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Background: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown., Methods: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization., Results: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001)., Conclusions: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27., Competing Interests: Potential conflicts of interest. J. M. reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Gilead Sciences, and Pfizer, including participation on a data and safety monitoring board or advisory board (DSMB) for MSD, Gilead, and Pfizer. T. L. reports payment for participation on virtual European Society for Blood and Marrow Transplantation meeting. J. P. D. reports consulting fees from F2G and Gilead Sciences, including payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F2G, Gilead Sciences, and Pfizer, and unpaid leadership or fiduciary role in other board, society, committee, or advocacy group for the European PCR Initiative Foundation. C. R. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Sandoz and support for attending meetings and/or travel for Gilead, MSD, Pfizer, and Sandoz. N. B. reports participation as the chair on a DSMB for the SHORT trial and roles as the president of the Dutch Society of Hematology (unpaid), Treasurer Board member for HOVON (unpaid), chair of the Horizonscan WP Hematology Dutch Healthcare Institute (vacancy fee), and member of the board of supervisors for Matchis (compensation according to Dutch law). D. S. reports grants or contracts from Pfizer, Novartis, BMS, AbbVie, MSD, and Takeda, including consulting fees from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, Janssen-Cilag, and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, and Janssen-Cilag; support for attending meetings and/or travel from Pfizer, Novartis, BMS, AbbVie, Takeda, MSD, and Janssen-Cilag; and a leadership or fiduciary role for other board, society, committee, or advocacy groups, paid or unpaid for Belgian College for Reimbursement of Orphan Drugs. F. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie and Sanofi; support for attending an international meeting from Novartis and Pfizer; and participation on a DSMB or advisory board for some academic studies (no fee) and Maatpharma (paid to institution). W. J. H. reports payment or honoraria for presentations from AbbVie, Amgen, AstraZeneca, Celgene/BMS, Gilead Sciences, and Janssen; support for attending meetings from IPSEN Pharma, Amgen, and Abbvie; and support for attending adboards for Amgen, Astrazeneca, Celgene/BMS, Gilead Sciences Janssen, MSD, and Sanofi-Aventis. B. V. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Sanofi, and Al Miral; support for attending meetings and/or travel for ViiV; and participation on a DSMB or advisory board for Pfizer. L. D. reports consulting fees from MSD, Pfizer, and Teva; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Pfizer, Teva, and Sandoz; support for attending meetings and/or travel from Sandoz; and participation on an advisory board for Pfizer. C. C. L. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Kite and support for attending meetings and/or travel for Gilead and Kite. C. S. P. reports book royalties from Elsevier and Thieme and honoraria for lectures from Canon Medical Systems. R. B. reports consulting fees from Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead; and support for attending meetings and/or travel for Gilead. P. E. V. reports research grants from ZonMw, Welcome Trust, Eurostars, EORTC, and RIVM; consulting fees from F2G, Gilead Sciences, and Pfizer; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences and Pfizer. F. L. reports research grants from Merck, Sharpe & Dohme, Gilead, Pfizer, and Novartis and consulting fees (advisory board) from Gilead and Pfizer. P. Y. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences Switzerland AG and Pfizer PFE Switzerland GmbH and support for Gilead Sciences Switzerland Sarl for TIMM, Trends in Medical Mycology. D. H. reports employment with Merck & Co. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The substantial progresses during the last decades in the field of infectious diseases have significantly improved their prevention, diagnosis and treatment. Basic and medical sciences have efficiently dealt with the challenges of emerging infections, infectious complications related to the increasing complexity of medical practices and marked slow-down in the development of new antimicrobial agents. During the worldwide crisis related to the COVID-19 pandemic, the « medical normality » has been put in stand-by, but medical advances have fortunately continued. In the present article we present new knowledge in the field of bacterial, viral and fungal infections, which may modify hospital and ambulatory practices. Significant achievements in the field of COVID-19 will be presented in a future article., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: The increasing incidence of candidemia and emergence of drug-resistant Candida species are major concerns worldwide. Long-term surveillance studies are needed., Methods: The Fungal Infection Network of Switzerland (FUNGINOS) conducted a 15-year (2004-2018), nationwide, epidemiological study of candidemia. Hospital-based incidence of candidemia, Candida species distribution, antifungal susceptibility, and consumption were stratified in 3 periods (2004-2008, 2009-2013, 2014-2018). Population-based incidence over the period 2009-2018 derived from the Swiss Antibiotic Resistance Surveillance System (ANRESIS)., Results: A total of 2273 Candida blood isolates were studied. Population and hospital-based annual incidence of candidemia increased from 2.96 to 4.20/100 000 inhabitants ( P = .022) and 0.86 to 0.99/10 000 patient-days ( P = .124), respectively. The proportion of Candida albicans decreased significantly from 60% to 53% ( P = .0023), whereas Candida glabrata increased from 18% to 27% ( P < .0001). Other non- albicans Candida species remained stable. Candida glabrata bloodstream infections occurred predominantly in the age group 18-40 and above 65 years. A higher proportional increase of C glabrata was recorded in wards (18% to 29%, P < .0001) versus intensive care units (19% to 24%, P = .22). According to Clinical and Laboratory Standards Institute, nonsusceptibility to fluconazole in C albicans was observed in 1% of isolates, and anidulafungin and micafungin nonsusceptibility was observed in 2% of C albicans and C glabrata . Fluconazole consumption, the most frequently used antifungal, remained stable, whereas use of mold-active triazoles and echinocandins increased significantly in the last decade ( P < .0001)., Conclusions: Over the 15-year period, the incidence of candidemia increased. A species shift toward C glabrata was recently observed, concurring with increased consumption of mold-active triazoles., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Candidemia is an opportunistic infection associated with high morbidity and mortality in patients hospitalized both inside and outside intensive care units (ICUs). Identification of patients at risk is crucial to ensure prompt antifungal therapy. We sought to assess risk factors for candidemia and death, both outside and inside ICUs., Methods: This prospective multicenter matched case-control study involved six teaching hospitals in Switzerland and France. Cases were defined by positive blood cultures for Candida sp. Controls were matched to cases using the following criteria: age, hospitalization ward, hospitalization duration, and, when applicable, type of surgery. One to three controls were enrolled by case. Risk factors were analyzed by univariate and multivariate conditional regression models, as a basis for a new scoring system to predict candidemia., Results: One hundred ninety-two candidemic patients and 411 matched controls were included. Forty-four percent of included patients were hospitalized in ICUs, and 56% were hospitalized outside ICUs. Independent risk factors for candidemia in the ICU population included total parenteral nutrition, acute kidney injury, heart disease, prior septic shock, and exposure to aminoglycoside antibiotics. Independent risk factors for candidemia in the non-ICU population included central venous catheter, total parenteral nutrition, and exposure to glycopeptides and nitroimidazoles. The accuracy of the scores based on these risk factors is better in the ICU than in the non-ICU population. Independent risk factors for death in candidemic patients included septic shock, acute kidney injury, and the number of antibiotics to which patients were exposed before candidemia., Discussion: While this study shows a role for known and novel risk factors for candidemia, it specifically highlights important differences in their distribution according to the hospital setting (ICU versus non-ICU)., Conclusion: This study provides novel risk scores for candidemia accounting for the hospital setting and recent progress in patients' management strategies and fungal epidemiology.

