Secondary Antifungal Prophylaxis Research Articles

The Effects of Mycophenolate Mofetil and Cyclosporine with Concomitant Posaconazole Tablets in the Early Stage of Allogeneic Hematopoietic Stem Cell Transplantation

Background： Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) mainly applied the “Beijing regimen”(cyclosporine + methotrexate + mycophenolate mofetil（MMF）). This approach significantly reduces the risk of graft-versus-host disease (GVHD), increases the risk of infection. Posaconazole can significantly reduce the incidence of invasive fungal disease (IFD) during the immunosuppressive phase. Cyclosporine and posaconazole have significant drug interactions, with MMF also have drug interactions. However, there is limited research about drug interactions of simultaneous three-drug combination. Objective： Explore the effects of MMF and cyclosporine with concomitant posaconazole in allo-HSCT patients within 30 days and the breakthrough incidence of IFD within 100 days post-transplantation. Method: A single-arm, open-label, prospective trial was conducted to evaluate posaconazole tablet (300 mg q12h oral d1,300 mg/d) as secondary antifungal prophylaxis in allo-HSCT patients (18-65 years old) with previous proven or probable IFD (ChiCTR2200059472). Posaconazole and cyclosporine were started when conditioning began, while MMF was used one day before infusion of stem cell for one month with fixed dose of 2 g/d. The plasma concentration of posaconazole and mycophenolic acid (MPA) which is the active ingredient of MMF, were monitored weekly, cyclosporine was monitored twice one week until 30 days post-transplantation. Results: Thirty patients from July 2022 to March 2023 were enrolled in the trial, included 16 males and 14 females, acute myelogenous leukemia 22, acute lymphoblastic leukemia 2, myelodysplastic syndrome 2, aplastic anemia 4. All patients underwent haploidentical HSCT. All patients had history of IFD(5 proven IFD, 13 probable IFD and 12 possible IFD). At week1, 2, 3 and 4 after conditioning, The mean plasma concentrations of posaconazole were 0.47±0.29ug/ml, 0.66±0.32ug/ml,0.72±0.40ug/ml and 0.91±0.32ug/ml（Figure 1）. The mean plasma concentrations of cyclosporine were 138.20±35.33ng/ml, 190.61±48.07ng/ml,245.46±37.31ng/ml and 253.56±45.19ng/ml（Figure 2）.The mean plasma concentrations of MPA at week 2, 3 and 4 were 0.35±0.15mg/L, 0.89±0.36mg/L and 1.18±0.58mg/L (Figure 3). After week 1, concentration of cyclosporine of 13 cases was below 150ng/ml and the dosage was increased by 25% of the original dose, at week 4, concentration of cyclosporine of 9 cases was above 250ng/ml and the dosage was decreased by 25%. After posaconazole reached steady state concentrations at week 2, while cyclosporine reached target concentrations after the dose increase, MPA did not reach target concentrations at week 2. The concentrations of MPA significant increase without changing the MMF dose and reached target concentrations at week 3 simultaneous three-drug combination. Cyclosporine concentrations increased significantly at week 4 with stable concentrations of MPA and posaconazole, and 30% of patients required dose reduction of cyclosporine. Only one patient was diagnosed as aspergillus fumigatus pneumonia through NGS of pulmonary alveolar lavage fluid. The breakthrough incidence of IFD was 3.33%. Conclusion: Different times of administration lead to different times of interaction among the three drugs. The combination of cyclosporine and MMF leads to decrease in MPA concentrations, but the concentration of MPA can rapidly increase when combined with posaconazole. When target concentration of MPA is not reached in the first week, it is recommended to suspend dose modification and TDM in the second week. However, the accumulation of cyclosporine was significant in the fourth week, and it was recommended that cyclosporine should be monitored and adjusted within three weeks after the three drugs were combined. The cumulative breakthrough incidence of 3.33% is lower than reported in literaturesuggesting that posaconazole appears to be effective for secondary prophylaxis of IFD after allo-HSCT.

The Impacts of Antiretroviral and Antifungal Treatments, and Tuberculosis Co-infection on Mortality and Relapse in Patients with Talaromyces Marneffei Infection

