Challenges and controversies of Invasive fungal Infections Mona Al-Dabbagh, MD, MHSc Assistant Professor of Pediatrics, COM-KSAU-HS Consultant Pediatric Infectious Diseases and Transplant Infectious Diseases KAMC, NGHA
Case presentation An 11 yrs. old boy, case of T cell lymphoblastic lymphoma,stage IV on LBL 09 (Arm LC ). Had residual disease after Induction and consolidation. In DI chemo, D# 29, last chemo was on 17/2/2017 Recent diagnosis of steroid induced DM, recently discharged from the ICU for DKA On 1/3/2017 Developed one seizure attack No fever, headache or photophobia Clinically: Conscious and alert with Lt sided weakness Neut: 1.4 Lymph: 0.3 Plt: 27 Started on Meropenem + + Vancomycin + Abelcet
Cont. case presentation CSF unremarkable Cultures -vehsv PCR ve MTB PCR ve Aspergillus PCR -ve Taken to OR on 13/3/2017 Pathology showed non specific inflammatory changes Cultures all -ve Fungal PCR ve MTB PCR -ve
Mar 21, 2017 Abelcet was switched to voriconazole
Cont. case presentation
Cont. case presentation Voriconazole level on Mar 28 was 7+ Voriconazole dose was reduced Voriconazole level repeated Apr 7 3.9
Jan 14, 2018
Questions to ask What is the role of Voriconazole Therapeutic drug monitoring (TDM) in management of invasive fungal infections (IFI)? How to achieve better diagnosis?
Objectives To present the role of therapeutic drug monitoring (TDM) in management of invasive fungal infections (IFI) Efficacy Safety To discuss the diagnostic challenges in IFI diagnosis.
Fungal infections in oncology and HSCT patients Candida and Aspergillus spp. Account for 71% of infections in HSCT and SOT recipients. Kontoyiannis et al. Clin Infect Dis. 2010 ;50(8):1091-100. The incidence of invasive Aspergillosis (IA) has increased by 357% since 1980 McNeil et al. CID 2001; 33:641-647 In post allogeneic SCT patients, nonrelapse mortality was markedly higher for patients with IFI than for those without IFI (60.0% vs. 20.0%, P=0.0204). Kobayashi et al. J paed. Haematol. Oncol, 2007:29: 786-791
most common IFI C. Albicans Antifungal prophylaxis with fluconazole (Goodman et al. NEJM. 1992) Shift away from C. albicans toward less susceptible non-c. albicans species (Pfaller et. al.antimicro b Agents Chemother. 2000) Breakthrough infections with highly resistant Aspergillus spp. (Pavie J, et al.. J Clin Microbiol. 2005 & Balajee SA, et al. Eukaryot Cell. 2005 ) Invasive As pergillosis became the most common IFI (Kontoyian nis et al. Clin Infect Dis. 2010 ) Emergence of a multidrugresistant variant of A. fumigatus (Verweij, et al. Lancet Infect Dis. 2009 ) 1980 1990 2000 2010 The Trend of Invasive Fungal Infections over time Itraconazole prophylaxis (Glasmache r et al. J. of Anti Ch. 2006) Increased incidence of Mucormycosi s (Bitar et al. Emer. Inf. Dis. 2009)
IFI are on the rise Increased number of immunocompromised populatiom Increase number of immunosuppressants +/- increased rate of GVHD Use of antifungal prophylaxis
Current Systemic Antifungal Drugs Fungicidal >90 % Fungicidal 10-50 % Fungistatic Inactive Amphotericin B Fluconazole Itraconazole Voriconazole Posaconazole Cryptococcosis and Coccidiosis Endemic Mycosis, Tinea and dematiaceous infections Scedosporiosis, Fusariousis Zygomycosis, Fusariousis Isavuconazole Caspofungin Micafungin Anidulafungin
Cytochrome P450 Interactions: Azoles CYP3A4 CYP2C9 CYP2C19 Drug Inhibitor Substrate Inhibitor Substrate Inhibitor Substrate FLU ITRA VORI POSA ISAVU
Voriconazole Interactions Vinca Alkaloids (CYP3A4 Inhibition) Cyclosporine (CYP3A4 Inhibition) Tacrolimus (CYP3A4 Inhibition) Sirolimus (CYP3A4 Inhibition)