Purpose: Adequate empirical antibiotic dose selection for critically ill burn patients is difficult due to extreme variability in drug pharmacokinetics. Therapeutic drug monitoring (TDM) may aid antibiotic prescription and implementation of initial empirical antimicrobial dosage recommendations. This study evaluated how gradual TDM introduction altered empirical dosages of meropenem and imipenem/cilastatin in our burn ICU., Methods: Imipenem/cilastatin and meropenem use and daily empirical dosage at a five-bed burn ICU were analyzed retrospectively. Data for all burn admissions between 2001 and 2011 were extracted from the hospital's computerized information system. For each patient receiving a carbapenem, episodes of infection were reviewed and scored according to predefined criteria. Carbapenem trough serum levels were characterized. Prior to May 2007, TDM was available only by special request. Real-time carbapenem TDM was introduced in June 2007; it was initially available weekly and has been available 4 days a week since 2010., Results: Of 365 patients, 229 (63%) received antibiotics (109 received carbapenems). Of 23 TDM determinations for imipenem/cilastatin, none exceeded the predefined upper limit and 11 (47.8%) were insufficient; the number of TDM requests was correlated with daily dose (r=0.7). Similar numbers of inappropriate meropenem trough levels (30.4%) were below and above the upper limit. Real-time TDM introduction increased the empirical dose of imipenem/cilastatin, but not meropenem., Conclusions: Real-time carbapenem TDM availability significantly altered the empirical daily dosage of imipenem/cilastatin at our burn ICU. Further studies are needed to evaluate the individual impact of TDM-based antibiotic adjustment on infection outcomes in these patients., (Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.)

