The efficacy and safety of fluconazole in preventing invasive fungal infection in very low birth weight infants: a systematic review and meta-analysis.

This meta-analysis aimed to assess the efficacy and safety of fluconazole for the prevention of invasive fungal infections (IFI) in very low birth weight infants (VLBWI) and to provide a basis for the clinical use. A detailed search of Pubmed, Embase, Cochrane Library and other databases was performed to carefully screen eligible randomized controlled clinical studies to assess the safety and efficacy of fluconazole in very low birth weight infants in terms of the incidence of invasive fungal infections, fungal colonization rate, and mortality. Our research indicated that the application of fluconazole did not result in intolerable adverse reactions in patients. Fluconazole is effective in preventing invasive fungal infections in very low birth weight infants without serious adverse effects. The dose and frequency of fluconazole in very low birth weight infants still needs to be evaluated in consequent studies.

Animal models of invasive mycoses.

Animal models of invasive fungal infections have been developed and are applied in a huge number of different animal species for a number of research purposes, for example, the study of pathogenesis, defense mechanisms, and therapeutic strategies. From the different models, which in most cases are based on the same fungal species and often the same strain, as in spontaneous human infections, fundamental results and knowledge of the diagnosis, progression, prophylaxis, and therapy have been achieved. However, in all models, one should be critical with respect to mimicking the disease entity of humans, which is often the focus of the research. In many of the models for instance, the time course is different to the one of humans, and in others, the propensity for localization and containment in specific organs does not parallel the situation in humans. Nevertheless, many animal models of invasive mycoses have proven valuable in a number of research areas. With regard to new generations of anti-mycotic drugs, the models play an essential role in demonstrating antifungal activity, as well as in demonstrating the absence of toxic side effects, a critical step which cannot be accomplished by in vitro studies.

[Clinical analysis of amphotericin B cholesteryl sulfate complex for injection in the treatment of invasive fungal disease for patients with hematological malignancies in 30 cases].

Objective: To assess the safety and effectiveness of amphotericin B cholesteryl sulfate complex for injection in the context of empirical and diagnostic antifungal therapy for patients with hematological malignancies in addition to invasive fungal illness. Methods: This single-arm clinical study enrolled 30 patients who received empirical and diagnostic-driven antifungal therapy for hematological malignancies combined with invasive fungal disease. The primary endpoint was safety. Response rate, fever duration, and treatment completion rate were all considered secondary objectives. Results: 30 participants were eventually enrolled in the study, and the treatment completion rate was 80.0% . Most adverse events were in grades 1-2. Infusion response was the most frequent adverse event (24/30, 80% ) . The overall response rate was 80.0% (24/30) . In 24 patients (80.0% ) , the fever persisted for 1 day. Conclusions: Treatment of invasive fungal illness in conjunction with hematological malignancies showed good efficacy and safety with amphotericin B cholesteryl sulfate complex for injection.

Infections in patients with lymphoproliferative diseases treated with targeted agents: SEIFEM multicentric retrospective study.

We describe the opportunistic infections occurring in 362 patients with lymphoproliferative disorders treated with ibrutinib and idelalisib in clinical practice. Overall, 108 of 362 patients (29·8%) developed infections, for a total of 152 events. Clinically defined infections (CDI) were 49·3% (75/152) and microbiologically defined infections (MDI) were 50·7% (77/152). Among 250 patients treated with ibrutinib, 28·8% (72/250) experienced one or more infections, for a total of 104 episodes. MDI were 49% (51/104). Bacterial infections were 66·7% (34/51), viral 19·6% (10/51) and invasive fungal diseases (IFD) 13·7% (7/51). Among the 112 patients treated with idelalisib, 32·1% (36/112) experienced one or more infections, for a total of 48 episodes. MDI were 54·2% (26/48). Bacterial infections were 34·6% (9/26), viral 61·5% (16/26) and IFD 3·8% (1/26). With ibrutinib, the rate of bacterial infections was significantly higher compared to idelalisib (66·7% vs. 34·6%; P = 0·007), while viral infections were most frequent in idelalisib (61·5% vs. 19·6%; P < 0·001). Although a higher rate of IFD was observed in patients treated with ibrutinib, the difference was not statistically significant (13·7% vs. 3·8% respectively; P = 0·18). Bacteria are the most frequent infections with ibrutinib, while viruses are most frequently involved with idelalisib.

Invasive fungal infections in patients treated with Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) inhibitors are increasingly used in untreated and previously treated chronic lymphocytic leukaemia (CLL) patients. Invasive fungal infections (IFI) were rarely observed in patients treated for CLL in the pre-BTK era. In this article, we describe two patients with CLL who developed an IFI during treatment with the BTK inhibitor ibrutinib. The atypical presentation and the serious course of this complication are described.

