Prophylaxis versus Diagnostics-driven approaches to treatment of Invasive fungal diseases. Y.L. Kwong Department of Medicine University of Hong Kong

Prophylaxis versus Diagnostics-driven approaches to treatment of Invasive fungal diseases Y.L. Kwong Department of Medicine University of Hong Kong

Pathogenic yeast Candida Cryptococcus Trichosporon Pathogenic mould Aspergillus Zygomycetes Fusarium Scedosporium

EORTC / MSG definition of IFD

EORTC / MSG definition of IFD Proven IFD Probable IFD Possible IFD

EORTC / MSG definition of IFD Proven IFD

EORTC / MSG definition of IFD Proven IFD Positive cytology and histopathology in a normally sterile site Positive culture in a normally sterile site

EORTC / MSG definition of IFD Proven IFD Positive cytology and histopathology in a normally sterile site Positive culture in a normally sterile site Cryptococcal antigen in CSF

EORTC / MSG definition of IFD Probable IFD

EORTC / MSG definition of IFD Probable IFD Host factor Neutropenia > 10 d, HSCT, T- cell suppressing Tx, steroids, immunocompromized

EORTC / MSG definition of IFD Probable IFD Host factor Neutropenia > 10 d, HSCT, T-cell suppressing Tx, steroids, immunocompromized Clinical criteria CT thorax: halo, air-crescent, cavitation CT brain with clinical signs CT abdomen Mycological criteria Positive cytology / histology or culture from a non-sterile site Galactomannan b-d-glucan

EORTC / MSG definition of IFD Possible IFD Host factor Neutropenia > 10 d, HSCT, T-cell suppressing Tx, steroids, immunocompromized Clinical criteria CT thorax: halo, aircrescent, cavitation CT brain with clinical signs CT abdomen

Invasive fungal infection Host factors 1. Neutropenia < 0.5 x 10 9 /L, > 10 days 2. Persistent fever > 4 days refractory to broad spectrum antibiotics 3. Temperature > 38 o C 4. Graft versus host disease (GVHD) > grade 2, or extensive chronic GVHD 5. Prolonged use of steroids (> 3 weeks) in the past 60 days

Immunocompromised patients 1. Intensive chemotherapy 2. solid organ allografting (anti-rejection regimens) 3. Haematopoietic stem cell transplantation (anti-gvhd regimen) 4. Infection with human immunodeficiency virus 5. Autoimmune diseases with treatment 6. Use of lymphoablative antibodies

Invasive fungal infection Clinical features Lower respiratory tract infection Major: Halo sign, air-crescent sign, cavity in consolidation Minor: respiratory symptoms, other radiologic features Sinonasal infection Major: erosion of sinus walls, extension to other structure, destruction of skull base Minor: upper respiratory symptoms, nasal, orbit, maxillary sinus, hard palate CNS infection Major: radiologic lesions Minor: CNS manifestations, abnormal CSF Disseminated infection Cutaneous lesions, intraocular lesions Disseminated chronic candidiasis Hepatosplenic candidiasis Candidemia

Halo sign on CT scanning

N N: solid nodular core N: nodular core Ground-glass arrows: ground perimeter glass or more than perimeter three-quarters of intermediate density, surrounding more than three quarters

Disseminated chronic candidiasis: Pulmonary and hepatosplenic candidiasis

Disseminated chronic candidiasis: hepatosplenic candidiasis

Fungal epidemiology data from Asia Hsu et al, Clin Microbiol Infect 2015

Fungal epidemiology data from Asia Roughly equal proportion of Candida and Aspergillus Reflects use of mould active anti-fungal prophylaxis, with decrease in Aspergillus and the emergence of resistant Candida Hsu et al, Clin Microbiol Infect 2015

Fungal epidemiology data from Asia Probably reflects inadequate use of mould active antifungal prophylaxis, hence predominance of Aspergillus Hsu et al, Clin Microbiol Infect 2015

Fungal epidemiology data from Asia Reflects no use of anti-fungal prophylaxis, and therefore the predominance of Candida Hsu et al, Clin Microbiol Infect 2015

