Antifungal therapy: Polyenes Antifungal therapy: Polyenes, - - PowerPoint PPT Presentation

Antifungal therapy: Polyenes Antifungal therapy: Polyenes, posaconazole, or prayers

Michael Kleinberg, MD, PhD Associate Professor of Medicine Head Infectious Diseases Section Head, Infectious Diseases Section Marlene and Stewart Greenebaum Cancer Center University of Maryland B lti M l d Baltimore, Maryland

Conflict of Interest Statement

• Lectures/Honoraria

Lectures/Honoraria

• None anymore

Consultant relationships

• Consultant relationships
• none
• Research
• Pfizer
• Equity holdings - none

Oth

• Other - none

Completing the Carbon Cycle:

The reason God created moulds

Human Zygomycosis:

Review of 929 infections in literature Review of 929 infections in literature

Underlying Conditions Percent

Diabetes 36 Malignancy 17 Bone marrow transplantation 5 p Solid organ transplantation 7 Fe chelation therapy 6 IV drug use 5

Roden MM et al., Clin Infect Dis (2005) 41:634-653

Zygomycosis: Sites of Infection yg y

Site of Infection % of 929 Patients Mortality (%) Patients

Rhinocerebral 21 62 Sino orbital 8 24 Sino-orbital 8 24 Sinusitis 8 16 Pulmonary 24 76 Pulmonary 24 76 Cutaneous 19 31 Disseminated 3 100 Disseminated 3 100 Gastrointestinal 7 85 Cerebral 9 79 Cerebral 9 79

Roden MM et al., Clin Infect Dis (2005) 41:634-653

Zygomycetes: Pooled Outcomes

10 bj t /t i l

Outcomes

100

s

• > 10 subjects/trial
• Success = improved + survived

FDA approved

50 75

Patients

A B ABLC ABCD L A B P

25

50 75 100 AmB ABLC ABCD L-AmB Posa

nse (%)

25 50

Respo

Herbrecht Eur J Clin Microbiol Infect Dis 2000;20:460-6; van Burik, Clin Infect Dis 2006;42:e61-5; Larkin, Infect Med 2003;17:113-120; Walsh Clin Infect Dis 1998;26:1383-1396;

Clinical Responses:

ABLC and Posaconazole ABLC and Posaconazole

100

91 65

75

Deteriorated

50 Percent

Stable Cured + Improved

25 P

Cured + Improved

Posaconazole ABLC Patient Status

Larkin JA, Montero JA Infect. Med. 2003 17:113-120; van Burik JH et al., Clin Infect Dis 2006;42:e61-65

Clinical Responses to ABLC

At End of Therapy At End of Therapy

100

31 34 65

75

Deteriorated

50

Percent

Stable Cured + Improved

25

P

Cured + Improved

First-line Second-line Total

Patient Status

Larkin JA, Montero JA Infect. Med. 2003 17:113-120.

Clinical Responses to ABLC:

End of Therapy End of Therapy

80 60

ts

Indeterminate D t i t d

40

• . of patient

Deteriorated Stable

20

No

Cured + Improved

Disseminated Liver Lungs Oropharynx Sinus Total

Site of Infection

Larkin JA, Montero JA Infect. Med. 2003 17:113-120.

Zygomycosis: Treatment yg y

Li id f l t d A h B

• Lipid-formulated Ampho B

– 5 – 7.5 mg/kg IV daily dosing – Consensus choice for 1st Rx because only IV choice

• Posaconazole
• Posaconazole

– 800 mg divided bid, tid, qid Must be given with fatty food and intact – Must be given with fatty food and intact gastric acid production to maximize bioavailability

Zygomycosis: Prayers Zygomycosis: Prayers

Does any of this antifungal

• utcomes data mean anything?
• utcomes data mean anything?

Zygomycosis: Non - Rx Determinants of Outcomes

• Early Rx with antifungals

– Chamilos et al., CID 2008 48:503-9

• High pathogen burden/overwhelming

infection infection

• Patient risk factors
• Patient risk factors

– Immunity is everything (almost)

• David Stevens tomorrow 8:35 AM

David Stevens, tomorrow 8:35 AM

Zygomycosis: Risk and I it Immunity: Case #1

38 yo female 3rd induction chemotherapy for relapsed AML.

• Complicated by fever, neutropenia Rx with Abx.
• New L lung nodular infiltrates. Rx with empirical

New L lung nodular infiltrates. Rx with empirical voriconazole for presumptive aspergillosis.

• Eventual progression to total L lung consolidation

p g g with CT evidence of necrosis coincident with bone marrow recovery.

Zygomycosis: Risk and I it Immunity: Case #1 (cont)

38 yo female 3rd induction chemotherapy for relapsed AML. O t ti t R ith i l

• Outpatient Rx with voriconazole.
• Four months later, developed hemoptysis. L

pneumonectomy by our gutsy chest surgeon pneumonectomy by our gutsy chest surgeon.

• Pathology showed mould consistent with

zygomycosis (cultures negative) zygomycosis (cultures negative).

• Patient doing well one year later on posaconazole

despite 4th AML relapse. despite 4 AML relapse.

Zygomycosis: Risk and I it Immunity: Case #2

17 yo male with new MDS with excess blasts and “worst combination of multiple poor prognosis tumor genetics ever seen”. Myeloablative chemo followed by MUD allo HSCTx. V i l h l i b t l

• Voriconazole prophylaxis by protocol.
• Complicated by severe skin and GI GVHD

leading to prolonged hospital stay and intense leading to prolonged hospital stay and intense anti-GVHD immune suppression.

Zygomycosis: Risk and I it Immunity: Case #2 (cont)

17 yo male with new MDS with blasts and “worst combination of multiple poor prognosis tumor genetics ever seen” Myeloablative chemo genetics ever seen . Myeloablative chemo followed by MUD allo HSCTx.

• Discharged home on immune suppression taper

Discharged home on immune suppression taper.

• Readmitted one month later in acute respiratory
• distress. Started immediately on lipid AmB.

y p

• Progressive dyspnea, transfer to MICU, died.
• Autopsy showed widespread zygomycosis

Autopsy showed widespread zygomycosis.

Zygomycosis and Treatment:

Final Comments

• Antifungals are probably important for

Antifungals are probably important for treatment.

– Paradoxically, more important but less effective in patients with irreversible immune deficits – Immune recovery or at least avoidance of – Immune recovery or, at least, avoidance of more immune suppression is an important Rx goal

• Lipid AmB and posaconazole antifungals
• f choice

S t d d t i – Success rates dependent on immune deficiency