Breakthrough Fungal Infection Research Articles

2709. Breakthrough fungal infection after isavuconazole primary prophylaxis in patients with hematologic malignancy and hematopoietic stem cell transplant: Systematic Review

Abstract Background Isavuconazole (ISA) is a relatively newer triazole with a broad spectrum of anti-fungal activity and has been used for both treatment and prophylaxis of invasive fungal infections (IFIs) in patients with hematologic malignancy (HM) and hematopoietic stem cell transplant (HSCT) with a more favorable side-effect profile as compared to other agents. Widespread prophylactic use of mold-active agents has resulted in a decline in the incidence of IFIs, but breakthrough (bIFIs) has been reported previously. Thus, we performed a systematic review of HM and HSCT patients receiving ISA as primary prophylaxis to determine incidence and clinical characteristics of bIFI in this vulnerable population. Methods We conducted a comprehensive literature search with search term of ISA, prophylaxis and either HM and/or HSCT in several search engines (Embase, Scopus Web of Science, MEDLINE and CENTRAL). The database search strategy was developed by an academic health science librarian. We excluded patients who had ISA as treatment or secondary prophylaxis. Results With initial search, 630 unique articles were identified and after reviewing abstracts, we finally conducted a full-text review of 70 articles, of which 27 studies were included (Figure), of which 17 studies included more than or equal to 10 patients on ISA prophylaxis. Overall, ISA was well tolerated during primary prophylaxis. Of note, of the 17 studies, 717 patients received ISA as primary prophylaxis, out of which 58 patients (8.1%) developed bIFI with range of 0%-20% and occurred 13-138 days after initiation (Table). ISA levels were checked in 6 studies with a plasma level between 1.5-6.3 μg/mL. Out of 58 bIFI cases, 33 cases were identified including 6 Mucorales spp., 3 Fusarium spp., 8 Candida spp and 14 Aspergillus spp. Most commonly used regimen for treatment of bIFI was combination of Liposomal amphotericin B with Posaconazole. Overall mortality after bIFI was 0%-66.7%. Conclusion Our systematic review shows a high incidence of bIFI in patients with underlying HM or HSCT receiving ISA prophylaxis. Caution should be used in patients receiving long term prophylaxis with ISA. Further studies are needed to assess for risk factors that predispose to bIFI in patients receiving ISA prophylaxis. Disclosures John M. Reynolds, MLIS, Pfizer Inc: Stocks/Bonds

COVID-19-Associated Pulmonary Fungal Infection among Pediatric Cancer Patients, a Single Center Experience.

Patients with COVID-19 are at risk of developing secondary complications such as invasive pulmonary aspergillosis and mucormycosis. This is a retrospective study including all cancer children diagnosed with COVID-19-associated pulmonary fungal infection (CAPFI) during the period 2020–2021. A total of 200 patients were diagnosed with COVID-19, out of which 21 (10%) patients were diagnosed with CAPFI, 19 patients (90%) with COVID-aspergillosis (CAPA), and 2 (10%) patients with COVID-mucormycosis (CAM). Patients with CAPFI were classified using the “2020 ECMM/ISHAM consensus criteria”; proven in 2 (10%) patients, probable in 12 (57%), and possible in 7 (33%) patients. Although the hematological malignancy patients were already on antifungal prophylaxis, breakthrough fungal infection was reported in 16/21 (75%), 14 (65%) patients had CAPA while on echinocandin prophylaxis, while 2 (10%) patients had CAM while on voriconazole prophylaxis. Overall mortality was reported in 8 patients (38%) while CAPFI-attributable mortality was reported in 4 patients (20%). In conclusion, clinicians caring for pediatric cancer patients with COVID-19 should consider invasive pulmonary fungal infection, even if they are on antifungal prophylaxis, especially with worsening of the clinical chest condition. A better understanding of risk factors for adverse outcomes may improve clinical management in these patients.

Antifungal Prophylaxis With Posaconazole in Immunocompromised Children Younger Than 13 Years.

