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Background: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P‐glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P‐glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. Methods: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. Results: Seventy‐eight serum triazole levels from 31 patients receiving ivosidenib‐containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. Conclusions: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high‐dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib. This study explores the cytochrome P450 induction effects of ivosidenib. Patients with acute myeloid leukemia or myelodysplastic syndrome receiving ivosidenib and concomitant triazole antifungals may require additional therapeutic drug monitoring of serum azole levels or empirically higher doses to overcome the CYP450 induction effects of ivosidenib. [ABSTRACT FROM AUTHOR]

Extensive efforts have focused on investigating the contributions of the intestinal microbiome to health and disease, including immunomodulation [[1]]. The mycobiome and chronic inflammatory bowel disorders In addition to the cancer and critically ill setting, the gut mycobiome has also been implicated in inflammatory GI disorders, to include Crohn disease and ulcerative colitis. However, the association of antifungal selection pressure to the constitution of the gut mycobiome and its direct or indirect consequences to the underlying GI pathology and microbiome are rather complex. Given the evidence for the immunomodulatory role of the gut mycobiota, it is important to consider the effects perturbation of the gut fungi may cause on human health and various disease states, including possibly sites distant from the gut, such as lungs [[47]] and central nervous system [[51]]. [Extracted from the article]

Prolonged courses of isavuconazole (ISA) are increasingly utilized in immunocompromised patients. Toxicities have been reported with long-term use of the other triazoles. We report the first real-life tolerability data in 50 patients with hematologic malignancy receiving ≥6 months of ISA. ISA was well tolerated in our ill patient population. [ABSTRACT FROM AUTHOR]

Summary: Fungal cholecystitis is an uncommon entity, and no cases of cholecystitis associated with mould infection have been reported. We present a case of acute Fusarium cholecystitis in a cytopenic patient with leukaemia who had disseminated fusariosis. We also review the published cases of fungal cholecystitis, which is most often caused by Candida species. Although it is rare, fungal cholecystitis should be part of the differential diagnosis of acute cholecystitis in high‐risk patients with predisposing factors for opportunistic fungal infections. [ABSTRACT FROM AUTHOR]

Voriconazole is a triazole antifungal with activity against a number of yeast and mold species including Candida, Aspergillosis, Fusarium, and Coccidioides. Invasive fungal infections are associated with high morbidity and mortality, prolonged treatment courses, and occasionally lifelong suppressive therapy. Voriconazole therapy can result in a number of acute toxicities that clinicians are frequently aware of including hepatotoxicity, visual disturbances, and hallucinations; however, there is limited experience with extended durations of voriconazole therapy. We describe the case of a 62-year-old man who developed Coccidioides meningitis as a result of prolonged neutropenia from treatment for chronic lymphocytic leukemia. He was initially treated with a number of different antifungal agents including voriconazole, liposomal amphotericin B, fluconazole, and itraconazole; however, he developed acute toxicity due to those agents. He was successfully re-challenged with voriconazole, and maintained therapeutic serum concentrations throughout treatment. As a result of prolonged voriconazole exposure of over 14 years, he has suffered a number of toxicities, most significantly including actinic keratosis, squamous cell carcinoma, and skeletal fluorosis. To our knowledge, this is the longest continuous use of voriconazole therapy currently in the literature. [ABSTRACT FROM AUTHOR]

Summary: Although the benefit for any type of antifungal prophylaxis in patients with acute myelogenous leukaemia is well accepted, less is known about the risk for invasive fungal infections (IFIs) and the optimal prophylaxis strategies in patients with acute lymphocytic leukaemia (ALL). Based on recent studies, ALL is a disease that appears to be associated with significant risk for IFIs. The pharmacokinetic interactions between azoles and vincristine, an antineoplastic agent that is part of modern combination chemotherapies in ALL, results in clinically significant neurotoxicity that makes the use of azoles problematic. However, a number of questions regarding azole‐vincristine interactions remain unanswered. In this viewpoint, we call for a renewed interest in antifungal prophylaxis studies in ALL in view of the availability of several non‐azole novel antifungal agents that are under preclinical and/or clinical development. This is clearly a major unmet need in modern clinical mycology. [ABSTRACT FROM AUTHOR]

