Serial monitoring of pancreatic stone protein for the detection of sepsis in intensive care unit patients with complicated abdominal surgery: A prospective, longitudinal cohort study.

PURPOSE: The objective of this study was to assess the performance of pancreatic stone protein (PSP) monitoring for the detection of sepsis, prediction of outcome and distinction between bacterial and fungal infections in intensive care unit (ICU) patients with complicated abdominal surgery. MATERIALS AND METHODS: In this prospective multicenter cohort study, patients with complicated abdominal surgery had serial PSP measurements during their ICU stay. Infectious episodes were classified as bacterial, fungal or mixed. PSPmax (maximal PSP value within 48 h of the diagnosis of infection) and ΔPSP (difference between PSPmax and the preceding PSP value) were used for analyses. RESULTS: PSPmax was obtained for 118 infectious episodes (68 patients). ΔPSP was available for 73 episodes (48 patients). Both PSPmax and ΔPSP were significantly higher in patients with sepsis and in patients with a fatal outcome. A PSPmax ≥124 ng/ml and a ΔPSP ≥34 ng/ml could detect sepsis with a sensitivity/specificity of 84%/54% and 69%/76%, respectively. There was no significant difference of PSPmax or ΔPSP between patients with bacterial/mixed versus fungal infections. CONCLUSIONS: Serial PSP monitoring may be an additional tool for the early detection of sepsis in patients with complicated abdominal surgery who are at high risk of severe infections.

[Invasive Campylobacter infections]. / Infections invasives à Campylobacter.

Campylobacter genus encompasses many species, among which C. jejuni, C. coli and C. fetus are the main human pathogens. C. jejuni/coli frequently cause self-limited enteritis in immunocompetent hosts and are seldomly associated with bacteriemia. C. fetus is less common as a human pathogen. It is rarely identified in fecal samples but can sometimes be isolated in blood samples from patients with comorbidities or immunosuppression. Campylobacter fetus bacteriemia is remarkable since it is associated with endovascular and deep-seated infections.

Le genre Campylobacter comprend plusieurs espèces pathogènes pour l'homme, en particulier C. jejuni, C. coli et C. fetus. C. jejuni et C. coli sont responsables d'entérites généralement spontanément résolutives chez l'individu sain, et peu fréquemment associées à des bactériémies. C. fetus est un pathogène méconnu, rarement identifié dans les échantillons fécaux mais parfois retrouvé dans des hémocultures, en particulier chez des patients présentant des comorbidités ou immunosupprimés. La bactériémie à C. fetus se distingue par son association avec des infections endovasculaires et des foyers infectieux profonds sans symptomatologie digestive.

Performance of the T2Candida Panel for the Diagnosis of Intra-abdominal Candidiasis.

Performance of T2Candida for detecting intra-abdominal candidiasis (IAC) was assessed in 48 high-risk patients. T2Candida sensitivity/specificity and positive/negative predictive values were 33%/93% and 71%/74%, respectively. IAC was present in 100% of cases with concordant positive T2Candida/1,3-beta-d-glucan and absent in 90% of concordant negative results. Combination T2Candida/1,3-beta-d-glucan may help guide treatment decisions.

Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines.

OBJECTIVES: Fluoroquinolone (FQ) prophylaxis was recommended in 2005 by European Conference on Infections in Leukemia (ECIL) for patients with prolonged neutropenia. In consideration of a worldwide increase in antibiotic resistance, the issue of FQ prophylaxis during neutropenia was re-evaluated. METHODS: Literature review of randomised controlled trials (RCT) and observational studies published in years 2006-2014 was performed. Their results were analysed in meta-analysis. Meta-regression model was applied to evaluate whether the rates of FQ resistance in community and hospital settings influenced the efficacy of FQ prophylaxis. The impact of FQ prophylaxis on colonisation and infection with resistant bacteria was reviewed. RESULTS: Two RCTs and 12 observational studies were identified. FQ prophylaxis did not have effect on mortality (pooled OR 1.01, 95%CI 0.73-1.41), but was associated with lower rate of bloodstream infections (BSI) (pooled OR 0.57, 95%CI 0.43-0.74) and episodes of fever during neutropenia (pooled OR 0.32, 95%CI 0.20-0.50). No effect of the background rate of FQ resistance on the efficacy of FQ prophylaxis was observed. In few studies, FQ prophylaxis resulted in an increased colonisation or infection with FQ- or multi-drug resistant strains. CONCLUSIONS: The possible benefits of FQ prophylaxis on BSI rate, but not on overall mortality, should be weighed against its impact in terms of toxicity and changes in local ecology in single centres.