Prophylaxis with posaconazole (PP) is effective in the prevention of invasive fungal infections in immunocompromised adult patients. However, evaluation of its effectiveness and safety in children is limited. The aim of the study was to describe the use of posaconazole as antifungal prophylaxis in children. We reviewed the medical records of immunocompromised patients younger than 13 years with hematologic diseases and post hematopoietic stem cell transplant (HSCT) who received antifungal PP at the Instituto Nacional de Salud del Niño San Borja (INSN-SB) in Lima, Peru, from January 2014 to December 2018. Fifty-six courses of PP were identified in 47 patients with a median age of 7.5 years (IQR, 4-10), 51.6% (n = 24) of whom were female. The main underlying medical conditions were aplastic anemia (n = 19, 33.9%), acute lymphoblastic leukemia (n = 18, 32.1%), acute myeloid leukemia (n = 14, 25.0%), and 34.1% had undergone HSCT. The median dose of posaconazole was 13.62 mg/kg/day (IQR, 12.0-16.8), and the median duration of PP was 24 days (IQR, 16-82). Gastrointestinal symptoms included abdominal pain (17.9%), nausea (16.1%), diarrhea (7.1%), and vomiting (3.6%). Elevated alanine aminotransferase and aspartate aminotransferase levels were observed in 9/35 patients (25.7%) and 10/51 (19.6%) patients, respectively. Five cases of breakthrough fungal infection were identified (8.9%). Patients younger than 13 years who received PP showed an increase in transaminase values, and the development of breakthrough fungal infections.

1301. Breakthrough Invasive Fungal Infections based on CYP2C19 Levels in Patients Who were on Voriconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) undergoing Induction Chemotherapy

BackgroundVoriconazole (Vori) is often used for prophylactic anti-fungal therapy in induction chemotherapy for Acute Myeloid Leukemia (AML) patients due to predictable absorption and an extended spectrum antifungal activity. Vori is metabolized predominately by CYP2C19 to metabolites with less antifungal activity. There has been a great interest in understanding CYP2C19 as it significantly affects drug metabolism and pharmacokinetics of numerous drugs including voriconazole.Approximately 39% of patients are genetically predicted to be CYP2C19 ultra-rapid or rapid metabolizers and thus are at an increased risk of breakthrough fungal infection. This study assesses the incidence of breakthrough invasive fungal infections (bIFI) at Moffitt Cancer Center based on CYP2C19 activity. bIFI is defined as new fungal infection while on vori, leading to treatment with liposomal amphotericin B, echinocandin, and/or different triazole.MethodsThis is a single-center retrospective analysis of patients who underwent induction chemotherapy for newly diagnosed AML and received voriconazole as the primary antifungal prophylaxis between July 2017 and June 2019. The patients enrolled were over 18 years old and did not have a history of stem cell transplant or solid organ transplant, Human Immunodeficiency Virus, relapsed AML or received systematic antifungal therapy 30 days prior. CYP2C19 were checked for each of the patients between July 2017 to June 2019 who were undergoing induction chemotherapy for newly diagnosed AML. It was checked within one week of admission. The patients were categorized as rapid metabolizers, intermediate metabolizers, normal metabolizers, and unknown CYP2C19.ResultsThere was an incidence of 20.2% (18/89) bIFI in patients who were on Vori in this study. Of these patients with bIFI infections, 15.7% (3/19) of patients were rapid metabolizers, 14.7% (5/34) were normal metabolizers, 28.5% (4/14) were intermediate metabolizers and 0% (0/3) were poor metabolizers. There were 31% (6/19) breakthrough infections in patients with unknown CYP2C19 characteristics.ConclusionThere is no significant statistical difference (p=0.6) among CYP2C19 categories with respect to breakthrough of invasive fungal infections at Moffitt Cancer Center between July 2017 - June 2019.Disclosures Rod Quilitz, Pharm D., Astellas (Advisor or Review Panel member)