To date, clinical data on long-term clinical outcomes, including 6-month mortality and relapse in talaromycosis (Tm) patients and impacts of ART and secondary antifungal prophylaxis are still lacking. We conducted a secondary data analysis from 6-month prospective observation of patients with culture-confirmed talaromycosis who participated in the Itraconazole versus Amphotericin B for HIV-associated Talaromycosis (IVAP) trial. The primary outcome was 6-month Tm mortality, while the secondary outcome was relapse. Multivariable Cox proportional hazard models were used to identify predictors of outcomes of interest. The median patient age was 34 years (IQR:30 – 38). The median pre-ART CD4 counts at baseline were 10 (IQR: 5-21) cells/µL. The cumulative 76/435 (17.4%) patients died, and Tm relapse was observed in 18/435 (4.1%) patients. The multivariable analyses showed that strong independent predictors of 6-month Tm mortality included ineffective ART (either absence of ART or ART failure) (HR = 6.26, 95% CI: 3.95 – 9.92, P < 0.001), and TB co-infection (HR =1.98, 95% CI: 1.23 – 3.17; P < 0.01). Induction antifungal treatment with itraconazole versus amphotericin B deoxycholate was significantly associated with Tm death in the univariable model, however, it became insignificant in the multivariable model. In addition, the significant risk factors for Tm relapse were ineffective ART, induction antifungal treatment with itraconazole than intravenous amphotericin B, and shorter duration of itraconazole secondary prophylaxis after completing induction therapy in-hospital (all with significant P-values). Antiretroviral therapy, antifungal treatment and tuberculosis co-infection were main predictors for 6-month Tm fatality as well as relapse. Keywords: Invasive fungal infections, Mortality, Relapse, Talaromyces marneffei, Vietnam.

Posaconazole oral suspension for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study

BackgroundThere is no consensus on the optimal secondary antifungal prophylaxis (SAP) regimen in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the efficacy and safety of posaconazole oral suspension as secondary prophylaxis of invasive fungal disease (IFD) for allo-HSCT patients.MethodsWe retrospectively reviewed clinical data from prior IFD patients who received posaconazole oral suspension as systemic antifungal prophylaxis between June 2016 and January 2021 and have a follow-up period of 1 year after HSCT. The clinical outcomes of patients with a prior history of IFD (n = 30) and those without (n = 93) were compared.ResultsThe 1-year cumulative incidence of prophylaxis failure was 58.3% in the group with prior history of IFD and 41.6% in the group without a prior history of IFD (p = 0.459). The cumulative incidence of proven, probable or possible IFD within 1 year after allo-HSCT was 23.1% in the group with prior history of IFD and 14.1% in the group without prior history of IFD (p = 0.230). There was no significant difference between the cumulative incidence of proven or probable IFD within 1-year after allo-HSCT in the group with a prior history of IFD and the group without (p = 0.807). Multivariate logistic regression revealed cytomegalovirus disease as risk factor for post-transplantation IFD occurrence in posaconazole oral suspension prophylaxis. There was not a significant difference in overall survival between the patients with IFD history and those without (P = 0.559).ConclusionsOur study support that allo-HSCT recipients with a prior history of IFD and normal GI absorption can choose posaconazole oral suspension as a safe and effective SAP option.

Clinical Characteristics and Risk Factors of Invasive Fungal Infections in Acute Leukemia Patients in Tropical Regions

To analyze the clinical characteristics and risk factors of invasive fungal infection (IFI) occurenced in patients with acute leukemia (AL) during treatment in tropical regions. The clinical data of 68 AL patients admitted to the Hainan Hospital of PLA General Hospital from April 2012 to April 2019 was retrospectively analyzed. Logistic regression analysis was used to analyze the factors affecting the occurrence of IFI in AL patients. Among the 68 patients, 44 were acute myeloid leukemia, 24 were acute lymphoblastic leukemia, 39 were male, 29 were female and the median age was 41(13-75) years old. The 68 patients received 242 times of chemotherapy or hematopoietic stem cell transplantation(HSCT), including 73 times of initial chemotherapy or inducting chemotherapy after recurrence, 14 times of HSCT, 155 times of consolidating chemotherapy. Patients received 152 times of anti-fungal prophylaxis, including 77 times of primary anti-fungal prophylaxis and 75 times of secondary anti-fungal prophylaxis. Finally, the incidence of IFI was 31 times, including 24 times of probable diagnosis, 7 times of proven diagnosis, and the total incidence of IFI was 12.8%(31/242), the incidence of IFI in inducting chemotherapy was 24.66%(18/73), the incidence of IFI in HSCT patients was 28.57% (4/14), the incidence of IFI in consolidating chemotherapy was 5.80% (9/155). Multivariate analysis showed that inducting chemotherapy or HSCT, the time of agranulocytosis ≥7 days, risk stratification of high risk were the independent risk factors for IFI in AL patients during treatment in tropical regions. The incidence of IFI in patients with AL in the tropics regions is significantly higher than that in other regions at homeland and abroad. Anti-fungal prophylaxis should be given to the patients with AL who have the high risk factors of inducting chemotherapy or HSCT, time of agranulocytosis ≥7 days and risk stratification of high risk.

