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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]

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]

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]

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]

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]

Abstract: Although gastrointestinal cytomegalovirus disease (GI-CMVd) is not common in cancer patients, it is associated with high morbidity and mortality. Herein, we review our 2-decade experience with GI-CMVd in such patient population at The University of Texas M.D. Anderson Cancer Center. Forty-seven patients were identified. Thirty-four patients (72%) had an underlying haematological malignancy, and 18 patients (38%) developed GI-CMVd following hematopoietic stem cell transplantation (HSCT). Nine (25%) of the 36 cancer patients with data available had AIDS. Upper-GI tract involvement was more common in patients with haematological malignancies than in those with solid tumours (P =0.02). Patients with AIDS were more likely to have colonic involvement than were those without AIDS (67% vs. 15%, P =0.006), and patients without AIDS were more likely to have gastric involvement (59% vs. 11%, P =0.01). The CMV-attributable mortality rate was 42%. Independent predictors of death by multivariate analysis included disseminated CMV and AIDS (P <0.01). The presentation of GI-CMVd varies according to the type of cancer, and AIDS. GI-CMVd is associated with a high mortality among cancer patients, particularly those with disseminated CMV disease or AIDS. [Copyright &y& Elsevier]

Abstract: Despite a decline in the frequency of gram-negative infections in cancer patients, there has been an increase in the proportion of such infections caused by nonfermentative gram-negative bacilli (NFGNB). We tested the in vitro activity of several quinolones against NFGNB isolated from cancer patients between February 2000 and February 2003, using a broth microdilution method. Ciprofloxacin was the most potent agent tested against Pseudomonas aeruginosa, although only 80% of isolates were susceptible to it. The newer quinolones (gatifloxacin, moxifloxacin, and garenoxacin) had better activity than ofloxacin, levofloxacin, and ciprofloxacin, against many other nonfermenters (Stenotrophomonas maltophilia, P. fluorescens, and P. putida). [Copyright &y& Elsevier]

We investigated the in vitro activity of sequential itraconazole and caspofungin against 10 isolates of Aspergillus fumigatus. Previous exposure of A. fumigatus to itraconazole resulted in dose-dependent enhanced effects of caspofungin and vice versa. Our finding suggests a preferential role for azole-caspofungin sequential combinations and merits further in vivo investigation. [Copyright &y& Elsevier]

The mammalian immune system has evolved the capacity to detect and destroy tumor cells. Tumors utilize multiple strategies to evade host immune surveillance, including the induction of the checkpoint molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) to suppress antitumor immunity. Pharmacologic blockade of these molecules with checkpoint inhibitors (CPIs) restores T cell function and prolongs survival in patients with various malignancies. Emerging evidence suggests that the same checkpoint pathways may play a crucial role during infections. Indeed, CPIs appear promising as immunotherapeutic agents in infectious diseases, although their efficacy varies depending on pathogen-, cell-, and organ-specific factors. More research will be necessary to clarify the effects and safety of CPIs on clinically relevant outcomes of human infection. Pharmacologic blockade of several immune checkpoint molecules promotes antitumor immunity and increases survival in patients with cancer. Evidence from ex vivo and animal models of infection suggests that immune checkpoint molecules regulate the host immune responses to promote pathogen clearance while limiting immune-mediated tissue injury. Both protective and detrimental effects of checkpoint molecule inhibition have been reported in experimental models of infection, depending on pathogen-, cell-, and organ-specific factors. Small, uncontrolled studies suggest that checkpoint molecule blockade may improve patient outcomes in certain infections. Controlled trials are urgently needed to determine the efficacy and safety of this approach. [ABSTRACT FROM AUTHOR]