A real-world prospective observational study on the efficacy and safety of liposomal amphotericin B in 426 patients with persistent neutropenia and fever

IntroductionInvasive fungal diseases are crucial causes of morbidity and mortality among patients with febrile neutropenia (FN). Though liposomal amphotericin B (L-AMB) is one of the agents recommended for first-line empirical antifungal therapy in patients with FN, large-scale clinical studies have not been performed in Japan. MethodsAn open-label prospective multi-center study was carried out to evaluate the safety and efficacy of L-AMB in Japanese patients with FN suspected of having fungal infection. ResultsOf the 426 patients registered, safety and efficacy evaluations were conducted for 424 and 399, respectively. By clinical response criteria using 5 composite endpoints, the response rate was 46.6% (186/399). The response rate by age were 54.5% (child: 30/55), 47.5% (adult: 97/204), 42.1% (elderly: 59/140) respectively. Regarding the composite endpoints, resolution of fever was observed in 61.2% (244/399), no breakthrough fungal infection in 99.0% (395/399), survival for 7 days or longer after the completion of treatment in 83.7% (334/399), no discontinuation of treatment due to toxicity or lack of efficacy in 60.9% (243/399), and successful treatment of any baseline fungal infection in 10/18. Adverse drug reactions (ADRs) developed in 61.1% (259/424), and frequent ADRs were hypokalemia, kidney dysfunction, and liver dysfunction, as previously reported. ConclusionsThe safety and efficacy profile of L-AMB in Japanese patients with FN suspected of having fungal infection were elucidated for the first time, through the analysis of a large number of cases including pediatric patients under real-world clinical settings collected in this nationwide study.

2122. Isavuconazonium for Invasive Fungal Therapy: Single-Center Pediatric Experience

BackgroundIsavuconazole (ISZ), dosed as the pre-drug isavuconazonium (ISM), is active against a wide variety of clinically important fungal pathogens. ISM is approved for the treatment of invasive aspergillosis and mucormycosis in adults ≥18 years of age. We present our experience with ISM to treat proven or to prevent fungal infection in pediatric patients.MethodsIn a retrospective review of patients who received ISM at our institution between April 2016 and April 2019, we abstracted demographic information, primary diagnosis, indication for ISM therapy, ISZ serum concentrations if available, and outcomes.ResultsOf 16 patients who received ISM, 12 were < 18 years of age (range 6–17 years). Underlying conditions included leukemia (n = 8), lymphoma (n = 1), post BMT (n = 1), diabetes (n = 1), and cardiac transplant (n = 1). Nine (75%) had proven invasive fungal infection with aspergillosis (n = 2), zygomycosis (n = 3), mixed aspergillosis and zygomycosis (n = 2), mixed Rhizopus and Scedosporium (n = 1), and pathology only (n = 1). Five of these 9 patients received combination ISM and liposomal amphotericin initially, followed by monotherapy with ISM in 4 patients after a mean of 26 days (range 6–63), and continued dual therapy in the fifth. The other 4 received liposomal amphotericin with or without other azoles prior to changing to ISM monotherapy. ISM dosing was 10 mg/kg q8h on days 1 and 2, followed by q24 thereafter, up to a maximum of 372 mg/dose. There were 19 measured ISZ serum concentrations obtained from 8 patients after >1 week of verified inpatient dosing, ranging from 1.0 to 7.5 mg/L, above the MIC in all cases when known. Five (42%) patients died of underlying non-mycological causes, 1 (8%) died of progressive scedosporiosis, and 6 (50%) improved. The two patients receiving ISM prophylaxis did not suffer a breakthrough fungal infection. ISM was well tolerated with no dose-limiting, drug-related toxicities noted.ConclusionISM is a well-tolerated therapeutic option in pediatric patients at risk for or with invasive mycosis. Only 1 of our 12 patients died from progressive fungal disease.Disclosures All authors: No reported disclosures.

