MANAGEMENT OF PULMONARY MYCOSIS

Transcription

1 MANAGEMENT OF PULMONARY MYCOSIS Eva Van Braeckel, MD, PhD Dpt. of Respiratory Medicine UZ Gent PENTALFA KU Leuven MANAGEMENT OF PULMONARY MYCOSIS 1. Antifungals 1. Acute invasive pulmonary aspergillosis 1. Chronic pulmonary aspergillosis 1

2 1. ANTIFUNGALS MANAGEMENT OF PULMONARY MYCOSIS ANTIFUNGAL MECHANISMS AZOLE S POLYENE S ECHINOCANDIN S 5- FLUCYTOSINE 2

3 POLYENES: AMPHOTERICIN B Fungicidal Broad spectrum Most fungi except A. terreus, Scedosporium, Trichosporon, C. glabrata Pharmacokinetics No oral bioavailability Elimination route unknown (urine and biliairy excretion <5%) T 1/ h POLYENES: AMPHOTERICIN B Deoxycholate formulation (Fungizone ) 1 mg/kg IV Lipid-based formulation Liposomal (Ambisome ) 3-5 mg/kg IV Lipid complex (Abelcet ) 5 mg/kg IV 3

4 POLYENES: AMPHOTERICIN B Side-effects: Deoxycholate formulation >> lipid-based formulations Infusion reactions, nephrotoxicity, hypokalemia, nausea TRIAZOLES Itraconazole (Sporanox ) Voriconazole (Vfend ) Posaconazole (Noxafil ) Isavuconazole (Cresemba ) [Fluconazole (Diflucan )] 4

5 TRIAZOLES: ITRACONAZOLE Spectrum: Aspergillus spp., endemic fungi, Sporothrix schenckii Oral solution Bioavailability not altered by gastric ph Optimal absorption on empty stomach (but even in presence of food higher serum concentrations than with capsule) Capsules Require food and acidic gastric ph for solubilization Dosing: 200 mg bid TRIAZOLES: VORICONAZOLE Spectrum: Enhanced activity against Aspergillus spp., Scedosporium apiospermum and Fusarium spp. Dosing: 6 mg/kg bid on day 1, followed by 4 mg/kg bid Oral formulations: bioavailability >90% on empty stomach ( with food) Hepatic metabolism (CYP2C19, CYP2C9, CYP3A4) Inter- and intra-individual variability in plasma levels (TDM) Side effects Short term: visual disturbances, hepatic toxicity, phototoxicity Long term: skin carcinogenesis, fluorosis IV formulation: nephrotoxicity of cyclodextrin solubilizer 5

6 TRIAZOLES: POSACONAZOLE Broad spectrum including Mucorales Formulations Oral suspension: intake with high-fat meal 200 mg qid Tablets: less variability, administration with food recommended 300 mg bid on day 1, followed by 300 mg od IV 300 mg bid on day 1, followed by 300 mg od Non-CYP450 hepatic metabolism, inhibitor of CYP3A4 Side effects: gastro-intestinal symptoms TRIAZOLES: ISAVUCONAZOLE Broad spectrum including Mucorales Formulations: Oral capsules: high bioavailability unaltered by food intake IV form: contains no cyclodextrin Prolonged T 1/2 of 130 h od following 6 loading doses over 2d High degree of tissue penetration Hepatic CYP3A4 metabolism drug interactions Side effects: GI, hepatotoxicity, shortening of QT interval 6

7 ECHINOCANDINS Caspofungin (Cancidas ) Anidulafungin (Ecalta ) Micafungin (Mycamine ) ECHINOCANDINS Spectrum: Fungistatic against Aspergillus spp., fungicidal against Candida spp. Only IV formulations Only caspofungin penetrates in CNS CYP450-independent metabolism Caspofungin: uptake via organic anion transporting polypeptide (OATP) drug interactions Anidulafungin: no hepatic metabolism but slow chemical degradation Mild adverse reactions, good tolerability 7