Liposomal Amphotericin B Induced Acute Reactions

Three formulations of amphotericin B are available: liposomal, lipid complex and conventional. The liposomal amphotericin B is more preferred agent than other formulations because of its tolerability, safety and potent antifungal activity. However, the liposomal amphotericin B can cause infusion-related reactions. In this case report, we aimed to report a patient who developed infusion-related reactions during the treatment with the liposomal amphotericin B but eventually tolerated the prolonged infusion. In this case report, we present a patient who developed an infusion-related reaction during The liposomal amphotericin B treatment. A 26-year-old male patient with acute promyelocytic leukemia was hospitalized for the third course of chemotherapy. Due to the invasive fungal infection history in previous hospitalizations, the liposomal amphotericin B 400 mg (IV, 5 mg/kg) once daily was initiated as secondary antifungal prophylaxis. Swelling in infusion site and chest pain were reported within 10 minutes of the liposomal amphotericin B administration, and the infusion rate was slowed down to 400 mg/6 hours from 400 mg/2 hours. All these reactions disappeared with prolonged infusion time. The patient received a total of 7 liposomal amphotericin B doses subsequently without any reaction during the chemotherapy cycle. In our experience, the liposomal amphotericin B-induced infusion-related reactions can be resolved by prolonging the infusion time.

Real-world assessment of the effectiveness of posaconazole for the prophylaxis and treatment of invasive fungal infections in hematological patients: A retrospective observational study.

The aim of the study was to analyze the efficacy of posaconazole for the prophylaxis and treatment of invasive fungal diseases (IFDs) in patients with hematological malignancies.In this retrospective observational multi-center study, 762 patients from 25 Chinese hematological centers were enrolled. Inclusion criteria were patients with hematological malignancy or they had undergone hematopoietic stem cell transplantation and received at least 1 dose of posaconazole. The primary endpoints were the observation of breakthrough rates and the clinical efficacy of posaconazole prophylaxis. The secondary endpoint was the efficacy of posaconazole for the treatment of IFDs.Of the 762 enrolled patients, 456 (59.8%) were prescribed posaconazole prophylactically while 243 (31.9%) received posaconazole as an IFD treatment (12 proven, 61 probable, 109 possible, and 61 unclassified IFD cases) for ≥7 days. The overall IFD breakthrough rate (probable cases) for the ≥4 days prophylactic treatment (n = 445) group was 1.6% (95% Cl: 0.6%–3.2%), with breakthrough rates of 2.6% for acute myeloid leukemia/myelodysplastic syndrome patients undergoing chemotherapy and 2.2% for hematopoietic stem cell transplantation patients. For primary antifungal prophylaxis, the breakthrough rate was 1.9% and for secondary antifungal prophylaxis 0%. The overall effective IFD remission rate of patients treated for ≥7 days with posaconazole was 56.0% and the effective remission rate of proven/probable/possible IFD cases was 59.3%. The effective remission rate of posaconazole as salvage therapy was 50% (95% CI: 32.4%–67.6%) including 75% (CI: 19.4%–99.4%) for Aspergillus infections.The present retrospective study confirmed posaconazole as IFD prophylaxis and medication for hematological malignancy patients undergoing various treatments in China.

Antifungal Combination Therapy in Children with Cancer-A 4-Year Analysis of Real-Life Data of Two Major Pediatric Cancer Centers.

Clinical data on antifungal combination therapy are limited, in particular in the pediatric setting. We analyzed real-life data collected in two major pediatric cancer centers over a period of 4 years. Patients were identified in an observational study on children with acute leukemia and lymphoma or undergoing hematopoietic cell transplantation. Out of 438 patients, 19 patients received 21 episodes of antifungal combination therapy. Therapy was mostly started for sepsis (n = 5) or clinical deterioration with pulmonary infiltrates (n = 10), and less often for periorbital swelling with suspected mold infection (n = 2), clinical deterioration and new skin lesions, secondary antifungal prophylaxis, a persistently elevated galactomannan index, or as pre-emptive treatment (n = 1 each). Diagnostics revealed proven, probable, and possible invasive fungal disease in two, seven and four episodes, respectively. Most regimens included caspofungin (n = 19), and treatment was initiated as first line therapy in 10 episodes. The median duration was 13 days (4–46 days). Nine of the 13 patients with proven, probable, or possible invasive fungal disease survived, which was comparable to patients receiving antifungal monotherapy. Our analysis demonstrates that combination therapy has mainly been prescribed in selected immunocompromised patients with clinical deterioration due to suspected invasive fungal disease or those with sepsis, and is well tolerated. Future studies need to better characterize clinical settings in which patients may benefit from antifungal combination therapy.

Invasive Aspergillosis (IA) in Acute Myeloid Leukemia (AML): When Is Prophylaxis Appropriate?