Infectious complications following treatment of acute myeloid leukemia (AML) are important causes of morbidity and mortality. The spectrum and complexity of these infections is reflected by the severe net state of immunosuppression of AML patients, that is dynamic and continuously changing, the polypharmacy, including the widespread use of anti-infectives and the complex epidemiology of severe and frequently resistant pathogens afflicting these patients. Infectious diseases (ID) consultants having a critical mass of expertise and intimate knowledge of the intricacies of leukemia care, add considerable value in improving outcomes of patients with AML who develop infections. Furthermore, pharmaco-economic considerations such as length of stay, choice of cost-effective anti-infective program, infection control and antibiotic stewardship strategies create a delicate interplay of the ID consultant and the ecosystem of care of AML patients. This is an increasingly recognized area of cross collaboration and a productive direction for future collaborative practice models and research. [ABSTRACT FROM AUTHOR]

Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic delays, impaired drug penetration, resistance to antifungal treatments, and inadequate restoration of immune function. To improve outcomes, future research should advance diagnostic methods (eg, molecular detection and fungus identification), develop antifungal compounds with enhanced CNS-directed efficacy, and further investigate crucial host defence mechanisms. [ABSTRACT FROM AUTHOR]

As regenerative medicine matures as a field, more promising technologies are being translated from the benchtop to the clinic. However, many of these strategies are designed with otherwise healthy hosts in mind and validated in animal models without other co-morbidities. In reality, many of the patient populations benefiting from drug delivery and tissue engineering-based devices to enhance wound healing also have significant underlying immunodeficiency. Specifically, patients suffering from diabetes, malignancy, human immunodeficiency virus, post-organ transplantation, and other compromised states have significant pleotropic immune defects that affect wound healing. In this work, we review the role of different immune cells in the regenerative process, highlight the effect of several common immunocompromised states on wound healing, and discuss different drug delivery strategies for overcoming immunodeficiencies. [ABSTRACT FROM AUTHOR]

Background: Historically, baseline neutropenia and lack of neutrophil recovery have been associated with poor outcomes in invasive aspergillosis (IA). It is unclear how treatment with the new Aspergillus-active triazoles isavuconazole and voriconazole affects outcomes in neutropenic patients with IA.Methods: A post hoc analysis of the Phase 3 SECURE trial assessed patients with neutropenia (neutrophil count <0.5 × 109/L for >10 days at baseline) with IA (proven/probable) who had received either isavuconazole or voriconazole. The primary endpoint was all-cause mortality (ACM) through day 42. ACM in patients with resolved versus unresolved neutropenia at day 7 and overall success at end of treatment (EOT) were also assessed.Results: One hundred and forty-two patients with neutropenia and IA were included (isavuconazole n = 78, voriconazole n = 64). ACM through day 42 (primary endpoint), day 7 and EOT were higher for patients with unresolved versus resolved neutropenia at each timepoint (day 42, unresolved: 45.0% isavuconazole, 45.2% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; day 7, unresolved: 31.0% isavuconazole, 29.8% voriconazole; resolved: 5.0% isavuconazole, 5.9% voriconazole; EOT, unresolved: 48.6% isavuconazole, 36.4% voriconazole; resolved: 5.0% isavuconazole, 14.3% voriconazole). ACM was significantly higher for isavuconazole-treated patients with unresolved versus resolved neutropenia (day 7, P = 0.031; day 42, P < 0.001; EOT, P < 0.001). In voriconazole-treated patients, ACM was significantly higher among patients with unresolved versus resolved neutropenia at day 42 (P = 0.002) and numerically higher at day 7 and EOT (P > 0.05 for both).Conclusions: Isavuconazole had comparable efficacy and safety to voriconazole in neutropenic patients with IA. Resolution of neutropenia was associated with improved outcomes. [ABSTRACT FROM AUTHOR]

The article discusses facts and opinions regarding Candida auris alert regarding the potential of multiple outbreaks of the multi-drug resistant Candida auris focusing on questions regarding its pathogenesis, epidemiology and infection control. Topics include early reports of C. auris infections, susceptibility to C. auris diseases, and the emergence of C. auris, as well as the public health challenge associated with C. auris actions need to be taken to manage its outbreaks.

Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous ( IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after ≥5 or ≥10 days. Primary endpoint was global response at end of IV therapy ( EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin ( MIC ≥8 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740). [ABSTRACT FROM AUTHOR]

In this review, we describe the epidemiology and clinical significance of resistance in Candida spp. and other non- Cryptococcus yeasts. The rise in echinocandin resistance, azole resistance and cross-resistance to two or more antifungal classes [multidrug resistance (MDR)] has been a worrisome trend, mainly in US large tertiary and oncology centres, particularly as it relates to Candida glabrata . Candida kefyr is also a concern as it can be resistant to echinocandins and polyenes, especially in patients with haematological malignancies. Lately, Candida auris has drawn a lot of attention: this uncommon Candida spp. is the first globally emerging fungal pathogen that exhibits MDR and strong potential for nosocomial transmission. Its almost simultaneous spread in four continents could be indicative of increasing selection pressures from the use of antifungal agents. Echinocandin non-susceptibility is also common among non- Candida , non- Cryptococcus yeasts. As Candida resistance patterns reflect, in part, institutional practices of antifungal administration, the benefits of antifungal stewardship protocols are increasingly recognised and endorsed in recent guidelines. Development of rapid diagnostic methods for detecting or ruling out the presence of candidaemia and antifungal resistance, as well as discovery of novel antifungals, are key priorities in medical mycology research. [ABSTRACT FROM AUTHOR]

The emergence of drug-resistant fungi poses a major threat to human health. Despite advances in preventive, diagnostic, and therapeutic interventions, resistant fungal infections continue to cause significant morbidity and mortality in patients with compromised immunity, underscoring the urgent need for new antifungal agents. In this article, we review the challenges associated with identifying broad-spectrum antifungal drugs and highlight novel targets that could enhance the armamentarium of agents available to treat drug-resistant invasive fungal infections. [ABSTRACT FROM AUTHOR]

The article examines the effectiveness of antifungal resistance as therapy for fungal infections. Information on the prevalence of resistant fungal infections as well as the raising number of patients with chronic immunosuppressing conditions, is highlighted. Also emphasized is the widespread use of triazoles for resistance in Candida and Aspergillus.

The author comments on the study "Statin Use May Be Associated With a Lower Risk of Invasive Aspergillosis in Lung Transplant Recipients" by A. P. C. Villalobos, F. Foroutan and S. Davoudi which appeared in the 2022 issue. Topics covered include the importance of the work, the use of statin as a surrogate marker of a better concomitant dysglycemia control that affects fungal risk and the implications for future studies.

Background: Mucormycosis is a rare but devastating fungal infection primarily affecting immunocompromised patients such as those with hematological malignancy, bone marrow and solid organ transplantation, and patients with diabetes, and, even more rarely, immunocompetent patients. The objective of this study was to assess the prevalence and burden, both clinical and economic, of mucormycosis among hospitalized patients in the U.S. Methods: This is a retrospective study using the Premier PerspectiveTM Comparative Database, with more than 560 participating hospitals covering 104 million patients (January 2005-June 2014). All hospitalizations in the database were evaluated for the presence of mucormycosis using either an ICD-9 code of 117.7 or a positive laboratory result for Mucorales. Hospitalizations were further required to have prescriptions of amphotericin B or posaconazole to be considered as mucormycosis-related hospitalizations. The prevalence of mucormycosis-related hospitalizations among all hospital discharges was estimated. Mortality rate at discharge, length of hospital stay, and readmission rates at 1 and 3 months were evaluated among mucormycosis-related hospitalizations. Cost per hospital stay and average per diem cost (inflated to 2014 USD) were reported. Results: The prevalence of mucormycosis-related hospitalizations was estimated as 0.12 per 10,000 discharges during January 2005-June 2014. It increased to 0.16 per 10,000 discharges if the definition of mucormycosis was relaxed to not require the use of amphotericin B or posaconazole. The median length of stay was 17 days, with 23% dead at discharge; readmission rates were high, with 30 and 37% of patients readmitted within one and three months of discharge, respectively. The average cost per hospital stay was $112,419, and the average per diem cost was $4,096. Conclusions: The study provides a recent estimate of the prevalence and burden of mucormycosis among hospitalized patients. The high clinical and economic burden associated with mucormycosis highlights the importance of establishing active surveillance and optimizing prophylactic and active treatment in susceptible patients. [ABSTRACT FROM AUTHOR]

A ca study is presented of a 56-year-old male with altered mental status. Analysis of persistent of central nervous system toxicity in a patient receiving posaconazole tablets after discontinuation of voriconazole drug due to supratherapeutic serum levels; magnatic resonance imaging scan of the brain and electroencephalogram was performed; and he was diagnosed of the same.

