It Takes Two to Make a Thing Go Right? Combination ...sites.utexas.edu/pharmacotherapy-rounds/files/2016/... · 1/15/2016  · Condition Antifungal Therapy Invasive Aspergillosis.

It Takes Two to Make a Thing Go Right? Combination Antifungal Therapy in Invasive Aspergillosis

Clarice Carthon, Pharm.D., BCPS PGY2 Solid Organ Transplant Pharmacy Resident

Department of Pharmacy, University Health System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio

January 15, 2016

Learning Objectives

1. Describe Aspergillus characteristics and the pathophysiology of invasive aspergillosis (IA)2. Identify the current recommended treatment options for IA3. Discuss the potential benefits and risks of utilizing combination antifungal therapy in IA4. Formulate an evidence-based recommendation for the appropriate use of combination

antifungal therapy in IA

C. CARTHON 2

I) Invasive Fungal Infections1-3

A) Fungal infections (mycoses) range from localized skin and soft tissue infections to fungemia withdisseminated disease to any organ system

B) Infections can manifest from asymptomatic colonization to invasive diseaseC) Fungi distinguished as yeasts, molds, or both (dimorphic fungi)

i) Yeastsa) Single cells reproduce by budding and grow by forming pseudohyphaeb) Acquired through breakdown of body’s normal mucosal and skin barriers

ii) Moldsa) Multicellular filamentous fungi made of hyphae

1) Reproduce by production of conidia or sporesb) Acquired through inhalation of spores spread by wind, water, and contact

iii) Dimorphic fungia) Capable of producing both hyphal and yeast-like forms depending on temperature

1) Typically grow as yeast at body temperature and as mold at room temperatureD) Primary endemic fungi: Blastomyces, Coccidioides, HistoplasmaE) Opportunistic fungi: Aspergillus, Candida, Cryptococcus, Fusarium, Zygomycetes

Figure 1. Fungus Classification.1

Fun

gus

Yeast

Candida

Cryptococcus

Trichosporon

Mold

Aspergillus

Fusarium

Scedosporium

Zygomycoses

Dimorphic

Histoplasma

Coccidioides

Blastomyces

Sporothrix

Paracoccidioides

C. CARTHON 3

II) Aspergillus2,3

A) Most common invasive mold

B) Microscopic morphologic features1

i) Hyaline, septate, dichotomously branched hyphae of uniform width

ii) Conidial heads may be spotted in cavitary lesions

C) Conidia ubiquitous in environment (e.g. air, soil, decaying matter) and hospital setting (e.g. air, showerheads, water storage tanks, potted plants)

D) Nineteen species (spp.) documented as agents of human disease4,5 i) Causative spp. accounting for majority of infections

a) A. fumigatus (70-80%)

b) A. flavus (13%)

c) A. niger (9%)

d) A. terreus (7%)

ii) Estimated annual incidence of invasive mycoses due to Aspergillus is 12-34 infections per

million population6-10

E) Aspergillosis classically defined as invasive, saprophytic, or allergic

III) Invasive Aspergillosis (IA)

A) Serious infection that usually affects immunocompromised patients

B) Portals of entry include skin, sinuses, lungs

i) The central nervous system (CNS), cardiovascular systems, and other tissues may become

infected as result of hematogenous dissemination or direct extension from infection

C) Incidence

i) Occurs most commonly in the lungs and sinuses a) Invasive pulmonary aspergillosis (IPA) occurs in setting of profound neutropenia

ii) Nearly two-thirds (61%) of patients with IA have underlying hematological malignancy (HM) or history of hematopoietic stem cell transplantation (HSCT)11

iii) The first population-based incidence estimates for IA suggested a yearly rate of 1-2 cases per 100,000 population10 a) Epidemiology of IA has since shifted due to increasing number of solid organ transplants

(SOT), HSCT, and newer immunosuppressive agents 1) 12-month incidence of 19% among SOT recipients12

D) Major cause of morbidity and mortality in immunocompromised patients ranging from 30-95%

i) One-year mortality in SOT recipients: 41%12

ii) One-year mortality in HSCT recipients: 75%13

E) Host factors i) HM, HSCT, SOT, inherited immunodeficiency ii) Patients within these groups that face the highest risk for IA2,11

a) Grade III-IV graft versus host disease (GVHD)

b) Receipt of steroids

c) Prolonged neutropenia

d) Age > 40 years

e) Receipt of infliximab or other anti-TNF therapy

F) Presentation

C. CARTHON 4

i) Usually occurs in ill patients from other medical conditions a) Difficult to determine which symptoms related to IA

