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BackgroundInvasive fungal diseases (IFDs) remain important causes of morbidity and mortality. The consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group have been of immense value to researchers who conduct clinical trials of antifungals, assess diagnostic tests, and undertake epidemiologic studies. However, their utility has not extended beyond patients with cancer or recipients of stem cell or solid organ transplants. With newer diagnostic techniques available, it was clear that an update of these definitions was essential.MethodsTo achieve this, 10 working groups looked closely at imaging, laboratory diagnosis, and special populations at risk of IFD. A final version of the manuscript was agreed upon after the groups' findings were presented at a scientific symposium and after a 3-month period for public comment. There were several rounds of discussion before a final version of the manuscript was approved.ResultsThere is no change in the classifications of "proven," "probable," and "possible" IFD, although the definition of "probable" has been expanded and the scope of the category "possible" has been diminished. The category of proven IFD can apply to any patient, regardless of whether the patient is immunocompromised. The probable and possible categories are proposed for immunocompromised patients only, except for endemic mycoses.ConclusionsThese updated definitions of IFDs should prove applicable in clinical, diagnostic, and epidemiologic research of a broader range of patients at high-risk.

Background Our aim in this study was to develop quality indicators (QIs) for outpatient parenteral antimicrobial therapy (OPAT) care that can be used as metrics for quality assessment and improvement. Methods A RAND-modified Delphi procedure was used to develop a set of QIs. Recommendations on appropriate OPAT care in adults were retrieved from the literature using a systematic review and translated into potential QIs. These QIs were appraised and prioritized by a multidisciplinary panel of international OPAT experts in 2 questionnaire rounds combined with a meeting between rounds. Results The procedure resulted in 33 OPAT-specific recommendations. The following QIs that describe recommended OPAT care were prioritized by the expert panel: the presence of a structured OPAT program, a formal OPAT care team, a policy on patient selection criteria, and a treatment and monitoring plan; assessment for OPAT should be performed by the OPAT team; patients and family should be informed about OPAT; there should be a mechanism in place for urgent discussion and review of emergent clinical problems, and a system in place for rapid communication; laboratory results should be delivered to physicians within 24 hours; and the OPAT team should document clinical response to antimicrobial management, document adverse events, and monitor QIs for OPAT care and make these data available. Conclusions We systematically developed a set of 33 QIs for optimal OPAT care, of which 12 were prioritized by the expert panel. These QIs can be used to assess and improve the quality of care provided by OPAT teams. [ABSTRACT FROM AUTHOR]

Background Isavuconazole was compared to caspofungin followed by oral voriconazole in a Phase 3, randomized, double-blind, multinational clinical trial for the primary treatment of patients with candidemia or invasive candidiasis. Methods Adult patients were randomized 1:1 to isavuconazole (200 mg intravenous [IV] three-times-daily [TID] for 2 days, followed by 200 mg IV once-daily [OD]) or caspofungin (70 mg IV OD on day 1, followed by 50 mg IV OD [70 mg in patients > 80 kg]) for a maximum of 56 days. After day 10, patients could switch to oral isavuconazole (isavuconazole arm) or voriconazole (caspofungin arm). Primary efficacy endpoint was successful overall response at the end of IV therapy (EOIVT) in patients with proven infections who received ≥1 dose of study drug (modified-intent-to-treat [mITT] population). The pre-specified noninferiority margin was 15%. Secondary outcomes in the mITT population were successful overall response at 2 weeks after the end of treatment, all-cause mortality at days 14 and 56, and safety. Results Of 450 patients randomized, 400 comprised the mITT population. Baseline characteristics were balanced between groups. Successful overall response at EOIVT was observed in 60.3% of patients in the isavuconazole arm and 71.1% in the caspofungin arm (adjusted difference -10.8, 95% confidence interval -19.9–-1.8). The secondary endpoints, all-cause mortality, and safety were similar between arms. Median time to clearance of the bloodstream was comparable between groups. Conclusions This study did not demonstrate non-inferiority of isavuconazole to caspofungin for primary treatment of invasive candidiasis. Secondary endpoints were similar between both groups. Clinical Trials Registration NCT00413218. [ABSTRACT FROM AUTHOR]

Background. Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy Methods. We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of ≤2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes Results. Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P 5 .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point Conclusions. Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC. [ABSTRACT FROM AUTHOR]

Background. Surgical site infections (SSIs) following total hip arthroplasty can lead to prolonged hospitalization, increased morbidity and mortality, and high costs. This article analyzes the effect of various parameters of surgical antibiotic prophylaxis on the risk of SSI following total hip arthroplasty. Methods. Data about SSI and potential prophylaxis-, patient-, and procedure-related risk factors were prospectively collected for 1922 patients who underwent elective total hip arthroplasty in 11 hospitals that participated in the Dutch intervention project, Surgical Prophylaxis and Surveillance. Multivariate logistic regression analysis was performed to correct for random variation among hospitals. Results. SSIs (superficial and deep) occurred in 50 patients (2.6%). The highest odds ratios for SSI were found in patients who received prophylaxis after incision (2.8, 95% confidence interval [CI], 0.9-8.6; P = .07), had an American Society of Anesthesiology score that was >2 (2.8, 95% CI, 0.8-9.2; P = .09), and experienced a duration of surgery that was >75th percentile (2.5; 95% CI, 1.1-5.8; p = .04). Prolonged prophylaxis after the end of surgery and the use of antibiotic-impregnated cement did not contribute to fewer SSIs in this study. Conclusions. This study suggests that intervention programs in search of amendable factors to prevent SSI should focus on timely administration of antibiotic prophylaxis. [ABSTRACT FROM AUTHOR]

Background. Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. Methods. We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. Results. Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- γ and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- γ. Administration of recombinant IFN-γ resulted in both restoration of immunological parameters and a sustained clinical recovery. Conclusions. Refractory meningitis may be due to defective TNF and IFN-γ production, and IFN-γ treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis. [ABSTRACT FROM AUTHOR]