Mortality associated with mucormycosis remains high despite current antifungals. Iron-starvation strategies have been shown to have promising activity against Mucorales. We hypothesized that iron starvation enhances apoptosis in Rhizopus oryzae. Apoptosis was characterized in R. oryzae transformed with RNAi plasmid targeting FTR1 expression (iron permease mutant) or empty plasmid grown in iron rich (0.125% FeCl3) and iron depleted media (YNB+1mM ferrozine and 1 mM ascorbic acid). Increased apoptosis was observed with dihydrorhodamine-123 and rhodamine-123 staining in the iron starved mutant FTR1 when compared to empty plasmid, followed by increased extracellular ATP levels. In addition, DNA fragmentation and metacaspase activity were prominent in FTR1. In contrast, Rhizopus strains grown in iron-rich medium displayed minimal apoptosis. Our results demonstrate a metacaspase dependent apoptotic process in iron deprived condition and further support the role of iron starvation strategies as an adjunct treatment for mucormycosis, a mechanism by which iron starvation affects R. oryzae. [ABSTRACT FROM AUTHOR]

The role of inhaled antifungals for prophylaxis and treatment of invasive fungal pneumonias remains undefined. Herein we summarize recent clinically relevant literature in high-risk groups such as neutropenic hematology patients, including those undergoing stem cell transplant, lung and other solid transplant recipients, and those with sequential mold lung infections secondary to viral pneumonias. Although there are several limitations of the available data, inhaled liposomal amphotericin B administered 12.5 mg twice weekly could be an alternative method of prophylaxis in neutropenic populations at high risk for invasive fungal pneumonia where systemic triazoles are not tolerated. In addition, inhaled amphotericin B has been commonly used as prophylaxis, pre-emptive, or targeted therapy for lung transplant recipients but is considered as a secondary alternative for other solid organ transplant recipients. Inhaled amphotericin B seems promising as prophylaxis in fungal pneumonias secondary to viral pneumonias, influenza, and SARS CoV-2. Data remain limited for inhaled amphotericin for adjunct treatment, but the utility is feasible. [ABSTRACT FROM AUTHOR]

Despite several chemotherapeutic and preventative advances, opportunistic fungal infections remain common unintended consequences of cancer treatment. Currently, cancer patients spend most of their time between treatments at home, where they can inadvertently come across potential hazards from environmental and food sources. Therefore, infection prevention measures are of the utmost importance for these patients. Although clinicians closely observe patients throughout their treatment courses in the hospital, the focus of clinical visits is predominantly on cancer care, and clinicians seldom provide recommendations for prevention of such infections. Herein, we provide practical recommendations for busy clinicians to help them educate patients regarding potential sources of fungal infections outside the hospital. [ABSTRACT FROM AUTHOR]

The article describes the case of a 41 year old man with B-cell acute lymphoblastic leukemia (ALL) who had allogeneic peripheral-blood stem-cell transplantation and later developed fever and abdominal pain. He participated in a phase-3 randomized, placenta-controlled clinical trial of antithymocyte globulin (ATG) given 3 days prior to stem-cell transplantation to prevent chronic graft-versus host disease. He was later diagnosed with invasive aspergillosis of the appendix.