The present study was to determine the in vitro activity of posaconazole (POS) against 385 Candida and 268 Aspergillus clinical isolates from China. We found that POS was active against 85.5% Candida and 94.4% Aspergillus isolates. Non–wild-type (non-WT) phenotype was found in a subset of Candida albicans (15.4%), Candida tropicalis (11.9%), Aspergillus fumigatus (4.1%), and Aspergillus flavus (17.4%) isolates. Cross-resistance to POS and other triazoles was seen. Gene sequencing showed that 4 C. albicans , 1 C. tropicalis , and 9 A. fumigatus isolates with cross-resistance to POS and other triazoles had mutations in ERG11 or CYP51A. In conclusion, POS has potent in vitro activity against most of Candida and Aspergillus isolates from China. Non-WT phenotype and those with cross-resistance to POS and other triazoles exist, frequently driven by mutations of ERG11 in Candida spp. and CYP51A in Aspergillus spp. • The susceptibility to posaconazole in Candida spp. and Aspergillus spp. from China was determined for the first time. • Posaconazole was active against most of Candida and Aspergillus isolates in this study. • Non-WT phenotype for posaconazole and those with cross-resistance to posaconazole and other triazoles exist. • Cross-resistance may be caused by mutations of ERG11 in Candida spp. and CYP51A in Aspergillus spp. [ABSTRACT FROM AUTHOR]

Objective: To assess whether there are preferences and avoidances for specific comparisons in a clinical trials agenda.Study Design and Setting: We tested for homophily (preference to compare agents against others in the same class) and co-occurrence (preference or avoidance of specific head-to-head comparisons) in the randomized trials agenda of antifungal agents. We searched MEDLINE and Cochrane Library databases for English language randomized trials evaluating systemic antifungals against Candida or Aspergillus in adults. We extracted data on compared regimens, sample size, publication year, indication (treatment/prophylaxis), and underlying disease.Results: One hundred forty-four trials (74 treatments, 70 prophylaxes) were found (n=27,497 patients). Among polyene and azole groups, agents were compared within the same class more often than across classes (homophily test P<0.001). Lipid amphotericin was compared almost entirely against conventional amphotericin (18 trials), with only three comparisons against azoles. Head-to-head comparisons of newer agents were avoided. Only one of 14 trials for echinocandins compared head-to-head two different echinocandins (P<0.001 for co-occurrence). Of 11 trials on newer azoles, only one compared a newer azole with an echinocandin (P<0.001 for co-occurrence).Conclusions: Trial networks for antifungals show that specific comparisons are preferred and others avoided, generating a potentially biased clinical research agenda. [ABSTRACT FROM AUTHOR]

Systemic fungal Infections are increasingly reported in immuno-compromised patients with hematological malignancies, recipients of bone marrow and solid organ allografts, and patients with AIDS. Mycoses may infiltrate endocrine organs and adversely affect their function or produce metabolic complications, such as hypopituitarism, hyperthyroidism or hypothyroidism, pancreatitis, hypoadrenalism, hypogonadism, hypernatremia or hyponatremia, and hypercalcemia. Antifungal agents used for prophylaxis and/or treatment of mycoses also have adverse endocrine and metabolic effects, including hypoadrenalism, hypogonadism, hypoglycemia, dyslipidemia, hypernatremia, hypocalcemia, hyperphosphatemia, hyperkalemia or hypokalemia, and hypomagnesemia. Herein, we review how mycoses and conventional systemic antifungal treatment can affect the endocrine system and cause metabolic abnormalities. If clinicians are equipped with better knowledge of the endocrine and metabolic complications of fungal Infections and antifungal therapy, they can more readily recognize them and favorably affect outcome. [ABSTRACT FROM AUTHOR]

Summary: Objectives: To determine the current spectrum of Gram-positive bloodstream infections (BSI) in patients with hematologic malignancies at our institution, and to determine the in vitro activity of various fluoroquinolones against clinical Gram-positive isolates collected from such patients. Methods: Institutional microbiology records from 493 consecutive episodes of Gram-positive BSI were reviewed. The in vitro activity of six fluoroquinolones against 477 clinical isolates was determined using an NCCLS approved, broth-dilution method. Results: The most common Gram-positive organisms isolated from the bloodstream of patients with hematological malignancies were coagulase-negative staphylococci (33%), Staphylococcus aureus (15%), viridans group streptococci (10%), and the enterococci (8%). Acute leukemias were the most common underlying malignancies, and 73% of patients were neutropenic when they developed their BSI. The newer generation quinolones – moxifloxacin and gatifloxacin – had the best overall in vitro activity against the Gram-positive isolates tested, and were at least 2 to 8-fold more potent than the early generation quinolones (ofloxacin and ciprofloxacin). Of the 477 isolates tested, 405 (85%) were from patients receiving quinolone (ciprofloxacin or levofloxacin) prophylaxis. Conclusions: In patients with hematologic malignancies, Gram-positive BSI are caused by a large number of bacterial species and many occur despite antimicrobial prophylaxis. The newer generation quinolones – moxifloxacin and gatifloxacin – have better in vitro activity against these organisms than early generation agents (ciprofloxacin and ofloxacin). [Copyright &y& Elsevier]

