EMERGING FUNGAL INFECTIONS Moucormycosis© by Author

EMERGING FUNGAL INFECTIONS Moucormycosis© by author

George Petrikkos, MD, ESCMID OnlineProfessor of InternalLecture Medicine Library and Infectious Diseases National and Kapodistrian University of Athens “ATTIKON” University Hospital [email protected]

• Epidemiology • Pathogenesis • Clinical presentation • Diagnosis • Treatment © by author ESCMID Online Lecture Library

EPIDEMIOLOGY

© by author ESCMID Online Lecture Library MUCORMYCOSIS Mucormycosis is the third invasive mycosis in order of importance after candidiasis and aspergillosis, but its frequency is rising and its fatality remains high.

100%

80%

60% culture 40% © by author 20% ESCMID Online Lecture Library Percentage of zygomycosis cases documentedbycases zygomycosis of Percentage 0% 1940s 1950s 1960s 1970s 1980s 1990s 2000s

Roden M, et al. Clinical Infectious Diseases 2005; 41:634–53 Incidence of invasive fungal infections after stem cell transplant, in USA, 2001-2006 (TransNet)

1,8 1,6 1,6 © by1,4 author 1,2 1,1 1 0,8 0,6 ESCMID Online (%) incidence 0,4 Lecture Library 0,3

-month cumulative cumulative 12 -month 0,2 0 Aspergillosis Candidiasis Zygomycosis

Kontoyiannis et al. 2009 submitted for publication © by author ESCMID Online Lecture Library Zygomycosis in Europe: Analysis of 230 Cases (CMI 2011)

• 230 cases from 2005 to 2007 • 13 countries • Median age of 50 years (1 month to 87 years) • 60% males • Hematological malignancies (44%), trauma (15%), HSCT (9%), and DM (9%) • Pulmonary (30%),© rhinocerebral by author (27%), soft tissue (26%), and disseminated (15%) • Rhizopus spp (34%), Mucor spp (19%), and ESCMIDLichteimia spp Online (19%) Lecture Library • Overall mortality 47%

Zygomycosis in Europe

UK 1 Netherlands 1 Turkey 2 Czech Republic 2 Finland 2 Norway 5 Russia 6 Spain 9 Austria 12 Belgium 16 France 21 Switzerland © by22 author Germany 35 Greece 36 ESCMIDItaly Online Lecture Library 60

G.Petrikkos, and the ECMM Zygomycosis Working Group, ICAAC, 2008. © by author ESCMID Online Lecture Library

Bitar et al. Emerg Infect Dis 2009; 15: 1395-1401 Incidence of zygomycosis in France, 1997-2006

0,14 0,12 0,1 0,08 0,06 0,04 0,02 © by author 0 ESCMID1997 1998 Online 1999 2000 Lecture 2001 2002 2003 Library 2004 2005 2006

Bitar et al. Emerg Infect Dis 2009; 15: 1395-1401 © by author ESCMID Online Lecture Library

Bitar et al. Emerg Infect Dis 2009; 15: 1395-1401 Zygomycosis in Tropical Areas: Experience from India Arunaloke Chakrabarti

Center for Advanced Research in Medical Mycology & WHO Collaborating Center Postgraduate Institute of Medical Education & Research Chandigarh© by – 160012,author India ESCMID Online Lecture Library

ISHAM Tokyo 2009 Geographic distribution of 461 cases of zygomycosis

Chandigarh 70% Mucorales – ? Better awareness Delhi 2% R. oryzae Expertise Rhizopus spp. A. elegans Better facilities

Calcutta 5% Entomophthorales

Vellore 6% ESCMID Online LectureMucorales Library 75% Entomophthorales 25%

Mycoses 2007; 50: 271 Zygomycosis in India Important observations

• Very high incidence • Rising trend in association with uncontrolled diabetes mellitus © by author

•ESCMID Emergence ofOnline renal zygomycosis Lecture Library • Emergence of Apophysomyces elegans

Arunaloke Chakrabarti ,ISHAM ,Tokyo, 2009 Summary & conclusions

• In India patients with uncontrolled diabetes needs serious attention [3(8%) revealed diabetes while investigating for zygomycosis] – 171million (2000) from 135million (1985) – 30 million in India • Nosocomial zygomycosis is gaining importance • Significant risk factor© by association author: renal failure in pulmonary; prematurity in gastrointestinal; transplantESCMID & GVHDOnline in disseminated Lecture Library zygomycosis; breach of skin, & steroid therapy in cutaneous variety Arunaloke Chakrabarti ,ISHAM ,Tokyo, 2009 South America: what epidemiological data do we have?