Evaluation of Risk Factors for Mortality in Febrile Neutropenia.

INTRODUCTION: We aimed to evaluate the epidemiology of infections and factors associated with mortality in patients with febrile neutropenia (FEN). METHODOLOGY: The adult patients, who developed FEN after chemotherapy due to a hematologic malignancy or a solid tumor in a training and research hospital were evaluated, retrospectively. The demographic data of the patients, underlying malignancy, administered antimicrobial therapy, microbiological findings, and other risk factors associated with mortality were evaluated. RESULTS: A total of 135 FEN episodes of 115 patients, who comprised of 72 (63%) patients with 89 FEN episodes due to hematologic malignancies (hemato-group) and 43 (37%) patients with 46 FEN episodes due to solid organ cancers (onco-group), were evaluated in the study. The median age was 47 years (range: 17-75 years) and 66 (57%) patients were male. A total of 12 patients (8.8%) died during 135 episodes of FEN including nine cases from hemato-group and three cases from onco-group. Those factors including a presence of pneumonia, advanced age, persistent fever despite an antimicrobial treatment, and need for mechanical ventilation in intensive care unit (ICU) with were determined as risk factors associated with mortality. CONCLUSIONS: Morbidity and mortality are more common in patients with hematological malignancies compared to patients with solid organ cancers due to prolonged neutropenia. In case of persistent fever, an invasive fungal infection (IFI) should be kept in mind in patients with hematologic malignancies and then antifungal treatment should be initiated. Although a persistent fever is also common in patients with solid tumors, the necessity of antifungal therapy is rare due to the short duration of neutropenia.

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.

Risk Factors Associated With Invasive Fungal Infections in Kidney Transplant Patients.

BACKGROUND: Kidney transplant recipients are at increased risk for developing invasive fungal infections (IFI). We queried the United States Renal Data System (USRDS) for risk factors for IFI in these patients. METHODS: Patients who underwent a kidney transplant between 2005 and 2008 were queried for an IFI diagnosis using ICD-9 codes. An IFI was defined as at least one documented diagnosis from one of the following: (1) Candida (candidemia); (2) Histoplasmosis; (3) Aspergillosis; (4) Cryptococcosis; (5) "Other" mycoses. Potential risk factors included demographics, certain comorbidities and immunosuppressive medications. To examine the relative risk (RR), simple bivariate models were used, followed by a comprehensive full model to estimate the adjusted RR (aRR). RESULTS: Of 57,188 kidney transplant patients, 1,218 had 1,343 IFI diagnoses, with a median time to infection of 495 days. "Other" mycoses accounted for the most IFI diagnoses (37%), followed by aspergillosis (22%). The risk for any IFI was increased with age ≥65 years. Diabetes (aRR = 1.71), bacterial pneumonia (aRR = 1.62) and UTI (aRR = 1.34) were the top 3 clinical risk factors for infection. Each of the IFI groups was also associated with individual risk factors. Therapy with mycophenolate mofetil was associated with a decreased risk of candidemia. CONCLUSIONS: Risk factors for IFI in renal transplant patients include demographic, medication-associated and clinical data, as well as organism-specific factors. These results offer an extensive clinical profile of risk for IFI, and may thus help inform the diagnosis and presumptive therapy of invasive fungal infections in renal transplant recipients.

Immunomodulatory effect of ibrutinib: Reducing the barrier against fungal infections.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is increasingly used in the treatment of chronic lymphocytic leukemia (CLL). Moreover, very promising results have been reported in other B-cell malignancies, including primary central nervous system lymphoma (PCNSL). Although well-tolerated in the majority of patients, ibrutinib demonstrates in some cases troublesome toxicities, including invasive fungal infections (IFIs). In the present review, we summarize clinical manifestations of IFIs in patients treated with ibrutinib, generally characterized by an early onset, mild clinical manifestations, asymptomatic/low symptomatic pulmonary localization and high incidence of central nervous system (CNS) involvement. IFI risk appears particularly increased in patients receiving ibrutinib associated with other immune modulator agents, especially with steroids or immune-chemotherapy. Moreover, the immunomodulatory effect of ibrutinib is described, pointing the attention on the involvement of specific molecules targeted by ibrutinib in innate and adaptive response to fungal infection. Overall, the findings indicate the ibrutinib may rapidly impair innate immune cell functions, while concomitantly restoring an effective protective potential of adaptive immune compartment. A correct awareness, especially when other predisposing factors are present, is warranted about the potential risk of IFIs in ibrutinib-treated patients.