Colistin is a last resort's antibacterial treatment in critically ill patients with multi-drug resistant Gram-negative infections. As appropriate colistin exposure is the key for maximizing efficacy while minimizing toxicity, individualized dosing optimization guided by therapeutic drug monitoring is a top clinical priority. Objective of the present work was to develop a rapid and robust HPLC-MS/MS assay for quantification of colistin plasma concentrations. This novel methodology validated according to international standards simultaneously quantifies the microbiologically active compounds colistin A and B, plus the pro-drug colistin methanesulfonate (colistimethate, CMS). 96-well micro-Elution SPE on Oasis Hydrophilic-Lipophilic-Balanced (HLB) followed by direct analysis by Hydrophilic Interaction Liquid Chromatography (HILIC) with Ethylene Bridged Hybrid--BEH--Amide phase column coupled to tandem mass spectrometry allows a high-throughput with no significant matrix effect. The technique is highly sensitive (limit of quantification 0.014 and 0.006 μg/mL for colistin A and B), precise (intra-/inter-assay CV 0.6-8.4%) and accurate (intra-/inter-assay deviation from nominal concentrations -4.4 to +6.3%) over the clinically relevant analytical range 0.05-20 μg/mL. Colistin A and B in plasma and whole blood samples are reliably quantified over 48 h at room temperature and at +4°C (<6% deviation from nominal values) and after three freeze-thaw cycles. Colistimethate acidic hydrolysis (1M H2SO4) to colistin A and B in plasma was completed in vitro after 15 min of sonication while the pro-drug hydrolyzed spontaneously in plasma ex vivo after 4 h at room temperature: this information is of utmost importance for interpretation of analytical results. Quantification is precise and accurate when using serum, citrated or EDTA plasma as biological matrix, while use of heparin plasma is not appropriate. This new analytical technique providing optimized quantification in real-life conditions of the microbiologically active compounds colistin A and B offers a highly efficient tool for routine therapeutic drug monitoring aimed at individualizing drug dosing against life-threatening infections., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Rationale: Life-threatening intraabdominal candidiasis (IAC) occurs in 30 to 40% of high-risk surgical intensive care unit (ICU) patients. Although early IAC diagnosis is crucial, blood cultures are negative, and the role of Candida score/colonization indexes is not established., Objectives: The aim of this prospective Fungal Infection Network of Switzerland (FUNGINOS) cohort study was to assess accuracy of 1,3-β-d-glucan (BG) antigenemia for diagnosis of IAC., Methods: Four hundred thirty-four consecutive adults with abdominal surgery or acute pancreatitis and ICU stay 72 hours or longer were screened: 89 (20.5%) at high risk for IAC were studied (68 recurrent gastrointestinal tract perforation, 21 acute necrotizing pancreatitis). Diagnostic accuracy of serum BG (Fungitell), Candida score, and colonization indexes was compared., Measurements and Main Results: Fifty-eight of 89 (65%) patients were colonized by Candida; 29 of 89 (33%) presented IAC (27 of 29 with negative blood cultures). Nine hundred twenty-one sera were analyzed (9/patient): median BG was 253 pg/ml (46-9,557) in IAC versus 99 pg/ml (8-440) in colonization (P < 0.01). Sensitivity and specificity of two consecutive BG measurements greater than or equal to 80 pg/ml were 65 and 78%, respectively. In recurrent gastrointestinal tract perforation it was 75 and 77% versus 90 and 38% (Candida score ≥ 3), 79 and 34% (colonization index ≥ 0.5), and 54 and 63% (corrected colonization index ≥ 0.4), respectively. BG positivity anticipated IAC diagnosis (5 d) and antifungal therapy (6 d). Severe sepsis/septic shock and death occurred in 10 of 11 (91%) and 4 of 11 (36%) patients with BG 400 pg/ml or more versus 5 of 18 (28%, P = 0.002) and 1 of 18 (6%, P = 0.05) with BG measurement less than 400 pg/ml. β-Glucan decreased in IAC responding to therapy and increased in nonresponse., Conclusions: BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture-negative IAC. This proof-of-concept observation in strictly selected high-risk surgical ICU patients deserves investigation of BG-driven preemptive therapy.

