Breakthrough Invasive Fungal Infections Research Articles

Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review.

Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

Liposomal amphotericin for secondary prophylaxis: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine the safety of liposomal amphotericin B (L-AMB) compared to other antifungal agents for secondary prophylaxis. We conducted a comprehensive search across international databases and reference lists of articles to compile all relevant published evidence evaluating the efficacy and safety of L-AMB versus other antifungals (NLAMB) for secondary prophylaxis against invasive fungal infections. Pooled estimates were calculated after data transformation to evaluate mortality, breakthrough infections, and the frequency of adverse effects, including hypokalemia and nephrotoxicity. Comparisons of breakthrough fungal infection and mortality between the L-AMB and NLAMB groups were performed. We identified 10 studies. The cumulative frequency of patients using L-AMB was 148, compared to 341 patients in the NLAMB group. The mortality rates in the L-AMB and NLAMB groups were 10% and 0%, respectively. However, based on the odds ratio, the mortality in the L-AMB group was lower than that in the NLAMB group. No significant difference was observed in breakthrough invasive fungal infections between the L-AMB and NLAMB groups. The frequencies of nephropathy and hypokalemia in the L-AMB group were 36% and 18%, respectively. Our findings indicate a lower incidence of mortality in the L-AMB group compared to the NLAMB group. No statistically significant difference was observed in the incidence of breakthrough infection between the two groups. L-AMB administration is associated with nephropathy and hypokalemia. However, the refusal to continue treatment due to adverse effects is not significantly high.

Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5days after initiation of ivosidenib with concomitant triazole. Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n=20 of 43 [47%]; voriconazole: n=27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500mg daily. This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

Venetoclax Plus Azacitidine, Low Dose Cytarabine, Aclarubicin and G-CSF (VA-CAG Regimen) for Newly Diagnosed Young Patients with Acute Myeloid Leukemia: A Prospective, Multicenter, Single-Arm Phase 2 Clinical Trial

Background: Venetoclax, in combination with hypomethylating agents or low-dose cytarabine, is approved for newly diagnosed acute myeloid leukemia (AML) patients who are over 75 years of age or not eligible for intensive chemotherapy, while the efficacy of venetoclax-based regimens in young fit AML patients still needs to be further explored. Although the combination of anthracycline and cytarabine has achieved a remission rate of about 70% in these patients, the low complete response rate in adverse-risk patients, strong adverse reactions, and long duration of myelosuppression limited the clinical benefit. We presumed that venetoclax plus azacitidine in combination with low-intensity regimens CAG (G-CSF priming, low dose cytarabine, and aclarubicin) could have a better composite complete remission with an acceptable safety profile. Methods: Patients who were newly diagnosed with AML aged from 18 to 65 years without active infection, bleeding and severe cardiopulmonary insufficiency were enrolled. Participants received induction as azacitidine 75 mg/m 2 subcutaneously once daily on days 1-7, cytarabine 10mg/m 2 subcutaneously q12h on days 1-7, aclacinomycin 12 mg/m 2 on days 1,3,5,7, granulocyte colony-stimulating factor 5µg/kg on days 1-7, and venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-21). Venetoclax dose was adjusted based on concomitant CYP3A inhibitors. The efficacy were evaluated by bone marrow morphology and flow cytometry on day 28 cycle 1. The primary endpoints were safety and the composite complete remission rate. This study was approved for ethical review and registered with ClinicalTrials.gov (NCT05662956). Results: Twenty-six patients from eight sites were enrolled between January 1, 2023, and June 20, 2023. The median age was 52 years (range, 18-63years). Thirteen patients (50.0%) had adverse risk, 7 patients (26.9%) had intermediate risk, and 6 patients (23.1%) had favorable risk. All 26 patients (100%) achieved complete remission after cycle 1, and 21 patients (80.8%) was MRD negative by flow cytometry. Two patients (7.7%) were treated with venetoclax for 14 days due to ineffective platelet transfusion and severe infection during treatment. Twenty-two patients (84%) used azole drugs to prevent fungal infection. The median myelosuppression time was 13 days (range, 5-22days), and the median red blood cell and platelet transfusions were 5.5u (range, 0-11.5u) and 30u (range, 0-170u), respectively. Eleven patients (42.3%) experienced infection (including pulmonary fungal infection, oral cold herpes, novel coronavirus infection, etc.), and two of them (7.7%) had a breakthrough invasive fungal infection, but with good management. The most common grade 3/4 adverse events included bone marrow suppression (92.3%), liver injury (19.2%), gastrointestinal reaction (11.5%) and coagulation dysfunction (3.8%).No treatment-related death occurred. Conclusion: VA-CAG regimen achieved high rates of complete remission and MRD negative in young adult fit patients with newly diagnosed AML. This combined regimen has an acceptable safety profile, with low incidence of infection and transfusion dependence.