R.G. Vitale, PhD The National Council of Cientific and Technological Researh (CONICET) and J.M. Ramos Mejía, Hospital. Mycology Section Buenos Aires, Argentina Fungal Biodiversity© byCentre, author CBS, The Netherlands

[email protected] ESCMID Online Lecture Library

ISHAM ,Tokyo ,2009 Case reports from S.America

Country No of Cases

Chile 1

Colombia 2

Venezuela 2

Brazil 15

Argentina 5 © by author ESCMID Online Lecture Library Conclusion

• Different clinical presentation can appear.

• Diagnosis was made by histology, clinical evidence and not always the fungi was cultured or identified.

• When identification was possible by culture the aetiological agents were: Aphophysomyces elegans, Rhizopus arrhizus, Absidia corymbifera, Actinomucor elegans, Cunninghamella bertholletiae, Mucor spp. © by author • AMB was the drug more common employed. Not always successful outcome was observed. ESCMID Online Lecture Library

R.G. Vitale ,ISHAM ,Tokyo ,2009 Conclusion cont/d

• There are not many cases published from South America. • 1988-2009: 28 cases reported. In 10 fungi was cultured and identified. Outcome: variable. • Cases might be© underestimated.by author •ESCMIDMore collaborative Online studies Lecture are needed. Library

R.G. Vitale ,ISHAM ,Tokyo ,2009 Zygomycosis: Epidemiology

• The incidence of Zygomycosis is approximately 1.7 cases per 1 000 000 inhabitants per year,which means 500 patients per year in the USA.1 • Post-mortem evaluation shows that zygomycosis is ten- to 50-fold less frequent than candidiasis or aspergillosis, and it appears one to five cases per 10 000 autopsies.2-4 • In patients undergoing allogenic bone marrow 5,6 transplantation the© incidence by author may be 2-3%. 1. Ree JR et al. Clin Infect Dis ; 27:1138-1147;1998. 2. Hotchi M et al. Am J Clin Pathol ;74:410-416;1980. ESCMID3. Tietz Online HJ et al. Mycosis Lecture (suppl 2); 81-85;1998. Library 4.Yamazaki T et al. J Clin Microbiol ; 37: 1732-1738;1999. 5. Maertens J et al. Bone Marrow Transplant ; 24:307-312;1999. 6. Marty FM et al . N Eng J Med ; 350:950-952 What is the true incidence of zygomycosis? • It is a rare disease. • Most studies consist of case reports or case series. • ECMM study: One case from UK and 60 from Italy. Obviously does not represent true incidence. © by author • More representative data in specific groups of patientsESCMID (eg leukemics, Online transplants) Lecture Library • Large registries are necessary to estimate the epidemiology better. Mortality Due to Mold Infections

100%

80% 64,0%

60% 52,0% 42,0% 40% % of patientsof % © by author 20%

0%ESCMID Online Lecture Library Aspergillus spp Zygomycetes Fusarium spp

11,802 patients (18 centers) Pagano L et al. Haematologica 2006;91:1068-1075. Kaplan-Meier curve showing probability of survival for 53 transplant recipients with various types of mold infections (Pp.153, by the Mantel-Cox test).

Mycelial Fungi and Transplantation • CID 2003:37 (15 July) • 227 Zygomycetes

• Everywhere in nature – Decaying vegetation and in soil • Common genera: Rhizopus, Absidia, Cunninghamella, Rhizomucor, Syncephalastrum, Saksenaea, Apophysomyces and Mucor © by author

ESCMID Online Lecture Library RESULTS: Isolated fungi (168) Rhizomucor 12% Saksenae sp. 0% Absidia sp. 19% Cunninghamella sp 5% Mucor sp 30% Rhizopus © by authorsp 33% ESCMIDApophysomyces Online Lecture Library sp 1%

G.Petrikkos, and the ECMM Zygomycosis Working Group, ICAAC, 2008. Mucorales organisms more frequently isolated. Data from 5 studies

• .

• Increasing incidence

• Vulnerable populations: – Diabetes mellitus (association with ketoacidosis) – Malignancy (mostly haematological) – Bone marrow transplantation – Solid organ transplantation – Intra-venous drug use – Deferroxamine therapy © by author – Trauma/Critical illness ESCMID Online Lecture Library • Voriconazole?