Invasive candidiasis ranges from 5 to 10 cases per 1,000 ICU admissions and represents 5% to 10% of all ICU-acquired infections, with an overall mortality comparable to that of severe sepsis/septic shock. A large majority of them are due to Candida albicans, but the proportion of strains with decreased sensitivity or resistance to fluconazole is increasingly reported. A high proportion of ICU patients become colonized, but only 5% to 30% of them develop an invasive infection. Progressive colonization and major abdominal surgery are common risk factors, but invasive candidiasis is difficult to predict and early diagnosis remains a major challenge. Indeed, blood cultures are positive in a minority of cases and often late in the course of infection. New nonculture-based laboratory techniques may contribute to early diagnosis and management of invasive candidiasis. Both serologic (mannan, antimannan, and betaglucan) and molecular (Candida-specific PCR in blood and serum) have been applied as serial screening procedures in high-risk patients. However, although reasonably sensitive and specific, these techniques are largely investigational and their clinical usefulness remains to be established. Identification of patients susceptible to benefit from empirical antifungal treatment remains challenging, but it is mandatory to avoid antifungal overuse in critically ill patients. Growing evidence suggests that monitoring the dynamic of Candida colonization in surgical patients and prediction rules based on combined risk factors may be used to identify ICU patients at high risk of invasive candidiasis susceptible to benefit from prophylaxis or preemptive antifungal treatment.

Invasive mould disease is a growing threat for immunocompromised patients. The optimum time to use mould-active antifungal agents is much debated. Current approaches to antifungal prophylaxis, early treatment (empirical and pre-emptive therapy) and treatment of documented mould infections in onco-haematology patients are discussed.

Purpose: Thirty to forty percent of patients with recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis develop intra-abdominal invasive candidiasis (IC). A corrected Candida colonization index (CCI) > or =0.4 is a powerful predictor of IC. Fluconazole prevents intra-abdominal IC in this setting, but azole-resistant Candida species are emerging. The aim of this study was to explore the efficacy and safety of caspofungin for prevention of intra-abdominal IC in high-risk surgical patients., Methods: Prospective non-comparative single-center study in consecutive adult surgical patients with recurrent gastrointestinal perforation/anastomotic leakage or acute necrotizing pancreatitis. Preventive caspofungin therapy (70 mg, then 50 mg/day) was given until resolution of the surgical condition. Candida colonization index and CCI, occurrence of intra-abdominal IC and adverse events were monitored., Results: Nineteen patients were studied: 16 (84%) had recurrent gastrointestinal perforation/anastomotic leakage and 3 (16%) acute necrotizing pancreatitis. The median duration of preventive caspofungin therapy was 16 days (range 4-46). The colonization index decreased significantly during study therapy, and the CCI remained <0.4 in all patients. Caspofungin was successful for prevention of intra-abdominal IC in 18/19 patients (95%, 1 breakthrough IC 5 days after inclusion). No drug-related adverse event requiring caspofungin discontinuation occurred., Conclusion: Caspofungin may be efficacious and safe for prevention of intra-abdominal candidiasis in high-risk surgical patients. This needs to be further investigated in randomized trials.

When requesting a blood level measurement in the context of "Therapeutic drug monitoring" (TDM), numerous aspects have to be considered in the pre-analytical and analytical area, as in the integration of associated clinical data. This review presents therapeutic classes for which a clinical benefit of TDM is established or suggested, at least in some settings. For each class of drugs, the main pharmacokinetic, pre-analytical, analytical and clinical aspects are evaluated in the scope of such a monitoring. Each step of the TDM process is important and none should be neglected. Additional clinical trials are however warranted to better establish the exact conditions of use for such a monitoring.