Idarubicin and Cytarabine with and without Midostaurin for FLT3-Mutated Acute Myeloid Leukemia

Background: One of the standards of intensive induction therapy for young patients with acute myeloid leukemia (AML) consists of 7 days of cytarabine and 3 days of either idarubicin 12mg/m 2 (IDA) or daunorubicin 60-90mg/m 2 (DNR) (7+3). Midostaurin (MIDO) is added to 7+3 for patients with FLT3-mutated AML. The pivotal trial that led to the approval of MIDO (RATIFY) used 60mg/m 2 of DNR as the anthracycline of choice. Although a direct comparison of IDA with DNR 60mg/m 2 is lacking, randomized studies have shown comparable results with DNR 90mg/m 2 and IDA. It is unclear if the addition of MIDO to IDA-based induction leads to improved outcomes when compared to 7+3 (IDA) alone. Methods: We conducted a retrospective analysis to compare outcomes of young patients (≤65y) with FLT3-mutated AML treated with IDA-based induction, with and without MIDO, at the University of Alabama at Birmingham (UAB) between January 2010 and Dec 2022. Results: There were 85 patients included in the analysis (MIDO=46, control=39). The baseline characteristics are shown in Table 1. The median age of the MIDO and control groups was 51.5y (19-65y) and 50.5y (20-65y), respectively. In the MIDO group, more patients had FLT3-ITD (89% vs. 72%, p&amp;lt;0.01) and NPM1 mutation (52% vs. 33%, p&amp;lt;0.01) compared to the control group. There was an overrepresentation of intermediate karyotype in the MIDO group (92% vs. 76%, p&amp;lt;0.01) and favorable karyotype in the control group (4% vs. 15%, p&amp;lt;0.01). Majority of the patients received micafungin (75%) in the MIDO group and either voriconazole or posaconazole (77%) in the control group. All patients in the MIDO group received at least 1 dose and 70% of the patients completed all 14 days during induction. Ten patients had to discontinue MIDO early due to adverse events (gastrointestinal=6, hepatic=3, rash=1). The composite complete remission (cCR) rate was higher in the control group (79%) compared to the MIDO group (71%) (p=0.01). In comparison, the protocol specified CR rate (by day 60) in the RATIFY trial was 59%. There were no significant differences between the two groups in terms of time to neutrophil and platelet recovery, breakthrough invasive fungal infections, febrile neutropenia and length of hospital stay. In the MIDO group, 22 patients received MIDO during consolidation chemotherapy. Twenty-two out of 46 and 25/39 patients proceeded to allogeneic stem cell transplantation (allo-SCT) in the MIDO and control group, respectively. The 4-year overall survival (OS) for the MIDO group was 50%, compared to 51% for the control group (p=0.1) (Figure 1). The 4-year OS for patients &amp;lt;60y was 54% and 55% in the MIDO and control group, respectively. Conclusion: This is the first study to compare the impact of adding MIDO to IDA-based induction versus IDA-based induction alone. Our findings suggest that IDA-based induction may result in a higher cCR rate, with or without the addition of MIDO, when compared to DNR 60mg/m 2 (as per RATIFY). The addition of MIDO to IDA-based induction did not result in increased toxicity. These results suggest that IDA-based induction, instead of DNR 60mg/m 2, should be considered for younger patients with AML. The added benefit of MIDO, in the context of 7+3 with IDA or even DNR 90mg/m 2, needs further investigation.

Breakthrough invasive fungal infections on isavuconazole prophylaxis in hematologic malignancy & hematopoietic stem cell transplant patients.

Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported. In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs. We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65μg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups. ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Invasive fungal infection following venetoclax and posaconazole co-administration.

The co-administration of venetoclax, a BCL-2 inhibitor, with a mould-active azole, such a posaconazole, has potential to both prevent invasive fungal infection (IFI) and reduce the required treatment dose, and cost, of venetoclax. Posaconazole drug-level monitoring is critical to ensuring adequate mould prophylaxis. A retrospective audit of 99 patients at a tertiary cancer centre, with myeloid malignancies co-prescribed venetoclax and posaconazole between January 2018 and April 2022, was undertaken to evaluate the adequacy of posaconazole prescribing and the rate of breakthrough IFI. Seventy-six patients (77%) had at least one posaconazole level measured in the study period, with 37% requiring a dose adjustment based on steady-state trough levels. Breakthrough IFI occurred in 4% of patients, typically within 1 month of commencing anti-mould prophylaxis. Close monitoring of posaconazole levels in venetoclax-treated patients, particularly in the early, outpatient setting, is critical.

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study.

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin ) was greater than three times higher than reported; moreover, midostaurin Cmin , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.

IFISTRATEGY: Spanish National Survey of Invasive Fungal Infection in Hemato-Oncologic Patients.

Recent advances in the treatment of hematologic malignancies have improved the overall survival rate, but the number of patients at risk of developing an invasive fungal infection (IFI) has increased. Invasive infections caused by non-Candida albicans species, non-Aspergillus molds, and azole-resistant Aspergillus fumigatus have been increasingly reported in recent years. We developed a cross-sectional multicenter survey which involved a total of 55 hematologists and infectious disease specialists from a total of 31 Spanish hospitals, to determine the most frequent strategies used for the management of IFIs. Data collection was undertaken through an online survey which took place in 2022. Regarding key strategies, experts usually prefer early treatment for persistent febrile neutropenia, switching to another broad-spectrum antifungal family if azole-resistant Aspergillus is suspected, broad-spectrum azoles and echinocandins as prophylactic treatment in patients receiving midostaurin or venetoclax, and liposomal amphotericin B for breakthrough IFIs after prophylaxis with echinocandins in patients receiving new targeted therapies. For antifungals failing to reach adequate levels during the first days and suspected invasive aspergillosis, the most appropriate strategy would be to associate an antifungal from another family.

Breakthrough invasive fungal infection among patients with haematologic malignancies: A national, prospective, and multicentre study

We describe the current epidemiology, causes, and outcomes of breakthrough invasive fungal infections (BtIFI) in patients with haematologic malignancies. BtIFI in patients with ≥7 days of prior antifungals were prospectively diagnosed (36 months across 13 Spanish hospitals) according to revised EORTC/MSG definitions. 121 episodes of BtIFI were documented, of which 41 (33.9%) were proven; 53 (43.8%), probable; and 27 (22.3%), possible. The most frequent prior antifungals included posaconazole (32.2%), echinocandins (28.9%) and fluconazole (24.8%)-mainly for primary prophylaxis (81%). The most common haematologic malignancy was acute leukaemia (64.5%), and 59 (48.8%) patients had undergone a hematopoietic stem-cell transplantation. Invasive aspergillosis, principally caused by non-fumigatus Aspergillus, was the most frequent BtIFI with 55 (45.5%) episodes recorded, followed by candidemia (23, 19%), mucormycosis (7, 5.8%), other moulds (6, 5%) and other yeasts (5, 4.1%). Azole resistance/non-susceptibility was commonly found. Prior antifungal therapy widely determined BtIFI epidemiology. The most common cause of BtIFI in proven and probable cases was the lack of activity of the prior antifungal (63, 67.0%). At diagnosis, antifungal therapy was mostly changed (90.9%), mainly to liposomal amphotericin-B (48.8%). Overall, 100-day mortality was 47.1%; BtIFI was either the cause or an essential contributing factor to death in 61.4% of cases. BtIFI are mainly caused by non-fumigatus Aspergillus, non-albicans Candida, Mucorales and other rare species of mould and yeast. Prior antifungals determine the epidemiology of BtIFI. The exceedingly high mortality due to BtIFI warrants an aggressive diagnostic approach and early initiation of broad-spectrum antifungals different than those previously used.