Roden, et al. Clin Inf Dis 2005;41:634-53. Kauffman, CID editorial 2004. Zygomycosis Underlying Diseases Other Diabetes 6% 13%

Burn Hema 3% malignancy 46%

Trauma 17% © by author

SO Immunocompetent: 2 transplantation Other ESCMID4% Onlinemalignancies LectureBMT Library 4% 7% G.Petrikkos, and the ECMM Zygomycosis Working Group, ICAAC, 2008. Predisposing conditions Clinical presentation Immunosuppression (malignancy) Respiratory tract infection, disseminated infection Metabolic (diabetes) Respiratory tract infection, rhinocerebral infection Deferoxamine therapy Disseminated infection Skin and soft tissue breakdown Primary cutaneous and soft tissue infection Intravenous illicit drug use Endocarditis, cerebral infection Neonatal prematurity Gastrointestinal infection, disseminated infection Malnourishment Gastrointestinal infection

• Voriconazole? © by author

ESCMID Online Lecture Library Risk factors and most common clinical presentation of zygomycosis Underlying disease in relation to the site of infection • Hem. malignancy correlated with pulmonary disease* – 30.16% patients with hematological malignancy had pulmonary zygomycosis – 55.88% patients with pulmonary zygomycosis had an underlying hematological malignancy • Diabetes correlated with rhinocerebral disease* – 58.82% patients with diabetes had rhinocerebral disease – 32.26% patients with© byrhinocerebral author disease had diabetes

*PearsonESCMID chi2 (48) Online 117.8697 Lecture pr=0.000 Library

G.Petrikkos, and the ECMM Zygomycosis Working Group, ICAAC, 2008. Does voriconazole prophylaxis favour breakthrough zygomycosis? YES

n° n° Voriconazole Treatmen patients cases administration t duration Marty et al, NEJM 124 HM 4 Prophylaxis or 36 d 2004; 350(9):950-2 Empirical

Clement et al; BMT HSCT 4 Prophylaxis or / 2004 Empirical Imhof et al, CID 139 6 Prophylaxis or 47 d 2004; 39(5):743-6 HSCT© by authorTarget therapy Siwek et al,CID 45 HSCT 4 Prophylaxis 185 d 2004;ESCMID 39(5):743-6 Online Lecture Library Vigouroux et al. CID 93 HM 4 Prophylaxis or 7-30 wks 2005; 40(4):e35-7 Target therapy Does voriconazole prophylaxis favour breakthrough zygomycosis? NO

N patients Zygomycosis

Wingard et al, ASH 2007 Voriconazole 305 2 Blood (ASH Annual Meeting Abstracts), 110, abstract 163 Fluconazole 295 3 © by author Marks et al, ICAAC 2009 Voriconazole 234 0 (M-1249a)

ESCMID OnlineItraconazole Lecture 255 Library0 • Intact mucosal and endothelial barriers serve as structural defenses against tissue invasion by Zygomycetes. • The mechanisms of attachment to and invasion of mucosal surfaces have not been fully clarified. • Spores may invade epithelium previously damaged by infection, cytotoxic chemotherapy or direct trauma. © by author

Kontoyiannis DP, Lewis RE. Invasive zygomycosis: update on pathogenesis, ESCMIDclinical manifestations Online and Lecture management. Infect Library Dis Clin N Am 2006;20:581-607.

• A greater understanding of the pathogenesis of the disease may lead to future therapies. For example, it is now clear that iron metabolism plays a central role in regulating mucormycosis infections and that deferoxamine predisposes patients to mucormycosis© by author by inappropriately supplying the fungus with ESCMIDiron. Online Lecture Library Brad Spellberg, John Edwards Jr.,1 and Ashraf Ibrahim Clinical Microbiology Reviews, July 2005, p. 556556-569,-569, Vol. 18, No. 3

• Classic enhancers of Zygomycetes virulence – corticosteroids – increased iron supply & – iron availability ©- treatment by author with deferoxamine

