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Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease. This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice–web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat [ITT] population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00412893. 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of −1·0% (95% CI −7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 [96%] receiving isavuconazole and 255 [98%] receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 [68%] vs 180 [69%]) and infections and infestations (152 [59%] vs 158 [61%]). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 [9%] vs 42 [16%]; p=0·016), eye disorders (39 [15%] vs 69 [27%]; p=0·002), and skin or subcutaneous tissue disorders (86 [33%] vs 110 [42%]; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. Astellas Pharma Global Development, Basilea Pharmaceutica International.

These updated guidelines replace the previous management guidelines published in 2001. The guidelines are intended for use by health care providers who care for patients who either have these infections or may be at risk for them.

Central venous catheters are essential for the treatment of patients with haematological malignancies and the recipients of stem-cell transplant. This patient population is, however, at high risk for catheter-related bloodstream infections that can result in substantial morbidity, mortality, and health-care-associated costs. Efficient prevention, early diagnosis, and effective treatment are essential to providing the best care to these patients. Although confirming the catheter as a source of infection remains challenging, the Infectious Diseases Society of America definition of catheter-related bloodstream infection remains the most precise definition to use in these patients. Gram-positive bacteria, particularly coagulase-negative Staphylococcus spp, remain the leading cause of catheter-related bloodstream infection, although an increase in Gram-negative bacteria as the causative agent has been noted. Although removal of the line and appropriate intravenous antibiotics remain the mainstay of treatment in most cases, novel technologies, including exchange with antibiotic-coated catheters and treatment with lock solutions, are particularly relevant in this patient population. In this Review we present the types of central venous catheters used in this patient population and analyse the different definitions of catheter-related infections, with an overview of their prevention and management.

An increasing number of observational studies have reported the persistence of symptoms following recovery from acute COVID-19 disease in non-cancer patients. The long-term consequences of COVID-19 are not fully understood particularly in the cancer patient population. The purpose of this study is to assess post-acute sequelae of SARS-CoV-2 infection (PASC) in cancer patients following acute COVID-19 recovery. We identified cancer patients at MD Anderson Cancer Center who were diagnosed with COVID-19 disease between March 1, 2020, and September 1, 2020, and followed them till May 2021. To assess PASC, we collected patients reported outcomes through questionnaires that were sent to patients daily for 14 days after COVID-19 diagnosis then weekly for 3 months, and then monthly thereafter. We also reviewed patients' electronic medical records to capture the persistence or emergence of new COVID19-related symptoms reported during any clinic or hospital encounter beyond 30 days of the acute illness and up to 14 months. We included 312 cancer patients with a median age of 57 years (18-86). The majority of patients had solid tumors (75%). Of the 312 patients, 188 (60%) reported long COVID-19 symptoms with a median duration of 7 months and up to 14 months after COVID-19 diagnosis. The most common symptoms reported included fatigue (82%), sleep disturbances (78%), myalgias (67%), and gastrointestinal symptoms (61%), followed by headache, altered smell or taste, dyspnea (47%), and cough (46%). A higher number of females reported a persistence of symptoms compared to males (63% vs. 37%; p=0.036). Cancer type, neutropenia, lymphocytopenia, and hospital admission during acute COVID-19 disease were comparable in both groups. Among the 188 patients with PASC, only 16 (8.5%) were re-admitted for COVID-related reasons. More than one out of two cancer patients, and more likely females, report PASC that may persist beyond 6 months and even 1 year. The most common symptoms are non-respiratory and consist of fatigue, sleep disturbance, myalgia, and gastrointestinal symptoms. Most of the cancer patients with PASC were managed on outpatient basis with only 8.5% requiring a COVID-19-related re-admission. This research is supported by the National Institutes of Health/National Cancer Institute under award number P30CA016672, which supports the MD Anderson Cancer Center Clinical Trials Office. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.

