Breakthrough Invasive Fungal Infections in the ... · Study Design Details Primary Outcome Secondary Outcomes Commentary Retrospective review in the U.S. (UT Southwestern) Pediatric

Breakthrough Invasive Fungal Infections in the Hematopoetic

Cell Therapy (HCT) Patient

Frank Tverdek PharmD BCPS AQ-ID CMQ

UT MD Anderson Cancer Center

@FTverdek

Disclosures

• Nothing to disclose

• This presentation will contain reference to off-label use of certain antifungals; reference to those instances will be verbalized

2

Objectives

• Define breakthrough invasive fungal infection

• Describe the pathogens breaking through current antifungal prophylactic regimens

• Identify an appropriate antifungal regimen for a breakthrough fungal infection

3

Defining Invasive Fungal Infection (IFI)

• Generally accepted IFI criteria for use in fungal literature: —European Organization for Research and Treatment of Cancer/Invasive Fungal Infections

Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

—Differentiates likelihood of IFI based on variety of objective parameters

• Proven IFI: demonstration of fungal elements in diseased tissue

• Probable IFI: presence of host factor putting patient at risk of IFI, clinical features of an IFI, presence of mycological evidence

• Possible IFI: presence of host factor putting patient at risk of IFI, clinical features of an IFI, absence of mycological evidence

De Pauw B. Clin Infect Dis. 2008. Jun 15; 46(12): 1813-1821.4

Probable Invasive Fungal Infection

Host Factors(Patient with HCT, prolonged

neutropenia)

Clinical evidence of

potential IFI(Radiologic, skin manifestations)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748676/figure/F1/ (last accessed 1/10/19)

https://www.cdc.gov/fungal/infections/stem-cell.html (last accessed 1/10/19)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748676/figure/F1/https://www.cdc.gov/fungal/infections/stem-cell.html

Probable Invasive Fungal Infection

Host Factors(Patient with HCT, prolonged

neutropenia)

Clinical evidence of

potential IFI(Radiologic, skin manifestations)

Mycological evidence of

disease(galactomannan, Beta-D-glucan)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748676/figure/F1/ (last accessed 1/10/19)

https://www.cdc.gov/fungal/infections/stem-cell.html (last accessed 1/10/19)

https://visualsonline.cancer.gov/details.cfm?imageid=9639 (last accessed 1/10/19)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748676/figure/F1/https://www.cdc.gov/fungal/infections/stem-cell.htmlhttps://visualsonline.cancer.gov/details.cfm?imageid=9639

Proven / Definite Invasive Fungal Infection

• Demonstration of pathogen in diseased tissue

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147702/figure/f0025/# (last accessed 1/10/19) 7

Aspergillus niger in lung tissue, 200X and 400x magnification

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147702/figure/f0025/

Breakthrough Invasive Fungal Infection (b-IFI)

• Breakthrough IFI defined as:— An invasive fungal infection (IFI) occurring during the exposure to an

antifungal drug

— Includes fungal organisms outside of spectrum of activity

• In contrast to:— Persistent IFI – ongoing IFI that continues to require antifungal therapy

— Refractory IFI – progression of IFI necessitating a change in antifungal therapy

— Relapsed IFI – reoccurrence of same fungal pathogen at same site subsequent to completion of initial fungal therapy

Cornely, O. A. Mycoses. 2019. 62(9): 716-729

Clinical Impact of Breakthrough Fungal Infection

Multicenter Swiss HCT Cohort Study

• Details— Review Time period: 2009 – 2013

— Total patients: 479

• Invasive Candida infections—2.3% of patients

—20% 12 - week mortality

• Invasive Mold infections—8.5% of patients

—58% 12 week mortality

Kuster, S.Transpl Infect Dis. 2018. 20(6): e12981.

Kontoyiannis, D.P. BMC Infect Dis. 2016 Dec 1;16(1):730.