Introduction: management strategies for IA in patients receiving intensive chemotherapy (CT) for AML remain a matter of debate. Although most centers adopted primary prophylaxis recommendations based on few trials with less-than-ideal comparators, it appears that the option between a preemptive/early diagnosis-driven strategy and a prophylactic one should take in account the local incidence of IA, as the number needed to treat differs considerably between institutions. Until 2012 our center followed a preemptive strategy, but the finding of an alarming increase in IA cases led us to adopt primary prophylaxis. Results were prospectively evaluated in the following years and are reported here.Methods: from January/06 to March/12 308 patients received 629 first-line or subsequent CT courses (377 induction, 252 consolidation) in which only secondary antifungal prophylaxis was allowed. From April/12 to May/16 197 patients received 378 courses (230 induction, 148 consolidation) under prophylactic voriconazole. In both periods patients were nursed in rooms with positive pressure and HEPA filters, and CT regimens were unchanged. IA cases were classified according to EORTC/MSG criteria. Incidence of IA, overall mortality and attributable (specific) mortality at 12 weeks were compared between the 2 periods.Results: in the first period 82 cases of IA (79 lung, 3 sinus) were diagnosed, 6 of which were proven, 43 probable and 33 possible. Half occured in induction, 33% in consolidation, and the remaining in second-line CT courses. Most cases were treated with voriconazole (only 5 received other antifungals, in a clinical trial setting) with a global success rate of 82%. Two of the 11 failures occured in complete remission (consolidation courses). Overall mortality at 12 weeks was 23% and attributable mortality was 12%. In this period 2 cases of rhinocerebral Mucor were diagnosed. In the second period 13 cases of IA (12 lung, 1 gut) occured, of which 1 was proven, 7 probable e 5 possible. Most (77%) arose during induction. Serious (grade 3/4) adverse effects of voriconazole needing interruption were infrequent and consisted mainly of hepatic enzymes increases in 5% of the patients. Success rate (diverse antifungals) was 85%. Overall mortality at 12 weeks was 23% with no attributable mortality. Incidence of IA (27% vs 6.6%) and attributable mortality were significantly different between the 2 periods (both p < 0.001).Conclusion: preemptive/early diagnosis-driven strategy is atractive, as it spares most patients the side effects of useless antifungals. However, in centers with a high incidence of IA like ours, prophylaxis becomes highly rewarding, leading to a very significant reduction in these life-threatening fungal infections. DisclosuresNo relevant conflicts of interest to declare.

Is Posaconazole Really Effective in Adolescent patients as a Prophylactic Agent: Experience of a Tertiary Care Center

Invasive fungal infections (IFIs) are a leading cause of morbidity and death in immunocompromised patients. Data on efficacy and pharmacokinetics of posaconazole in pediatric patients are rare (1 to 5). Herein, we retrospectively analyzed adolescent patients who had received posaconazole as antifungal prophylaxis. We retrospectively analyzed patients who received posaconazole as primary or secondary antifungal prophylaxis. A total of 34 adolescent patients, 19 men (55.9%) and 15 women (44.1%) with a mean age of 15.8±2.1 years were included. Twenty-five of 34 (73.5%) patients were on primary and nine of 34 (26.5%) patients were on secondary antifungal prophylaxis. Diagnosis of the patients receiving posaconazole as primary antifungal prophylaxis were acute myeloid leukemia (n=12, 48%), hematopoietic stem cell transplantation (n=7, 28%), acute lymphoblastic leukemia (n=5, 20%), and Fanconi aplastic anemia (n=1, 4%). Five patients (55.6%) with hematopoietic stem cell transplantation, 1 patient with acute myeloid leukemia (11.1%), 1 patient with Fanconi aplastic anemia (11.1%), and 2 (22.2%) patients with chronic granulomatous disease received posaconazole as secondary antifungal prophylaxis. Twelve of 25 (48%) patients receiving posaconazole as primary antifungal prophylaxis were complicated by IFI; 4 of them were proven, 6 probable, and 2 with possible IFI. Three of 9 patients (33.3%) receiving posaconazole as secondary antifungal prophylaxis was complicated by IFI (P=0.29), 2 of them were probable and 1 was possible IFI. Five of 25 patients (20%) receiving posaconazole as primary prophylaxis died because of IFI. Improvement of antifungal prophylaxis in patients with high risk of invasive infections seems clearly necessary, and analyzing serum posaconazole levels and individualizing dosing may be 1 approach to improve outcomes.

Invasive Fungal Disease Following Myeloablative Cord Blood Transplantation for Patients with Hematological Malignancies

Objective: Invasive fungal disease (IFD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited data is available on its clinical features after cord blood transplantation (CBT) for patients with hematological malignancies. Method: We retrospectively reviewed 63 patients who underwent myeloablative CBT at our institution between July 2013 and June 2019 with a median follow-up of 14 months. Micafungin, Voriconzole or Posaconazole was used for IFD prophylaxis. Results: Eight patients were identified as having an IFD, including 2 with proven IFD, 1 with probable IFD, and 5 with possible IFD. The most common prophylaxis regimen is micafungin (68.2%, 43/63). The incidence rate of IFD in the primary antifungal prophylaxis (PAP) and secondary antifungal prophylaxis (SAP) groups were 11.3% and 25% (P=0.488). The OS of day at +100, six months and +200 in the IFD and No IFD groups were 62.5% vs. 86.9% (P=0.1), 50 % vs.78.2% (P=0.07), and 50% vs.75.9% (P=0.094), respectively. The 3-year probabilities of overall survival (OS) in the IFD and No IFD groups were 50% and 60.5%, respectively (p=0.316). The incidence rate of Non-relapse Mortality in the IFD and No IFD groups were 42.9% and 30%, respectively (p=0.319). Conclusion: Antifungal prophylaxis could help to reduce the incidence of IFD after CBT for patients with hematological malignancies. Figure Disclosures No relevant conflicts of interest to declare.