[Evaluation of psychosocial difficulties and needs of persons living with HIV in a nurse consultation]. / Evaluation des difficultés psychosociales des personnes VIH au sein d'une consultation infirmière.

Despite the improvements in antiretroviral therapy, the psychosocial management of persons living with HIV remains complex and requires a multidisciplinary approach. An auto-evaluation scale of psychosocial difficulties and needs was used by a team of nurses working in an HIV outpatient clinic. After 3 years of experience, this well-accepted tool revealed a high prevalence of psychosocial difficulties within this population, including psychological health, financial situation and sexual life. This instrument also allowed implementing a number of targeted nurse interventions to improve the management of these patients.

Malgré les progrès effectués dans le domaine des traitements antirétroviraux, la prise en charge psychosociale des patients vivant avec le VIH reste complexe et nécessite une approche multidisciplinaire. Une échelle d'auto-évaluation des difficultés et besoins d'aides psychosociaux a été utilisée par une équipe d'infirmières travaillant dans une consultation ambulatoire VIH. Après 3 ans d'expérience, cet outil, très bien accepté par les patients, a permis de révéler une prévalence importante de difficultés psychosociales dans cette population, touchant notamment la santé psychique, la situation financière et la sexualité. Cet outil a permis en outre de mettre en place un certain nombre d'interventions infirmières ciblées pour améliorer la prise en charge des patients.

ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients.

The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies for various types of infection in patients with hematologic malignancies or hematopoietic stem cell transplantation recipients. Meetings are held every two years since 2005 and evidence-based recommendations are elaborated after evaluation of the literature and discussion among specialists of nearly all European countries. In this manuscript, the ECIL group presents the 2015-update of the recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis. Current data now allow a very strong recommendation in favor of echinocandins for first-line therapy of candidemia irrespective of the underlying predisposing factors. Anidulafungin has been given the same grading as the other echinocandins for hemato-oncological patients. The beneficial role of catheter removal in candidemia is strengthened. Aspergillus guidelines now recommend the use of either voriconazole or isavuconazole for first-line treatment of invasive aspergillosis, while first-line combination antifungal therapy is not routinely recommended. As only few new data were published since the last ECIL guidelines, no major changes were made to mucormycosis recommendations.

Radial Ultrasound-Assisted Transbronchial Biopsy: A New Diagnostic Approach for Non-Resolving Pulmonary Infiltrates in Neutropenic Hemato-Oncological Patients.

The role of radial-endobronchial ultrasound (R-EBUS) assisted transbronchial biopsy (TBB) for the diagnosis of peripheral pulmonary lesions is well established. However, no study has addressed its safety and value in hemato-oncological patients presenting with non-resolving infiltrates during persistent febrile neutropenia. To assess safety and feasibility of R-EBUS assisted TBB in severe thrombocytopenic and neutropenic patients. Over a period of 18 months, eight patients were assessed with R-EBUS assisted TBB after adequate platelet transfusion. This technique allowed precise localisation and sampling of the pulmonary lesions in seven of eight patients. In the seven patients, R-EBUS assisted TBB enabled treatment optimization. Invasive fungal infection was diagnosed in four patients, idiopathic acute fibrinous and organising pneumonia in three patients, and a granulomatous inflammation of undetermined origin in one patient. Importantly, no complications, such as bleeding, were observed. R-EBUS assisted TBB is a promising and safe procedure for the evaluation of nonresolving pulmonary infiltrates in febrile neutropenic hemato-oncological patients.

Association of lectin pathway proteins with intra-abdominal Candida infection in high-risk surgical intensive-care unit patients. A prospective cohort study within the fungal infection network of Switzerland.