Abstract: We present 2 cases of HIV-related cryptococcal meningitis, persisting after 3 and 9 months, respectively, of standard treatment. Both patients were treated successfully with a salvage regimen consisting of the combination of liposomal amphotericin B (3 mg/kg), intravenous voriconazole, and subcutaneous recombinant interferon γ-1b (200 μg thrice weekly). Voriconazole was administered at an increased dose (5 mg/kg, twice daily) to overcome interactions with co-administered ritonavir. In both patients, resolution of clinical signs and symptoms, as well as sterilization of cerebrospinal fluid cultures occurred after 10 weeks of salvage therapy. No major side effects were encountered. At the end of treatment, both patients were placed on maintenance therapy with oral fluconazole; no recurrence has been observed after 4 years of follow-up. [Copyright &y& Elsevier]

The aim of the study was to assess the association inflammation with symptom burden in patients with acute myeloid leukemia (AML), assessed before and during remission induction chemotherapy (IC). Patients with AML (n = 95) were followed from baseline (before IC) to the third week of IC for severity of self-reported somatic symptoms (assessed with the MD Anderson Symptom Inventory) and plasma levels of 13 inflammation-related biomarkers (n = 64). A composite symptom burden severity score was computed as the average score of the six most severe somatic symptoms i.e., fatigue, disturbed sleep, drowsiness, dry mouth, lack of appetite, and pain. Results from cross-sectional analyses showed that inflammation was weakly associated with symptom burden before IC (multiple regression model, explained variance = 10%) but this association grew stronger during IC (week 3 explained variance = 35%). About half of the sample showed a change over time in symptom severity. These changes were not reflected in similar changes over time in inflammatory markers, suggesting that it is the absolute concentration of a given inflammatory marker at a given time point rather than its relative change over time that is of importance. In conclusion, inflammation was strongly associated with symptom burden only during IC, possibly because expression of cytokines only then becomes relevant for regulation of symptom burden. While the current study does not allow for determination of causality, the results suggest that AML patients might benefit from anti-inflammatory interventions during treatment to alleviate somatic symptom experience. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised haematological malignancy patients. In this study, the efficacy and safety of caspofungin, voriconazole or the combination as primary and salvage therapy in patients with IA were compared. The study included 181 patients with haematological malignancies and IA who received primary or salvage therapy with caspofungin, voriconazole or the combination. In total, 138 patients who received treatment for ≥7 days were analysed; 86 underwent primary antifungal therapy (15 with caspofungin, 38 with voriconazole and 33 with both). Among the salvage therapy patients, 17 received caspofungin, 24 received voriconazole and 35 received both. In the primary therapy group, no difference in therapy response was found, but caspofungin was associated with higher IA mortality rates. A multivariate competing risk analysis of primary antifungal therapy revealed that voriconazole was independently associated with lower IA-associated mortality rates than caspofungin (hazard ratio = 0.2, 95% confidence interval 0.06–0.96; P = 0.04). In the salvage therapy group, the three treatment groups had similar responses and IA-associated mortality rates. The combination of voriconazole and caspofungin did not result in better outcomes compared with voriconazole alone, as primary or salvage therapy, in haematological malignancy patients. However, voriconazole was associated with a lower Aspergillus -associated mortality rate compared with caspofungin monotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hepatitis C virus (HCV) is a known carcinogen with considerable genetic heterogeneity: six different genotypes have been identified. HCV genotype distribution varies from country to country. In the United States, the most prevalent genotypes are 1a, and 1b followed by genotypes 2, and 3. Objectives: To examine whether the distribution of HCV genotypes differed by cancer status among patients in the same area. Study design: We reviewed epidemiologic and virological data of 636 patients with HCV infection evaluated at 3 institutions in Houston, Texas, in 2008 and 2009. Results: We included 129 cancer patients (53 with hematologic malignancies and 76 with solid tumors), 333 immunocompetent patients, and 102 HIV-co-infected patients. The prevalence of genotype 1 (G-1) was 66% among cancer patients, 84% among immunocompetents (P =0.00004), and 99% among HIV-co-infected patients (P <0.00001). G-2 and G-3 were more common in cancer patients than other patients. Demographics, risk factors, and duration of HCV infection were similar between cancer and immunocompetent patients. G-1 was more prevalent in immunocompetents (84%) than in patients with hepatocellular carcinoma (74%, P =0.08) or lymphoma (59%, P =0.001). G-2 was more prevalent in lymphoma patients (24%) than in immunocompetents (8%, P =0.003); cancer risk was 3 times as great with G-2 as with other genotypes (OR 3.72, 95% CI 1.38–9.76). Conclusions: This multicenter retrospective study provides evidence of differences in HCV genotype distribution by underlying disease among geographically related patients and suggests a possible greater carcinogenic potential of some variants. Large-scale prospective studies are warranted to investigate HCV genotype distribution in other regions. [Copyright &y& Elsevier]