Secondary antifungal prophylaxis in allogeneic hematopoietic stem cell transplant recipients with invasive fungal infection.

Invasive fungal infection (IFI) is a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. A previous history of IFI is not an absolute contraindication for allo-HSCT, particularly in the era of secondary antifungal prophylaxis (SAP). Prompt diagnosis and therapy are essential for HSCT outcome. The charts of 58 allo-HSCT recipients [median age:29.5 (16-62); M/F:41/17] who had a previous history of IFI were retrospectively reviewed. Possible IFI was demonstrated in 32 (55.2%), probable in 13 (22.4%) and proven in 13 patients (22.4%). All patients received SAP [liposomal amphoterisin B (n ꞊ 35), voriconazole (n ꞊ 17), caspofungin (n ꞊ 2), posaconazole (n ꞊ 1), combination therapy (n = 3)] which was started on the first day of the conditioning regimen. Treatment success was better in the voriconazole group when compared to the amphotericin B arm (100% vs 69.2%; p = 0.029). Development of breakthrough IFI was more frequent in patients on amphotericin B prophylaxis (42.4% vs 23.1%; p = 0.036). Clinical and radiological response were achieved in 13 of 18 patients (72.2%) who developed breakthrough infection. Overall survival of the study population was 13.5% at a median follow-up of 154 (7-3285) days. Fungal mortality was found to be 23%. Overall survival was better in the voriconazole arm, without statistical significance (90% vs 65.8%, p > 0.05). Secondary antifungal prophylaxis is considered to be an indispensible strategy in patients with pre-HSCT IFI history. Voriconazole seems to be a relatively better alternative despite an underlying necessity of larger prospective trials.

INVASIVE ASPERGILLOSIS AND MUCORMYCOSIS IN ONCOHEMATOLOGICAL PATIENTS

In the retrospective multicenter study during 2007–2017 we included 59 oncohematological patients with mucormycosis and 541 patients with invasive aspergillosis. Our study showed that mucomorhycosis more often developed in children and adolescents (p = 0.001), and after «graft versus host» disease development (p = 0.0001). Patients with mucormycosis were more immunosuppressed: severe neutropenia was in 88 % vs. 82 %, median duration of neutropenia ‒ 30 days vs. 14 days, p = 0.0001, lymphocytopenia – 77 % vs. 65 %, median duration of lymphocytopenia – 25 days vs. 14 days, p = 0.001. The main sites of infection were lungs, nevertheless in patients with mucormycosis it was less frequent (73 % vs. 97 %, p = 0.02), but more frequent were ≥2 organs involvement (42 % vs. 8 %, p = 0.001) and paranasal sinuses involvement (15 % vs. 6 %, p = 0.04). Typical clinical features of mucomorhycosis were localized pain syndrome (53 % vs. 5 %, p = 0.0001), hemoptysis (32 % vs. 6 %, p = 0.001), on lung computed tomography scan – pleural effusion (53 % vs. 7 %, p = 0.003), lesions with destruction (38 % vs. 8 %, p = 0.0001) and “a reverse halo” symptom (17 % vs. 3 %). The overall 12-week survival was significantly lower in patients with mucormycosis (49 % vs. 81 %, p = 0.0001). In both groups unfavorable prognosis factors were: ≥2 organs involvement (p = 0.0009) and concomitant bacterial or viral infection (p = 0.001 and p = 0.008 respectively). In mucormycosis patients favorable prognosis factor was remission of underlying disease (p = 0.006), in invasive aspergillosis patients – early bronchoscopy (p = 0.003), voriconazole use (p = 0.0007) and secondary antifungal prophylaxis (p = 0.0001).