• dramaticallyESCMID Online Zygomycetes Lecture Library pathogenicity Chamilos G et al. PNAS; 2008 vol. 105 no. 27: 9367–9372 © by author ESCMID Online Lecture Library Chamilos G et al. PNAS; 2008 vol. 105 no. 27: 9367–9372 • Needlestick exposures have been implicated in zygomycotic infections, occurring at the site of medicine injection, catheter insertion sites, injection sites for illicit drug use and tattooing. • Insect bites or stings© by authorhave also been implicated. ESCMID Online Lecture Library Adam RD, Hunter G, DiTomasso J, Comerci G Jr.Mucormycosis: emerging prominence of cutaneous infections. Clin Infect Dis 1994; 19:67–76. • Minor trauma by lemon tree thorn. • A patient who had a brother with soft tissue zygomycosis was taking care of him, changing the dressings. She had an abdominal scar due to previous cholecystectomy and she reported scratching it. She developed abdominal soft tissue zygomycosis. © by author

ESCMID Online Lecture Library

Petrikkos GL, Skiada A, Sambatakou H, et al. Mucormycosis: Ten year experience in a tertiary-care center in Greece. Eur J Clin Microbiol Infect Dis 2003;22:753–756 • Burrell SR, et al. Apophysomyces elegans infection associated with cactus spine injury in an immunocompetent pediatric patient. Pediatr Infect Dis J 1998; 17: 663–4. • Blair JE et al. Locally invasive cutaneous Apophysomyces elegans infection acquired from snapdragon© patch by author test. Mayo Clin Proc 2002; 77: 717–20. • NitroglycerinESCMID Onlinepatch. Petrikkos Lecture et al.Library Eur J Clin Microbiol Infect Dis 2003;22:753–756 © by author • «...His left index finger was swollen and tender, with ESCMIDmultiple puncture Online wounds Lecture on the distal Library phalanx. There was loss of sensation and power in the left arm...» •«C. bertholletiae was isolated from the pus swab of the patient’s finger»

• Intravenous intake of illicit drugs contaminated with Zygomycetes sporangiospores can produce disseminated and cerebral zygomycosis even in immunocompetent hosts.

• Mead JH, Lupton GP, Dillavou CL, et al. Cutaneous Rhizopus infection. Occurrence as a postoperative complication associated with an elasticized adhesive dressing. JAMA ESCMID Online Lecture Library1979;242(3):272 –4. • Mitchell SJ, Gray J, Morgan ME, et al. Nosocomial infection with Rhizopus microsporus in preterm infants: association with wooden tongue depressors. Lancet 1996;348(9025):441–3.

ESCMID Online Lecture Library

• Only two survived. Apophysomyces elegans

The most frequenly observed clinical manifestations  Rhinocerebral and  pulmonary zygomycosis

While cases have been described  gastrointestinal  cutaneous © by author  disseminated  andESCMID miscellaneous Online Lecture Library Rhino-cerebral Mucormycosis  It is the most frequent presentation overall and classically affects diabetics with ketoacidosis.

 Usually presents with facial and/or eye pain, proptosis and progressive signs of involvement of orbital structures (muscles, nerves and vessels). © by author  Common complications include cavernous sinus and ESCMIDinternal carotid Online artery thrombosis. Lecture Library

 Fatality 40%-50% Rhino-cerebral Mucormycosis Pathogenesis • Acquired by the inhalation of spores • Infection starts in the nasal turbinates then spreads to involve the orbits and the brain • Mucor is angioinvasive and can lead to infarction of infected tissues © by author ESCMID Online Lecture Library Rhino-cerebral zygomycosis

© by author ESCMID Online Lecture Library Rhinocerebral Zygomycosis Clinical Presentation • Acute – Fever – Facial pain – Nasal congestion – Epistaxis – Changes in vision – Changes in mentation • Spreads to palate, orbits and brain © by author • Can lead to tissue necrosisESCMID and eschar Online Lecture Library formation Rhinocerebral Mucormycosis Clinical Presentation • Exam findings – Tissue necrosis – Changes in sensation – Vision loss © by author – Proptosis and globe fixation ESCMID– Bony erosions Online on CT Lecture Library – Maxillary and ethmoid sinuses most common Rhinocerebral Mucormycosis Presentation

• Chronic – Visual changes – Neurological complaints – Proptosis and globe fixation – Mass lesions and bony erosions on CT © by author

ESCMID Online Lecture Library Pulmonary Mucormycosis Clinical manifestations

*Very similar to invasive bronchopulmonary aspergillosis - results in pulmonary infarction & necrosis • Patients with hematological malignancies (lymphoma, leukemia) are particularly© at byhigh author risk ESCMID Online Lecture Library Pulmonary Mucormycosis in a Diabetic Patient