Why do lung transplant patients discontinue triazole prophylaxis?

Lung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination. We conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined. During the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P=0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P<0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P<0.05). Itraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.

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.

Clinical study on posaconazole for the prophylaxis or salvage treatment of invasive fungal disease in patients with hematological diseases

Objective To investigate the efficacy and safety of posaconazole in the prophylaxis or salvage treatment of invasive fungal disease (IFD) in patients with hematological diseases. Methods 25 patients with hematological diseases receiving posaconazole treatment from Feb 2014 to Feb 2015 were analyzed retrospectively. The patients'average age was 32.6 years old (16-64 years old). 18 patients received posaconazole for IFD prophylaxis, and 7 patients for IFD salvage treatment. Results 18 patients receiving posaconazole for IFD prophylaxis had no clinical manifestation of IFD (that is no case of breakthrough fungal infection) during treatment or in the 12 weeks after treatment, and the average prophylaxis period was 21 d (14-35 d). Among 7 patients receiving posaconazole for IFD salvage treatment, 6 patients were effective, including 4 cases cured and 2 cases effective. There were no obviously side effects of posaconazole in these patients. Conclusion Posaconazole has good clinical response for IFD in the hematologic diseases patients whether in prophylaxis or in salvage treatment. Key words: Mycoses; Posaconazole; Treatment outcome

Safety and Efficacy of Intermittent Intravenous Administration of High-Dose Micafungin

Background. The use of mold-active azoles for antifungal prophylaxis after allogeneic stem cell transplantation (SCT) is hindered by adverse events and drug–drug interactions. Higher doses of echinocandins administered intermittently may be an alternative in this setting. Methods. This was a single-center, observational 5-year study to characterize the safety and efficacy of intermittent administration of high-dose intravenous micafungin (≥5 doses of ≥300 mg micafungin 2–3 times weekly) in patients with acute leukemia and allogeneic SCT recipients. Results. A total of 104 patients (84 allogeneic SCT recipients and 20 patients with leukemia) received intermittent high-dose intravenous micafungin, 83 (79.8%) as prophylaxis. Large variability in the micafungin dosing regimen was observed; 78 (75%) patients received >75% of their course as 300 mg micafungin 3 times weekly. Liver function tests decreased from baseline to end of treatment (EOT; P < .001). Patients with normal baseline liver function (n = 55 [52%]) maintained similar enzyme levels throughout the study. For patients with abnormal baseline liver function (n = 49 [47%]), liver function tests significantly improved from baseline to EOT (P ≤ .005). Duration and/or micafungin dosing algorithms were not associated with liver toxicity at EOT. There were no significant changes in renal function, and infusion-related reactions or deaths were not observed. Five of 83 (6.0%) patients in the prophylaxis group developed a breakthrough fungal infection. Conclusions. In this largest cohort of patients to date, intermittent administration of high-dose micafungin was well tolerated, without any associated liver or renal function abnormalities, and may be considered an alternative antifungal prophylactic strategy. Prospective studies are needed to further validate these findings.

Posaconazole: An Update of Its Clinical Use.

Posaconazole (PCZ) is a relatively new addition to the azole antifungals. It has fungicidal activities against Aspergillus fumigatus, Blastomyces dermatitidis, selected Candida species, Crytopcoccus neoformans, and Trichosporon. PCZ also has fungistatic activities against Candida, Coccidioides, selected Fusarium spp., Histoplasma, Scedosporium and Zygomycetes. In addition, combining the drug with caspofungin or amphotericin B results in a synergistic interaction against A. fumigatus, C. glabrata and C. neoformans. The absorption of PCZ suspension is enhanced when given with food, nutritional supplements, and carbonated beverages. Oral administration of PCZ in divided doses also increases its bioavailability. PCZ has a large volume of distribution and is highly protein bound (>95%). The main elimination route of PCZ is fecal. PCZ is an inhibitor of the CYP3A4 enzyme; therefore, monitoring for drug-drug interactions is warranted with other CYP3A4 substrates/inhibitors/inducers. The most common adverse effects include headache, fatigue, nausea, vomiting and elevated hepatic enzymes. PCZ, with its unique antifungal activities, expands the azole class of antifungal agents. Because of its limit in formulation, PCZ oral suspension is recommended in immunocompromised patients with functional gastrointestinaltracts who fail conventional antifungal therapies or who are suspected to have a breakthrough fungal infection. However, a delayed-release tablet formulation and intravenous (IV) injection became available in 2014, expanding the use of PCZ in other patient populations, including individuals who are unable to take oral formulations.

