Person:

Marty, Francisco

Background: Invasive fungal disease (IFD) causes significant morbidity and mortality in hematologic malignancy patients with high-risk febrile neutropenia (FN). These patients therefore often receive empirical antifungal therapy. Diagnostic test-guided pre-emptive antifungal therapy has been evaluated as an alternative treatment strategy in these patients. Methods: We conducted an electronic search for literature comparing empirical versus pre-emptive antifungal strategies in FN among adult hematologic malignancy patients. We systematically reviewed 9 studies, including randomized-controlled trials, cohort studies, and feasibility studies. Random and fixed-effect models were used to generate pooled relative risk estimates of IFD detection, IFD-related mortality, overall mortality, and rates and duration of antifungal therapy. Heterogeneity was measured via Cochran’s Q test, I2 statistic, and between study τ2. Incorporating these parameters and direct costs of drugs and diagnostic testing, we constructed a comparative costing model for the two strategies. We conducted probabilistic sensitivity analysis on pooled estimates and one-way sensitivity analyses on other key parameters with uncertain estimates. Results: Nine published studies met inclusion criteria. Compared to empirical antifungal therapy, pre-emptive strategies were associated with significantly lower antifungal exposure (RR 0.48, 95% CI 0.27–0.85) and duration without an increase in IFD-related mortality (RR 0.82, 95% CI 0.36–1.87) or overall mortality (RR 0.95, 95% CI 0.46–1.99). The pre-emptive strategy cost $324 less (95% credible interval -$291.88 to $418.65 pre-emptive compared to empirical) than the empirical approach per FN episode. However, the cost difference was influenced by relatively small changes in costs of antifungal therapy and diagnostic testing. Conclusions: Compared to empirical antifungal therapy, pre-emptive antifungal therapy in patients with high-risk FN may decrease antifungal use without increasing mortality. We demonstrate a state of economic equipoise between empirical and diagnostic-directed pre-emptive antifungal treatment strategies, influenced by small changes in cost of antifungal therapy and diagnostic testing, in the current literature. This work emphasizes the need for optimization of existing fungal diagnostic strategies, development of more efficient diagnostic strategies, and less toxic and more cost-effective antifungals.

Mucormycosis is a life-threatening fungal disease in patients with hematological malignancies. The diagnosis of pulmonary mucormycosis is particularly challenging. We describe 3 mucormycosis cases with an uncommon presentation in patients whose cavitary lung disease was attributed to well documented bacterial infection, although evolution and reassessment established mucormycosis as the underlying disease.

Abstract Background: Timely diagnosis of IM remains a major challenge in clinical mycology. Because of the lack of specific diagnostic methods for IM and the frequently fulminant nature of this infection, IM-associated mortality remains high. Methods: We examined breath volatile metabolite profiles in a neutropenic murine model of IM, using the 3 Mucorales species that most commonly cause human IM - Rhizopus arrhizus var. arrhizus, R. arrhizus var. delemar, and R. microsporus - and for comparison, Aspergillus fumigatus. We infected female balb/c mice (N = 4 per group) treated with cyclophosphamide and cortisone followed by intranasal administration of 106 conidia of each species. 3 days post-infection, we collected breath samples from each mouse via tracheostomy using a flexiVent murine ventilator, examining breath volatile metabolites using thermal desorption gas chromatography/tandem mass spectrometry (GC-MS/MS). We also sampled breath prospectively from five patients eventually diagnosed with proven IM caused by R. microsporus, analyzing breath volatile metabolites using thermal desorption GC-MS/MS. Results: Each Mucorales species produced a consistent profile of breath sesquiterpene secondary metabolite VOCs in our murine models, which distinguished these species from each other and from murine invasive aspergillosis (Figure A). These fungi shifted their secondary metabolism significantly in vivo, compared with their previously characterized in vitro metabolism. We found overlapping VOC sesquiterpene metabolites between breath samples from the murine model of R. microsporus infection and 5 of 5 patients with R. microsporus IM, with additional sesquiterpene secondary metabolites detected in patient breath, compared with the murine IM model (Figure B). In one patient with serial breath samples, these sesquiterpenes declined in abundance and disappeared with antifungal therapy, in parallel with clinical improvement (Figure C). Conclusion: The three Mucorales species that cause most human IM have distinct breath sesquiterpene profiles that can be used to identify these infections in vivo noninvasively. These profiles distinguish these infections from each other and from aspergillosis, and may be useful in monitoring clinical response to treatment. Disclosures F. M. Marty, Astellas Pharma US: Consultant and Grant Investigator, Consulting fee and Grant recipient; Chimerix: Consultant and Grant Investigator, Consulting fee and Grant recipient; Fate Therapeutics: Scientific Advisor, Consulting fee; Gilead Sciences: Consultant and Grant Investigator, Consulting fee and Grant recipient; LFB: Consultant, Consulting fee; Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; Roche Molecular Systems: Consultant, Consulting fee; Shire: Consultant and Grant Investigator, Consulting fee and Grant recipient; D. P. Kontoyiannis, Pfizer: Research Contractor, Research support and Speaker honorarium; Astellas: Research Contractor, Research support and Speaker honorarium; Merck: Honorarium, Speaker honorarium; Cidara: Honorarium, Speaker honorarium; Amplyx: Honorarium, Speaker honorarium; F2G: Honorarium, Speaker honorarium