Primary or Secondary Prophylaxis with Voriconazole Compared with Posaconazole for Prevention of Invasive Fungal Infections After Hematopoietic Stem Cell Transplantation

Background Invasive fungal infections (IFI) remain a serious complication in hematopoietic stem cell transplantation (HSCT) patients and are associated with increased costs, morbidity, and mortality. Posaconazole (PCZ) and voriconazole (VCZ) are frequently utilized as antifungal prophylaxis in this population. To date, no direct comparison between PCZ and VCZ exists for the prevention of IFI in adult HSCT patients.Methods A retrospective cohort analysis of HSCT patients aged ≥18 years who received ≥28 continuous days of primary (PPPx) or secondary (SPPx) antifungal prophylaxis with either VCZ or PCZ between February 26, 2003 and September 30, 2015 at Barnes-Jewish Hospital was conducted. Patients who received PPPx or SPPx with both VCZ and PCZ were analyzed following intention to treat of the initial agent received. Patients who received both PPPx and SPPx were included once for both PPPx and SPPx. The primary outcome of interest was development of possible, probable, or proven IFI as defined by EORTC/MSG guidelines. In the SPPx patients, development of IFI was confirmed as a distinct event from primary IFI based on manual chart review and radiographic evidence.ResultsOverall, there were 472 patients included; 402 in the VCZ group and 70 in the PCZ group. At baseline, patients in the PCZ group had more graft vs. host disease (GVHD) prior to prophylaxis (27.1% vs. 16.7%, P = 0.04) and were more likely to be on SPPx (60% vs. 41%, P < 0.01). There were 22 and 1 IFI events in the VCZ and PCZ groups, respectively, which corresponded to a crude incidence rate of 0.345 and 0.077 per 1000 person-days of prophylaxis. Figure 1 displays the Cox proportional hazard model which was completed in the backwards stepwise method accounting for gender, transplant type, GVHD prior to prophylaxis, disease remission, and PPPx or SPPX. The hazard ratio for development of IFI while on prophylaxis between VCZ and PCZ was 5.22 (95% CI: 0.69–39.4; P = 0.11) after controlling for PPPx or SPPx.ConclusionThere was not a significant difference between rates of IFI in HSCT patients who received antifungal prophylaxis with VCZ compared with PCZ. Our data trends towards favoring PCZ but is limited by low rates of IFI. Larger, prospective analyses are necessary to confirm our findings.Figure 1.Cox model for IFI rates.Disclosures W. Powderly, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Astellas: Grant Investigator, Research grant

Eficacia del tratamiento y de la profilaxis antifúngica secundaria en la histoplasmosis asociada al sida. Experiencia del Hospital de Infecciosas Francisco J. Muñiz, de la ciudad de Buenos Aires

BackgroundClassic histoplasmosis is a systemic endemic mycosis due to Histoplasma capsulatum var. capsulatum. A significant reduction in the morbidity and mortality of AIDS-related histoplasmosis has been observed since the introduction of highly active antiretroviral therapy (HAART) and secondary antifungal prophylaxis. AimsThe aim of this study was to determine the current state of prognosis and treatment response of HIV-positive patients with histoplasmosis in the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires City. MethodsA retrospective study was conducted using the demographic, clinical, immunological and treatment data of 80 patients suffering from AIDS-related histoplasmosis. ResultsOf the 80 cases studied 65 were male, the median age was 36 years, with 73.7% of the patients being drug addicts, 82.5% of the patients was not receiving HAART at diagnosis, and 58.7% of the cases had less than 50 CD4+ cells/μl at the beginning of the treatment. The initial phase of treatment consisted of intravenous amphotericin B and/or oral itraconazole for 3 months, with 78.7% of the cases showing a good clinical response. Only 26/63 patients who were discharged from hospital continued with the follow-up of the HAART, secondary prophylaxis with itraconazole or amphotericin B. Secondary prophylaxis was stopped after more than one year of HAART if the patients were asymptomatic, had two CD4+ cell counts greater than 150cells/μl, and undetectable viral loads. No relapses were observed during a two-year follow up after prophylaxis was stopped. ConclusionsThe treatment of histoplasmosis in HIV-positive patients was effective in 78.8% of the cases. The combination of HAART and secondary antifungal prophylaxis is safe, well tolerated, and effective. The low adherence of patients to HAART and the lack of laboratory kits for rapid histoplasmosis diagnosis should be addressed in the future. The usefulness of primary antifungal prophylaxis for cryptococcosis and histoplasmosis HIV-positive patients should be studied.

Recurrent invasive pulmonary aspergillosis or breakthrough fungal infection in a child after haploidentical hematopoietic stem cell transplantation

Invasive fungal infections (IFI) are devastating and life-threatening infections affecting especially immunocompromised patients. We report on a case of a 14-year-old boy with myelodysplastic syndrome (MDS), after haploidentical hematopoietic stem cell transplantation, in whom invasive pulmonary aspergillosis (IA) was diagnosed and successfully treated with subsequent (despite the secondary antifungal prophylaxis) IA or breakthrough infection development. Thanks to intensive and broad spectrum antifungal treatment (voriconazole upfront therapy, followed by a combination of voriconazole and micafungin, and eventually by the amphotericin B lipid complex), significant improvement was accomplished.

Antifungal prophylaxis of patients undergoing allogenetic hematopoietic stem cell transplantation in China: a multicenter prospective observational study.