Fatal Breakthrough Mucormycosis in an Acute Myelogenous Leukemia Patient while on Posaconazole Prophylaxis.

Posaconazole is a new oral triazole with broad-spectrum antifungal activity. Posaconazole has also shown a significant advantage of preventing invasive fungal infection compared to fluconazole or itraconazole in patients with prolonged neutropenia. Indeed, posaconazole has been commonly used for antifungal prophylaxis in patients undergoing remission induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. We experienced a case of fatal mucormycosis despite posaconazole prophylaxis. To our knowledge, this is the first reported case of fatal breakthrough mucormycosis in a patient receiving posaconazole prophylaxis during remission induction chemotherapy in Korea. This case demonstrated that breakthrough fungal infection can occurs in patients receiving posaconazole prophylaxis because of its limited activity against some mucorales.

A Randomized, Controlled, Prospective Study for Efficacy of Micafungin Versus Itraconazole As Empirical Antifungal Therapy for Febrile Neutropenic Patients with Acute Leukemia

Background: Micafungin, one of the powerful ecchinocandins, needs to be clarified its efficacy and safety of empirical therapy on febrile neutropenic patients compared with other anti-fungal drugs such as azole compounds.Methods: A randomized, multi-center, prospective study (age-, sex-, diagnosis-, risk-controlled) was conducted for a comparison of efficacy and safety between micafungin and intravenous itraconazole as an empirical therapy on febrile neutropenic patients with acute leukemia. Anti-fungal drugs (study drug, micafungin; control drug, itraconazole) were administrated for sustained high fever following appropriate empirical antibiotic therapy (°Ã 3 days of combination antibiotics). The overall success rate [if the patient meets all of the following criteria: (1) no breakthrough fungal infection; (2) survived for 7 days past the end of the therapy; (3) no premature discontinuation; (4) disappearance of fever during neutropenia; (5) successfully treated base-line fungal infection] and side effects were evaluated. And duration of fever and neutropenic fever were estimated and compared between two groups.Results: A total of 134 patients with acute leukemia were enrolled in the study (86 patients with AML, 41 patients with ALL, 7 patients with secondary leukemia). The overall success rate of micafungin and itraconazole was 63.6% and 53.2%, respectively (p = NS) (Figure 2). However, duration of fever and duration of neutropenic fever were significantly shorter in micafungin group (p = 0.0007, p = 0.0118, respectively) and survival benefit was marginal (OS, median months, 10.93 vs. 4.77, p = NS) (Figure 1). Grade III-IV adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase level (2 vs. 4), electrolytes imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred at 7 and 13 patients in micafungin (10.4%) and itraconazole (18.8%) group, respectively. All adverse events were manageable however, 4 patients died of progression of infection in each group.Conclusion: This randomized, controlled, prospective study documented that micafungin, when compared with itraconazole, showed significantly superior effect on shortening the duration of fever and neutropenic fever, resulting in marginal survival benefit on acute leukemia patients who are suffering from life-threatening neutropenic period under anti-leukemic therapy. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

O2-7-4 - Micafungin Compared with Voriconazole for Empirical Antifungal Therapy in Patients with Neutropenia and Persistent Fever