8 ANTIFUNGAL RESISTANCE Verweij et al., Drug Resist Updates 2015 ANTIFUNGAL RESISTANCE 8

9 BELGIAN REIMBURSEMENT CRITERIA Prescribing restrictions on almost all antifungals Limitations: Mainly based on EORTC criteria Unadapted to pulmonary patients ANTIFUNGAL PIPELINE Need for new antifungals 1 Mortality invasive aspergillosis 30-50% Emergence of drug resistance Shortcomings of current antifungals: 2 Voriconazole: drug interactions, toxicity, necessity for TDM Posaconazole: licensed for salvage therapy but no data to support first-line use Polyenes: toxicity concerns, IV only Echinocandins: excellent safety profile but little experience in primary treatment of IPA 1 Denning and Bromley, Science 2015; 2 Maertens et al., Lancet

10 2. ACUTE INVASIVE PULMONARY ASPERGILLOSIS MANAGEMENT OF PULMONARY MYCOSIS Denning and Bromley, Science 2015 MANAGEMENT OF IPA: GUIDELINES Primary: voriconazole Alternative: liposomal amphotericin B Salvage therapy: echinocandin or posaconazole Continuation therapy: voriconazole or itraconazole Limper et al., AJRCCM 2011; Kousha et al., Eur Resp Rev

11 MANAGEMENT OF IPA: GUIDELINES Primary therapy: voriconazole vs. amphotericin B Salvage therapy: posaconazole in patients intolerant of or refractory to amphotericin B and/or itraconazole Herbrecht et al., NEJM 2002 Walsh et al., CID 2007 MANAGEMENT OF IPA: NEW PLAYER Maertens et al., Lancet

12 MANAGEMENT OF IPA: NEW PLAYER Isavuconazole Non-inferior to voriconazole for primary treatment of suspected invasive mould disease Well tolerated compared to voriconazole (fewer AEs) Of note: voriconazole used at licensed dose without TDM Maertens et al., Lancet 2015 COMBINATION THERAPY IN IPA Combination therapy as salvage therapy Retrospective case series Caspofungin + liposomal amphotericin B 1 Caspofungin + voriconazole 2 Combination therapy as primary therapy Prospective multicentre observational study Caspofungin + voriconazole vs. liposomal amphotericin 3 1 Kontoyiannis et al., Cancer 2003; 2 Marr et al., CID 2004; 3 Singh et al. Transplantation

13 COMBINATION THERAPY IN IPA Combination therapy as primary therapy Randomized double-blind placebo-controlled multicenter study: voriconazole + anidulafungin Marr et al., Ann Int Med 2015 Primary endpoint: all cause mortality at 6 weeks Marr et al., Ann Int Med

14 Outcomes in the positive galactomannan subgroup Cumulative incidence of death in mitt population with probable IPA based on radiographic abnormalities & pos. GM 6-week mortality rate by range of maximum serum GM index values at baseline Marr et al., Ann Int Med 2015 Conclusions First RCT to address combination therapy for IA Combination therapy (voriconazole/anidulafungin) associated with a substantial, but not statistically significant, reduction in overall mortality Marr et al., Ann Int Med

15 AZOLE RESISTANCE Verweij et al., Drug Resist Updates 2015 DURATION OF ANTIFUNGAL THERAPY IN IPA Individualised (clinical and radiological response) Often prolonged (several months to >1 year) Prerequisites for discontinuation Clinical and radiographic resolution Microbiological clearance Reversal of immunosuppression Reinstating therapy in case of resumed immunosuppression, additional cytotoxic therapy or HSCT Limper et al., AJRCCM 2011; Kousha et al., Eur Resp Rev

16 MANAGEMENT OF IPA: SURGERY Surgical resection Limited role: invasion of bone, burn wounds, epidural abscesses and vitreal disease Indications for thoracic surgery: Massive haemoptysis Pulmonary lesions close to great blood vessels or pericardium Residual localised pulmonary lesions in patients with continuing immunosuppression or those who are expected to have immunosuppressive therapy in the future MANAGEMENT OF IPA: IMMUNOMODULATION Colony-stimulating factors G-CSF and GM-CSF in neutropenic patients IFN-γ in chronic granulomatous disease patients (Granulocyte transfusion) Decrease immunosuppression (!) 16