Requisites of adequate antifungal treatment 1. Diagnosis (radiologic / biomarkers) 2. Fungal culture 3. Species identification 4. In vitro susceptibility testing 5. Drug level monitoring

Types of antifungal treatment Barnes, JAC 2013

Types of anti-fungal treatment Risk factors Clinical signs Radiologic signs Biomarkers Microbiological Culture Fungal load Disease progression + + + + 1 + + + ± ± + Prophylactic 2 Pre-emptive Empirical Therapeutic Targeted 1: may already be positive even in pre-emptive 2: secondary prophylaxis when +ve for previous IFI Targeted: biomarkers +ve indicating the likely organisms

Risk factors Clinical signs Radiologic signs Biomarkers Microbiological Culture Fungal load Disease progression Types of anti-fungal treatment Prophylaxis + + + + 1 + + + ± ± + Prophylactic 2 Pre-emptive Empirical Therapeutic Targeted 1: may already be positive even in pre-emptive 2: secondary prophylaxis when +ve for previous IFI Targeted: biomarkers +ve indicating the likely organisms

Risk factors Clinical signs Radiologic signs Biomarkers Microbiological Culture Fungal load Disease progression Types of anti-fungal treatment Possible / Probable + + + + 1 + + + ± ± + Prophylactic 2 Pre-emptive Empirical Therapeutic Targeted 1: may already be positive even in pre-emptive 2: secondary prophylaxis when +ve for previous IFI Targeted: biomarkers +ve indicating the likely organisms

Risk factors Clinical signs Radiologic signs Biomarkers Microbiological Culture Fungal load Disease progression Types of anti-fungal treatment Proven + + + + 1 + + + ± ± + Prophylactic 2 Pre-emptive Empirical Therapeutic Targeted 1: may already be positive even in pre-emptive 2: secondary prophylaxis when +ve for previous IFI Targeted: biomarkers +ve indicating the likely organisms

Types of antifungal treatment Rogers et al, BJH 2011

Mechanisms of anti-fungal drugs Amphotericin B Binds to ergosterol, altering cell membrane permeability, thus causing leakage of cell components and cell death Azole (fluconazole, itraconazole voriconazole, posaconazole) Interferes with fungal cytochrome P450, decreasing ergosterol synthesis, and inhibiting fungal cell membrane formation Echinocandins (caspofungin, micafungin, anidulafungin) Inhibition of 1,3-b-D-glucan synthase, resulting in decrease in 1,3-b-D-glucan formation, hence osmotic instability and cellular lysis

Liposomal amphotericin B Trade name Route Half-life (hr) Dosage adjustment in renal impairment Dosage adjustment in liver impairment Interaction with immunosuppressive agents AmBisome IV 7-10 Not necessary No information serum level of cyclosporine

Trade name Route Half-life (hr) Dosage adjustment in renal impairment Dosage adjustment in liver impairment Interaction with immunosuppressive agents Remarks Voriconazole VFend IV and oral 6 Not necessary for oral, precaution for IV because of the vehicle Reduce maintenance dose to 50% serum level of cyclosporine, sirolimus and tacrolimus for oral administration 1 hr before or after a meal

Posaconazole Trade name Route Half-life (hr) Dosage adjustment in renal impairment Dosage adjustment in liver impairment Noxafil oral 20-66 Not necessary No information Interaction with immunosuppressive agents Remarks serum level of cyclosporine, sirolimus and tacrolimus Taken with meals 1. FDA approved for prophylaxis in HSCT, GVHD and prologned neutropenia in MDS/AML 2. Lipophilic and penetrates CNS, eye and bones, with high volume of distribution 3. Active in the treatment of Rhizopus microsporus

Caspofungin Trade name Route Half-life (hr) Volume of distribution (L/Kg) Dosage adjustment in renal impairment Dosage adjustment in liver impairment Interaction with immunosuppressive agents Cancidas IV 9-11 0.14 (9.8L for 70 kg) Not necessary Reduce maintenance dose to 35 mg tacrolimus level, cyclosporine level of caspofungin (by about 50%)

Micafungin Trade name Route Half-life (hr) Volume of distribution (L/Kg) Dosage adjustment in renal impairment Dosage adjustment in liver impairment Interaction with immunosuppressive agents Mycamine IV 11-17 0.22-0.24 (16L for 70 kg) Not required Mild moderate, not require, severe no information sirolimus (21%) cyclosporine (16%)