Retrospective Review Mucormycosis in US - Premier Database

• Details— Review Time period: 2005 – 2014

— Total Patients: 555 cases out of 47 million

— Underlying HCT in 63 of 555

• Hospitalization —Length of stay (median): 17 (1-259) days

— Mortality (In-hospital): 23%

— Readmission (1 month): 23%

— Cost per hospital stay (SD): $112,419, (159,144)

SD: standard deviation

Contributory Factors to b-IFI

• General risk factors—Neutropenia depth and duration

—High fungal inoculum exposure

—Central venous catheters (specifically for Candida spp. infections)

• HCT specific factors—Allogeneic transplants (alloHCT) at more risk than autologous transplants (aHCT)

—Early IFI (pre-engraftment): mucositis and profound neutropenia conspire

—Late IFI: GVHD, corticosteroid (> 0.3 mg/kg/day) and cumulative immunosuppressive use

• Mold active agents typically reduce overall incidence of b-IFI

• Risk factors hold similar for both adult and pediatric IFI

Lionakis, M. S. Clin Infect Dis. 2018. 67(10): 1621-1630.

Epstein D.J. J Antimicrob Chemother. 2018; 73 Suppl 1: i60- i72

HCT: hematopoietic cell transplantation

GVHD: graft-versus-host disease

ARS Slide #1 -> Objective 1

The following scenario best describes a breakthrough fungal infection (b-IFI)

a) A patient was receiving caspofungin for a C. albicans fungemia, and was switched to oral fluconazole today to facilitate transition to home

b) A patient with invasive pulmonary Aspergillosis is receiving voriconazole, pulmonary function is worsening and amphotericin liposomal is added to their regimen

c) A patient is receiving isavuconazole for invasive pulmonary Aspergillosis, now multiple blood cultures show growth of C. glabrata

d) A patient completed caspofungin therapy 6 days ago for C. krusei fungemia, now showing multiple blood cultures positive from 1 day ago with growth of C. krusei

ref

Current State of IFI Prophylaxis

https://www.nccn.org/professionals/physician_gls/PDF/infections.pdf (last accessed 12/1/19)

Groll A.H. Lancet Oncol 2014; 15: e327–40

Science M. Pediatr Blood Cancer 2014; 61:393–400

Adults Pediatrics

HCT Indication First line Second line First line Second line

Autologous w/ mucositis Fluconazole or Micafungin None Fluconazole1 Micafungin1

Autologous w/o

mucositisNone None Fluconazole1 Micafungin1

Allogeneic Fluconazole or MicafunginVoriconazole, posaconazole, or

amphotericin BFluconazole

Voriconazole, itraconazole,

micafungin or amphotericin B

Significant GVHD PosaconazoleVoriconazole, echinocandin or

amphotericin BPosaconazole Voriconazole or itraconazole

1 For patients with neutropenia anticipated for > 7 days

Fluconazole IFI Prophylaxis in HCT

• Prior to fluconazole, hepato-splenic candidiasis was a major cause of morbidity and mortality in the immunocompromised patient

• Fluconazole -> reduced morbidity and mortality in HCT patients by preventing IFI

• Fluconazole’s limited spectrum of activity characterizes its b-IFI—Non-C. albicans, Candida spp. (i.e. C. glabrata, C. krusei)

—Aspergillus spp.

—Mucor spp.

• Development of multiple mold active agents

Orasch, C. J Infect. 2018. 76(5): 489-495.

Voriconazole IFI Prophylaxis in HCT

Study Design Details Primary Outcome Secondary Outcomes Commentary

Multicenter,

prospective,

double-blinded

study in the U.S.

Voriconazole

200mg PO BID

(N= 295)

compared to

fluconazole 400mg

PO daily ( N= 305)

for day 0-100 post

standard high-risk

HCT

Study period:

2003 - 2006

Fewer b-IFIs in

voriconazole arm vs.

fluconazole: 7.3% vs.

11.2%; p=0.12

Overall mixture of

Candida spp.,

Aspergillus spp. &

Mucor spp.