Background: Invasive fungal infections (IFIs) are life-threatening complications in neutropenic patients with hematological malignancies. Because early diagnosis of IFI is difficult, new noninvasive, culture-independent diagnostic tools are needed to improve clinical management. Recent studies have reported that detection of 1,3-beta-D-glucan (BG) antigenemia may be useful for diagnosis of IFI. The aim of the present prospective study was to evaluate the usefulness of monitoring BG in patients undergoing chemotherapy for acute leukemia., Methods: BG antigenemia was measured by a colorimetric assay twice weekly in the absence of fever and daily in the presence of fever. IFIs were classified according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group., Results: During 190 consecutive neutropenic episodes (median duration, 22 days; range, 7-113 days) in 95 patients, 30 proven or probable IFIs (13 aspergillosis, 15 candidiasis, and 2 mixed IFIs) were diagnosed. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of 2 consecutive BG values > or =7 pg/mL for diagnosis of proven or probable IFI was 0.63 (95% confidence interval, 0.44-0.79), 0.96 (95% confidence interval, 0.89-0.98), 0.79 (95% confidence interval, 0.57-0.92), 0.91 (95% confidence interval, 0.84-0.95), and 0.89, respectively. The time interval between onset of fever as first sign of IFI and BG antigenemia was significantly shorter than the time to diagnosis of IFI by clinical, microbiological, radiological, and/or histopathological criteria (P < .001). BG values >50 pg/mL were observed in only 2 patients, both of whom experienced failure of antifungal therapy., Conclusion: Monitoring of BG antigenemia is a useful noninvasive method for early diagnosis of IFI in patients with acute leukemia.

Background: Voriconazole is the therapy of choice for aspergillosis and a new treatment option for candidiasis. Liver disease, age, genetic polymorphism of the cytochrome CYP2C19, and comedications influence voriconazole metabolism. Large variations in voriconazole pharmacokinetics may be associated with decreased efficacy or with toxicity., Methods: This study was conducted to assess the utility of measuring voriconazole blood levels with individualized dose adjustments., Results: A total of 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A large variability in voriconazole trough blood levels was observed, ranging from 5.5 mg/L (a level possibly associated with toxicity) in 31% of cases. Lack of response to therapy was more frequent in patients with voriconazole levels 1 mg/L (15 [12%] of 39 patients; P=.02). Blood levels >1 mg/L were reached after increasing the voriconazole dosage, with complete resolution of infection in all 6 cases. Among 16 patients with voriconazole trough blood levels >5.5 mg/L, 5 patients (31%) presented with an encephalopathy, including 4 patients who were treated intravenously with a median voriconazole dosage of 8 mg/kg per day, whereas none of the patients with levels

A panel of infectious disease specialists, clinical microbiologists and hospital epidemiologists of the five Swiss university hospitals reviewed the current literature on the treatment of invasive fungal infections in adults and formulated guidelines for the management of patients in Switzerland. For empirical therapy of Candida bloodstream infection, fluconazole is the drug of choice in non-neutropenic patients with no severe sepsis or septic shock or recent exposure to azoles. Amphotericin B deoxycholate or caspofungin would be the treatment option for patients with previous azole exposure. In neutropenic patients, empirical therapy with amphotericin B deoxycholate is considered first choice. In patients with severe sepsis and septic shock, caspofungin is the drug of first choice. For therapy of microbiologically-documented Candida infection, fluconazole is the drug of choice for infections due to C. albicans, C. tropicalis or C. parapsilosis. When infections are caused by C. glabrata or by C. krusei, caspofungin or amphotericin B deoxycholate are first line therapies. Treatment guidelines for invasive aspergillosis (IA) were stratified into primary therapy, salvage therapy and combination therapy in critically ill patients. Voriconazole is recommended for primary (ie upfront) therapy. Caspofungin, voriconazole (if not used for primary therapy) or liposomal amphotericin B are recommended for salvage therapy for refractory disease. Combination therapy with caspofungin plus voriconazole or liposomal amphotericin B should be considered in critically ill patients. Amphotericin B deoxycholate is recommended as initial therapy for the empirical therapy in patients with neutropenia and persistent fever with close monitoring of adverse events.