OBJECTIVES: Human studies on the role of mannose-binding lectin (MBL) in patients with invasive candidiasis have yielded conflicting results. We investigated the influence of MBL and other lectin pathway proteins on Candida colonization and intra-abdominal candidiasis (IAC) in a cohort of high-risk patients. METHODS: Prospective observational cohort study of 89 high-risk intensive-care unit (ICU) patients. Levels of lectin pathway proteins at study entry and six MBL2 single-nucleotide polymorphisms were analyzed by sandwich-type immunoassays and genotyping, respectively, and correlated with development of heavy Candida colonization (corrected colonization index (CCI) ≥0.4) and occurrence of IAC during a 4-week period. RESULTS: Within 4 weeks after inclusion a CCI ≥0.4 and IAC was observed in 47% and 38% of patients respectively. Neither serum levels of MBL, ficolin-1, -2, -3, MASP-2 or collectin liver 1 nor MBL2 genotypes were associated with a CCI ≥0.4. Similarly, none of the analyzed proteins was found to be associated with IAC with the exception of lower MBL levels (HR 0.74, p = 0.02) at study entry. However, there was no association of MBL deficiency (<0.5 µg/ml), MBL2 haplo- or genotypes with IAC. CONCLUSION: Lectin pathway protein levels and MBL2 genotype investigated in this study were not associated with heavy Candida colonization or IAC in a cohort of high-risk ICU patients.

High-throughput hydrophilic interaction chromatography coupled to tandem mass spectrometry for the optimized quantification of the anti-Gram-negatives antibiotic colistin A/B and its pro-drug colistimethate.

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.

Impact of targeted antifungal prophylaxis in heart transplant recipients at high risk for early invasive fungal infection.

BACKGROUND: Invasive fungal infection (IFI) is associated with high mortality after heart transplantation (HTx). After two undiagnosed fatal cases of early disseminated fungal infections in our heart transplant program, a retrospective analysis was conducted to identify risk factors for the development of IFI and implement a new antifungal prophylaxis policy. METHODS: Clinical characteristics of HTx recipients hospitalized in our center (2004-2010) were recorded (Period 1), and risk factors associated with IFI were investigated using Cox regression analysis. From October 2010 to October 2012 (Period 2), targeted caspofungin prophylaxis was administered to all recipients at high risk for IFI, based on the results of the Period 1 analysis. RESULTS: During Period 1, 10% (6/59) of the patients developed IFI at a median onset of 9 days after transplantation. By multivariate analysis, the use of posttransplant extracorporeal membrane oxygenation (ECMO) was the strongest predictor for fungal infection (OR, 29.93; 95% CI, 1.51-592.57, P=0.03), whereas renal replacement therapy (RRT) and Aspergillus colonization were significant predictors only by univariate analysis. During Period 2, only 4% (1/26) of the patients developed IFI. In patients at high risk for IFI, antifungal prophylaxis was administered to 17% (4/23) in Period 1 versus 100% (13/13) in Period 2 (P<0.01). By survival analysis, antifungal prophylaxis was associated with a reduction in 90-day IFI incidence (HR, 0.14; 95% CI, 0.03-0.84, P=0.03) and 30-day mortality (HR, 0.25; 95% CI, 0.09-0.8, P=0.02). CONCLUSION: Extracorporeal membrane oxygenation was identified an important risk factor for IFI after HTx, and its use may require targeted administration of antifungal prophylaxis in the immediate posttransplant period.

[Infectious diseases]. / Maladies infectieuses.

The recommendations for the treatment of gonorrhea have been changed: ceftriaxone 500 mg IM plus azithromycin 1 g PO is recommended. Prophylaxis of recurrent cellulitis with penicillin 250 mg 2 x/d PO may be considered. E. coli ESBL does not require contact isolation anymore. Fecal transplantation seems so far to be the most effective treatment of recurrent C. dificile. Two new respiratory viruses, Middle East Coronavirus (MERS-CoV) and avian-origin Influenza A (H7N9) have been reported. Oral valganciclovir treatment reduces the risk of hearing loss in congenital CMV infection. An outbreak of mould infections of the central nervous system has been described in the United States following injection of contaminated steroids.

Polymorphisms in tumor necrosis factor-α increase susceptibility to intra-abdominal Candida infection in high-risk surgical ICU patients*.