Fungal free survival at

180 days similar (75%

vs 78%; p=0.49)

Relatively low incidence of

GVHD

Largely driven by positive

galactomannan as evidence of

IFI, “Probable IFI”

Trend towards less Aspergillus

spp. breakthrough in

voriconazole arm

14Wingard, J. R. Blood. 2010 116(24): 5111-5118.

• Other retrospective studies have combined assessment of b-IFI during both prophylaxis and treatment

—Mucorales (zygomycetes) is the most common breakthrough pathogen• Typically occurring late post-transplant, especially during GVHD treatment

• Mucor spp. considered to be resistant, often with high MIC values to voriconazole

• Often manifesting in sinus and pulmonary infection

—Resistant Candida spp.• Most commonly C. glabrata and C. krusei

• Documented high MICs to voriconazole, ~2mcg/ml

• Often manifesting as fungemia

Imhof, A. Clin Infect Dis. 2004. 39(5): 743-746.

Kim, S. B. Med Mycol. 2017. 55(3): 237-245.

Voriconazole b-IFI in HCT Patients

Voriconazole IFI Prophylaxis in Pediatric HCT

16


Retrospective

review in the U.S.

(UT Southwestern)

Pediatric HCT

patients

(N=84)receiving

primary antifungal

prophylaxis with

voriconazole (n=64)

or Liposomal

amphotericin B (n=25)

or Micafungin (n=16)

Study period: 2012-

2016

IFI per 1000 prophylaxis days

• Voriconazole: 1.17

• Liposomal amphotericin:

2.67

• Micafungin: 2.08

• No statistical comparison

Total of 21 b-IFIs, most

were ‘possible’ IFI

• 5 total with positive

Beta-D-glucan testing

• 1 mold not speciated

• 1 positive

galactomannan

Unclear which IFIs

attributed to each

agent

Voriconazole b-IFI

was possible IFI in

8/9 cases

Median age 9

years old, (range

0-21)

Bui, A. J Pediatr Pharmacol Ther. 2019. Vol 24(3):220-226.

Posaconazole Suspension IFI Prophylaxis in HCT

17


Phase 3,

multicenter,

randomized,

double blinded

Posaconazole

200mg PO TID

(N= 301)

compared to

fluconazole 400mg

PO daily (N= 299)

for prophylaxis in

HCT with GVHD

Study period:

1999 - 2003

Decrease in b-IFI rate

• 5.3% posaconazole

vs. 9% fluconazole

(p= 0.07)

Invasive Aspergillus:

• Posaconazole 2%

vs Fluconazole 7%

(p=0.006)

Mortality:

• Posaconazole 1%

vs. fluconazole 4%,

(p=0.46)

b-IFI in posaconazole group:

• Three Aspergillus spp. by

positive galactomannan test

• One of each of the following

pathogens

• Candida glabrata

• Pseudallescheria spp.

• Trichosporin spp.

• Mold not specified

Older posaconazole suspension

Ullmann AJ. N Engl J Med. 356;4: 335-3347

Posaconazole IFI Prophylaxis – Newer Formulations

• Retrospective review of 343 cases of posaconazole prophylaxis at MD Anderson Cancer Center in patients with hematologic malignancy

• HCT represented 20% of patients with 30% of HCT with GVHD

• Overall rate of b-IFI of 2%

Tverdek F.P. Antimicrob Agents Chemother. 2017. 61:e00188-17.

