fungemia in the setting of acute lymphocytic leukemia (final)-1

TA M A R A B Y S T R A KP 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)

Objectives

Evaluate a patient case Understand the transition from empiric to organism

specific antifungal therapyLearn about the increasing incidence of trichosporon

infection in immunocompromised patientsReview the mechanism of action, drug interactions,

pharmacokinetics, and adverse events related to treatment with voriconazole

Apply voriconazole trough-based dosing to the patient case

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.

JD Initial Presentation

Subjective CC: “Sickly appearance” Chills Decreased appetite lately Fatigue Abdominal pain Headache N/V/D Muscle pain

JDInitial 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

JDInitial 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

1 Week Later…

New onset abdominal pain Tachypnea at 42 breathes/minMicropapullar rash over upper & lower extremities and trunk

(including face, palms and soles) w/ pus, ulcerations and crustingPersistent fever > 5 days up to 41.9ºCCRP = 8.92 and risingSevere neutropenia ANC = 0Suspect fungal infection pending culturesContinue vancomycin and FlagylD/C ceftazidime, start meropenem

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

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

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

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.

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]

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

T. Asahii

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

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 cellsTriazoles are first line (voriconazole, fluconazole, itraconazole)Voriconazole exhibited the best in vitro activity against all species tested

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

Head-to-Head Comparison of Inhibitory and Fungicidal Activities of five triazoles against Trichosporon asahii

N=90 clinical isolates testedResults 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

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

Voriconazole A Triazole Antifungal

http://www.pharmacy4world.com/voriconazole-200mg-2369610.htmlhttp://www.life-worldwide.org/fungal-diseases/voriconazole

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/5772604DRUGDEX® System (electronic version). Voriconazole. Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited: 11/11/2016).

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.

(VFEND) Voriconazole Prescribing Information

Available IV, PO tablets, and oral suspensionSafety & efficacy not established in age < 12 Max: 350 mg/doseThe 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.

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


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


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


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, blurrinessCNS (3-16%) hallucination, HA, chills

GI (12%) N > V > DHepatotoxicity (3-12%)

Rash (7%)Fever (6%)

QTc<

2%

Voriconazole Trough MonitoringBeST 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


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/mLThen decrease dose 50%

Adverse Event Contact Attending

Voriconazole Trough MonitoringBeST Statement Cont.


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

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

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

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

Questions or Comments

References1. 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;50:405-4153. 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.

fungemia in the setting of acute lymphocytic leukemia (final)-1

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