ChestESCMID roentgenogram showingOnline CECT Lecture chest showing Library cavitary consolidation consolidation in left lingular lobe in left lung and fresh infiltrates in right lung

Anuradha et al Indian Journal of Medical Microbiology, (2006) 24 (3):222-4 Pulmonary Zygomycosis

ESCMIDCT scan of the Online chest with Lecture a cavitary infiltrate Library in the left upper lobe with interstitial changes and effusions bilaterally (nodules not demonstrated in this image

Juliette L. Wohlrab,et all CHEST / 120 / 3 / SEPTEMBER, 2001 Cutaneous Mucormycosis It has been reported with minor trauma, insect bites, contaminated dressings and patches, wounds, and burns. The necrotic© lesions by author progressively evolve from the epidermis into ESCMID Online Lecture Library dermis and even muscle and bone. Cutaneous and subcutaneous Mucormycosis

* Clinical manifestations Local traumatic implantation of fungal elements through the skin, especially in patients with extensive burns, diabetes or steroid induced hyperglycemia and trauma. Lesions vary considerably© by author in morphology but include plaques, pustules, ulcerations, deep ESCMIDabscesses and Online ragged Lecturenecrotic patches. Library

Cutaneous Mucormycosis

Necrotic eschar

© by author ESCMID Online Lecture Library Cutaneous Mucormycosis Major Diagnostic Criteria – Rapid progression of a painful, necrolytic cutaneous ulcer with an irregular, violaceous and undermined border • Margin expansion of 1 to 2 cm per day or 50% increase in ulcer size in one month • Pain usually out or proportion to size of ulceration • Ulcer typically preceded by a papule, pustule or bulla

• Usually necessitates© skinby biopsy author

ESCMID Online Lecture Library Gastrointestinal Mucormycosis

Usually affects premature neonates and patients with severe malnutrition May involve the stomach, ileum, and colon Clinical picture mimics intra-abdominal abscess. The diagnosis is often made at autopsy © by author ESCMID Online Lecture Library Gastrointestinal and Abdominal Mucormycosis Symptoms

•Symptoms of abdominal mucormycosis vary and depend on the site and extent of involvement. • Nonspecific abdominal pain, atypical peptic ulcer, diarrhea, "coffee© by authorground" hematemesis (regardingESCMID blood), Online and Lecturebloody stools Library are recorded. •Disseminated Mucormycosis • Clinical manifestations • May involve virtually any organ • Can spread from lungs, sinus, or rarely form the gastrointestinal tract • Most commonly seen in people who are immunosuppressed,© by author IV drug users, or hematological malignancies ESCMID Online Lecture Library Disseminated mucormycosis in a child with leukemia in remission

Diagnosis requires a high index of suspicion and painstaking examination of tissue sample. © by author ESCMID Online Lecture Library Clinician: CT, clinical situation

Laboratory diagnostic:

DIRECT INDIRECT

Culture Antigens © Microscopicby author Cell wall PCR componentes ESCMID Online Lecture LibraryAntibody Biopsy, Blood, SPECIMENS: Swab,…….. Blood,BALs… …..

Microscopy and culture are the most heavily relied diagnostic techniques of today! (Aydil et al., 2007).

Yet, the conventional© by diagnosticsauthor fail often OR are too slow ESCMIDOr require Online invasive Lecture procedures! Library (Chandrasekar, Leukemia & Lymphoma 2009) Zygomycetes wide non septate hyphae with right angle branching

© by author ESCMID Online Lecture Library Mucormycosis • Laboratory Identification – Zygomycetes are the fastest growing moulds – They can completely fill a Petri culture dish within two to three days under optimum growth conditions (a clue used for identification) – Their hyphae are hyaline but their spores are usually gray to black sometimes giving the colony an overall© by gray author to black appearance like dirty snow ESCMID Online Lecture Library Laboratory Isolation

 Inoculate the clinical material onto Sabouraud dextrose agar and incubate at 30°C.  A medium containing cycloheximide is not used because these fungi are sensitive to cycloheximide.  Sterile bread in a test tube may recover Zygomycetes when other media fail.  A noninoculated tube of sterile bread is necessary for quality control, since Zygomycetes are commonly associated with bread.

. The tissue reaction is usually slight.

. Acute suppurative inflammation predominates with focal areas of granulomatous inflammation.

.ESCMIDThe organism Online characteristically Lecture invades Library the walls of adjacent blood vessels, producing thrombosis and infarction, but rarely disseminates through the vessels.

