excretion
 less than 2% unchanged
 Renal clearance, children:141.9 mL/hr/kg
 No adjustment is necessary for oral dosing in patients with renal impairment
 Intravenous voriconazole should be avoided in patients with moderate to
severe renal impairment (CrCl < 50 mL/min)
 Dialyzable
VFEND (voriconazole)[package insert]. Pfizer Inc. New York (NY) 2015.

25. CYP Substrates – voriconazole
inhibition increases levels
CYP Inducers – decrease
voriconazole levels
• Terfenadine
• Astemizole
• Cisapride
• Sirolimus
• Pimozide
• Quinidine
• Rifabutin
• Rifampin
• Ritonavir
• St. Johns wort
• Carbamazepine
• Fluconazole
• Rifabutin
Voriconazole Contraindications
VFEND (voriconazole)[package insert]. Pfizer Inc. New York (NY) 2015.

26. Voriconazole Side Effects
DRUGDEX® System (electronic version). Voriconazole. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited:
11/11/2016).
Visual (21%) Photophobia, blurriness
CNS (3-16%) hallucination, HA, chills
GI (12%) N > V > D
Hepatotoxicity (3-12%)
Rash (7%)
Fever (6%)
QTc
< 2%

27. Voriconazole Trough Monitoring
BeST Statement
Measure just prior (within 30min) of
dose on Day 5 of therapy
Trough Goal: 1.0 - 5.5 mcg/mL
Measure weekly thereafter once
therapeutic
Connecticut Childrens Medical Center. Voriconazole dosing and monitoring in pediatric patients requiring treatment doses. BeST statement. June 2013.

28. Trough Adjustment
Initial Trough < 1 mcg/mL Increase daily dose 50%
Repeat Trough < 1 mcg/mL Increase BID  TID
Any Trough > 5.5 mcg/mL Hold until < 5.5 mcg/mL
Then decrease dose 50%
Adverse Event Contact Attending
Voriconazole Trough Monitoring
BeST Statement Cont.
Connecticut Childrens Medical Center. Voriconazole dosing and monitoring in pediatric patients requiring treatment doses. BeST statement. June 2013.

29. Patient Dosing/Trough Record
Original Dose Trough Level (mcg/mL) Dose Change
9mg/kg IV BID 20.3 (not true trough) Hold dose
4.5mg/kg IV BID Re-test and get 2.0 Back to 9mg/kg IV BID
9mg/kg IV BID 0.7 (Low) 9mg/kg IV TID
9mg/kg IV TID 1.2 None
9mg/kg IV TID 5.7 (High) 8mg/kg IV TID
8mg/kg IV TID 6.8 (High) Hold dose
Restart at 7mg/kg IV BID 0.4 (Low) 7mg/kg IV TID

30. Patient Dosing/Trough Record Cont.
Original Dose Trough Level (mcg/mL) Dose Change
7mg/kg IV TID 1.7, 1.5, 3.6, 1.5, 0.9 None
7mg/kg IV TID 0.5 (Low) 10mg/kg IV TID
10mg/kg IV TID 0.2 (Low) 15mg/kg IV TID
15mg/kg IV TID 11 (High) 12.5mg/kg IV TID
12mg/kg IV TID 1.6, 1.6, 4.4, 3.4, 2.1, 1.7 12.5mg/kg PO TID

31. 4 Months Later…
The patient has survived 5 transfers to and from the PICU.
Imaging and clinical signs show steady improvement. Six
voriconazole troughs in a row are within the therapeutic range.
He is discharged on voriconazole 12.5mg/kg PO suspension TID
given through his G tube.
He has also restarted chemotherapy with 2 rounds of NECTAR
for his relapsed ALL.
NECTAR = Nelarabine, Etoposide and Cyclophosphamide in
T-ALL Relapse

32. Summary
Immunocompromised patients are at a much higher risk
for opportunistic fungal infection
Trichosporon spp. are often resistant to antifungal therapy
due to the production of biofilm
Voriconazole has the greatest inhibitory effect against
Trichosporon spp.
Voriconazole trough levels can be extremely
unpredictable due factors such as genetic variability,
nonlinear metabolism, and drug-drug interactions
The benefits of treatment typically outweight the risks in
patients with fungemia

33. Questions or Comments

34. References
1. Li J, Li Y, Huang B, Zheng D, Chen M, Zhou Z. Drug-induced modulation of T
lymphocytes as a potential mechanism of susceptibility to infections in patients
with multiple myeloma during bortezomib therapy. Cell Biochem Biophys. 2015;
71(1):457-64
2. Konstantinos Leventakos et al. Clin Infect Dis. 2010;50:405-415
3. van Schie RM, Brüggemann RJ, Hoogerbrugge PM, te Loo DM. Effect of azole
antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemia.
J Antimicrob Chemother. 2011;66(8):1853-6.
4. Maves RC. Medscape. Trichosporon infections. URL:
http://emedicine.medscape.com/article/230705-overview [accessed 2016 Nov 16]
5. Iturrieta-González IA, Padovan AC, Bizerra FC, Hahn RC, Colombo AL. Multiple
species of Trichosporon produce biofilms highly resistant to triazoles and
amphotericin B. PLoS One. 2014;9(10):e109553.
6. Mitchell KF, Zarnowski R, Andes DR (2016) Fungal Super Glue: The Biofilm Matrix
and Its Composition, Assembly, and Functions. PLoS Pathog 12(9): e1005828
7. Hazirolan G, Canton E, Sahin S, Arikan-Akdagli S. Head-to-head comparison of
inhibitory and fungicidal activities of fluconazole, itraconazole, voriconazole,
posaconazole, and isavuconazole against clinical isolates of Trichosporon asahii.
Antimicrob Agents Chemother. 2013;57(10):4841-7.
8. DRUGDEX® System (electronic version). Voriconazole. Truven Health Analytics,
Greenwood Village, Colorado, USA. Available at:
http://www.micromedexsolutions.com/ (cited: 11/11/2016).
9. Connecticut Childrens Medical Center. Voriconazole dosing and monitoring in
pediatric patients requiring treatment doses. BeST statement. June 2013.
10. VFEND (voriconazole)[package insert]. Pfizer Inc. New York (NY) 2015.