BK virus (BKV) is a human polyomavirus that remains latent in the urinary tract epithelium in most individuals. However, in immunocompromised states, including after hematopoietic stem cell transplantation (HSCT), BKV may reactivate and cause infection predominantly affecting the bladder, commonly manifested as hemorrhagic cystitis. Renal insufficiency, occasionally requiring hemodialysis, is not uncommon and was previously attributed to medications or the development of tubulointestitial nephritis. We report a series of 6 HSCT recipients who developed obstructive uropathy of the upper urinary tract system secondary to inflammation and hemorrhage involving the upper uroepithelium, causing ureteral stenosis. Temporary placement of a percutaneous nephrostomy catheter relieved the obstruction and significantly improved kidney function, successfully preventing progression to more advanced renal disease in these patients. [Copyright &y& Elsevier]

Abstract: We determined the in vitro galactomannan reactivity of isolates recovered from 17 patients with invasive phaeohyphomycosis, 4 of whom had positive galactomannan antigenemia. All isolates were nonreactive using the galactomannan immunoassay. Galactomannan antigenemia in patients with phaeohyphomycosis should raise the possibility of concomitant invasive aspergillosis. [Copyright &y& Elsevier]

Among cancer patients with Candida glabrata (the Candida species with the slowest in-vitro growth) fungemia, time-to-positive blood culture reporting (TTR) was shorter in catheter-associated candidemia (mean±standard deviation: 67±35 h) than in candidemia from other sources (79±31, P <.01). TTR<48 h was 92% specific for catheter-associated C. glabrata fungemia. [ABSTRACT FROM AUTHOR]

Abstract: This study was performed to evaluate retrospectively the efficacy and safety of caspofungin monotherapy for candidaemia in patients with cancer. The medical records were reviewed of 63 consecutive adult patients with cancer who had candidaemia treated with caspofungin alone for at least 3 consecutive days at The University of Texas M.D. Anderson Cancer Center (March 2001–February 2007). Twenty patients (32%) had haematological malignancies. Most of the candidaemia cases (54%) were caused by non-albicans Candida spp. The most frequent isolates were C. albicans (38%) followed by Candida parapsilosis (21%), Candida tropicalis (16%) and Candida glabrata (10%). In vitro susceptibility studies showed that of 30 Candida isolates tested, only one C. parapsilosis isolate had a caspofungin minimum inhibitory concentration >1μg/mL. The clinical and mycological response rates after 7 days of treatment with caspofungin were 78% and 77%, respectively. The overall mortality rate was 5% on Day 7, 12% on Day 14 and 21% on Day 30. The 30-day Candida-attributable mortality rate was 11% and was significantly higher in patients with fluconazole-resistant or susceptible-dose-dependent Candida isolates. Caspofungin was well tolerated in all patients. Although selection of candidaemic patients with cancer who received caspofungin monotherapy may have accounted for the favourable outcomes, it was observed that caspofungin had efficacy and safety comparable with those in candidaemic patients without malignancy. [Copyright &y& Elsevier]