OBJECTIVES: To evaluate the influence of genetic polymorphisms on the susceptibility to Candida colonization and intra-abdominal candidiasis, a blood culture-negative life-threatening infection in high-risk surgical ICU patients. DESIGN: Prospective observational cohort study. SETTING: Surgical ICUs from two University hospitals of the Fungal Infection Network of Switzerland. PATIENTS: Eighty-nine patients at high risk for intra-abdominal candidiasis (68 with recurrent gastrointestinal perforation and 21 with acute necrotizing pancreatitis). MEASUREMENTS AND MAIN RESULTS: Eighteen single-nucleotide polymorphisms in 16 genes previously associated with development of fungal infections were analyzed from patient's DNA by using an Illumina Veracode genotyping platform. Candida colonization was defined by recovery of Candida species from at least one nonsterile site by twice weekly monitoring of cultures from oropharynx, stools, urine, skin, and/or respiratory tract. A corrected colonization index greater than or equal to 0.4 defined "heavy" colonization. Intra-abdominal candidiasis was defined by the presence of clinical symptoms and signs of peritonitis or intra-abdominal abscess and isolation of Candida species either in pure or mixed culture from intraoperatively collected abdominal samples. Single-nucleotide polymorphisms in three innate immune genes were associated with development of a Candida corrected colonization index greater than or equal to 0.4 (Toll-like receptor rs4986790, hazard ratio = 3.39; 95% CI, 1.45-7.93; p = 0.005) or occurrence of intra-abdominal candidiasis (tumor necrosis factor-α rs1800629, hazard ratio = 4.31; 95% CI, 1.85-10.1; p= 0.0007; ß-defensin 1 rs1800972, hazard ratio = 3.21; 95% CI, 1.36-7.59; p = 0.008). CONCLUSION: We report a strong association between the promoter rs1800629 single-nucleotide polymorphism in tumor necrosis factor-α and an increased susceptibility to intra-abdominal candidiasis in a homogenous prospective cohort of high-risk surgical ICU patients. This finding highlights the relevance of the tumor necrosis factor-α functional polymorphism in immune response to fungal pathogens. Immunogenetic profiling in patients at clinical high risk followed by targeted antifungal interventions may improve the prevention or preemptive management of this life-threatening infection.

ß-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis.

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-ß-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. ß-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.

Multiplex ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification in human plasma of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, anidulafungin, and caspofungin.

Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 µl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 µg/ml; those of echinocandin quantification, 0.06 to 0.1 µg/ml), accurate (intra- and interassay biases of -9.9 to +5% and -4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 µg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC-MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research.

[A short journey through spirochetal infections]. / Les spirochètes dans tous leurs etats.

Spirochetal infections present with a variety of clinical syndromes and epidemiologic features. Diagnosis remains challenging for the clinician because of the often protean clinical presentation and poor performance of stan-dard microbiological tests. We present 3 clinical cases, illustrating interesting or unusual features of these infections. First, we present a case of leptospirosis acquired in Switzerland after a rat bite. We then present a case of early disseminated Lyme disease with multiple erythema migrans, lymphopenia, thrombocytopenia and liver enzyme elevation. Finally, we present a case of secondary syphilis in an HIV-positive man, complicated by sensorineural deafness. For each case we highlight and discuss the specific epidemiological, clinical and therapeutic features.

Suicide in HIV-infected individuals and the general population in Switzerland, 1988-2008.

OBJECTIVE: High rates of suicide have been described in HIV-infected patients, but it is unclear to what extent the introduction of highly active antiretroviral therapy (HAART) has affected suicide rates. The authors examined time trends and predictors of suicide in the pre-HAART (1988-1995) and HAART (1996-2008) eras in HIV-infected patients and the general population in Switzerland. METHOD: The authors analyzed data from the Swiss HIV Cohort Study and the Swiss National Cohort, a longitudinal study of mortality in the Swiss general population. The authors calculated standardized mortality ratios comparing HIV-infected patients with the general population and used Poisson regression to identify risk factors for suicide. RESULTS: From 1988 to 2008, 15,275 patients were followed in the Swiss HIV Cohort Study for a median duration of 4.7 years. Of these, 150 died by suicide (rate 158.4 per 100,000 person-years). In men, standardized mortality ratios declined from 13.7 (95% CI=11.0-17.0) in the pre-HAART era to 3.5 (95% CI=2.5-4.8) in the late HAART era. In women, ratios declined from 11.6 (95% CI=6.4-20.9) to 5.7 (95% CI=3.2-10.3). In both periods, suicide rates tended to be higher in older patients, in men, in injection drug users, and in patients with advanced clinical stage of HIV illness. An increase in CD4 cell counts was associated with a reduced risk of suicide. CONCLUSIONS: Suicide rates decreased significantly with the introduction of HAART, but they remain above the rate observed in the general population, and risk factors for suicide remain similar. HIV-infected patients remain an important target group for suicide prevention.