Anidulafungin Trade name Route Half-life (hr) Volume of distribution (L/Kg) Dosage adjustment in renal impairment Dosage adjustment in liver impairment Interaction with immunosuppressive agents Eraxis IV 24-26 0.5 (35L for 70 kg) Not necessary Not necessary Not known

Caspofungin 1.Empirical treatment for presumed fungal infections in febrile neutropenic patients 2.Treatment of candidemia and other Candida infections (intra-abdominal abscesses, esophageal, peritonitis, pleural space) 3.Treatment of invasive Aspergillus infections in patients who are refractory or intolerant of other therapy

Micafungin 1.Treatment of esophageal candidiasis 2.Candida prophylaxis in patients undergoing hematopoietic stem cell transplantation

Anidulafungin 1. Treatment of candidemia and other forms of Candida infections (including those of intra-abdominal, peritoneal, and esophageal locus)

Liposomal amphotericin B 1.Empirical therapy for presumed fungal infection in neutropenic fever 2. Systemic fungal infections (Aspergillus, Candida, Cryptococcus)

Voriconazole 1. Treatment of invasive aspergillosis 2. Treatment of esophageal candidiasis 3. Treatment of candidemia (in non-neutropenic patients) 4. Treatment of disseminated Candida infections of the skin and viscera 5. Treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium spp (including Fusarium solani) in patients intolerant of, or refractory to, other therapy 6. Prophylaxis after allogeneic HSCT

Posaconazole 1.Prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients (hematopoietic stem cell transplantion with graft-versus-host disease, prolonged neutropenia secondary to chemotherapy for hematologic malignancies) 2. Treatment of oropharyngeal candidiasis (including patients refractory to itraconazole and/or fluconazole)

Antifungal prophylaxis

Yes Prophylaxis No Yes Yes Yes Yes Yes Is the disease likely? Is the disease a serious one? Is the disease difficult to treat? Is the prophylaxis effective? Is the prophylaxis safe? No No No No No

Efficacy of anti-fungal prophylaxis Neutropenic patients 1. Proven or probable IFDs: 7 patients (2%) on posaconazole 25 patients (8%) on fluconazole or itraconazole (absolute reduction: posaconazole group, 6%; 95% confidence interval, 9.7 to 2.5%; P<0.001). 2. Invasive aspergillus: fewer patients in the posaconazole group than other groups (2 [1%] vs. 20 [7%], P<0.001). 3. Survival significantly longer for patients on posaconazole than patients on fluconazole or itraconazole (P = 0.04).

Efficacy of anti-fungal prophylaxis Acute GVHD 1. Proven / probable aspergillosis: Significantly fewer in posaconazole vs fluconazole (2.3% vs. 7.0%; odds ratio, 0.31; 95% CI, 0.13-0.75; P=0.006). 2. Breakthrough IFDs: Significantly fewer in posaconazole vs fluconazole (2.4% vs. 7.6%, P = 0.004), particularly aspergillosis (1.0% vs. 5.9%, P = 0.001). 3. Death from IFDs Fewer in posaconazole (1%, vs. 4% than fluconazole group; P = 0.046).

Efficacy of anti-fungal prophylaxis Myeloablative allogeneic HSCT 1. IFDs Trend towards fewer IFDs in voriconazole vs fluconazole (7.3% vs 11.2%; P = 0.12) 2. Aspergillus infections: Trend towards fewer IA in voriconazole vs fluconazole (9 vs 17; P = 0.09) 3. Frequency of empiric antifungal therapy Trend towards fewer in voriconazole vs fluconazole (24.1% vs 30.2%, P = 0.11)

Efficacy of anti-fungal prophylaxis Myeloablative allogeneic HSCT 1. Success of prophylaxis (>100 days of Tx, no IFDs at Day 180): Significantly higher with voriconazole than itraconazole (48.7% vs. 33.2%, P < 0.01) 2. Prophylaxis tolerable for 100 days: Significantly higher with voriconazole than itraconazole (53.6% vs. 39.0%, P < 0.01; median total duration 96 vs. 68 days). 3. Need of systemic antifungals Significantly fewer with voriconazole than itraconazole (29.9% vs. 41.9%, P<0.01)