Abstract: Ethylene diamine tetra-acetic acid (EDTA) is an anticoagulant with antibiofilm-enhancing activity. We therefore used an in vitro biofilm model to determine the activity of amphotericin B lipid complex (ABLC) with or without EDTA against Candida embedded in biofilm on silicone disk surfaces. Clinical blood isolates from cancer patients infected with Candida albicans or Candida parapsilosis were used. Silicone disks were colonised with C. albicans or C. parapsilosis and were sequentially incubated in plasma and then in Mueller–Hinton broth containing 105 colony-forming units of each organism. All tests were performed in triplicate. The disks were subsequently placed and incubated for 6h and 8h in solutions containing ABLC alone, EDTA alone, ABLC+EDTA or broth (control). Disks were then removed, sonicated and colony counts were determined. ABLC+EDTA (30mg/mL) was significantly more effective than ABLC, EDTA and control against C. parapsilosis at 6h (P ≤0.01) and against C. albicans at 8h (P ≤0.04). In patients with catheter-related candidaemia when catheter removal is not feasible, the combination of ABLC+EDTA may be considered for antifungal catheter lock solution as part of a catheter salvage therapy. [Copyright &y& Elsevier]

Tumor necrosis factor a (TNF-alpha) blockade has emerged as a useful therapy for collagen vascular diseases or graft-vs-host disease. Fungal infections complicating such therapy have been reported sporadically. MEDLINE and PubMed databases (from January 1, 1966, to June 1, 2007) were searched for reports of invasive fungal infections (IFIs) associated with the 3 available anti-TNF- alpha agents, ie, infliximab, etanercept, and adalimumab. Of the 281 cases of IFI associated with TNF-alpha inhibition, 226 (80%) were associated with infliximab, 44 (16%) with etanercept, and 11 (4%) with adalimumab. Fungal infections associated with infliximab occurred a median of 55 days (interquartile range [IQR], 15-140 days) after initiation of therapy and 3 infusions of the medication (IQR, 2-5), whereas those associated with etanercept occurred a median of 144 days (IQR, 46-240 days) after initiation of therapy. The median age of patients was 58 years (IQR, 44-68 years), and 62% were male. Use of at least 1 other immunosuppressant medication, typically a systemic corticosteroid, was reported during the course of the fungal infection in 102 (98%) of the 104 patients for whom data were available. The most prevalent IFIs were histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergillosis (n equals 64 [23%]). Pneumonia was the most common pattern of infection. Of the 90 (32%) of 281 cases for which outcome information was available, 29 fatalities (32%) were recorded. Tumor necrosis factor a blockade is associated with IFI across a range of host groups. A high index of suspicion in patients treated with TNF-alpha antagonists is recommended because the course of such infections can be serious or fulminant, and rapid access to health care should be provided. Surveillance of IFIs complicating TNF-alpha blockade and other biologic therapies is warranted through well-organized prospective patient registries. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor α (TNF-α) blockade has emerged as a useful therapy for collagen vascular diseases or graft-vs-host disease. Fungal Infections complicating such therapy have been reported sporadically. MEDLINE and PubMed databases (from January 1, 1966, to June 1, 2007) were searched for reports of Invasive fungal Infections (IFIs) associated with the 3 available antl-TNF-α agents, le, infliximab, etanercept, and adalimumab. Of the 281 cases of IFI associated with TNF-α Inhibition, 226 (80%) were associated with Infliximab, 44 (16%) with etanercept, and 11 (4%) with adailmumab. Fungal Infections associated with infliximab occurred a median of 55 days (Interquartile range [IQR], 15-140 days) after Initiation of therapy and 3 infusions of the medication (IQR, 2-5), whereas those associated with etanercept occurred a median of 144 days (1QR, 46-240 days) after initiation of therapy. The median age of patients was 58 years (1QR, 44-68 years), and 62% were male. Use of at least I other Immunosup-pressant medication, typically a systemic corticosterold, was reported during the course of the fungal Infection In 102 (98%) of the 104 patients for whom data were available. The most prevalent IFis were histoplasmosis (n=84 [30%]), candidiasis (n=64 [23%]), and aspergiliosis (n=64 [23%]). Pneumonia was the most common pattern of Infection. Of the 90 (32%) of 281 cases for which outcome Information was available, 29 fatalities (32%) were recorded. Tumor necrosis factor a blockade Is associated with IFI across a range of host groups. A high index of suspicion In patients treated with TNF-α antagonists Is recommended because the course of such Infections can be serious or fulminant, and rapid access to health care should be provided. Surveillance of IFIs complicating TNF-a blockade and other biologic therapies Is war- ranted through well-organized prospective patient registries. [ABSTRACT FROM AUTHOR]