BackgroundAntifungal prophylaxis is currently regarded as the gold standard in situations with allo-genetic hematopoietic stem cell transplantation (allo-HSCT). However, the epidemiological information regarding prophylaxis of invasive fungal diseases (IFDs) is not clear in China.MethodsWe report the first large-scale (1053 patients) observational study of the prophylaxis and management of IFDs among patients with allo-HSCT in China.ResultsThe incidence rates of IFD after primary antifungal prophylaxis (PAP), secondary antifungal prophylaxis (SAP), and non-prophylaxis were 22.7 vs. 38.6 vs. 68.6 %, respectively (P = 0.0000). The median time from transplantation to IFD was 45 days in PAP patients, 18 days in SAP patients, and 12 days in non-prophylaxis patients. Aspergillus spp. represents the most common type of fungal infection. Independent risk factors for IFD in allo-HSCT patients with PAP were age, having human leukocyte antigen (HLA)-haploidentical or matched unrelated donor, decreased albumin levels, and the use of itraconazole as the prophylactic antifungal agent. Among SAP transplant recipients, there was no significant risk factor for IFDs. The incidence rates of overall survival (OS) in the PAP, SAP, and no prophylaxis groups were 85.07, 78.80, and 74.82, respectively (P = 0.01).ConclusionsThis observational study indicates that prophylaxis of IFD is helpful to reduce the incidence of IFDs and improve the OS of patients after allo-HSCT.

Invasive fungal infections in recipients of allogeneic hematopoietic stem cell teens and young adults

Background. Despite of modern methods of diagnosing, prevention and treatment, invasive fungal disease (IFD) remains actual problem after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Data of IFD in adolescents and young adults (15–25 y.o.) after allo-HSCT are limited. The aim of the study was to estimate of incidence, etiology, clinical signs and outcome of IFD in adolescents and young adults recipients of allo-HSCT. Materials and methods. In retrospective single center study from Jan 2013 to Dec 2014 were included 80 pts after first allo-HSCT in the clinic of Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg. EORTC/MSG 2008 criteria for IFD diagnosis were used. “Active IFD” means IFD diagnosed just before HSCT. Results. Incidence of IFD before allo-HSCT was 18.8 % (n = 15): invasive aspregillosis (IA) (n = 11), invasive candidiasis (IC) (n = 3) and 1 patient had two IFD (IA + IC). Complete response to antifungal therapy was in 40 %, partial – 26.7 %, “active” IFD – 33.3 %. Secondary antifungal prophylaxis was made predominantly with voriconazole (80%). Patients without IFD before HSCT (n = 65) received primary antifungal prophylaxis predominantly with fluconazole (85 %). Cumulative incidence of IFD-events at 1 year after allo-HSCT was 15 %, at 2 years – 18.8 % including new cases of IFD (n = 14) and relapse of IFD (n = 1) after allo-HSCT with median day of oncet +43 (14–577). Incidence of IA was 15 %, IC – 2.5 %, pneumocystis pneumonia (PCP) – 1.25 %. IFD risk factors after allo-HSCT (< 0.05) were: age < 18 years, non-malignant diseases, active disease at the moment of HSCT, neutropenia grade IV more than 20 days, acute “graft-versus-host” disease. First-line therapy were: IA – voriconazole (58.3 %), IC – echinocandins (100 %), PP – co-trimoxazole (100 %). 12-weeks overall survival (OS) from day of IFD diagnosis after allo-HSCT was 93.3 %, IA – 91.7 %. All patients with IC and PCP alive. 100-days OS after allo-HSCT was 85 %, 2-year OS after allo-HSCT – 67.5 %. There was no difference in OS in patients with or without IFD before allo-HSCT. Conclusion . Incidence of IFD in adolescents and young adults before allo-HSCT was 18.8 %. Only one patient relapsed with IA after allo-HSCT. Incidence of IFD after allo-HSCT (1 year) was 15 %. The main IFD was invasive aspergillosis. 12-weeks overall survival from IFD diagnosis after allo-HSCT was 93.3 %. IFD before and after allo-HSCT did not impair the outcome of the transplantation in adolescents and young adults.

Primary or Secondary Antifungal Prophylaxis in Resource-limited Settings

Patients with malignancy are vulnerable and inclined to invasive fungal infections (IFIs). The incidence of invasive fungal infection increases with the severity and duration of neutropenia. IFI is rarely seen in patients undergoing chemotherapy with a low myelotoxic risk, as in the treatment of solid tumors. Invasive aspergillosis (IA) is mortal and common in patients with hematological malignancies or hematopoietic stem cell transplantation due to severe neutropenia or immunosuppression [1]. IA is a mortal and relapsing infection in those patients group. Primary prophylaxis is implemented to prevent IA before occurring IA. Seconder prophylaxis is implemented to prevent relapsing of previous IA [2]. Fluconazole, itraconazole, amphotericin B, posaconazole, voriconazole, micafungin were reported to be used for prophylaxis in patients with hematological malignancies [3,4].