Efficacy of anti-fungal prophylaxis Pechlivanoglou et al, JAC 2014

Antifungal prophylaxis Pros 1. Policy easy to adopt 2. Requires less intensive manpower 3. Peace of Mind (may be false!) 4. Decreases the number of IFDs caused by Candida

Antifungal prophylaxis Cons 1. Drug toxicity and drug interactions 2. Drug level monitoring required 3. Interferes with biomarker monitoring 4. Cost (? cost-effective analysis) 5. Breakthrough IFDs can still occur 6. Potential of inducing resistant organisms

ECIL guidelines for primary antifungal prophylaxis Maertens et al, Bone Marrow Transplant 2011

Diagnostics-driven approach

Diagnosis of invasive aspergillosis Guinea & Bousa, Myopathologia 2014

Diagnosis of invasive aspergillosis Fungal culture 1. Slow and low sensitivity 2. Allows species identification and potentially in vitro antifungal sensitivity 3. Cannot differentiate between colonization and actual invasive infection

Diagnosis of invasive aspergillosis Galactomannan (serum) 1. A component of Aspergillus, penicillium and histoplasmosis cell wall that is released from hyphae during fungal growth 2. Appears earlier than fever and clinical signs / findings 3. Lower sensitivity in non-neutropenic patients 4. Lower sensitivity if prophylactic anti-fungals used 5. Not useful in other mould infections 6. False positive with pipercillin / tazobactem

Diagnosis of invasive aspergillosis Galactomannan (BAL) 1. Optimal cutoff levels not determined as BAL procedure is not standardized 2. Useful in both neutropenic and non-neutropenic patients 3. Also affected by the use of b-lactams, although to a lesser extent

Diagnosis of invasive aspergillosis b-d-glucan 1. Pan-fungal marker, not from cryptococcus and zygomycetes 2. Does not distinguish aspergillus from other fungi. 3. Two consecutive positive values (usually within one week) have very high specificity (~99%), positive (~85%) and negative predictive value (~90%); but low sensitivity (~50%) 4. False positives in patients receiving albumin, intravenous immunoglobulin, and haemodialysis 5. Not afected by anti-fungal treatment

Diagnosis of invasive aspergillosis Aspergillus polymerase chain reaction 1.Technically demanding, including a good protocol for fungal wall disruption enabling adequate DNA extraction, optimal target (conserved regions), and quantification 2.Not standardized 3.Does not reliably distinguish between colonization and invasive infection 4.Concomitant galactomannan assay increases sensitivity in serum and specificity in BAL

Diagnostics-driven approach Pros 1. Only treating patients with IFDs 2. May reduce health care cost

Diagnostics-driven approach Cons 1. Requires intensive monitoring 2. Dedicated team of clinicians, radiologists, microbiologists and pulmonary physicians needed 3. Logistics of diagnostic tests (galactomannan, b-d-glucan, PCR) must be practical (long holidays, weekends) 4. Delay between fever and initiation of antifungal treatment 5. Potential impact on future treatment options if IFD becomes established

Prophylaxis versus empirical / diagnostics-driven Maertens et al, JAC 2011

Logistics of prophylactic approaches Morrissey et al, Intern Med J 2014

Logistics of empiric / diagnostics-driven approaches Morrissey et al, Intern Med J 2014

Strategies at Queen Mary Hospital for haematological patients Low-risk patients (no prophylaxis or fluconazole) Lymphoma on R-CHOP or similar regimens Standard-risk patients (itraconazole prophylaxis) AML patients on induction therapy Lymphoid malignancies on lymphodepleting treatment or prolonged corticosteriod therapy Autologous HSCT High-risk patients (voriconazole / posaconazole prophylaxis) Relapsed / refractory haematological malignancies Allogeneic HSCT High-risk patients (echinocandin prophylaxis) High-risk patients not tolerating oral treatment, or have impaired liver function

Breakthrough invasive fungal infections during echinocandin prophylaxis Chan et al, Ann Hematol 2014

Acknowledgement