Breakthrough invasive fungal infection in patients with myeloid malignancy receiving posaconazole tablet prophylaxis: clinical features, risk factors, and posaconazole profiles.

Posaconazole (PSC) delayed-release tablet prophylaxis is the standard of care for preventing invasive fungal infection (IFI) in patients with acute myeloid leukemia undergoing myelosuppressive chemotherapy. The clinical features, risk factors, and PSC profiles of breakthrough IFI (bIFI) in patients receiving PSC tablet prophylaxis were investigated. A single-center retrospective cohort study was conducted, including adult patients with myeloid malignancy who received prophylactic PSC tablets while undergoing chemotherapy from June 2016 to June 2021. Logistic regression analysis was used to identify risk factors for breakthrough IFI. A receiver operating characteristic curve was used to predict the relationship between PSC trough level at steady-state and breakthrough IFI. A total of 434 patients with myeloid malignancy who received PSC tablets were screened. Ten patients with bIFI were compared with 208 non-IFI patients. There were four proven and six probable IFI cases, nine due to Aspergillus and one due to Fusarium species. The bIFI patients had higher in-hospital mortality (30.0%) than the non-IFI patients (1.9%; P<0.001). History of allogeneic hematopoietic stem cell transplantation (OR 6.27; 95% CI 1.63-24.09), prolonged neutropenia≥28 days (OR 4.33; 95% CI 1.20-15.70), and low plasma PSC concentration<0.7μg/mL (OR 16.33; 95% CI 4.15-64.26) were risk factors for bIFI. The optimal cut-off value of plasma PSC concentration predicting bIFI was 0.765μg/mL (sensitivity, 60.0%; specificity, 91.3%; area under the curve, 0.746). bIFI was not uncommon in patients with myeloid malignancy receiving PSC tablets prophylaxis and associated with poor outcomes. Therapeutic drug monitoring may still be necessary, even in patients receiving PSC tablets.

Epidemiology and Factors Associated with Treatment Success of Invasive Fungal Infections Among Newly Hematologic Malignancy Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant in Thailand.

Invasive fungal infection (IFI) causes disability/death in patients with hematologic malignancy (HM) receiving chemotherapy or hematopoietic stem cell transplant (HSCT). There is limited epidemiological data, treatment outcomes, and factors associated with IFI treatment success in Thailand. This study aimed to identify factors associated with IFI treatment success among new HM patients receiving chemotherapy or HSCT, determine IFI incidence among HM patients receiving chemotherapy or HSCT, and the IFI incidence of a breakthrough in patients receiving primary antifungal prophylaxis, and identify antifungal drugs susceptibility. This study reviewed the charts of patients aged ≥ 15 years with newly HM who received chemotherapy or HSCT between January 2016 and June 2021 at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. The 2020 EORTC/MSG criteria were used to diagnose IFI. IFI treatment success factors were evaluated using logistic regression. Ninety-two patients with 107 episodes of IFI met the inclusion criteria. IFI incidence on proven and probable cases among newly HM patients receiving chemotherapy or HSCT was 7%. Most infections (38.3%) occurred during the induction-phase chemotherapy. Aspergillosis (35.5%) was the commonest IFI, followed by candidiasis (11.2%), Pneumocystis jirovecii pneumonia (8.4%), mucormycosis (3.7%), and others, respectively. The 12-week IFI treatment success rate was 67.3%. It was associated with age < 60 years, absence of coinfection, and the receipt of appropriate empirical therapy on the first day of IFI diagnosis. The incidence of breakthrough IFI from proven and probable cases in patients receiving primary antifungal prophylaxis was 6.1%. Most fungal pathogen isolates were still highly susceptible to antifungal drugs. The IFI treatment success in patients with HM or HSCT in our study was high. Close monitoring of coinfected patients aged ≥ 60 is recommended. Appropriate antifungal drugs are essential for clinical outcomes.

Breakthrough Invasive Fungal Infection After Coadministration of Venetoclax and Voriconazole.

Venetoclax requires a 75% dose reduction when coadministered with voriconazole. In a 10-year historical cohort of treatment with venetoclax, we did not observe a worse hematologic outcome in patients who received voriconazole prophylaxis versus those who did not. Subtherapeutic voriconazole levels and a triazole exposure history may contribute to breakthrough invasive fungal infection.