About 20 species of rapidly growing mycobacteria species that are capable of infecting human beings and causing bloodstream infections have been identified. Many more of these species are being discovered worldwide, especially in resource-poor settings. These microorganisms have been known to cause outbreaks and pseudo-outbreaks. Although rapidly growing mycobacteria are not highly virulent or life threatening, they have a high predisposition to create biofilms and to colonise and infect intravascular catheters. Early detection and identification of specific species can help to estimate predictable antimicrobial susceptibility patterns. However, because susceptibility data originate from developed countries, studies in resource-poor settings urgently need to be done. The best outcome of cure without recurrence depends on a combination of at least 4 weeks of treatment with two or more active antimicrobial agents, plus removal of the intravascular catheter. We review and discuss the epidemiology, pathogenesis, diagnosis, management, and outcomes of rapidly growing mycobacterial bloodstream infections.

Background. Phaeohyphomycosis is a rare opportunistic fungal infection. To assess the range of clinical presentations and outcomes of phaeohyphomycosis in patients with cancer, we reviewed cases diagnosed at the M. D. Anderson Cancer Center (Houston, TX). Methods. We searched the microbiology laboratory records for dematiaceous molds that had been isolated during the period from January 1989 through March 2008. Demographic and clinical data were abstracted from patients' medical records. Invasive phaeohyphomycosis was defined according to the criteria of the European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycosis Study Group for proven or probable invasive fungal disease. Archived dematiaceous mold isolates were tested for antifungal drug susceptibility. Results. Of 348 isolates of dematiaceous fungi recovered, only 39 isolates (11%), recovered from 39 patients, were associated with proven or probable invasive fungal disease (33 proven and 6 probable). The incidence rate of phaeohyphomycosis increased from 1.0 to 3.1 cases per 100,000 patient-days during the study period ( P=.006 ). Of these 39 patients, 14 (36%) had a breakthrough infection while receiving prophylactic or empirical antifungal therapy. Sites of infection were the lungs (15 [38%] of 39 patients), skin (15 [38%]), sinuses (14 [36%]), and bloodstream (7 [18%]). Thirteen patients (33%) had a disseminated infection. Values of the serum galactomannan index were measured for 11 (28%) of 39 patients. The galactomannan index value was elevated (>0.5) in 5 (45%) of these 11 patients. The mortality rate at 12 weeks was 33%. Cox regression analysis revealed a significantly higher risk of death for patients with disseminated infection (hazard ratio, 5.7; P=.03 ) and a lower risk for patients who recovered from neutropenia within 30 days (hazard ratio, 0.2; P=.04 ). Isolates were frequently not susceptible to voriconazole and caspofungin. Conclusions. Although rare, dematiaceous molds are increasingly encountered in immunosuppressed patients with cancer. The propensity of these fungi for dissemination and for resistance to antifungal drugs presents management challenges.

BackgroundAnecdotal evidence suggests a rise in zygomycosis in association with voriconazole (VRC) use in immunosuppressed patients MethodsWe performed prospective surveillance of patients with zygomycosis (group A; n=27) and compared them with contemporaneous patients with invasive aspergillosis (group B; n=54) and with matched contemporaneous high-risk patients without fungal infection (group C; n=54). We also performed molecular typing and in vitro susceptibility testing of Zygomycetes isolates ResultsNearly all patients with zygomycosis either had leukemia (n=14) or were allogeneic bone marrow transplant recipients (n=13). The Zygomycetes isolates (74% of which were of the genus Rhizopus) had different molecular fingerprinting profiles, and all were VRC resistant. In multivariate analysis of groups A and C, VRC prophylaxis (odds ratio [OR], 10.37 [95% confidence interval {CI}], 2.76–38.97]; P=.001), diabetes (OR, 8.39 [95% CI, 2.04–34.35]; P=.003), and malnutrition (OR, 3.70 [95% CI, 1.03–13.27]; P=.045) were found to be independent risk factors for zygomycosis. Between patients with zygomycosis (after excluding 6 patients with mixed mold infections) and patients with aspergillosis, VRC prophylaxis (OR, 20.30 [95% CI, 3.85–108.15]; P=.0001) and sinusitis (OR, 76.72 [95% CI, 6.48–908.15]; P=.001) were the only factors that favored the diagnosis of zygomycosis ConclusionsZygomycosis should be considered in immunosuppressed patients who develop sinusitis while receiving VRC prophylaxis, especially those with diabetes and malnutrition