Adapted from Table 4

Patient Age Sex Malignancy alloHCT IFI site PathogenProphylaxis

(Days)

Posaconazole

level

42-day

outcome

1 56 M MM Yes Lung Yeast 13 1,490 Death

2 54 F CLL No BloodRhodotorula

spp.7 None Improved

3 58 F MDS Yes Lung Penicillium spp. 9 1,400 Death

4 46 M AML No LungAspergillus

flavus3 None Death

5 57 F AML No Skin Fusarium spp. 14 1,960 Improved

6 72 F AML No LungPositive for

galactomannan 16 1,160 Improved

7 61 M AML Yes BloodPositive for

galactomannan 46 1,770 Death

8 65 M MDS No LungPositive for

galactomannan 12 1,810 Worsened

MM- Multiple Myeloma; CLL- Chronic Lymphocytic Leukemia; MDS-Myelodysplastic Syndrome; AML- Acute Myelogenous Leukemia

• Retrospective review of posaconazole prophylaxis cases at OHSU

• N= 547 patients; ~20 HCT, 18% with GVHD

• B-IFI rate: 1.6%

Posaconazole Prophylaxis – Newer Formulations

Furuno, J. P. Antimicrob Agents Chemother. 2018. 62(10).

Adapted from Table 3

APL- Acute Promyelocytic Leukemia; CML- Chronic Myelogenous Leukemia

Diagnosis HCTPosaconazole

FormulationIFI Class Site of infection

Identified fungal

organism

Prophylaxis

(Days)

Posaconazole

Level (ng/ml)

APL No Suspension Probable Lung/trachea Aspergillus fumigatus 15 None

CML No Suspension Probable Lung/trachea Positive galactomannan 18 280

AML No Suspension Proven Skin Fusarium proliferatum 17 1820

AML No Tablet Probable Lung Positive galactomannan 25 1800

AML No Tablet Proven Lung Cryptococcal antigen None

GVHD Allogeneic Suspension Proven Blood Candida glabrata 12 1070

AML No Tablet Proven Sinuses Mucor species 66 900

AML Allogeneic Tablet Proven Sinuses Zygomyces species 13 None

AML No Suspension Proven Lung Aspergillus niger 5 None

AML No Suspension Probable Lung Positive galactomannan 7 None

HCT Allogeneic Suspension Proven Lung Aspergillus species 44 2090

GVHD Allogeneic Tablet Proven Blood Candida glabrata 78 1200

AML Allogeneic Tablet Proven Sinuses No culture growth 39 None

AML No Tablet Proven Blood Candida tropicalis 13 1600

Isavuconazole IFI Prophylaxis In High-Risk Patients

20

Study Design Details Primary

Outcome

Secondary Outcomes Commentary

Retrospective

review in the U.S.

(Oregon Health &

Science

University

Hospital)

Review of isavuconazole

prophylaxis for high-risk

immunocompromised

patients (N=98)

Study period:

2016 - 2017

B-IFI rate:

• 8.2% per

patient

• 5.8% per

course

Mortality in 58% of

patients within range of

7-34 days post

diagnosis

HCT details:

• History of HCT in 36%

patients

• GVHD in 22% of total HCT

Considerable increase in b-IFI

as compared to previous

institutional posaconazole b-IFI

rates of 1.6% in similar patients

Bowen, C. D. Mycoses. 2019. 62(8): 665-672.

Fontana, L. Clin Infect Dis. 2019 Apr 8. pii: 5431181.

Isavuconazole IFI Prophylaxis in High Risk PatientsAdapted from Table 2

Patient Age/Sex Malignancy HCT Pathogen IFI ClassNeutropenia

(Days)

Prophylaxis

(Days)