Objective: To compare the management of invasive candidiasis between infectious disease and critical care specialists., Design and Setting: Clinical case scenarios of invasive candidiasis were presented during interactive sessions at national specialty meetings. Participants responded to questions using an anonymous electronic voting system., Patients and Participants: Sixty-five infectious disease and 51 critical care physicians in Switzerland., Results: Critical care specialists were more likely to ask advice from a colleague with expertise in the field of fungal infections to treat Candida glabrata (19.5% vs. 3.5%) and C. krusei (36.4% vs. 3.3%) candidemia. Most participants reported that they would change or remove a central venous catheter in the presence of candidemia, but 77.1% of critical care specialists would start concomitant antifungal treatment, compared to only 50% of infectious disease specialists. Similarly, more critical care specialists would start antifungal prophylaxis when Candida spp. are isolated from the peritoneal fluid at time of surgery for peritonitis resulting from bowel perforation (22.2% vs. 7.2%). The two groups equally considered Candida spp. as pathogens in tertiary peritonitis, but critical care specialists would more frequently use amphotericin B than fluconazole, caspofungin, or voriconazole. In mechanically ventilated patients the isolation of 10(4) Candida spp. from a bronchoalveolar lavage was considered a colonizing organism by 94.9% of infectious disease, compared to 46.8% of critical care specialists, with a marked difference in the use of antifungal agents (5.1% vs. 51%)., Conclusions: These data highlight differences between management approaches for candidiasis in two groups of specialists, particularly in the reported use of antifungals.

Invasive mycoses have emerged as a major cause of morbidity and mortality. Epidemiological studies have shown that surgery services have the highest rate of Candida infections in the hospital. In addition to classical risk factors, heavy Candida colonization, recurrent gastrointestinal perforations, and acute pancreatitis are frequently associated with invasive candidiasis. Because prompt initiation of antifungal therapy is critical for cure but difficult to accomplish, prevention of fungal infections may play an important role in this clinical setting; however, few prophylactic or preemptive studies have been done to date. The choice, route of administration, and dose of the antifungal and comparator regimens and the use of clinically relevant and robust study end points are critical for the trial design. Various criteria have been used to identify patients at risk of candidiasis: surgical condition, presence of multiple risk factors, colonization indexes, or expected length of stay in the intensive care unit. Some are not selective enough, and others are time consuming and expensive. Rigorous selection of high-risk patients is crucial to optimize the risk-benefit ratio of preventive antifungal strategies. The aim is to maximize chances of reducing morbidity and mortality while minimizing treatment costs, exposure of low-risk patients to adverse events, and emergence of resistant fungal strains.

Candida species are among the most common bloodstream pathogens in the United States, where the emergence of azole-resistant Candida glabrata and Candida krusei are major concerns. Recent comprehensive longitudinal data from Europe are lacking. We conducted a nationwide survey of candidemia during 1991-2000 in 17 university and university-affiliated hospitals representing 79% of all tertiary care hospital beds in Switzerland. The number of transplantations and bloodstream infections increased significantly (P<.001). A total of 1137 episodes of candidemia were observed: Candida species ranked seventh among etiologic agents (2.9% of all bloodstream isolates). The incidence of candidemia was stable over a 10-year period. C. albicans remained the predominant Candida species recovered (66%), followed by C. glabrata (15%). Candida tropicalis emerged (9%), the incidence of Candida parapsilosis decreased (1%), and recovery of C. krusei remained rare (2%). Fluconazole consumption increased significantly (P<.001). Despite increasing high-risk activities, the incidence of candidemia remained unchanged, and no shift to resistant species occurred.

Chemotherapy-related neutropenia is frequently complicated by infections. In granulocytopenic cancer patients, the early empiric administration of broad-spectrum antibiotics is the cornerstone of the management and has dramatically decreased the infection-related mortality. Several intravenous antibiotic regimens have been shown to be effective and well tolerated, especially monotherapies with broad-spectrum beta-lactams. The analysis of the outcome of febrile neutropenic patients has allowed the differentiation of those at high risk from those at low risk of infectious complications. In low risk patients, oral antibiotic regimens have been shown as effective as intravenous regimens. Running studies will allow to determine the advantages and limits of an outpatient management.