Objective Enterococcus species are the third most common organisms causing central line-associated bloodstream infections (CLABSIs). The management of enterococcal CLABSI, including the need for and timing of catheter removal, is not well defined. We therefore conducted this study to determine the optimal management of enterococcal CLABSI in cancer patients. Methods We reviewed data for 542 patients diagnosed with Enterococcus bacteremia between September 2011 to December 2018. After excluding patients without an indwelling central venous catheter (CVC), polymicrobial bacteremia or with CVC placement less than 48 h from bacteremia onset we classified the remaining 397 patients into 3 groups: Group 1 (G1) consisted of patients with CLABSI with mucosal barrier injury (MBI), Group 2 (G2) included patients with either catheter-related bloodstream infection (CRBSI) as defined in 2009 Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection by the Infectious Diseases Society of America (IDSA) or CLABSI without MBI, and Group 3 (G3) consisted of patients who did not meet the CDC criteria for CLABSI. The impact of early (< 3 days after bacteremia onset) and late (3–7 days) CVC removal was compared. The composite primary outcome included absence of microbiologic recurrence, 90-day infection-related mortality, and 90-day infection-related complications. Results Among patients in G2, CVC removal within 3 days of bacteremia onset was associated with a trend towards a better overall outcome than those whose CVCs were removed later between days 3 to 7 (success rate 88% vs 63%). However, those who had CVCs retained beyond 7 days had a similar successful outcome than those who had CVC removal < 3 days (92% vs. 88%). In G1, catheter retention (removal > 7 days) was associated with a better success rates than catheter removal between 3 and 7 days (93% vs. 67%, p  = 0.003). In non-CLABSI cases (G3), CVC retention (withdrawal > 7 days) was significantly associated with a higher success rates compared to early CVC removal (< 3 days) (90% vs. 64%, p  = 0.006). Conclusion Catheter management in patients with enterococcal bacteremia is challenging. When CVC removal is clinically indicated in patients with enterococcal CLABSI, earlier removal in less than 3 days may be associated with better outcomes. Based on our data, we cannot make firm conclusions about whether earlier removal (< 3 days) could be associated with better outcomes in patients with Enterococcal CLABSI whose CVC withdrawal is clinically indicated. In contrast, it seemed that catheter retention was associated to higher success outcome rates. Therefore, future studies are needed to clearly assess this aspect.

Background. Conventional amphotericin B—based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a ⩾70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species. Methods. In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy. Results. Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia. Conclusion. These results suggest that posaconazole is useful for the treatment of invasive fusariosis.

Background. We investigated whether caspofungin and other echinocandins have immune-enhancing properties that influence human polymorphonuclear neutrophil (PMN)-mediated mold hyphal damage. Materials and methods. Using aniline blue staining, we compared patterns of β-glucan exposure in Aspergillus fumigatus, Aspergillus terreus, Rhizopus oryzae, Fusarium solani, Fusarium oxysporum, Scedosporium prolificans, and Scedosporium apiospermum hyphae after caspofungin exposure. We also determined PMN-mediated hyphal damage occurring with or without preexposure to caspofungin or with preexposure to the combination of caspofungin and anti-β-glucan monoclonal antibody, using 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-sH-tetrazolium hydroxide (XTT) assay. Results. Preincubation with caspofungin (32 µg/mL for R. oryzae; 0.0625 µg/mL for other isolates) increased exposure to β-glucan. PMN-induced damage increased after caspofungin exposure and was further augmented by the addition of anti-β-glucan antibody. Preincubation with micafungin or anidulafungin had similar effects on PMN-induced damage of A. fumigatus hyphae. Finally, preexposure of A. fumigatus, but not S. prolificans, to caspofungin induced expression of Dectin-1 by PMN. Conclusions. The results of the present study suggest inducement of β-glucan unmasking by echinocandins and enhancement of PMN activity against mold hyphae, thereby supporting the immunopharmacologic mode of action of echinocandins.