Oral Hypoglycemics (CYP2C9 Inhibition) Voriconazole Interactions Vinca Alkaloids (CYP3A4 Inhibition) Methadone*** (CYP3A4 Inhibition) Warfarin* (CYP2C9 Inhibition) Cyclosporine (CYP3A4 Inhibition) Ergot Alkaloids (CYP450 Inhibition) Efavirenz** (CYP3A4 Inhibition) Benzodiazepines (CYP3A4 Inhibition) Calcium Channel Blockers (CYP3A4 Inhibition) Methadone*** (CYP3A4 Inhibition) Tacrolimus* (CYP3A4 Inhibition) (CYP3A4 Inhibition) Alfentanil (CYP3A4 Inhibition) Sirolimus (CYP3A4 Inhibition) Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) Phenytoin* (CYP2C9 Inhibition) Ritonavir (CYP3A4 Inhibition) HMG-CoA Reductase Inhibitors (Statins) Rifabutin* (CYP3A4 Inhibition) Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**
Twenty-four studies were analyzed. Included studies on patients with Hematologic malignancies, HSCT and SOT The study examined the effect of TDM on efficacy and safety
Relationship between TDM and successful outcome
Relationship between TDM and successful outcome by the indication for treatment: a) Therapeutic, b) Empiric & Therapeutic, C) Prophylactic
Relationship between TDM and Toxicity
Relationship between TDM and: a) Hepatotoxicity, b) neurotoxicity
Voriconazole TDM TDM should be performed within 2 to 5 days of initiating voriconazole prophylaxis and should be repeated in case of: suspicious adverse events dose changes of interacting drugs.
Diagnostic strategies to improve the diagnosis of IFI
Diagnosis of IFI is very challenging Increased spectrum of fungal pathogens Diversity of clinical and radiological presentations in immunocompromised hosts. None of the currently available diagnostic tests provides sufficient sensitivity and specificity alone combination of multiple diagnostic strategies.
Serum Galactomannan (GM) assay Meta-analysis of 30 studies ODI cut-off of 0.5 (7 studies) SEN, 78% (61% to 89%) SPE, 81% (72% to 88%). ODI cut-off of 1.0 (12 studies) SEN,75% (59% to 86%) SPE, 91% (84% to 95%) ODI cut-off of 1.5 (17 studies) SEN, 64% (50% to 77%) SPE, 95% (91% to 97%). Leeflang et al. Cochrane Database Syst Rev. 2008
BAL GM assay Meta-analysis of 13 studies Proven or probable IA SEN, 0.90 (95% CI; 0.79-0.96) SPE, 0.94 (95% CI; 0.90-0.96) PLR, 14.87 (95% CI; 8.89-24.90) NLR, 0.10 (95% CI; 0.04-0.24). Proven IA SEN, 0.94 (95% CI 0.86-0.98) SPE, 0.79 (95% CI 0.68-0.86) PLR, 4.41 (95% CI 2.87-6.77) NLR, 0.07 (95% CI 0.03-0.09) Guo et al. Chest. 2010
The role of molecular assays Journal of Clinical Microbiology 2014; 52 (10) Included 25 studies assessing PCR assays on blood specimens (serum or whole blood) from high-risk hematology patients (n= 2,595)
SROC curve of PCR performance Positive LR of 3.5 Negative LR of 0.21 When having two positive PCR test specificity increased to 95% and a sensitivity of 64% for IFI Positive likelihood ratio of 12.8. Journal of Clinical Microbiology 2014; 52 (10)
Journal of Clinical Microbiology 2012; 50 (11) Comparison was done between PCR in BAL fluid versus GM in BAL fluid 19 studies included
Fungal PCR from BAL Proven or probable IFI from all 19 studies Sensitivity: 90.2% (77.2-96.1%) Proven or probable IFI from only 9 studies with strict EORTC IFI case definition Sensitivity: 77.2% (62-87.6% Specificity: 96.4% (93.3 t- 98.1%) Specificity 93.5% (90.6-95.6%),
Fungal PCR from BAL
IDSA recommendations toward PCR assays
Summary Voriconazole TDM should aim for serum concentrations between 1.0 and 6.0 mg/l during therapy to optimize clinical success and minimize toxicity. PCR from either blood or BAL show moderate performance. When PCR assays are used, results should be considered in conjunction with other diagnostic tests and the clinical context