Trough

Level

Isavuconazole

MICb-IFI Therapy Outcome

1 74/F AML N Aspergillus spp Probable 26 10 6.3 ND Isavuconazole Death

2 71/M AML N Aspergillus spp Probable 18 15 ND ND Isavuconazole Alive

3 30/M R/R AML N Aspergillus Probable 180 125 3.3 ND Ambisome Alive

4 57/M R/R AML NFusarium

dimerumProbable 25 8 ND ND Isavuconazole Death

5 45/F R/R AML Y Fusarium spp Proven 9 9 ND ND Ambisome Alive

6 64/F R/R AML N A. fumigatus Probable 38 13 3.7 ND Voriconazole Alive

7 65/M R/R AML N A. fumigatus Probable 38 40 4.3 ND Voriconazole Death

8 60/M R/R AML NRhizopus

microsporusProven 11 14 ND ND

Ambisome,

posaconazoleAlive

9 64/F MF Y A. fumigatus Probable 16 12 ND 0.5 Micafungin Death

10 67/M R/R ALL Y Syncephalastrum Probable 27 22 ND 2 Posaconazole Death

11 53/F AML N A. fumigatus Possible 21 20 3.4 ND Micafungin Death

R/R – Relapsed refractory; AML- Acute Myelogenous Leukemia; MF- Myelofibrosis; ND- not done

Isavuconazole b-IFI in Retrospective “Real- World” use

Fung, M. Clin Infect Dis. 2018 Sep 14;67(7):1142-1143.

Rausch, C. Clin Infect Dis. 2018 Oct 30;67(10):1610-1613.

Patient Age/ Sex

Disease and

Transplant

Status

Neutropenia Indication IsavuconazoleISA Level

(mcg/ mL)

Breakthrough

Infection

Isavuconazole

MIC

Treatment

b-IFIResponse

1 44 FALL s/p

alloHCT5 months Prophylaxis 2 months 2.8 Pneumonia NA

Ambisome,

voriconazoleImprovement

2 63FMultiple

Myeloma8 days Pneumonia 4 months NA Pneumonia NA

Ambisome,

voriconazole,

posaconazole

Improvement

3 68MHeart/Renal

transplantN/A Prophylaxis 1 month 2.2 Pneumonia 0.5

Ambisome,

caspofungin,

lobectomy

Death

4 65M

Aplastic

anemia s/p

alloHCT

1 month Prophylaxis 13 days NAPneumonia,

fungemia4

Ambisome,

caspofungin,

voriconazole

Death

5 37M AML 4 months Prophylaxis 5 weeks NA Pneumonia 0.5

Ambisome,

caspofungin,

voriconazole

Death

Itraconazole IFI Prophylaxis in HCT

• Itraconazole is a mold active triazole with a spectrum of activity that includes Candida spp. and Aspergillus spp.

• Early formulations of itraconazole were highly variable in attaining therapeutic levels

—Capsule and liquid formulations often poorly absorbed

—Limited absorption in patients with mucositis

• Prophylaxis studies varied with respect to efficacy vs. comparators like fluconazole, voriconazole and posaconazole

• Limited efficacy possibly due to lack of therapeutic drug monitoring (TDM) and suboptimal exposure

• “Super- bioavailable” itraconazole; SUBA- itraconazole developed

Nield, B., et al. J Antimicrob Chemother. 2019. 74(10): 3049-3055.

SUBA- Itraconazole IFI Prophylaxis in Heme and HCT

24

Study Design Details Primary Outcome Secondary

Outcomes

Commentary

Retrospective

cohort study in

Sydney,

Australia

(Royal Prince

Alfred Hospital)

Reviewed SUBA-

itraconazole for IFI

prophylaxis in patients

with hematologic

malignancy and HCT

(N=74 patients, 98

episodes)

Study period: 2016-2018

b-IFI rate:

• 5% overall by

episode

• One C. glabrata

fungemia

• Five possible b-IFI

Mortality: 4%

• Patient with C.

glabrata b-IFI died

Four b-IFI patients

received voriconazole

and with subsequent

neutrophil recovery

and improved

HCT details:

• History of HCT in 62% of

patients

Small scale study, larger

comparative evaluations

warranted

Nield, B. J Antimicrob Chemother. 2019; 74: 3049-3055

Micafungin IFI Prophylaxis in HCT

25

Study

Design

Details Primary Outcome Secondary Outcomes Commentary

Phase 3,

multicenter,

randomized,

double-

blinded

Micafungin (MICA)

50mg IV daily (N=

425) compared to

fluconazole (FLUC)

400mg IV daily (N=

457) for IFI

prophylaxis in HCT

during pre-

engraftment period

Study period: 1999-

2000

Efficacy:

• 80% micafungin

• 73.5% fluconazole

• p=0.03

b-IFI (MICA vs. FLUC):

• 1.6% vs. 2.4%, p=0.481

Micafungin b-IFI:

• Candida spp. (4)

• Probable Aspergillus spp. (1)

Fluconazole b-IFI:

• Candida spp. (2)

• Aspergillus spp.