Real-life comparison of posaconazole versus fluconazole for primary antifungal prophylaxis during remission-induction chemotherapy for acute leukemia

Patients undergoing remission-induction intensive chemotherapy for acute leukemia are at high risk for life-threatening invasive fungal infections (IFIs). Primary antifungal prophylaxis with posaconazole has been shown to reduce the incidence of IFI compared to fluconazole, but real-life data are limited and the effect on mortality remains unclear. This retrospective cohort study compared fluconazole and posaconazole as primary prophylaxis in real-life practice over a 10-year period, in a Canadian hospital. A total of 299 episodes were included (fluconazole, n = 98; posaconazole, n = 201), of which 68% were first inductions. The underlying hematologic malignancy was acute myeloid leukemia or myelodysplastic syndrome in 88% of episodes and acute lymphoblastic leukemia in 9%. Overall, 20 cases of IFI occurred (aspergillosis, n = 17; candidiasis, n = 3) and 14 were considered as breakthrough IFI. IFI incidence was significantly lower in the posaconazole group (3.5% versus 13.2%; p = 0.001). Empirical or targeted antifungal therapy was also reduced in the posaconazole cohort. Mortality was similar in both groups. In a real-life setting in Canada, primary posaconazole prophylaxis reduces the incidence of IFI during remission-induction chemotherapy, compared to fluconazole.

Invasive Fungal Breakthrough Infections under Targeted Echinocandin Prophylaxis in High-Risk Liver Transplant Recipients

Invasive fungal infections (IFIs) are frequent and outcome-relevant complications in the early postoperative period after orthotopic liver transplantation (OLT). Recent guidelines recommend targeted antimycotic prophylaxis (TAP) for high-risk liver transplant recipients (HR-LTRs). However, the choice of antimycotic agent is still a subject of discussion. Echinocandins are increasingly being used due to their advantageous safety profile and the increasing number of non-albicans Candida infections. However, the evidence justifying their use remains rather sparse. Recently published data on breakthrough IFI (b-IFI) raise concerns about echinocandin efficacy, especially in the case of intra-abdominal candidiasis (IAC), which is the most common infection site after OLT. In this retrospective study, we analyzed 100 adult HR-LTRs undergoing first-time OLT and receiving echinocandin prophylaxis between 2017 and 2020 in a tertiary university hospital. We found a breakthrough incidence of 16%, having a significant impact on postoperative complications, graft survival, and mortality. The reasons for this may be multifactorial. Among the pathogen-related factors, we identified the breakthrough of Candida parapsilosis in 11% of patients and one case of persistent IFI due to the development of a secondary echinocandin resistance of an IAC caused by Candida glabrata. Consequently, the efficacy of echinocandin prophylaxis in liver transplantation should be questioned. Further studies are necessary to clarify the matter of breakthrough infections under echinocandin prophylaxis.

A Brief Review on Covid-19 associated Mucormycosis

Mucormycosis or Zygomycosis is defined as an insidious mycosis by members of the Mucorales and zygomycotic species. Mucormycosis is rare but severe invasive fungal infection. Infection with human corpuscles occurs in superficial form in the outer ear, nails, skin and visceral forms manifest in lung, gastrointestinal, and cerebral types. Mucormycosis is associated with exposure to high levels of airborne fungal contamination. In the context of COVID-19, India has seen an increasing number of incidents. The majority of the cases documented are related to the inappropriate use of corticosteroids in COVID-19 patients. Diabetes mellitus (73.5%), ma-lignancy (9.0%), and organ transplantation are among the main risk factors for mucormycosis in Indians (7.7 percent). In diabetic patients, Mucormycosis develops as a destructive and potentially fatal condition. Diabetic ketoacidosis accelerates fungal invasion. Risk factors include uncontrolled diabetes mellitus, especially ketoacidosis, steroid use, age, neutropenia Mucormycosis diagnosis involves a careful examination of clinical manifestations, magnetic resonance imaging modalities, early use of computed tomography (CT). Mucormycosis can impair the nose, sinuses, orbit, CNS, pulmonary, gastro-intestinal tract (GIT), skin, jaws bones, joints, heart, kidney, and mediastinum. Newer generation antifungal treatments such as amphotericin B, ketoconazole, itraconazole, and voriconazole. There are several formulations of amphotericin B available, including liposomal and lipid-based amphotericin, the colloidal diffusion of amphotericin for most common fungal infections. Breakthrough invasive fungal infections persist when new azoles, posaconazole, and isavuconazole are introduced, despite their anti-mucoral activity.