Mucormycosis is increasingly encountered in immunosuppressed patients, such as those with haematological malignancies or stem cell transplantation. We present a descriptive analysis of 121 cases of mucormycosis from the Prospective Antifungal Therapy Alliance® registry (July 2004 to December 2008). Patients with proven or probable mucormycosis were enrolled and followed prospectively for 12 weeks. The most common underlying disease and site of infection were haematologic malignancy (61.2%) and lungs (46.3%) respectively. Rhizopus ( n = 63; 52.1%) was the most commonly isolated species, followed by Mucor ( n = 28; 23.1%), other or unknown ( n = 17; 14.0%), Rhizomucor ( n = 9; 7.4%) and Lichtheimia ( n = 4; 3.3%). The 12-week Kaplan-Meier survival probability for all patients was 0.41; however, there was large variation in survival probabilities between species, with highest survival probability observed for Lichtheimia (0.5), followed by Rhizopus (0.47), Mucor (0.40), unknown Mucormycetes species (0.40), other Mucormycetes species (0.17) and Rhizomucor (0.15). Prior use of voriconazole decreased 12-week survival probability. Survival probability was higher in patients receiving amphotericin B by Day 3 (0.72) vs. those who started amphotericin B therapy after Day 3 (0.33). The low survival probability observed underscores the importance of further studies of mucormycosis. Optimal treatment selection and timing may improve prognosis. [ABSTRACT FROM AUTHOR]

This commentary focuses on critical challenges in the epidemiology, pathogenesis, host defense, laboratory detection, diagnosis, and treatment of the ongoing tragedy of iatrogenic meningitis caused by Exserohilum rostratum. Advances in understanding of this infection may reduce suffering and save lives.The tragedy of the ongoing epidemic of meningitis caused by Exserohilum rostratum brings into focus the epidemiology, risk factors, pathogenesis, diagnosis, and treatment of a multitude of opportunistic mold infections of the central nervous system. Herein we provide our perspective regarding the translational research objectives of this infection that are needed to make an impact on this important healthcare crisis. [ABSTRACT FROM PUBLISHER]

We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial ( Staphylococcus aureus and Pseudomonas aeruginosa) and fungal ( Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm3) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia. [ABSTRACT FROM AUTHOR]

Background. Mini-host models are simple experimental systems to study host-pathogen interactions. We adapted a Drosophila melanogaster infection model to evaluate the in vivo effect of different mechanisms of linezolid (LNZ) resistance in Staphylococcus aureus.Methods. Fly survival was evaluated after infection with LNZ-resistant S. aureus strains NRS119 (which has mutations in 23S ribosomal RNA [rRNA]), CM-05 and 004-737X (which carry cfr), LNZ-susceptible derivatives of CM-05 and 004-737X (which lack cfr), and ATCC 29213 (an LNZ-susceptible control). Flies were then fed food mixed with LNZ (concentration, 15–500 µg/mL). Results were compared to those in mouse peritonitis, using LNZ via oral gavage at 80 and 120 mg/kg every 12 hours.Results. LNZ at 500 µg/mL in fly food protected against all strains, while concentrations of 15–250 µg/mL failed to protect against NRS119 (survival, 1.6%–20%). An in vivo effect of cfr was only detected at concentrations of 30 and 15 µg/mL. In the mouse peritonitis model, LNZ (at doses that mimic human pharmacokinetics) protected mice from challenge with the cfr+ 004-737X strain but was ineffective against the NRS119 strain, which carried 23S rRNA mutations.Conclusions. The fly model offers promising advantages to dissect the in vivo effect of LNZ resistance in S. aureus, and findings from this model appear to be concordant with those from the mouse peritonitis model. [ABSTRACT FROM AUTHOR]

The incidence of mucormycosis has increased drastically in immunocompromised patients. Also the array of targets whose inhibition results in Mucorales death is limited. Recently, researchers identified mitochondria as important regulators of detoxification and virulence mechanisms in fungi. In this context, targeting the mitochondrial respiratory chain may provide a new platform for antifungal development. We hypothesized that targeting respiratory pathways potentiates triazoles activity via apoptosis. We found that simultaneous administration of antimycin A (AA) and benzohydroxamate (BHAM), inhibitors of classical and alternative mitochondrial pathways respectively, resulted in potent activity of posaconazole (PCZ) and itraconazole (ICZ) against Rhizopus oryzae. We observed cellular changes characteristic of apoptosis in R. oryzae cells treated with PCZ or ICZ in combination with AA and BHAM. The fungicidal activity of this combination against R. oryzae was correlated with intracellular reactive oxygen species accumulation (ROS), phosphatidylserine externalization, mitochondrial membrane depolarization, and increased caspase like activity. DNA fragmentation and condensation assays also revealed apoptosis of R. oryzae cells. These apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine. Taken together, these findings suggest that the use of PCZ or ICZ in combination with AA and BHAM makes R. oryzae exquisitely sensitive to treatment with triazoles via apoptosis. This strategy may serve as a new model for the development of improved or novel antifungal agents. [ABSTRACT FROM AUTHOR]