1) Lung symptoms (i) Fever, chest pain, dry cough, dyspnea, possible hemoptysis

2) Other symptoms can develop if infection spreads from lungs to other parts of body ii) Radiologic findings include pleura-based, wedge shaped densities or cavitary lesions iii) Computed tomography (CT) findings14

a) Halo-sign 1) Appears in early IA 2) An area of low attenuation surrounding a nodular lesion

(i) Represents edema or bleeding surrounding ischemic area b) Air crescent sign

1) Occurs later in course of disease 2) Caused by contraction of infarcted tissue and signifying cavitation of nodular lesions

(i) Associated with neutrophil recovery

Figure 2. Signs of IA on Chest CT.

14

G) Diagnosis

i) Three levels of certainty of invasive aspergillosis defined: proven, probable, and possible ii) Definitions standardized in 2002 and most recently updated in 200815

a) Proven invasive fungal disease requires one of the following: 1) Microscopic analysis

(i) Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are identified accompanied by evidence of associated tissue damage

2) Culture (i) Recovery of mold or “black yeast” in a specimen obtained by sterile procedure

from normally sterile and clinically or radiologically abnormal site consistent with infectious process

3) Blood (i) Yields mold in context of a compatible infectious disease process (ii) Recovery of Aspergillus spp. from blood cultures invariably represents

contamination b) Probable invasive fungal disease requires presence of host factor, clinical criterion, and

mycological criterion (i) Host factors

1. Recent history of neutropenia related to onset of disease

C. CARTHON 5

2. Receipt of allogeneic HSCT

3. Prolonged use of corticosteroids (minimum dose 0.3 mg/kg/day prednisone

equivalent for 13 weeks)

4. Treatment with immunosuppressants within past 90 days

5. Inherited severe immunodeficiency (ii) Clinical criteria for lower respiratory tract fungal disease

1. Presence of 1 of 3 signs on chest CT: a. Dense, well-circumscribed lesions(s) with or without a halo sign b. Air-crescent sign c. Cavity

(iii) Mycological criteria 1. Direct test (cytology, direct microscopy, or culture)

a. Mold in sputum, bronchoalveolar lavage (BAL) fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of following: i. Presence of fungal elements indicating a mold ii. Recovery by culture of a mold (e.g. Aspergillus species)

2. Indirect tests (detection of antigen or cell-wall constituents) a. Galactomannan (GM) antigen detected in plasma, serum, BAL fluid, or

cerebrospinal fluid b. β-d-glucan detected in serum

c) Possible invasive fungal disease meets the criteria for a host factor and clinical criterion, but mycological criteria absent

IV) IA Treatment16,17 A) Several antifungals have in vitro, in vivo, and clinical activity against Aspergillus spp.

Table 1. Antifungal Spectrum of Activity Against Aspergillus spp.22

Organism

Antifungal Agent

Polyene Azoles Echinocandins

AMB Itra Vori Posa Isa Caspo Mica Anid

Aspergillus spp. A. flavus A. fumigatus A. niger A. terreus

+ ± + + -

+ + + ± +

+ + + + +

+ + + + +

+ + + + +

+ + + + +

+ + + + +

+ + + + +

NOTE: (+) activity against organism; (±) variable activity against organism; (-) no activity against organism; Fluconazole and flucytosine have no activity AMB- amphotericin B; Itra- itraconazole; Vori- voriconazole; Posa- posaconazole; Isa- isavuconazole; Caspo- caspofungin; Mica- micafungin; Anid- anidulafungin

B) Early initiation of antifungal therapy warranted while evaluation conducted if strong suspicion

i) Associated with high morbidity and mortality especially when diagnosis and treatment delayed18-20

ii) Response to treatment and survival can be improved if specific antifungal treatment is initiated at early stage of infection a) Initiation upon identification of halo sign by chest CT associated with significantly better

response to treatment and improved survival21

C. CARTHON 6

C) Immunosuppressive medications should be discontinued or decreased if possible D) Antifungals FDA-approved for IA treatment

a) Primary: amphotericin B deoxycholate (D-AMB), voriconazole, isavuconazonium sulfate b) Salvage: caspofungin, itraconazole

E) Recommendations for treatment of IA Table 2. Infectious Disease Society of America (IDSA) Recommendations for Treatment of IA.16