Antifungal Prophylaxis with Posaconazole in Allogeneic Hematopoietic Stem Cell Transplantation Using Sirolimus for Prevention of Graft-Versus-Host Disease

Invasive fungal infections (IFI) have emerged as a leading cause of morbidity and infection-related mortality among allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients over the past two decades. Several new drugs have recently been introduced as antifungal prophylaxis, supported by results of prospective randomized trials. In agreement with the international guidelines, a mold-active antifungal prophylaxis is strongly recommended in high-risk patients receiving allo-HSCT, considering efficacy, different pharmacokinetic, drug-drug interactions, and toxicity profile of the various antifungal drugs.Posaconazole, a triazole with broad-spectrum antifungal activity and a favorable toxicity profile, is the drug of choice for patients with graft versus host disease (GVHD). Consequently, posaconazole prophylaxis in allo-HSCT recipients is administered in combination with immunosuppressive drugs for GVHD prophylaxis and/or treatment, most commonly cyclosporine (CsA) or tacrolimus.Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), largely used for GVHD prevention and treatment, but extensively metabolized by CYP3A4. As posaconazole strongly inhibits CYP3A4 its coadministration with sirolimus is contraindicated by the manufacturer of posaconazole, and up to now poorly described in literature.In the San Raffaele Haematology and Bone Marrow Transplantation Unit, from 2010 to 2015, we retrospectively identified sixty-six patients that received posaconazole oral suspension as primary (n=43) or secondary (n=23) antifungal prophylaxis after allo-HSCT.The majority of patients were affected by acute leukaemia (67%), not in remission at time of allo-HSCT (55%), and with a previous allo-HSCT reported for 50% of them, carrying an high risk for developing a post-transplant IFI. Median follow up was 357 days (range 43-1884) after HSCT. Posaconazole administration was given for a median of 221 days (range 13-966).Thirty-two patients (49%) received posaconazole during engraftment phase, while 28 (42%) and 19 (29%) patients for IFI prophylaxis in the setting of acute or chronic GvHD respectively.A concomitant administration of sirolimus was performed in 49 patients (74%). Sirolimus concentrations were monitored two times a week, while posaconazole was controlled in patients' serum on a weekly basis, during the first two months of treatment.We observed a 55-70% steady-state dose reduction of sirolimus in 19 patients, after posaconazole introduction. Alternatively, patients with ongoing posaconazole prophylaxis received an initial empiric sirolimus dose reduction at 1 mg/day.The co-administration of posaconazole and sirolimus resulted safe. Discontinuation was reported mainly in patients with documented IFI, who required a change of the antifungal drug. No adverse events potentially associated with sirolimus overexposure (i.e. sinusoidal obstructive syndrome, sirolimus-related thrombotic microangiopathy) were reported, although one-third of the patients experienced a transient and moderate elevation of sirolimus serum levels in the first week of coadministration.In this analysis post-transplant IFI occurred in 14 cases. The risk of developing IFI was influenced by type of prophylaxis, resulting in 12% and 39% of IFI during primary and secondary prophylaxis respectively (p value 0.013; OR 4.89, CI 1.39-17.11). However the most significant and strong association was reported in concomitant with insufficient posaconazole serum levels (<0.5 ml/L), a known reported limitation of the oral solution formulation especially in patients with intestinal GVHD and/or diarrhea (p value <0,0001; OR 35.14, CI 6.43-192).In patients with adequate posaconazole serum levels (>0.5 ml/L) the incidence of IFI was 5%, supporting the utility of therapeutic drug monitoring (TDM) in such conditions and generating interest for the use of the upcoming posaconazole tablets with improved bioavailability in allo-HSCT recipients.In our experience concurrent sirolimus and posaconazole use was well tolerated, with a 55% to 70% sirolimus dose reduction at posaconazole initiation and close monitoring of serum sirolimus and posaconazole trough levels in the first months of co-administration. DisclosuresNo relevant conflicts of interest to declare.

Secondary antifungal prophylaxis in hematological malignancy patients with previous invasive fungal disease

Invasive fungal disease (IFD) causes a high morbidity and mortality in patients with hematological malignancies. Reactivation of IFD after chemotherapy or hematopoietic stem cell transplantation (HSCT) is very common and associated with poor prognosis. Secondary antifungal prophylaxis (SAP) is effective in preventing IFD recurrence. With effective SAP, a history of IFD is not an absolute contraindication to allogeneic HSCT or continuation of high-dose chemotherapy. In recent years, a variety of antifungal drugs such as voriconazole, itraconazole, AmB and caspofungin have been found to be effective for SAP. However, its management during granulocytopenia and immunosuppression remains challenging. This review summarizes the current status of SAP in patients with hematological malignancies.