Background & Aims: Data on acute exacerbation and reactivation of chronic hepatitis C virus (HCV) infection following chemotherapy are very limited. We sought to characterize the episodes of acute exacerbation and viral reactivation of HCV infection in cancer patients. Methods: The medical records of HCV-infected patients seen at our institution (2008–2009) were analyzed retrospectively. Acute exacerbation was defined as greater than 3-fold increase in serum level of alanine aminotransferase, and viral reactivation as ⩾1log10 IU/ml increase of HCV viral load following chemotherapy. Results: Acute exacerbation occurred in 33 (11%) of 308 patients with proven HCV infection. Patients with acute exacerbation more often had underlying hematological malignancies (73% vs. 29%; p <0.001) and lymphopenia (6% vs. 0%; p = 0.01) than patients without it. In multivariate analysis, underlying hematological malignancies (p= 0.02; odds ratio, 3.2; 95% confidence interval, 1.2–8.7) and use of rituximab (p = 0.004; odds ratio, 4.2; 95% confidence interval, 1.6–10.9) were associated with acute exacerbation. Patients with acute exacerbation received higher median cumulative dose of rituximab than those without exacerbation. Discontinuation of chemotherapy due to liver dysfunction was more common in patients with acute exacerbation than in patients without it (45% vs. 11%; p <0.001). Eight (36%) of 22 patients with known pre- and post-chemotherapy viral load had viral reactivation. Conclusions: Acute exacerbation and reactivation of chronic HCV infection occur often after chemotherapy. Liver dysfunction can lead to discontinuation of potentially life-saving chemotherapy in nearly one-half of the patients with exacerbation of HCV infection. [ABSTRACT FROM AUTHOR]

Candida osteomyelitis most frequently presents subacutely with local symptoms but minimally elevated inflammatory biomarkers, hematogenous dissemination caused by C. albicans involving vertebrae in adults and femur/humerus in children, high relapse rate requiring extended therapy (median 3 months), and often surgical intervention.Background. The epidemiology, pathogenesis, clinical manifestations, management, and outcome of Candida osteomyelitis are not well understood.Methods. Cases of Candida osteomyelitis from 1970 through 2011 were reviewed. Underlying conditions, microbiology, mechanisms of infection, clinical manifestations, antifungal therapy, and outcome were studied in 207 evaluable cases.Results. Median age was 30 years (range, ≤ 1 month to 88 years) with a >2:1 male:female ratio. Most patients (90%) were not neutropenic. Localizing pain, tenderness, and/or edema were present in 90% of patients. Mechanisms of bone infection followed a pattern of hematogenous dissemination (67%), direct inoculation (25%), and contiguous infection (9%). Coinciding with hematogenous infection, most patients had ≥2 infected bones. When analyzed by age, the most common distribution of infected sites for adults was vertebra (odds ratio [OR], 0.09; 95% confidence interval [CI], .04–.25), rib, and sternum; for pediatric patients (≤18 years) the pattern was femur (OR, 20.6; 95% CI, 8.4–48.1), humerus, then vertebra/ribs. Non-albicans Candida species caused 35% of cases. Bacteria were recovered concomitantly from 12% of cases, underscoring the need for biopsy and/or culture. Candida septic arthritis occurred concomitantly in 21%. Combined surgery and antifungal therapy were used in 48% of cases. The overall complete response rate of Candida osteomyelitis of 32% reflects the difficulty in treating this infection. Relapsed infection, possibly related to inadequate duration of therapy, occurred among 32% who ultimately achieved complete response.Conclusions. Candida osteomyelitis is being reported with increasing frequency. Localizing symptoms are usually present. Vertebrae are the most common sites in adults vs femora in children. Timely diagnosis of Candida osteomyelitis with extended courses of 6–12 months of antifungal therapy, and surgical intervention, when indicated, may improve outcome. [ABSTRACT FROM AUTHOR]