• Probable (3)

• Proven (4)

Mortality (MICA vs. FLUC): :

• 4.2% vs. 5.7% ; p=0.322

Micafungin non-inferior to

fluconazole during the

pre-engraftment period

Overall low rate b-IFI

Micafungin with

potentially less b-IFI due

to Aspergillus spp.

van Burik JA. Clin Infect Dis. 2004;39:1407-16.

Caspofungin IFI Prophylaxis in HCT

26


Retrospective

cohort study in

U.S.

(MD Anderson

Cancer Center)

Review of

caspofungin IFI

prophylaxis in

patients with HCT

(N= 123)

Study period:

2002-2005

B-IFI rate:

• 7.3% of patients

Infection with:

• Mixed Aspergillus spp.

infection (2)

• Aspergillus terreus (1)

• Candida glabrata (1)

• Candida tropicalis (1)

• Rhizopus spp. (1)

• Exserohilum spp. (1)

• Cryptococcus spp. (1)

• Unspeciated mold (1)

Mortality:

• 4.1% by day 100

• 4 of 5 with b-IFI

HCT details:

• GVHD in 40.7% of patients

Dosing:

• 85% 50mg IV daily

• 15% 35mg IV daily

Chou LS. Pharmacotherapy. 2007;27(12):1644–1650

Echinocandin Prophylaxis Efficacy

• Since the early studies, multiple smaller retrospective studies performed and meta-analyses in HCT and hematologic malignancy

—In pre-engraftment phase similar efficacy to fluconazole

—During GVHD treatment, anti-mold azoles likely superior as higher rates of b-IFI

• Further characterization of breakthrough Candida spp., such as C. tropicalis demonstrate mutations leading to potential tolerance to echinocandins

Epstein DJ. J Antimicrob Chemother. 2018; 73 Suppl 1: i60- i72.

ARS Slide #2-> Objective 2

Which of the following fungal infections would be least likely to occur as b-IFI in a patient receiving posaconazole prophylaxis during treatment for acute GVHD:

A) Candida albicans fungemia

B) Aspergillus fumigatus pulmonary infection

C) Mucor spp. sinusitis

D) Galactomannan positive pulmonary infection

General Approach to b-IFI Assessment

• Evaluate the current antifungal regimen—Confirm patient was actually receiving prophylaxis

• Oral azoles can be expensive for patients

• Do they understand the dosing and frequency (i.e. 1 vs. 3 posaconazole tablets)

—Evaluate likelihood of adequate absorption for oral agents

• Severe mucositis?

• Inability to swallow tablet/capsules?

—Evaluate for presence of any drug-drug interactions

—Review any TDM

—Consider assessing antifungal serum level at diagnosis of b-IFI to evaluate potential for suboptimal exposure (i.e. itraconazole, posaconazole, voriconazole)

Therapeutic targets for Azole Therapy

• Voriconazole —Prophylaxis target >1.0 mcg/ml

—Treatment target 2-5.5 mcg/ml

• Posaconazole—Substantial controversy exists as to optimal target

—Possibly more than 500… 700 ng/ml for prophylaxis?

• Itraconazole—Prophylaxis target > 1.0 mcg/ml

• Unclear for Isavuconazole

• A practical approach is to determine how close your patient’s level is to the average level in the prophylaxis studies

Hussaini, T. Pharmacotherapy. 2011;31(2):214–225.

Furuno, J. P. Antimicrob Agents Chemother. 2018. 62(10).