Condition Antifungal Therapy

Invasive Aspergillosisa

Primary Therapy Voriconazole: 6 mg/kg IV Q12H x 1 day 4 mg/kg IV Q12H; 200 mg PO BID Alternative Therapy L-AMB: 3-5 mg/kg/day IV ABLC: 5 mg/kg/day IV Caspofungin: 70 mg IV load 50 mg daily Micafungin: 100-150 mg IV daily Posaconazole: 200 mg PO suspension QID 400 mg PO suspension BID Itraconazole: 600 mg/day PO tablets x 3 days 400 mg/day PO tablets

Aspergillosis Refractory to Voriconazole

1. Change to different drug class 2. Use combination of agents 3. Surgical resection of infected tissue may be useful

L-AMB = liposomal amphotericin B; ABLC = amphotericin B lipid complex a Primary combination therapy not routinely recommended due to lack of clinical data. Addition of another

antifungal or switch to another drug class for salvage therapy considered on a case-by-case basis

F) Few randomized controlled trials (RCT) on IA treatment G) Voriconazole recommended for primary treatment of IA16

i) Largest IA RCT demonstrated superiority vs. D-AMB a) Landmark trial23 – Herbrecht et al. 2002 b) Assessed global response at week 12 in immunocompromised patients > 12 years old

with proven or probable IA 1) Successful outcomes

(i) Complete response: resolution of all clinical signs and symptoms and more than 90% of lesions due to IA that were visible radiologically

(ii) Partial response: clinical improvement and > 50% improvement in radiological finding

2) Unsuccessful outcomes (i) Stable response: absence of change from baseline or an improvement < 50% (ii) Failure: worsening disease

c) Treatment success: voriconazole 53% vs. D-AMB 32% (95% CI 10.4 to 32.9) d) Survival: voriconazole 71% vs. D-AMB 58% (HR, 0.59; 95% CI 0.40 to 0.88)

H) Combination therapy i) Rationale24

a) Achieves synergy, broadens combined spectrum of activity, or lowers dosing of agents with prominent side effects

C. CARTHON 7

Figure 3. Targets of Systemic Antifungal Agents.

22

ii) Controversy - interactions between combination antifungal pairings not well understood a) Combination of AMB and azoles

1) Antagonistic25,26 (i) Antagonism has been described in vitro and in vivo for azole-polyene

combinations against Aspergillus 1. Polyenes bind to ergosterol in fungal cell membrane 2. Azoles inhibit synthesis of ergosterol

(ii) Antagonism found at combinations with higher concentrations of AMB (>0.125 mg/L)27

2) Synergistic27 (i) Synergy found with in vitro combinations with low concentrations of AMB

(<0.125 mg/L) (ii) For itraconazole-resistant isolates, synergistic interactions noted at high

concentrations of itraconazole (>0.5 mg/L) b) Combination of AMB and echinocandins28

1) Caspofungin and AMB synergistic or synergistic-to-additive for at least half of isolates tested

2) Antagonism not observed c) Combination of azoles and echinocandins

1) In vitro, synergy detected in majority of interactions and no antagonism observed29 2) Synergistic interaction detected in animal models30,31

iii) Concerns a) Attenuation of activity b) Increased resistance or toxicity c) Increased cost d) Drug interactions

iv) Salvage therapy

C. CARTHON 8

a) The IDSA 2008 guideline states combination antifungal drugs from different classes other than those in the initial regimen may be used

Table 3. Combination Therapy as Salvage IA Treatment.32-35

Author (n) Patient Population* Intervention Results

Aliff et al. 2003 30 Documented or possible

IA refractory to AmB Caspo + L-AMB

Favorable antifungal response in 60% of

patients

Kontoyiannis et al. 2003 48 Documented or possible

IA Caspo + L-AMB Overall response rate 42%

Marr et al. 2004a 47 Documented IA that failed

AmB

Vori vs.

Vori +Caspo

↑ 3-month survival (p= 0.048) and↓ mortality (p=

0.011) in combo group

Maertens et al. 2006b 53 Documented IA refractory

to standard therapy Caspo + mold-active

antifungal

Treatment success at end of therapy 55% and day 84

49% Survival at day 84 55%

* All patient populations had hematologic malignancies a Only study with comparison group

b Only study with prospective study design, remainder retrospective

IA- invasive aspergillosis; AMB- amphotericin B; Caspo- caspofungin; L-AMB- liposomal amphotericin B; Vori- voriconazole

v) But can two make a thing go right from the beginning?

a) Recommendations from IDSA and the American Society of Transplantation (AST) in regards to primary combination therapy

IDSA 200816 AST 201317

“Primary combination therapy is not routinely recommended based on lack of

clinical data.”