Azole resistance in Aspergillus species may be on the rise, with significant potential implications for the management of invasive aspergillosis. The main mechanism of azole resistance in Aspergillus fumigatus is via alterations of the target enzyme CYP51A. Such azole resistance is either primary or secondary (in the setting of prior azole exposure) and can be derived either from single or multiple mutations. Irrespective of the amino acid substitution type in CYP51A, azole-resistant Aspergillus isolates are always itraconazole resistant. There is significant variability among studies and centers in the prevalence of azole resistance, and this is a multifactorial issue. Nevertheless, the exact frequency of azole resistance is unknown, in part because of the low culturability of the fungus in patients with aspergillosis. This work aims to provide an overview of the current knowledge in Aspergillus azole resistance and raises questions for future research and practical implications in the management of aspergillosis. [ABSTRACT FROM AUTHOR]

Abstract: Invasive fungal infections (IFIs) have emerged as a major cause of morbidity and mortality amongst critically ill patients. Cancer patients admitted to the Intensive Care Unit (ICU) have multiple risk factors for IFIs. The vast majority of IFIs in the ICU are due to Candida spp. The incidence of invasive candidiasis (IC) has increased over recent decades, especially in the ICU. A shift in the distribution of Candida spp. from Candida albicans to non-albicans Candida spp. has been observed both in ICUs and oncology units in the last two decades. Timely diagnosis of IC remains a challenge despite the introduction of new microbiology techniques. Delayed initiation of antifungal therapy is associated with increased mortality. Therefore, prediction rules have been developed and validated prospectively in order to identify those ICU patients at high risk for IC and likely to benefit from early treatment. These rules, however, have not been validated in cancer patients. Similarly, major clinical studies on the efficacy of newer antifungals typically do not include cancer patients. Despite the introduction of more potent and less toxic antifungals, mortality from IFIs amongst cancer patients remains high. In recent years, aspergillosis and mucormycosis have also emerged as significant causes of morbidity and mortality amongst ICU patients with haematological cancer. [Copyright &y& Elsevier]

The article offers information on the clinical research issues regarding a formidable infection called Mucormycosis which occurs mostly in people with weakened immune systems. Study of the distribution and patterns of health-events and health-characteristics of the patients suffering form this infection is discussed. The challenges faced in devising innovative and effective clinical trials for providing treatment to the infected patients are presented.

Mucormycosis is a devastating disease and can occur in patients with a variety of risk factors, the most important of which are immunosuppression, anatomic barrier breakdown, iron overload, and hyperglycemia/ acidosis. Similarly to what occurs with Aspergillus, the host stimulates an innate immune response against the challenging sporangiospores and invading hyphae of Zygomycetes. This article discusses the host defense to different Zygomycetes, its augmentation, and its subsequent impact on the outcome of mucormycosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: [ABSTRACT FROM AUTHOR]

Background. The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. Methods. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. Results. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versushost disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelvemonth cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matchedrelated allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. Conclusions. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design. [ABSTRACT FROM AUTHOR]

The article presents a retrospective study on the cause and clinical outcome of Extreme Leukocytosis in patients with nonhematologic cancer. The study identified 3770 cancer patients over a three year period. Results of the study revealed that hematopoietic growth factors, infections, corticosteroids, and paraneoplastic leukomoid reaction were the etiologies of leukocytosis. It concludes that in patients with cancer, infection was an uncommon cause for extreme leukocytosis.