Histopathology

• PAS stain

PAS stain Grocott stain Mucormycosis Histopathology Stained Tissue

Hematoxalin and Eosin Methenamine Silver PCR

• Several approaches, many studies for distinct pathogens without clinical validation • New breakthroughs preclude further analysis of many molecular diagnostics • Lack of commercial methods: – No standardization© by author – No quality control •ESCMID Lack of comparative Online Lecturemulticenter Library studies Direct association between premortem diagnosis as Mucormycosis and survival

100 Premortem Diagnosis 90 Survival 80

50 Early diagnosis

40 30 © by author 20 Percentage of Cases of Zygomycosis of Cases Percentage 10ESCMID Online Lecture Library 0 1940-1949 1950-1959 1960-1969 1970-1979 1980-1983 Time Period Parfrey NA,Medicine,1986;65:113-23 •TREATMENT

100% 82,9% 80% 65,7%

60% 48,6%* 40%

0% ESCMIDOverall, n=70Online Lecture≤6, n=35 Library>6, n=35 Days from symptoms to initiation of appropriate Tx.

*p=0.029, ≤6 days vs. >6 days Chamilos G, et al. Abstract #M-619, ICAAC 2007 Days from Symptoms to Initiation of Appropriate Therapy

100%

80%

60%

CART identified breakpoint 40%

0% ESCMID0 5 Online10 15 Lecture 20 25 30 Library 35 40 45 Days from symptoms to initiation of appropriate therapy

Chamilos G, et al. Abstract #M-619, ICAAC 2007 Concepts in Treatment of Mucormycosis (Zygomycosis) • Primary Therapy – Amphotericin B • lipid formulation of amphotericin B • deoxycholate amphotericin B • Surgical resection of infected tissue • Reversal of© immune by author impairment • Complicated management is difficult ESCMIDin resource-challenged Online Lecture environments Library Treatment of Zygomycosis

. Surgical debridement has remained a key feature of the management of zygomycosis. . All necrotic tissue should be removed when possible and repeatedly if needed. . Survival of zygomycosis in patients treated only medically was much worse than that for patients who underwent© by author combined medical and surgical therapy ESCMID Online Lecture Library Rhinocerebral mucormycosis Surgical intervention

© by author ESCMID Online Lecture Library Rhinocerebral mucormycosis Surgical intervention • Mark Tatum of Kentucky (seen below; after surgery, with and without facial prosthetic) survived from rhinocerebral zygomycosis in 2000. Surgery was required to remove infected tissue. .

He died five years later on February 26, 2005 Mucormycosis Medical therapy

Reversal of underlying predisposing condition. -Reversal of the metabolic disturbance -Reversal of immunosuppression© by author Antifungal therapy ESCMID Online Lecture Library Guidelines for the Diagnosis and Treatment of Mucormycosis

© by author ESCMID Online Lecture Library Recommendation for first line (part 1) Management includes antifungal therapy, control of underlying conditions and surgery. A II Antifungal therapy AmB deoxycholate C II Liposomal AmB B II 1 ABLC B II 1 ABCD C II Posaconazole CIII2 Combination therapy CIII © by author 1 Liposomal amphotericin B should be preferred in CNS infection and/or renal failure. 2 No dataESCMID to support its useOnline as first line Lecture treatment. May beLibrary used as an alternative when amphotericin B is absolutely contraindicated. Recommendation for first line (part 2) Management includes antifungal therapy, control of underlying conditions and surgery. A II Control of underlying condition A II 3 Surgery - rhino-orbito-cerebral A II - soft tissue A II - localized pulmonary lesion B III - disseminated CIII4 Hyperbaric oxygen CIII

© by author 3 Control of underlying condition includes control of diabetes, hematopoietic growth factor if neutropenia, discontinuation/tapering of steroids, reduction of immunosuppressive therapy. 4 SurgeryESCMID should be considered Online on Lecturea case by case Library basis, using a multi- disciplinary approach. Recommendation for second line and maintenance therapy Second line Management includes antifungal therapy, control of underlying disease and surgery. A II

Posaconazole BII Combination lipid AmB and caspofungin BII Combination lipid AmB and posaconazole CIII Combination with deferasirox CIII

Maintenance therapy © by author Posaconazole B III 5 5 Overlap of a few days (at least 5) with first line therapy to obtain appropriateESCMID serum levels. Online Monitoring Lecture of serum levels Library might be indicated Questions

• Dosing • Length of treatment