“Potential benefits of combination therapy may be best realized when used as initial

therapy…”

Figure 4. Timeline of Primary Combination Therapy Trials.

Herbrecht et al. Landmark trial

2002

Denning et al.

2004

Singh et al. 2006

IDSA IA Guidelines

2008

Caillot et al. 2007

AST Guidelines

2013

Marr et al. 2015

C. CARTHON 9

V) Combination Therapy as Primary IA Treatment Data

Denning DW, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 2006; 53:337–49.36

Overview

Trial Design Open-label, non-comparative, multinational study

Objective Evaluate safety and efficacy of micafungin, when administered alone or in combination with other systemic antifungal agents, in patients with proven or probable IA

Methods

Patients Inclusion

Adult and pediatric patients of any age from 1998 to 2002

o Except premature neonates

Proven or probable invasive infection due to Aspergillus spp.

o Only pulmonary aspergillosis enrolled as probable cases

Exclusion

Pregnant or nursing

Liver transaminases > 10x upper limit of normal (ULN)

Total bilirubin > 5x ULN

Alkaline phosphatase > 5x ULN

Life expectancy < 5 days

Intervention Primary group: patients newly diagnosed IA who received ≤ 48 h of systemic antifungal therapy received micafungin alone (75 mg daily or 1.5 mg/kg/ day for weight ≤ 40 kg or in combination with another agent

Outcome Treatment success based on global response at end of therapy (EOT)

Statistical Analyses Primary endpoint analyzed by key demographic variables and fungal infection risk factors

Summary statistics for each assessment time and changes from baseline generated

Two-sided 95% confidence interval (CI) based on large sample normal approximation of binomial distribution

Results

Baseline Characteristics

Primary Therapy Group (n=29)

Micafungin combination (n=17)

Micafungin alone (n=12)

Mean age (years) 33.6 50.8

Sex, male, n (%) 13 (76.5) 9 (75.0)

Race, white, n (%) 15 (88.2) 9 (75.0)

Neutropenic, n (%) 5 (29.4) 2 (16.7)

Underlying conditions, n (%) HSCT Allogenic GVHD Autologous Chemotherapy Leukemia Solid organ transplant Kidney Liver Lung Heart HIV/AIDS Others

6 (35.3) 6 (35.3) 2 (11.8)

--

6 (35.5) 2 (11.8) 1 (5.9)

-- --

1 (5.9) 1 (5.9)

2 (11.8)

3 (25.0) 3 (25.0) 1 (8.3)

--

3 (25.0) 3 (25.0)

-- 1 (8.3)

-- 2 (16.7)

-- 3 (25.0)

C. CARTHON 10

Outcome

Efficacy at end of therapy

Primary Therapy Group (n=29)

Micafungin combination (n=17)

Micafungin alone (n=12)

Favorable response, n (%) Complete response Partial response

5 (29.4) 2 (11.8) 3 (17.6)

6 (50.0) --

6 (50.0)

Not successful, n (%) Stabilization Progression

12 (70.6) 3 (17.6) 9 (52.9)

6 (50.0) 2 (16.7) 4 (33.3)

Conclusions

Author Conclusion Micafungin as primary or salvage therapy proved efficacious and safe in high-risk IA patients

Critique Small sample size

Non-randomized, open-label

Combination therapy group poorly defined

Low micafungin dose

Take Home Points Licensing trial for micafungin

Initial report of primary combination therapy in humans

More favorable outcomes seen in micafungin alone group

Singh N, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study. Transplantation 2006; 81: 320–326.37

Overview

Trial Design Prospective, multicenter, observational study

Objective Assess efficacy and tolerability of voriconazole + caspofungin when used as primary therapy for IA in SOT recipients compared to those who received L-AMB monotherapy

Methods

Interventions Combination therapy group SOT recipients between 2003 and 2005 receiving voriconazole + caspofungin combination as primary therapy for IA Standard dosages of voriconazole and caspofungin employed as therapy

Control group Derived from existing databases of SOT recipients between 1999-2002 receiving L-AMB as primary therapy for IA L-AMB mean dose ~ 5 mg/kg/day

Outcomes Primary outcome: survival and response to therapy at 90 days

Secondary outcomes: in vitro testing of isolates to combination therapy correlated to clinical outcome, adverse events (AEs)