Subtherapeutic concentrations of posaconazole tablet: determining risk factors and effectiveness of a standardized dose adjustment in hematology inpatients

Posaconazole is indicated for antifungal prophylaxis in hematology patients at high-risk of invasive fungal infections (IFI). Consensus guidelines recommend maintaining steady-state trough concentrations above 0.7 mg/L; however, upto one-third of patients return subtherapeutic concentrations which is associated with breakthrough IFI. This retrospective observational study of 496 concentrations from 90 hematology inpatients prescribed posaconazole tablet (PCZ-tab) between May 2017 and May 2019 identified 24% (n = 121) of posaconazole concentrations were subtherapeutic after the dosage of 300 mg daily. On multivariable analyses, diarrhea (p = 0.002), male gender (p = 0.018), and concurrent regular metoclopramide (p = 0.002) were significantly associated with subtherapeutic posaconazole concentrations. Eighty-nine percent of patients (n = 16) who underwent dose adjustment to 200 mg twice daily successfully achieved target posaconazole concentrations at first steady-state measurement. This study confirms that therapeutic drug monitoring of posaconazole remains necessary as subtherapeutic posaconazole concentrations are relatively common, and that dose adjustment of 200 mg twice daily, safely enabled achievement of therapeutic concentrations.

Exposure-Response Relationship of Posaconazole Suspension in Theprophylaxis of Invasive Fungal Infections in Patients with Acute Myeloid Leukemia.

Antifungal prophylaxis with posaconazole has demonstrated a reduction in the risk of death due to Invasive fungal infections (IFI)in patients with acute myeloid leukemia (AML) during induction therapy. However, various factors affect the plasma levels of posaconazole and can potentially limit its efficacy. Therapeutic drug monitoring (TDM) can help optimize the dose, but literature is scant from centers with a high IFI burden. This study aimed to evaluate the proportion of de-novo AML patients on induction who could achieve the target level of 700ng/mL with posaconazole prophylaxis,factors that can influence the plasma levels, and the impact of plasma posaconazole levels on incidence of IFI. Patients with AML on induction therapy with no baseline IFI were enrolled at our tertiary cancer center which has high prevalence of IFI. These patients received posaconazole suspension as prophylaxis. Daily plasma levels were measured from Day 4 till Day 12 of posaconazole prophylaxis. All patients were monitored for the development of IFI. The data on adverse events, concomitant drugs, mucositis, vomiting, and diarrhea were recorded. A total of 411 samples from fifty patients were collected. Only 177 out of 411 samples had levels > 700 ng/mL. The median trough level was 610 ng/mL (range30-3000 ng/mL). The median time to achieve target trough concentration was four days (range 4-12 days) from the start of induction.Thirty-eight (76%) patients achieved target plasma levels by day 12 of induction.The median plasma level on day 12 was 690 ng/mL (range,30-1270) in patients who achieved target levels as compared to 340 (50-560) ng/mL in those who did not. Twenty-six (52%) patients had IFI in our study, and the median time to develop breakthrough IFI was 14 days (range 4-24 days). Median and range of plasma levels were 690 ng/ml (30-2410; n = 22) in those who developed IFI, while 590 ng/mL (50-2300 n = 24) in those who did not. The odds of developing IFI in patients who did not achieve the threshold trough concentration of 700 ng/mL was 7.14 (95% CI; 1.35-37.75, p = 0.0206). Occurrence of vomiting (p = 0.02), diarrhea (p = 0.0008), mucositis (p = 0.003) had adverse impact on achievement of target plasma posaconazole levels. A significant proportion of patients receiving posaconazole prophylaxis fail to achieve target plasma levels which can result in high risk of development of IFI. Occurrence of diarrhea, vomiting and mucositis can adversely affect the achievement target plasma levels.

