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#IDsky This was a great presentation by Dr Girmenia Highly recommend!

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Posa vs itra/flu during induction showed clear benefit in development of IFI

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So what do we do? Continue antifungal drug for at least 4 weeks and until PMN recovery and objective s/sx of improvement and then switch to secondary antifungal ppx with anti- mold activity Consider reduced intensity conditioning regimen

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Despite this, keep in mind that more than 2/3 remain alive with pre SCT IA, and the allo SCT is potentially curative. We have to weigh the risk of relapsed AML, losing out transplant window, having underlying disease undermine our efforts to control the infection.

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Major prognostic determinants of IFD relapse post HSCT How to make a risk calculation in your 🧠

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Risk factors associated with invasive fungal infection include duration of neutropenia, time from IFI and HSCT, type of antifungal used, and presence of GVHD. And recurrent IFI was associated with higher mortality

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#IDSky In pts w/prior IFD had high risk of post HSCT IFD (typically early post transplant)

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#IDsky AML is the primary hematologic malignancy associated with invasive fungal infection What a great slide looking at the mutations we see in AML, very rare pts with MRD post induction and not need to proceed with allo HSCT as shown in green box

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#IDsky Deasy et al showed that inoculation w neisseria lactamica reduced meningococcal carriage from 24% -> 14% Will we be looking at snot🤧👃 microbiota transplants in the future? doi.org/10.1093/cid/...

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#IDsky Fascinating lecture on the respiratory microbiome Our understanding of the resp microbiome has changes dramatically but the commensals may actually be protective against pathogenic bacteria

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Final conclusions Recommends posa or isavu because of side effect profile For refractory cases, consider azole switch, l-amb, combination therapy. Still waiting for further findings for Olorofilm

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#IDsky What about new agents? Olorofilm did fairly well in this particular population who had refractory disease or drug intolerance to other agents But 10% with hepatotoxicity But I think it did not get FDA approval in 2023 from what I remember so investigation is still ongoing

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Repeat BAL aspergillus Ag was strongly positive So since this pt was on posa -> switch to isavu +|- echinocandin Perhaps if critically ill, consider ambisome Experts mention considering next gen sequencing to see if this is actually A. Fumigatus

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In this case vignette, pt w/AML and invasive aspergillosis was started on posa and dose of ivosidenib was reduced. But pt’s imaging got worse after 3 weeks So is it failure of drug vs immune reconstitution? Drug levels therapeutic This pt was still persistently neutropenic so bronch was repeated

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#IDsky Website to check fungal drug interactions and adjustments

But keep in mind, pts resistant to vori tend to be resistant also to isavu, and pts resistant to itra tend to be resistant to posa

What about azole resistance? Becoming more common in western Europe Second slide shows azole resistance rates in chronic aspergillosis pts who had azole exposure

#IDsky Any role in combination antifungal therapy? This study showed no difference with combined vs monotherapy at 6 and 12 wks although there may be a subset of pts w/+serum/BAL Aspergillus GM who had a benefit

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Posa vs vori showed fairly similar results as well 6 week mortality ~20% Also a strong CYP3A4 inhibitor Fewer treatment related events but can see pseudohyperaldosteronism

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#IDsky SECURE trial showed similar efficacy comparing vori vs isavu Isavu is far better tolerated, not necessary to check levels, lft abnormalities and visual sx less common - shortens qtc

But remember that vori can cause sig drug drug interactions and there is interindividual variability in pts (rapid metabolizers and ultra rapid metabolizers) - need to monitor levels - vision changes (flashing lights) - photosensitivity (use sunscreen)

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#IDsky Mechanism of antifungal action Vori better than deoxy ambisome (70% vs 57% survival)

Dx of aspergillosis Fungal cx is low yield (~50%) Serum/BAL aspergillus Ag may be helpful for neutropenic pts, possibly not so much in non neutropenic pts Pcr is sensitive but need to differentiate bw infxn vs colonization Urine Aspergillus Ag is new - will see how it pans out in clinical practice

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#IDsky What is the best agent for invasive aspergillosis?

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Final conclusions Data doesn’t support combo tx and HD LAMB, but could be considered for CNS infection, large areas of necrosis, high MIC BUT source control with surgery, early tx. Don’t be scared to use LAMB as nephrotoxicity concerns may be overrated and other factors may be contributing

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But what causes the nephrotoxicity? We order iv fluids with Lamb, and the pt gets fluid overloaded, then we give diuretics -> renal failure We should perhaps micromanage these pts and determine who needs ivfs and how much Adjunctive calcineurin inhibitors with azoles and higher levels -> arf

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So do we risk higher toxicity with higher dosing? Maybe, some studies say yes, some say no.

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Comparator review suggested no clinical difference but largely were skin and bone infections (easier infections to tx) - only 10 pts in high dose LAMB - nephrotoxicity was not worse with high dose

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But we frequently do higher dosing because it is a high mortality illness with a lot of tissue destruction, difficult penetration Ambizygo suggested possible better response with higher dosing and although kidney dysfunction was common, it was commonly reversible

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However in this study, l-amb had higher killing with higher dosing although there was no survival benefit in 🐁

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Only high dose LAMB recommended in CNS disease and SOT But again… based on animal models And really the benefit was seen with abelcet, not lipo ambisome

What about clinical evidence? Not great… Only @bradspellberg.bsky.social group showed benefit with echinocandin combo therapy So not recommended in guidelines

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🐁 models show benefit with combination therapy but are these signals of benefit type 1 errors and is this able to be extrapolated to people

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#IDsky does higher dosing of L-amB matter for mucorales? Does combination therapy provide any benefit? By Dr Farmakiotis at Beth Israel Highly angioinvasive nature of mucorales and increased LAMB MIC compared to other molds

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#IDsky Outcomes of pts with CLABSI receiving antibiotic lock therapy An underutilized therapy we should use more to salvage catheters!

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