Fungal diagnostic testing and therapy: navigating the neutropenic period in children with high-risk leukemia

Children, adolescents, and young adults receiving intensive chemotherapy for acute myeloid leukemia or high-risk or relapsed acute lymphoblastic leukemia sustain prolonged periods of neutropenia that predispose them to invasive fungal disease (IFD). For many decades the standard of care for these patients was to initiate empirical antifungal therapy after a period of prolonged fever and neutropenia. Recent publications have yielded important evidence on the utility of different diagnostic and therapeutic approaches aimed at reducing the impact of IFD among these patients during these vulnerable periods. This case-based review highlights and interprets the published data to provide context for the IFD diagnostic and therapeutic recommendations proposed in multiple published guidelines. Personalized approaches are offered at points where evidence is lacking. Time points where specific knowledge gaps exist are identified along the clinical trajectory of the prolonged neutropenic period to illustrate areas for future investigation.

Assessment of Micafungin Dosage Regimens in Patients with Cancer Using Pharmacokinetic/Pharmacodynamic Modeling and Monte Carlo Simulation

Micafungin is widely used for invasive candidiasis, especially in critically ill patients and those with cancer, and for empirical antifungal therapy in patients with neutropenic fever. This is the first study to investigate the pharmacokinetics and disposition parameters of micafungin in patients with cancer. In this observational pharmacokinetic study, blood samples were collected and analyzed using high-performance liquid chromatography. Pharmacokinetic parameters were estimated using Monolix 4.4 software. The plasma micafungin concentrations were measured in a total of 133 samples from 19 patients. In the final two-compartment model with linear elimination, the estimated micafungin clearance (CL) was significantly higher in patients with cancer than in those without cancer (1.2 vs. 0.6 L/h, p = 0.012), whereas other parameters did not significantly differ between the two groups. Aspartate and alanine transaminases and body weight significantly influenced micafungin CL in patients, with and without cancer. Overall, the probability of target attainment increased with increasing doses and decreased with higher MICs in both groups. In simulations, the patients without cancer achieved higher pharmacokinetic/pharmacodynamic targets with a 90% probability for all simulated doses, compared to the patients with cancer. Micafungin demonstrated dose-proportional linear pharmacokinetics in both the patients with and those without cancer. The estimated micafungin CL was significantly higher in patients with cancer, suggesting a need for increased dosage, especially for Candida spp. with high MICs, in these patients. Further studies should assess the efficacy and optimum dosage of micafungin for the treatment and prevention of febrile neutropenia (FN) in patients with cancer.

Development of a Method of Measuring β-D-Glucan and Its Use in Preemptive Therapy for Invasive Fungal Infections

Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal infections. However, many studies have indicated that antifungals were not necessary for over half of patients, and several detriments of empirical therapy were noted, e.g., antifungals caused adverse reactions, an increase in drug-resistant fungi was a possibility, and medical costs soared. β-D-glucan (BDG) is a component of clinically important fungi such as Aspergillus and Candida. The G-test was developed in Japan as a way to measure BDG in serum using a coagulation factor from the blood of the horseshoe crab. Pre-emptive antifungal therapy based upon serodiagnosis with a BDG or galactomannan assay and CT imaging has been introduced. With pre-emptive antifungal therapy, the prognosis is equivalent to that with empirical therapy, and the dose of the antifungal has been successfully reduced. Measurement of BDG has been adopted widely as a method of diagnosing IFIs and is listed in the key guidelines for fungal infections and febrile neutropenia.

A Retrospective Study of Invasive Fungal Disease Treated by High Dosage Micafungin Therapy VS Standard Micafungin Therapy Among Patients with Hematologic Diseases.

Background: The standard (150mg/day) micafungin treatment regimen, is an effective and well tolerated empirical therapy for invasive fungal disease (IFD) among hematologic patients; however, experience with high dosage (200-300mg/day) micafungin treatment is limited. We retrospectively evaluated both safety and effectiveness of micafungin as an empirical antifungal therapy via standard and high dosage treatments for IFD.Methods: Patients were considered to be qualified for this analysis if they were proven, probable, or possible diagnosed as IFD. Patients without any previous exposure to an echinocandin were included; for those who changed treatment dosages and had previously received another systemic therapy except fluconazole for prevention were excluded. Safety and effectiveness were evaluated in all participated patients. IFD was diagnosed and classified according to standards defined by both 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 Consensus Group.Results: Totally 72 hematologic patients participated this study. 45 patients were received a standard (150mg/day)micafungin treatment, and 27 patients were received a high dosage (200-300mg/day)micafungin treatment. Neutropenia status were similar between two groups (37.78% and 33.33%), so were other underlying risk factors. The mean duration of therapy were 15.27 days (Range: 7-47 days) in standard micafungin group, and 14.96 days (Range: 7-51 days) in high dosagemicafungin group. Drug related adverse events (AEs) occurred in 11.11% of patients received the standard regimen, and 14.81% of patients received the high dosage regimen (difference, 3.70%; 95% confidence interval [CI], -5.75% to 10.89%; statistically insignificant). The most common drug related AEs in the standard and high dosage treatment groups were liver dysfunction. Only 1 patient discontinued standard micafungin treatment, because liver function test value is 5 times greater than the upper limit of normal value. 86.67% of patients from standard treatment group, and 88.89% of patients from high dosage treatment group had favorable overall responses (difference, 2.22%; 95% CI, -4.94% to 8.64%; statistically insignificant).Conclusion: Both micafungin dosing treatments were effective, and well tolerated among hematologic patients with invasive fungal infection. Therefore, there hasn’t arisen any safety concern of high dosage(200-300mg/day) micafungin treatment.

Case Report: Proven Diagnosis of Culture-Negative Chronic Disseminated Candidiasis in a Patient Suffering From Hematological Malignancy: Combined Application of mNGS and CFW Staining

Chronic disseminated candidiasis (CDC) is a severe complication with high morbidity and mortality in patients with hematological malignancies who have undergone chemotherapy. Blood or sterile liver biopsy cultures are negative due to recurrent empirical antifungal therapy. With the escalating resistance to azole-based antifungal drugs in infection by Candida species, pathogen identification is becoming increasingly important for determining definitive diagnosis and treatment strategy. In this case report, we present, for the first time, diagnostic confirmation of a culture-negative CDC case with Candida tropicalis infection using a combination of metagenomics next-generation sequencing and calcofluor white staining.

(1,3)-β-d-Glucan-based empirical antifungal interruption in suspected invasive candidiasis: a randomized trial

Background (1,3)-β-d-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis. Methods This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-d-glucan was negative ((1,3)-β-d-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-d-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment. Results We randomized 108 patients into the (1,3)-β-d-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1–3] in the (1,3)-β-d-glucan group vs. 10 days [6–13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94–8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-d-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-d-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23). Conclusions In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-d-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population. Trial registration ClinicalTrials.gov, NCT03117439, retrospectively registered on 18 April 2017