Statistical Analyses Chi-square or Fisher’s exact test to compare demographics between groups

Cox Proportional Hazard estimation model to evaluate risk factors for 90-day mortality

Multivariate model to evaluate the efficacy of treatment

Results

Baseline Characteristics

Combination therapy (n=40)

L-AMB (n=47)

Mean age, years 49 51

Sex, male, n (%) 19 (47.5) 32 (68.1)

Race, white , n(%) 31 (77.5) 37 (77.7)

C. CARTHON 11

Type of Transplant, n (%) Kidney Heart Liver Lung Small bowel Other/Multi-organ

4 (10.0) 9 (22.5) 8 (20.0)

13 (32.5) 1 (2.5)

5 (12.5)

12 (25.5) 9 (19.1)

16 (34.0) 9 (19.1)

-- 1 (2.1)

Primary immunosuppression, n (%) Tacrolimus Cyclosporine Steroids

32 (80.0) 6 (15.0) 36 (90)

33 (70.2) 12 (25.5) 41 (87.2)

Site of infection, n (%) Pulmonary Sinus CNS Other site Disseminated

37 (92.5)

-- 1 (2.5)

7 (17.5) 4 (10.0)

41 (87.2)

2 (4.3) 2 (4.3)

8 (17.0) 6 (12.8)

Renal failure, n (%) 17 (42.5) 21 (44.7)

Aspergillus spp., n(%) A. fumigatus A. flavus A. terreus A. niger

27 (71.1) 4 (11.4) 3 (8.5) 1 (2.8)

38 (80.9)

4 (8.5) 2 (4.3) 3 (6.4)

Type of infection, n (%) Proven Probable

22 (55.0) 18 (45.0)

24 (51.1) 23 (48.9)

Primary Outcome

Combination therapy (n=40)

L-AMB (n=47)

P value

Survival 67.5% 51% 0.11

Successful outcome, n (%) Complete response Partial response

28 (70.0) 7 (17.5)

21 (52.5)

24 (51.0) 10 (21.3) 14 (29.8)

0.08 0.79

0.048

Unsuccessful outcome, n (%) Stable Failure

12 (30.0) 1 (2.5)

11 (27.5)

23 (48.9) 13 (27.7) 10 (21.3)

0.08 0.001 0.62

Secondary Outcomes

In vitro synergy observed in 7/22 (32%) isolates; no indication of antagonism

Survival at 90 days did not correlated with in vitro synergistic interactions o Synergy documents in 2/8 fatal cases and 5/14 nonfatal cases (p=0.99)

↑ CNI level, ↑transaminases, GI events, visual disturbances, hallucinations, and rash most common AEs in combination group

No discontinuation of antifungal therapy for intolerance or AEs

Combination therapy independently associated with ↓mortality in patients with: o Renal failure (HR 0.32, 95% CI 0.12-0.85, p=0.02) o A. fumigatus infection (HR 0.37, 95% CI 0.16-0.84, p=0.019)

Conclusions

Author Conclusion Voriconazole + caspofungin combination was independently associated with reduced mortality in SOT recipients with renal failure

C. CARTHON 12

Critique Small sample size

Non-randomized

Historical bias

Used different drug classes as comparator

Included mechanically ventilated patients

Evaluated in vitro PK data and no evidence of antagonism

Take Home Points Patient population = SOT

Combination = azole + echinocandin

Reduced mortality with combination (32.5%) compared to L-AMB (49%)

More favorable outcomes seen in combination group

Caillot D, et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients with hematologic malignancies: a randomized pilot study (Combistrat trial). Cancer 2007;110: 2740–2746.38

Overview

Trial Design Multicenter, pilot, prospective, randomized open trial in France

Objective Compare high dose L-AMB vs. standard-dose L-AMB + caspofungin based on assumption that both regimens more effective than 3 mg/kg/day of L-AMB monotherapy

Methods

Patients Inclusion

Aged ≥ 10 years

Proven or probable IA according to the EORTC/MSG criteria

Immunocompromised

Exclusion

Life expectancy <30 days

HSCT in past 6 months

Chronic invasive fungal infection

Prior antifungal therapy ≥96 hours documented IA

Serum creatinine >2x ULN

Serum transaminases >5x ULN

Interventions Combination group L-AMB 3 mg/kg/day + caspofungin for at least 14 days

High-dose monotherapy group L-AMB 10 mg/kg/day for at least 14 days

Outcomes Primary outcome: favorable responses at EOT Secondary outcomes: time to favorable or complete response, survival at EOT and week 12