17 3. CHRONIC PULMONARY ASPERGILLOSIS MANAGEMENT OF PULMONARY MYCOSIS Science Photo Library CHRONIC PULMONARY ASPERGILLOSIS (CPA) Denning et al., ERJ

18 ORAL TRIAZOLE THERAPY OF CPA Data based on cohort studies or case reports Only 2 prospective phase II trials Comparison of IV micafungin vs. voriconazole 1 Equal efficacy (60 vs. 53%), safety assessment favours micafungin (26 vs. 61% AEs) Oral itraconazole vs. no antifungal therapy 2 Itraconazole superior to supportive therapy alone in CCPA (76 vs. 36%) No studies comparing 2 oral triazole drugs directly Drug efficacy analysis based on composite score 1 Kohno et al., J Infect 2010; 2 Agarwal et al., Mycoses 2013 ORAL TRIAZOLE THERAPY OF CPA To treat or not to treat? Type of disease or clinical phenotype Eligibility for surgical treatment General recommendation: Outpatient triazole therapy likely provides some therapeutic benefit in cases of progressive and/or symptomatic CPA Prevention or treatment of life-threatening haemoptysis (SoR A and QoE II) Standard of care in chronic cavitary pulmonary aspergillosis (CCPA) Stabilisation of clinical and radiological manifestations Denning et al., ERJ

19 ORAL TRIAZOLE THERAPY OF CPA Denning et al., ERJ 2016 ORAL TRIAZOLE THERAPY OF CPA Treat as acute invasive aspergillosis 3 Standard of care 1 Long-term itraconazole treatment: 2 - Stabilising patients general condition - Limited impact on breathlessness 1 Denning et al., ERJ 2016; 2 Denning et al., CID 2003; 3 IDSA-ATS Guidelines,

20 DURATION OF ANTIFUNGAL THERAPY IN CPA Denning et al., ERJ 2016 IV ALTERNATIVES FOR TREATMENT OF CPA Denning et al., ERJ

21 LOCAL THERAPY FOR CPA Local cavity therapy with amphotericin B 1 Alternative to surgical resection Delivery through endobronchial or percutaneous transthoracic needle Complications: cough, chest pain, pneumothorax, endobronchial reflux Aerosolized/nebulized amphotericin B 2 Adjunctive therapy in fungal infections refractory to standard therapy Complications: cough, bronchospasm, chest pain 1 Denning et al., ERJ 2016; 2 Safdar et al., Pharmacotherapy 2013 IMMUNOMODULATORY TREATMENT IN CPA Decrease immunosuppression Corticosteroids accelerate disease progression without adequate antifungal therapy Interferon-γ immunotherapy? If impairment in IFNγ- and IL12-dependent pathways Denning et al., ERJ

22 MANAGEMENT OF HAEMOPTYSIS Tranexamic acid 500 mg tid Bronchial artery embolisation Surgery Denning et al. ERJ 2016 INDICATIONS FOR SURGERY Definitive treatment option for single aspergilloma in patients with adequate pulmonary function Complete resection of aspergilloma Avoid spillage of fungal elements into pleural space Severe haemoptysis (after catheter embolisation) * CCPA refractory to medical management (incl. multiazole resistance)* *Provide antifungal coverage to prevent Aspergillus empyema Farid et al., J Cardiothorac Surg 2013; Denning et al. ERJ

23 TAKE HOME MESSAGES When treating chronic pulmonary mycosis Always try to obtain culture and antimycogram Be creative and persuasive Take the time to explain antifungal drug intake recommendations to your patient (over and over again) Perform regular TDM when using voriconazole Be reluctant to stop antifungal treatment if immunosuppression is continued Think of surgery (which is almost never an option: extensive/bilateral disease, poor pulmonary function, risk of fistulisation) Be patient Eva's Gedacht, 2016 ::: Questions? ::: 23