Objectives: Patients with haematological malignancy who experience persistent fever and neutropenia often receive empirical antifungal therapy for the prevention and early treatment of invasive fungal infections. Micafungin (MCFG), a member of the echinocandin class of compounds, may be an effective alternative that is better tolerated than voriconazole (VRCZ).Methods: We conducted a randomised, cooperative group, open-label trial, comparing the efficacy and safety of micafungin with those of voriconazole as empirical antifungal therapy in febrile neutropenic patients with haematological malignancy. A successful outcome was defined as the fulfilment of all components of a 5-part composite endpoint.Results: Efficacy was evaluated in 100 patients (MCFG: 50, VRCZ: 50). Overall, favourable responses were observed in 52.0% of MCFG and 34.0% of VRCZ recipients (p = 0.069). There were no significant differences between the 2 groups in the rates of successful treatment of baseline fungal infection, absence of breakthrough fungal infection, survival for ≥7 days after treatment completion, or resolution of fever in the setting of neutropenia. Premature study discontinuation occurred less often in the MCFG group than in the VRCZ group (p = 0.001). Fewer patients who received MCFG experienced drug-related adverse events (p = 0.002).Conclusions: MCFG is as effective as and is generally better tolerated than VRCZ when given as empirical antifungal therapy in patients with persistent fever and neutropenia.

Micafungin compared with caspofungin for the treatment of febrile episodes in neutropenic patients with hematological malignancies: A retrospective study.

Invasive fungal infections are associated with morbidity and mortality in neutropenia secondary to hematological malignancies. Empirical antifungal agents are used to reduce their consequences. Caspofungin is the only echinocandin approved for this indication. Micafungin was compared with caspofungin for the treatment of patients with hematological malignancies and prolonged neutropenia. A retrospective cohort study was conducted involving patients who had hematological malignancies with profound neutropenia for a minimum of 10 days, and received empirical micafungin or caspofungin for a minimum of five days, between April 2005 and November 2009. Successful outcome was based on a composite end point: survival for a minimum of seven days following antifungal cessation, successful treatment of baseline fungal infection, absence of adverse events and absence of breakthrough fungal infection. Fungal infections were defined according to revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC-MSG) criteria, with modification of the diagnostic imaging criteria. Micafungin had similar overall success to caspofungin (60.4% [29 of 48] versus 57.3% [47 of 82], respectively; P=0.729). Survival was higher in the micafungin group compared with the caspofungin group (100% [48 of 48] versus 89% [73 of 82]; P=0.02). No baseline invasive fungal infections were identified in the micafungin group, compared with three proven infections treated successfully with caspofungin (3.7%; P=0.18). Three proven breakthrough infections were observed in the micafungin group (three of 48 [27.3%]) compared with none in the caspofungin group (zero of 82; P=0.02). Micafungin has similar efficacy to caspofungin as empirical antifungal therapy in febrile neutropenic patients with hematological malignancies. Verification of these results in a prospective trial is warranted.

Breakthrough disseminated cryptococcosis during micafungin therapy

Echinocandins are not active against basidiomycetous yeasts, such as Cryptococcus neoformans, Trichosporon, and Rhodotorula species, and zygomycosis. We present a patient with renal failure and candidemia, who developed a breakthrough fungal infection with cryptococcemia and cryptococcuria while receiving micafungin therapy.

Posaconazole, a prophylactic therapy in patients with haematological cancer: drug use evaluation study

BackgroundPosaconazole (PSZ), is an antifungal prophylactic therapy that is used in haematological cancer patients. In 2010, PSZ was added to the formulary of the National Centre for Cancer Care &...

Utility of Voriconazole Monitoring and Factors Affecting Its Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation. Single Center Experience From India.