Abstract: Introduction: Invasive pulmonary aspergillosis (IPA) is a leading cause of infection-associated death in immunosuppressed patients. Early detection and early administration of antifungal therapy are critical factors in improving outcome for patients with IPA. Here, we evaluated the imaging properties of a 111In-labeled cyclic peptide targeted to Aspergillus fumigatus in an immunosuppressed murine model of IPA. Methods: A cyclic peptide c(CGGRLGPFC)-NH2 was labeled with 111In by means of diethylenetriaminepentaacetic acid (DTPA). Two days after intranasal inoculation of 17.5×106 conidia of A. fumigatus, mice were injected 111In-DTPA-c(CGGRLGPFC)-NH2 intravenously. Biodistribution data were obtained at 2 h, and γ-images were acquired at 10 min and 2 h after radiotracer injection. Healthy mice were used as controls. In addition, a group of infected mice were co-injected with the radiotracer and unlabeled c(CGGRLGPFC)-NH2 to evaluate the inhibition of radiotracer''s binding to infected lungs. Autoradiographs of lungs from infected and healthy mice were compared with corresponding photographs of transaxial sections of the lung tissues stained for A. fumigatus hyphae. Results: The labeling efficiency was >98%, with specific radioactivity of up to 74 MBq/nmol peptide. Significantly higher uptake of 111In-DTPA-c(CGGRLGPFC)-NH2 was observed in the lungs of mice infected with A. fumigatus than in those of healthy mice (0.37±0.06 %ID/g vs. 0.14±0.02 %ID/g, P=.00044). Simultaneous injection with unlabeled peptide reduced radioactivity in the infected lungs by 41% (P=.0037). Increased radioactivity in the lungs of infected mice was visible in γ images at both 10 min and 2 h after radiotracer injection. Moreover, autoradiography confirmed radiotracer uptake in infected lungs, but not in the lungs of healthy mice or infected mice co-injected with unlabeled peptide. Conclusions: γ-Imaging with 111In-DTPA-c(CGGRLGPFC)-NH2 clearly delineated experimental IPA in mice. Peptides directly targeting fungi therefore may be valuable agents for noninvasive detection of opportunistic mycoses. [Copyright &y& Elsevier]

This article discusses findings of a study, which evaluated the bone marrow iron stores in patients with leukemia as well as recipients of allogeneic hematopoietic stem cell transplantation with invasive aspergillosis (IA) and those without fungal infections. IA is considered a risk among patients with leukemia and those who have undergone hematopoietic stem cell transplantation.

The article present a case study of a 68-year-old woman was treated for invasive mold lung infection with oral POSA 300 mg/day after failure with 1 month of voriconazole (VRC). It mentions that tree weeks after starting POSA, she developed hypertension and decreased potassium. It also mentions that blood pressure and electrolytes remained normal throughout isavuconazole (ISA) treatment.

Invasive mold infection is a major cause of morbidity and mortality among severely immunocompromised individuals. We discuss the challenges involved in the design and interpretation of salvage antifungal trials, focusing on mold infection. We suggest that patients with refractory fungal infection be analyzed separately from those with intolerance to standard regimens because of the poorer prognosis of the former group. We propose a composite outcome assessment in which refractory infection is defined as infection associated with the worsening of at least 2 of the following 3 types of criteria: clinical, radiologic, and mycologic. Confounding variables, including heterogeneity in host factors, initial antifungal therapy, and selection bias, are discussed. Although randomized studies would provide the most credible results, the lack of an adequate number of patients to meet prespecified stratification criteria for all confounding variables makes such studies impractical. Given that randomized studies are unrealistic, studies involving carefully selected, matched, contemporaneous control subjects are likely to be the most useful alternative. [ABSTRACT FROM AUTHOR]

Advancements in early diagnosis and the introduction of effective agents have improved the rates of response of aspergillosis to primary antifungal therapy. These changes allow the subsequent continuation of cytotoxic chemotherapy and/or performance of hematopoietic stem cell transplantation in an increasing number of patients with hematological malignancies. These developments have increased interest in secondary prophylaxis of aspergillosis, because the resumption of myelotoxic chemotherapy in these patients is associated with high rates of relapse of this opportunistic mycosis in the absence of prophylaxis. However, the risk factors for relapsing invasive aspergillosis and the strategies for reducing risk are not well defined. Furthermore, differentiating aspergillosis relapse from reinfection with a new Aspergillus isolate is problematic when using the available laboratory tools. We summarize the existing knowledge regarding the pathogenesis of, risk factors for, and natural history of relapsing invasive aspergillosis and review the limited data regarding the role of secondary antifungal prophylaxis. [ABSTRACT FROM AUTHOR]