A case report of disseminated histoplasmosis and concurrent cryptococcal meningitis in a patient treated with ruxolitinib.

BACKGROUND: Ruxolitinib is a highly potent janus kinase inhibitor that places its users at risk for various bacterial infections and viral reactivation. However new reports are also emerging that suggest greater immunosuppression and risk for fungal disease. CASE PRESENTATION: We report the case of a 51 year-old veteran from Guam, treated with ruxolitinib for polycythemia vera, who developed disseminated histoplasmosis and concurrent cryptococcal meningitis. CONCLUSION: This case draws attention to the degree of immunosuppression that may be seen with this drug and the need for heightened vigilance for opportunistic infections in those treated with inhibitors of janus kinase/signal transducers and activators of transcription (JAK/STAT) such as ruxolitinib.

Histoplasmosis Following Systemic Immunomodulatory Therapy for Ocular Inflammation.

PURPOSE: Histoplasmosis is a known complication of systemic immunosuppressive therapy, particularly among patients who are receiving tumor necrosis factor α inhibitors. There are limited data on the development of disseminated or pulmonary histoplasmosis among patients who are receiving systemic immunosuppressive medication for noninfectious ocular inflammation. DESIGN: Retrospective case series. METHODS: We reviewed all patients with uveitis or scleritis who subsequently developed pulmonary or disseminated histoplasmosis at the Mayo Clinic in Rochester, Minnesota between September 1, 1994 and July 1, 2017, with a 3:1 age- and sex-matched control cohort who did not develop histoplasmosis. This was a single institutional study examining patients that developed histoplasmosis after the initiation of systemic immunomodulatory therapy (IMT). Patients had to develop either disseminated or pulmonary histoplasmosis while receiving systemic immunosuppressive therapy and have an ophthalmic examination at Mayo Clinic Rochester. The control group was comprised of patients who received systemic IMT for ocular inflammation but did not develop histoplasmosis. RESULTS: Nine cases of histoplasmosis were identified: 2 disseminated and 7 pulmonary. Both patients with disseminated histoplasmosis were taking tumor necrosis factor α inhibitors. Seven of the 9 patients received systemic antifungal medication, including both disseminated cases. Over a median follow-up of 4.4 years, none of the patients died, and there were no recurrences of histoplasmosis. When compared to the control cohort, there was no correlation between length of time on IMT and the risk of histoplasmosis. CONCLUSIONS: Ocular inflammation patients on systemic immunomodulatory therapy may develop pulmonary or disseminated histoplasmosis. Most cases require treatment with systemic antifungal medication, but it might not be necessary to stop systemic immunomodulatory medication for ocular inflammation. Ophthalmologists should be aware that patients receiving systemic immunomodulatory therapy have a higher risk of developing Histoplasma infections. Prompt diagnosis and treatment using the expertise of an infectious diseases specialist may ensure low mortality for these patients.

Epidemiology and risk factors for invasive fungal infections during induction chemotherapy for newly diagnosed acute myeloid leukemia: A retrospective cohort study.

This study investigated the epidemiology and risk factors associated with invasive fungal infections (IFIs) during induction chemotherapy in a cohort of Taiwanese patients with newly-diagnosed acute myeloid leukemia (AML). IFIs are a significant complication in the management of immunocompromised cancer patients; such infections are associated with a high incidence of morbidity and mortality, particularly in many South-Asian countries, where IFI rates are increasing. We retrospectively analyzed IFI incidence data from 105 patients with newly diagnosed AML at a single center undergoing their first course of induction chemotherapy without primary antifungal prophylaxis between November 2008 and December 2014. Of 21 cases documented as proven/provable IFIs 16 (76%) were invasive aspergillosis, 2 (10%) were mucormycosis infections, and 3 (14%) were proven yeast infections. The lung was the most commonly affected site (n = 16; 76%); 2 patients (10%) developed fungal sinusitis. IFI cases were more often males (P = 0.020). In multivariate analysis, patients with neutropenia lasting>30 days were more than twice as likely to develop IFI (OR, 2.24 [95% CI, 2.81-31.11], P<0.001). We also confirmed patients with smoker and receiving parenteral nutrition during chemotherapy were significant associated with IFIs. Our findings suggest that antifungal prophylaxis should be considered for patients with AML during induction chemotherapy, particularly in patients from Southeastern Asia, an area of potentially high IFI rates. We recommend that clinicians determine which patients receiving induction chemotherapy for AML are at high risk of developing IFI, to allow for targeted therapeutic prophylaxis.