Statistical Analyses Chi-square test to compare primary endpoints of treatment groups

Chi-square tests or Cochran-Mantel-Haenszel tests for secondary endpoints’ qualitative data Kaplan-Meier method to estimate time-to-event secondary endpoints

Results

Baseline Characteristics

High-dose L-AMB (n=15)

Combination (n=15)

Mean age, years 57.3 49.9

Sex, male, n (%) 10 (67) 11 (73)

Underlying condition Acute myeloid leukemia Chronic lymphocytic leukemia Myeloproliferative disorders Acute lymphoid leukemia

10 (67) 3 (20) 2 (13)

--

14 (93)

-- --

1 (7)

Median duration of neutropenia before inclusion, 15 [3-58] 31.5 [3-115]

C. CARTHON 13

days [range]*

IPA Proven Probable

3 (20)

12 (80)

1 (7)

14 (93)

Primary Outcomes High-dose L-AMB (n=15)

Combination (n=15)

Overall response at EOT Favorable*, n (%)

Complete, n Partial, n

Unfavorable, n (%) Stable, n Failure, n Missing value, n

4 (27)

-- 4

11 (73) 6 4 1

10 (67)

-- 10

5 (33) 4 1 --

Secondary Outcomes

Time to favorable treatment response, days Mean ± SD Median [range]

14 ± 0.8

14 [13-15]

19.3 ± 9.3 14 [10-38]

Survival at EOT 14 (93) 15 (100)

Survival at week 12 12 (80) 15 (100)

Median time on study drug, days [range] 17 [4-24] 18 [10-35]

* p <0.05

Study drug AEs (n=28) less frequent in combination (n=4) than in high-dose group (n=28) o 1 serious AE (renal disorder) related to high-dose monotherapy group o 2-fold ↑ in creatinine occurred in 4/17 (23%) in high-dose group compared to 1 (7%)

in combination group

Conclusions

Author Conclusion L-AMB + caspofungin combination promising as therapy for IA compared to monotherapy

Critique Small sample size, pilot study

Randomized, open-label

No severity of illness score

Did not study standard of practice

Unaware of AmBiLoad Trial results39

Take Home Points Patient population = HM

Combination = polyene + echinocandin

Mortality with combination (0%) compared to high-dose L-AMB (20%)

Difference in favorable outcomes seen in combination group statistically significant

↑ nephrotoxicity in the high-dose L-AMB group

Marr KA, Schlamm H, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis. Annals of Internal Medicine 2015; 162:81-89.40

Overview

Trial Design Randomized, double-blind, placebo-controlled multicenter trial

Objective Assess safety and efficacy of voriconazole + anidulafungin compared with voriconazole monotherapy for treatment of IA

C. CARTHON 14

Methods

Patients Inclusion

Age ≥16 years

Underlying HM or HSCT

Diagnosis of possible, probable, or proven IA

Exclusion

Receipt of systemic antifungal drugs for treatment of IA for > 96 hours before study entry

Severe liver dysfunction

Karnofsky score < 20

Noninfectious death anticipated within 30 days

Mechanical ventilation

Receiving interacting drugs, such as rifampin

Interventions Intention-to-treat (ITT) population include all treated patients with data review committee (DRC)-confirmed diagnosis of possible, probable, or proven IA

o Modified ITT (mITT) population included only treatment patients with a DRC-confirmed diagnosis of proven or probable IA

All received standard voriconazole dosing (caveat: PO dose 300 mg BID) to complete 6 weeks of treatment AND

o IV anidulafungin 200 mg day 1, then 100 mg daily OR placebo for min. 2 weeks and up to max. 4 weeks

Outcomes Primary outcome: all-cause mortality at 6 weeks in mITT population Secondary outcome: all-cause mortality at 12 weeks and 6-week mortality in multiple pre-specified subgroups that were predicted to have prognostic significance at baseline

Statistical Analyses Kaplan–Meier for mortality rates and compared by Z test

Cochran-Mantel-Haenszel stratum weights for adjusted analysis

Univariate and multivariate Cox proportional hazards regression analyses of baseline characteristics to identify independent predictors of death

Post hoc analyses conducted for those enrolled with probable IA according to + GM antigen

To determine sample size, estimated 6-week mortality of 19% in monotherapy group and 7.6% in combination group

o mITT (n=250) to reject the null hypothesis of no treatment effect with 70% power

Results

Baseline Characteristics

Monotherapy (n=142)