Abstract: Background: Abnormal liver function test (LFT) results are common in patients with hematologic abnormalities, making the assessment of drug-related hepatotoxicity difficult. Studies based on elevated LFT levels have found that use of liposomal amphotericin B (L-AMB) was associated with increased hepatotoxicity compared with amphotericin B (AMB)/deoxycholate or amphotericin B lipid complex (ABLC). Because LFT abnormalities are multifactorial in severely immunocompromised patients, uncertainty remains regarding the clinical significance of these laboratory findings. Objective: The aim of this study was to present the hepatic histopathologic findings on autopsy in patients who had hematologic malignancies and fungal infections and had received L-AMB or ABLC. Methods: This study was conducted at The University of Texas M.D. Anderson Cancer Center, Houston, Texas. Records from 1995 to 2004 of patients who had received L-AMB or ABLC for ≥7 days, within 30 days before death, were reviewed by 1 investigator. Hepatic autopsy slides were independently reviewed by another investigator (pathologist) in a blinded fashion. Histopathologic evidence of amphotericin-related hepatotoxicity was predetermined based on histopathologic abnormalities reported in animal studies (eg, macrophage vacuolation, multifocal hepatocellular necrosis). Based on data from animal studies and in view of the lack of studies in humans, multifocal necrosis, fatty infiltration, macrophage vacuolation, and/or “foamy macrophage” accumulation were all considered histopathologic abnormalities associated with the use of lipid formulations of AMB. Results: Data from 64 patients were included (32 patients per group). The demographic characteristics were comparable between the ABLC and L-AMB groups (median ages, 47.5 and 53.0 years, respectively; male, 44% and 53%; white, 75% and 78%; median weight, 67 and 78 kg; active underlying malignancy, 84% and 78%). There were no significant between-group differences in cumulative dose (6 and 7 g), median daily dose (both, 5 mg/kg), or median duration of treatment (19.5 and 19.0 days). Abnormal results (>5 x from baseline) on LFT were found in 12 (38%) and 10 (31%) patients who received ABLC and L-AMB, respectively, but these findings were thought to be associated with concomitant use of triazoles (4/12 [33%] and 1/10 [10%] patients, respectively), hepatotoxic antibiotics (8/12 [67%] and 5/10 [50%]), and/or other hepatotoxic medications (2/12 [17%] and 1/10 [10%]). Nonspecific abnormalities were observed on histopathology in 94% of patients. There was no evidence of histopathologic abnormalities reported in animal toxicity studies of lipid AMB, such as macrophage vacuolation or multifocal hepatocellular necrosis. Conclusions: Although abnormal results on LFT and/or histopathologic changes in liver were found in 92% of these debilitated patients with hematologic malignancy, direct histopathologic evidence of toxicity associated with lipid formulations of AMB was not established in our study. [Copyright &y& Elsevier]

Summary: Mini-host models have emerged as simple experimental systems to study the pathogenesis and host innate immune responses in fungal invaders and also to test drug efficacy against these organisms. A growing number of medically important fungi, including Aspergillus spp, Candida spp, Cryptococcus spp, and species in the class Zygomycetes, have been shown to infect and kill invertebrates such as roundworms, fruit flies, and wax moths. These studies have shown that several genes implicated in the virulence of fungi in mammalian models also have a similarly important pathogenic role in mini-host organisms. These mini-host models provide a unique opportunity of simultaneously exploring the molecular mechanisms of fungal pathogenicity and candidate agents with antifungal activity. Furthermore, the fact that some of these mini-hosts have well-defined genetics and conserved innate immunity offers the advantage of a comprehensive analysis of the molecular aspects of host immune response. We examine the relevance, advantages, and pitfalls of experimental systems of fungal infections in various mini-hosts and compare them with what is known in experimental systems in mammalian animal models. [Copyright &y& Elsevier]