The azole antifungal fluconazole possesses only fungistatic activity in Candida albicans and, therefore, this human pathogen is tolerant to this agent. However, tolerance to fluconazole can be inhibited when C. albicans is exposed to fluconazole combined with the immunosuppressive drug cyclosporin A, which is known to inhibit calcineurin activity in yeast. A mutant lacking both alleles of a gene encoding the calcineurin A subunit (CNA) lost viability in the presence of fluconazole, thus making calcineurin essential for fluconazole tolerance. Consistent with this observation, tolerance to fluconazole was modulated by calcium ions or by the expression of a calcineurin A derivative autoactivated by the removal of its C-terminal inhibitory domain. Interestingly, CNA was also essential for tolerance to other antifungal agents (voriconazole, itraconazole, terbinafine, amorolfine) and to several other metabolic inhibitors (caffeine, brefeldin A, mycophenolic acid, fluphenazine) or cell wall-perturbing agents (SDS, calcofluor white, Congo red), thus indicating that the calcineurin pathway plays an important role in the survival of C. albicans in the presence of external growth inhibitors. Several genes, including PMC1, a vacuolar calcium P-type ATPase, were regulated in a calcineurin- and fluconazole-dependent manner. However, PMC1 did not play a direct role in the survival of C. albicans when exposed to fluconazole. In addition to these different properties, calcineurin was found to affect colony morphology in several media known to modulate the C. albicans dimorphic switch. In particular, calcineurin was found to be essential for C. albicans viability in serum-containing media. Finally, calcineurin was found to be necessary for the virulence of C. albicans in a mice model of infection, thus making calcineurin an important element for adequate adaptation to the conditions of the host environment.

Leptospirosis is a rare disease in Switzerland. However its incidence is probably underestimated, due to its broad spectrum of presentations, including subclinical benign forms and the ictero-hemorragic form of the Weil's syndrome, whose mortality is high. We describe here a case of Weil's syndrome acquired in Switzerland with a favourable outcome under antibiotherapy. Even in the absence of any travel, the association of an acute renal insufficiency and jaundice with only moderate hepatic cytolysis should lead to the suspicion of leptospirosis. Clinical and epidemiological aspects of the disease are discussed in the article.

High performance liquid chromatography (HPLC) is the reference method for measuring concentrations of antimicrobials in blood. This technique requires careful sample preparation. Protocols using organic solvents and/or solid extraction phases are time consuming and entail several manipulations, which can lead to partial loss of the determined compound and increased analytical variability. Moreover, to obtain sufficient material for analysis, at least 1 ml of plasma is required. This constraint makes it difficult to determine drug levels when blood sample volumes are limited. However, drugs with low plasma-protein binding can be reliably extracted from plasma by ultra-filtration with a minimal loss due to the protein-bound fraction. This study validated a single-step ultra-filtration method for extracting fluconazole (FLC), a first-line antifungal agent with a weak plasma-protein binding, from plasma to determine its concentration by HPLC. Spiked FLC standards and unknowns were prepared in human and rat plasma. Samples (240 microl) were transferred into disposable microtube filtration units containing cellulose or polysulfone filters with a 5 kDa cut-off. After centrifugation for 60 min at 15000g, FLC concentrations were measured by direct injection of the filtrate into the HPLC. Using cellulose filters, low molecular weight proteins were eluted early in the chromatogram and well separated from FLC that eluted at 8.40 min as a sharp single peak. In contrast, with polysulfone filters several additional peaks interfering with the FLC peak were observed. Moreover, the FLC recovery using cellulose filters compared to polysulfone filters was higher and had a better reproducibility. Cellulose filters were therefore used for the subsequent validation procedure. The quantification limit was 0.195 mgl(-1). Standard curves with a quadratic regression coefficient > or = 0.9999 were obtained in the concentration range of 0.195-100 mgl(-1). The inter and intra-run accuracies and precisions over the clinically relevant concentration range, 1.875-60 mgl(-1), fell well within the +/-15% variation recommended by the current guidelines for the validation of analytical methods. Furthermore, no analytical interference was observed with commonly used antibiotics, antifungals, antivirals and immunosuppressive agents. Ultra-filtration of plasma with cellulose filters permits the extraction of FLC from small volumes (240 microl). The determination of FLC concentrations by HPLC after this single-step procedure is selective, precise and accurate.