Multicenter Registry of Patients Receiving Systemic Mold-Active Triazoles for the Management of Invasive Fungal Infections.

Introduction‘Real-world’ data for mold-active triazoles (MATs) in the treatment of invasive fungal infections (IFIs) are lacking. This study evaluated usage of MATs in a disease registry for the management of IFIs.MethodsData were collected for this multicenter, observational, prospective study from 55 US centers, between March 2017 and April 2020. Eligible patients received isavuconazole, posaconazole, or voriconazole as MAT monotherapy (one MAT) or multiple/sequenced MAT therapy (more than one MAT) for prophylaxis or treatment. Patients were enrolled within 60 days of MAT initiation. The primary objective was to characterize patients receiving a MAT and their patterns of therapy. The full analysis set (FAS) included eligible patients for the relevant enrollment protocol, and the safety analysis set (SAF) included patients who received ≥ 1 MAT dose.ResultsOverall, 2009 patients were enrolled in the SAF. The FAS comprised 1993 patients (510 isavuconazole; 540 posaconazole; 491 voriconazole; 452 multiple/sequenced MAT therapies); 816 and 1177 received treatment and prophylaxis at study index/enrollment, respectively. Around half (57.8%) of patients were male, and median age was 59 years. Among patients with IFIs during the study, the most common pathogens were Aspergillus fumigatus in the isavuconazole (18.2% [10/55]) and voriconazole (25.5% [12/47]) groups and Candida glabrata in the posaconazole group (20.9% [9/43]); the lungs were the most common infection site (58.2% [166/285]). Most patients were maintained on MAT monotherapy (77.3% [1541/1993]), and 79.4% (1520/1915) completed their MAT therapies. A complete/partial clinical response was reported in 59.1% (591/1001) of patients with a clinical response assessment. Breakthrough IFIs were reported in 7.1% (73/1030) of prophylaxis patients. Adverse drug reactions (ADRs) were reported in 14.7% (296/2009) of patients (3.9% [20/514] isavuconazole; 11.3% [62/547] posaconazole; 14.2% [70/494] voriconazole).ConclusionsIn this ‘real-world’ study, most patients remained on their initial therapy and completed their MAT therapy. Over half of patients receiving MATs for IFIs had a successful response, and most receiving prophylaxis did not develop breakthrough IFIs. ADRs were uncommon.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-022-00661-5.

Infectious complications in acute graft‐versus‐host disease after liver transplantation

Graft-versus-hostdisease (GVHD) following liver transplantation (LT) is rare but can lead tosignificant mortality. The leading cause of death following GVHD diagnosis isinfectious complications. However, there is a lack of clear descriptions concerning infection and antimicrobial management patterns. Our study aims toprovide the focused details of all infectious complications of acute GVHDfollowing LT. We retrospectively reviewed all adult LT recipients with acute GVHD at Mayo Clinic's Transplant Centers from January 1, 2010, to December 31, 2021. Detailed characteristics of infection in each case were described. Among 4,585 LTs performed during this period, 12 (0.3%) patients developed acuteGVHD. The median time from transplantation to GVHD diagnosis was 49.0 days [IQR 31.5-99.0]. Ten (83.3%) patients developed severe infections leading tomortality. The most common cause of infection was nosocomial bacteremia fromenteric bacteria such as vancomycin-resistant enterococci and gram-negative bacilli. Other infections included breakthrough invasive fungal infections,cytomegalovirus (CMV) reactivation, and Clostridioides difficile colitis. Antimicrobial prophylaxis strategies in most cases were based on the degree of neutropenia-these include levofloxacin for bacterial prophylaxis, nebulized pentamidine for Pneumocystis jiroveci pneumonia prophylaxis, posaconazole for invasive fungal prophylaxis, and valganciclovir based on CMVstatus. All GVHD patients with severe infections succumbed to thesecomplications. Ourstudy reiterates that despite prophylaxis, infectious complications in GVHDfollowing LT are common and lead to exceptionally high mortality. Individualizedantimicrobial treatment, prophylaxis and monitoring strategies remain a criticalcomponent of GVHD management. Further study to optimize these practices isrequired.