Combination therapy (n=135)

Mean age, years 51.6 52.2

Sex, male, n (%) 82 (57.7) 74 (54.8)

Race, white, n (%) 98 (69.0) 99 (73.3)

Mean BMI, kg/m2 24.0 24.0

Mean Karnofsky score 65.0 65.4

Median baseline serum GM antigen, ng/mL 0.51 0.52

Underlying conditions, n (%) Allogenic HSCT Autologous HSCT Hematologic condition Neutropenia

42 (29.6)

3 (2.1) 97 (68.3) 87 (61.3)

44 (32.6)

5 (3.7) 86 (63.7) 78 (57.8)

Diagnosis of IA, n (%) Probable GM antigen and/or BAL fluid Histopathology/culture or cytology

110 (77.5) 30 (21.1)

108 (80.0) 24 (17.8)

C. CARTHON 15

Proven Use of antifungal Mold-active antifungal Prior IA treatment < 96 h of study

2 (1.4)

10 (7.0) 105 (73.9)

3 (2.2)

11 (8.1) 96 (71.1)

Outcomes Mortality Outcomes in Modified Intention-to-Treat Population

Monotherapy (n=142)

Combination therapy (n=135)

Treatment Difference (95% CI)

Overall 6-wk, n (%) 39 (27.8) 26 (19.5) -8.3 (-19.0 to 1.5)

Overall 12-wk mortality 55 (39.4) 39 (29.3) -10.1 (-21.4 to 1.1)

Data Review Committee-Adjudicated Outcomes in the MITT Population

Monotherapy (n=142)

Combination therapy (n=135)

Treatment Difference (95% CI)

Global response, n (%) Successful (overall)

Complete Partial

Failure Stable Failure Not evaluable

61 (43.0) 17 (12.0) 44 (31.0)

19 (13.4)

7 (4.9) 55 (38.8)

44 (32.6)

8 (5.9) 36 (26.7)

26 (19.3)

8 (5.9) 57 (42.3)

-10.4 (-21.6 to 1.2) -- --

-- -- --

Conclusions

Author Conclusion Treatment of IA with voriconazole + anidulafungin combination associated with a nonsignificant but clinically meaningful survival benefit in patients with HM or HSCT

Critique Large, RCT

Worldwide sampling of patients

Power not met

Intervention compared to standard of practice

Different primary endpoint than prior studies

Enrolled functional patients

Take Home Points Only RCT comparing combination therapy to voriconazole

Patient population = HM, HSCT

Combination = azole + echinocandin

6-week mortality with combination (19.5%) vs. voriconazole (27.8%)

VI) Summary of evidence

A) Limited studies evaluating combination therapy as primary treatment strategy

B) Patient populations

i) Mainly examined in HM, HSCT and SOT patients with proven or probable IA

ii) Small sample sizes except for Marr et al.

C) Treatment regimens

i) Denning combination with micafungin unknown

ii) Caillot examined combination of L-AMB + echinocandin

iii) Singh and Marr evaluated voriconazole in combination with echinocandins

D) Outcomes

i) Favorable outcomes observed in combination therapy groups

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ii) ↓ Mortality observed in combination therapy groups

E) Only one study compared combination therapy to recommended first line treatment

VII) Summary

A) IA is serious life-threatening complication in immunocompromised patients

B) Voriconazole is currently the first-line treatment recommended by IDSA

C) Primary combination therapy has been shown in the literature to improve outcomes and reduce

mortality

VIII) Recommendations

A) Primary IA therapy with voriconazole + echinocandins combination

i) Utilize in immunocompromised patients (e.g. HM, HSCT, SOT) with probable or proven IA

ii) Initiate combination as soon as possible

a) May add echinocandin within 48-96 hours of the initiation of voriconazole

iii) Monitor

a) Chest CT

b) Renal function

c) Liver function tests

iv) Duration

a) Echinocandin for at least 2 weeks

b) Voriconazole for minimum of 6-12 weeks

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IX) References

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8. Hajjeh RA, Sofair AN, Harrison LH, et al. Incidence of bloodstream infections due to Candida species and invitro susceptibilities of isolates collected from 1998 to 2000 in a population-based active surveillance program.J Clin Microbiol. 2004;42:1519–27.

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11. Pfaller MA, Diekema DJ. Epidemiology of Invasive Mycoses in North America. Crit Rev Microbiol. 2010;36(1):1-53

12. Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections amongorgan transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010;50(8):1101-11.

13. Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ, et al. Prospective surveillance forinvasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of theTransplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50(8):1091-100.

14. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, et al. Increasing volume andchanging characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomographyscans in patient with neutropenia. J Clin Oncol. 2001;19(1):253-9.

15. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al; European Organization forResearch and Treatment of Cancer/Invasive Fungal Infections Cooperative Group. Revised definitions ofinvasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive FungalInfections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses StudyGroup (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46:1813-21.

16. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: Clinical practice guidelines of theInfectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360.

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27. Meletiadis J, te Dorsthorst DT, Verweij PE. The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis ofcomplex pharmacodynamic interactions. Int J Antimicrob Agents. 2006;28:439–49.

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34. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis. ClinInfect Dis. 2004;39:797–802.

35. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncomparative study of caspofungin incombination with other antifungals as salvage therapy in adults with invasive aspergillosis. Cancer.2006;107:2888–97.

36. Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemicantifungal agents, for the treatment of acute invasive aspergillosis. J Infect Dis. 2006;53:337–49.

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Appendix A. Antifungals Used in Aspergillosis.

Drug Dose Forms Interactions Cost/day (AWP) Clinical Pearls

Amphotericin B deoxycholate Fungizone®

0.7-1.0 mg/kg/d IV

Nephrotoxins

--

Saline loading may ↓ nephrotoxicity Premeds (APAP, prednisone) may lessen infusion related reaction Meperidine can be given for rigors

Liposomal amphotericin B

Ambisome®

3-6 mg/kg/d IV IV $227.37

Less nephrotoxicity but similar efficacy Infusion reactions including flushing, hypoxic, and chest or flank pain (can be reduced or prevented with diphenhydramine)

Lipid complex amphotericin B

Abelcet® 3-6 mg/kg/d IV IV $620.95

Caspofungin Cancidas®

70 mg x1, then 50 mg daily

IV ↑ to 70 mg daily with

inducers IV (70)$336.49 IV (50) $323.86

Static against molds Poor CSF, urine, and eye penetration

Micafungin Mycamine®

100 mg daily IV None clinically

significant

IV $179.33

Anidulafungin Eraxis®

200 mg x1, then 100 mg daily

IV IV $172.62

Itraconazole Sporanox®

200 mg TID x 3, then 200 mg BID

Tablet Capsule

Oral solution

Inhibits 3A4, PGP 3A4 substrate

Caps $77.86 Tab $60.44 Sol $68.84

TDM- add concentrations of itraconazole and active metabolite(hydroxyitraconazole) Capsules- take with food and acidic conditions Oral solution- take on empty stomach

Voriconazole Vfend®

6 mg/kg BID x2, then 4 mg/kg BID

Tablet Oral suspension

IV

Inhibits 3A4, 2C19, 2C9 2C19, 2C9, 3A4

substrate

Tabs $94.77 Susp $150.92

IV $429.21

“Rule of 30”- visual disturbances in 30% of patients, 30 mins post-dose, last 30 mins IV- contains cyclodextrin (builds up with renal failure) Highly bioavailable, PO=IV

Posaconazole Noxafil®

200 mg QID 400 mg BID Oral suspension

Inhibits 3A4

Susp $222.54

Oral suspension- NOT equivalent to tablets or IV forms Increased absorption with high-fat meal, acidic conditions, higher frequency (q6h) No absorption benefit with >800 mg/day

300 mg BID x 2, then 300 mg daily

Tablet IV

Tab $166.90 IV $508.70

Tablets – no absorption issues with fat/acid but cannot be crushed IV- contains cyclodextrin (builds up with renal failure)

Isavuconazole Cresemba®

372 mg TID x 6, then 372 mg daily

Capsule IV

Inhibits 3A4, PGP 3A4 substrate

Caps $134.26 IV $228.72

Isavuconazonium sulfate (186 mg contains 100 mg isavuconazole) NOT formulated with cyclodextrin May shorten QT interval (dose-related)

Appendix B. Karnofsky Performance Status Scale

100 Normal no complaints; no evidence of disease 50 Requires much assistance and frequent medical care

90 Able to do normal activities; minor signs or symptoms 40 Disabled; requires special care and assistance

80 Normal activity with efforts; some signs or symptoms 30 Severely disabled; hospital admit, death not imminent

70 Cares for self; cannot do normal activity or active work 20 Very sickactive supportive treatment necessary

60 Requires occasional assistance, can care for most of needs 10 Moribund; fatal processes progressing rapidly