Tverdek F.P. Antimicrob Agents Chemother. 2017. 61:e00188-17.

General Approach to b-IFI Treatment

31

Consider goals of care

• Malignancy treatment status?

• Neutrophil recovery?

• What are the patient’s wishes?


32





Likely Pathogens

• Review prophylaxis drug spectrum of activity

• Recall the common culprits

• Review microbiology history


33





Evaluate for comorbid conditions

• Renal and hepatic status?

• Oral vs. IV routes?

• Concomitant bacterial infections?

• Interacting medications?

Likely Pathogens









34

Evaluate for comorbid conditions

• Renal and hepatic status?

• Oral vs. IV routes?

• Concomitant bacterial infections?

• Interacting medications?

Likely Pathogens




Review antifungal treatment history

• Check for any intolerances in the past

• Insurance coverage concerns?

Amphotericin B Therapy

• Amphotericin therapy remains the broadest spectrum antifungal

• It is considered the first line therapy in b-IFI when the pathogen is unknown—Mold infections breaking through any of the mold-active azoles

—For Candida spp. infections in which resistance to echinocandins may suspected

• Delays in initiation of amphotericin associated with increased mortality• 70 patients with zygomycosis (Mucor spp. Infection) at MD Anderson Cancer Center

• Regression tree analysis identified 6 days as threshold for worse outcomes

• The 12 week mortality was 82.9% vs. 48.6% for 6 or more days and less than 6 days initiation, respectively

Lionakis, M. S. Clin Infect Dis. 2018. 67(10): 1621-1630.

Chamilos G. Clin Infect Dis. 2008;47:503-9

Choosing Additional Treatment Agents

• Amphotericin based therapy is often a shorter term solution as it is associated with nephrotoxicity

• Consideration of an additional agent or an altogether different agent than amphotericin b is debatable

• Some experts recommend changing the azole once b-IFI occurs—Voriconazole -> posaconazole—Posaconazole -> voriconazole or isavuconazole—Isavuconazole -> voriconazole for suspected Aspergillosis, posaconazole for suspected Mucor

spp.

• Addition of echinocandin to azole therapy as potential strategy—Based on a combination anidulafungin/voriconazole study for invasive Aspergillosis—Demonstrated combo therapy improved outcomes in patients who recovered neutrophils and had

galactomannan-positive IFI

• Very sparse data on treating b-IFI and more studies needed

fLionakis, M. S. Clin Infect Dis. 2018. 67(10): 1621-1630.

Marr, K.A. Ann Intern Med. 2015. Jan 20;162(2):81-9.


• What regimen is most appropriate for a HCT patient with b-IFI, manifesting as new pulmonary infection with two consecutive positive galactomannan values, while receiving posaconazole for prophylaxis during treatment of GVHD. Patient is otherwise stable from renal and hepatic standpoint. Plans are to remain hospitalized for the next 2-3 weeks.

A) Fluconazole monotherapy

B) Caspofungin monotherapy

C) Amphotericin liposomal plus voriconazole

D) Amphotericin liposomal plus fluconazole

ref


• What agent is likely to have the broadest chance of targeting b-IFI in a patient receiving posaconazole prophylaxis?

A) Voriconazole

B) Caspofungin

C) Amphotericin liposomal

D) Isavuconazole

ref

Questions?

ref

Recommended References

• Lionakis, M.S., et.al. Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions. Clin Infect Dis. 2018 Oct 30;67(10):1621-1630.

• Cornely, O.A., et.al. Defining breakthrough invasive fungal infection-Position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology. Mycoses. 2019 Sep;62(9):716-729.

• Epstein, D.J., et.al. Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematologicalmalignancies. J Antimicrob Chemother. 2018 Jan 1;73(suppl_1):i60-i72.

Documents

Breakthrough Invasive Fungal Infections in the ... · Study Design Details Primary Outcome Secondary Outcomes Commentary Retrospective review in the U.S. (UT Southwestern) Pediatric