AbstractAbstract 3035 Background:Voriconazole (vori) is used for prophylaxis against fungal infections in BMT. Under and over-dosing of vori may influence the efficacy and safety of therapy, respectively. There is large variability in vori exposure following standard dose administration. Utility of Therapeutic Drug Monitoring (TDM) of vori in patients with invasive mycoses has been demonstrated and recommended that trough concentrations should be maintained between 1–5.5 μg/mL. Based on these observations we started TDM of vori in BMT patients at our centre to target trough plasma concentration of 1–6 μg/mL. Few reports are available on the TDM of vori in BMT. We report our experience. Methods:All patients (autologous-65, allogeneic-64) who received vori prophylaxis during peritransplant period between September 2008 and January 2012 were included. Vori prophylaxis was started atleast 3 days prior to start of conditioning regimen in all patients before April 2011. Since April 2011, patients undergoing autologous transplant received vori 1 day after completion of chemotherapy. All patients above 12 years received oral loading dose of 6 mg/kg (upto maximum of 400 mg) 12 hourly on first day followed by 4mg/kg as maintenance. Intravenous dosing was used if patients had severe mucositis or developed febrile neutropenia. Patients less than 12 years received 7mg/kg 12 hourly continuously. Vori levels were measured on 5th-7th day after start of loading dose. Subsequent levels were done 2– 4 weekly till discontinuation of drug. If first level was < 1 or > 6 μg/ml, each dose was increased or decreased by 50% respectively and levels repeated after a week. Vori was continued for at least 100 days for all patients undergoing allogeneic transplant and longer if patients were on steroids due to graft vs host disease. Autologous transplant patients received it for 28 days. Incidence of breakthrough fungal infection was recorded as definite (blood culture positivity or histological evidence), probable (CT scan evidence with positive fungal PCR or galactomannan positivity) or possible (CT evidence only). Demographic and laboratory factors affecting the levels evaluated were age, sex, height, weight, body surface area (BSA), liver and renal function parameters. Concomitant drugs being used were recorded for any effect on vori levels. Vori levels in plasma were determined by a validated HPLC assay. Paired samples were compared using t-test or Wilcoxin sign rank test. Influence of covariates on vori levels were analyzed by linear regression with backward elimination. Interaction between concomitant drugs and their effects on vori levels was determined by ANCOVA after adjusting for baseline values. Results:One hundred twenty-nine patients were monitored during this period. The median age was 24.6 years. The median number of TDM was 3 (1–32) per patient. High inter and intra-patient variability was observed (coefficient of variation = 73% and 45% respectively). Twenty-eight patients (21.7%) had trough levels < 1 μg/mL after the first monitoring. Twenty-one patients had their dose modified after first monitoring (16 due to very low levels and 5 due to high levels). Thirteen (80%) patients achieved target trough concentration after dose escalation. Dose reduction resulted in sub-optimal levels in 3 of 5 patients. Twenty – four patients who had adequate levels at first TDM had fall in level below 1 μg/mL subsequently during the 2nd or 3rd TDM. This coincided with the introduction of steroids for treatment. Introduction of steroids significantly reduced vori trough levels (presteroid mean- 2.67 μg/ml, post steroid mean- 1.47μg/ml; P=0.014).Similarly use of cyclosporine (CSA) also significantly decreased vori levels (pre CSA mean-2.65μg/ml, post CSA mean-1.91μg/ml; P=0.023). The effect of steroids and CSA on vori levels were independent of each other. None of the demographic or laboratory parameters influenced vori levels. Breakthrough fungal infections were seen in 5 patients (definite-1, probable-3, possible-1). Conclusions:Voriconazole level monitoring should be done in all patients who are on steroids and CSA post transplant. No demographic or laboratory parameter affected voriconazole levels in our study. Incidence of breakthrough fungal infection is low in patients who are monitored with drug levels. Disclosures:No relevant conflicts of interest to declare.

Multicenter Study of Posaconazole Therapeutic Drug Monitoring: Exposure-Response Relationship and Factors Affecting Concentration

Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H(2) antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.

Caspofungin as antifungal prophylaxis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis

BackgroundPediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB.MethodsWe retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day) and another 60 patients received CAS (50 mg/m2/day) as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively.ResultsNo proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT.ConclusionProphylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.