Summary: Posaconazale is a new triazole drug being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections. In-vitro and in-vivo studies showed that posaconazole has broad-spectrum activity against most Candida species, Cryptococcus neoformans, Aspergillus species, Fusarium species, zygomycetes, and endemic fungi. Posaconazole is given orally two to four times daily. This triazole is widely distributed in the body, metabolised mainly by the liver, and is well tolerated, even in long-term courses. Adverse events are generally mild and include headache and gastrointestinal complaints. Posaconazole has shown promising clinical efficacy against life-threatening fungal infections that are often refractory to the currently available antifungal therapies—eg, invasive aspergillosis, fusariosis, and the emerging zygomycosis. [Copyright &y& Elsevier]

Abstract: Invasive aspergillosis (IA) can occur despite prior prophylactic or empiric use of triazoles or amphotericin B (AMB). Although profound immunosuppression may account for breakthrough IA, resistance of Aspergillus to antifungals may also play a role. To examine this question, we measured the minimal inhibitory concentration of 105 Aspergillus isolates recovered from 105 cancer patients (64 with IA, 41 with Aspergillus colonization) to AMB, itraconazole (ITC), and voriconazole (VRC) using the National Committee for Clinical Laboratory Standards (NCCLS) M38-A microdilution and E-test methods. We also determined the minimal fungicidal concentration (MFC) of these agents and the minimal effective concentration (MEC) of caspofungin (CAS) using standardized methods. We then collected information regarding pre-exposure to AMB or triazoles (fluconazole, ITC, VRC) within 3 months before Aspergillus isolation. Pre-exposure of cancer patients to AMB or triazoles was associated with increased frequency of non-fumigatus Aspergillus species. Aspergillus isolates recovered from patients who previously received AMB exhibited higher E-test AMB MICs compared with isolates from patients without prior AMB exposure (P = 0.01). In addition, the AMB MICs by E-test were higher in triazole–pre-exposed patients compared with those not exposed to triazoles (P = 0.001). The ITC and VRC MICs by E-test were not affected by prior AMB or triazole exposure. Finally, neither the AMB, ITC, and VRC MICs and MFCs by NCCLS method nor CAS MECs showed such changes. In conclusion, cancer patients with positive Aspergillus cultures who are pre-exposed to AMB or triazoles have high frequency of non-fumigatus Aspergillus species. These Aspergillus isolates were found to be AMB-resistant by the more sensitive E-test method. [Copyright &y& Elsevier]

Invasive aspergillosis (IA) caused by inherently more antifungal-resistant non-fumigatus Aspergillus species has become an important life-threatening complication in severely immunocompromised patients with cancer. The purpose of this study was to compare the relative incidence of, risk factors for, and in vitro correlation of amphotericin B and itraconazole with the clinical outcome of IA caused by Aspergillus fumigatus with those of IA caused by non-fumigatus Aspergillus spp. in patients with cancer. A retrospective search of our tertiary care cancer center’s microbiology laboratory reports from 1998–2001 revealed 40 patients with cancer and IA. A non-fumigatus Aspergillus species caused IA in 28 (70%) of those patients. A. fumigatus was the predominant cause of late-onset IA after bone marrow transplantation (p = 0.05), whereas IA due to non-fumigatus Aspergillus spp. was more common in patients with neutropenia (p = 0.01). The minimum inhibitory concentration (50/90) and minimum fungicidal concentration (50/90) for amphotericin B were higher in the non-fumigatus Aspergillus spp. group than in the A. fumigatus one. The Aspergillus species distribution in IA cases in our institution shows a predominance of the more antifungal-resistant or -tolerant non-fumigatus Aspergillus spp. [Copyright &y& Elsevier]

We compared the in vitro pharmacodynamics of isavuconazole, voriconazole, and posaconazole against 92 clinical isolates from documented cases of invasive aspergillosis, mucormycosis, fusariosis, and phaeohyphomycosis. Whereas inhibitory and fungicidal concentrations of these triazoles were predictably similar with the exception of Mucorales , isavuconazole appeared to have improved pharmacodynamics against Fusarium solani. [ABSTRACT FROM AUTHOR]