Christina Orasch

β-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-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.

Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients

OBJECTIVES A knowledge of current epidemiology and resistance patterns is crucial to the choice of empirical treatment for bacteraemias in haematology and cancer patients. METHODS A literature review on bacteraemias in cancer patients considered papers published between January 1st 2005 and July 6th 2011. Additionally, in 2011, a questionnaire on the aetiology and resistance in bacteraemias, and empirical treatment, was sent to participants of the European Conference on Infections in Leukemia (ECIL) meetings; recipients were from 80 haematology centres. RESULTS For the literature review, data from 49 manuscripts were analysed. The questionnaire obtained responses from 39 centres in 18 countries. Compared with the published data, the questionnaire reported more recent data, and showed a reduction of the Gram-positive to Gram-negative ratio (55%:45% vs. 60%:40%), increased rates of enterococci (8% vs. 5%) and Enterobacteriaceae (30% vs. 24%), a decreased rate of Pseudomonas aeruginosa (5% vs. 10%), and lower resistance rates for all bacteria. Nevertheless the median rates of ESBL-producers (15-24%), aminoglycoside-resistant Gram-negatives (5-14%) and carbapenem-resistant P. aeruginosa (5-14%) were substantial, and significantly higher in South-East vs. North-West Europe. CONCLUSIONS The published epidemiological data on bacteraemias in haematology are scanty and mostly dated. Important differences in aetiology and resistance exist among centres. Updated analyses of the local epidemiology are mandatory to support appropriate empirical therapy.

Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011)

The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4th European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists.

Candida species distribution and antifungal susceptibility testing according to European Committee on Antimicrobial Susceptibility Testing and new vs. old Clinical and Laboratory Standards Institute clinical breakpoints: a 6-year prospective candidaemia survey from the fungal infection network of Switzerland

We analyzed the species distribution of Candida blood isolates (CBIs), prospectively collected between 2004 and 2009 within FUNGINOS, and compared their antifungal susceptibility according to clinical breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in 2013, and the Clinical and Laboratory Standards Institute (CLSI) in 2008 (old CLSI breakpoints) and 2012 (new CLSI breakpoints). CBIs were tested for susceptiblity to fluconazole, voriconazole and caspofungin by microtitre broth dilution (Sensititre® YeastOne™ test panel). Of 1090 CBIs, 675 (61.9%) were C. albicans, 191 (17.5%) C. glabrata, 64 (5.9%) C. tropicalis, 59 (5.4%) C. parapsilosis, 33 (3%) C. dubliniensis, 22 (2%) C. krusei and 46 (4.2%) rare Candida species. Independently of the breakpoints applied, C. albicans was almost uniformly (>98%) susceptible to all three antifungal agents. In contrast, the proportions of fluconazole- and voriconazole-susceptible C. tropicalis and F-susceptible C. parapsilosis were lower according to EUCAST/new CLSI breakpoints than to the old CLSI breakpoints. For caspofungin, non-susceptibility occurred mainly in C. krusei (63.3%) and C. glabrata (9.4%). Nine isolates (five C. tropicalis, three C. albicans and one C. parapsilosis) were cross-resistant to azoles according to EUCAST breakpoints, compared with three isolates (two C. albicans and one C. tropicalis) according to new and two (2 C. albicans) according to old CLSI breakpoints. Four species (C. albicans, C. glabrata, C. tropicalis and C. parapsilosis) represented >90% of all CBIs. In vitro resistance to fluconazole, voriconazole and caspofungin was rare among C. albicans, but an increase of non-susceptibile isolates was observed among C. tropicalis/C. parapsilosis for the azoles and C. glabrata/C. krusei for caspofungin according to EUCAST and new CLSI breakpoints compared with old CLSI breakpoints.

Association of Alcohol Consumption and HIV Surrogate Markers in Participants of the Swiss HIV Cohort Study

Background:Alcohol consumption may affect the course of HIV infection and/or antiretroviral therapy (ART). The authors investigated the association between self-reported alcohol consumption and HIV surrogate markers in both treated and untreated individuals. Design:Prospective cohort study. Methods:Over a 7-year period, the authors analyzed 2 groups of individuals in the Swiss HIV Cohort Study: (1) ART-naïve individuals remaining off ART and (2) individuals initiating first ART. For individuals initiating first ART, time-dependent Cox proportional hazards models were used to assess the association between alcohol consumption, virological failure, and ART interruption. For both groups, trajectories of log-transformed CD4 cell counts were analyzed using linear mixed models with repeated measures. Results:The authors included 2982 individuals initiating first ART and 2085 ART naives. In individuals initiating first ART, 241 (8%) experienced virological failure. Alcohol consumption was not associated with virological failure. ART interruption was noted in 449 (15%) individuals and was more prevalent in severe compared with none/light health risk drinkers [hazard ratio: 2.24, 95% confidence interval: 1.42 to 3.52]. The association remained significant even after adjusting for nonadherence. The authors did not find an association between alcohol consumption and change in CD4 cell count over time in either group. Conclusions:No effect of alcohol consumption on either virological failure or CD4 cell count in both groups of ART-initiating and ART-naive individuals was found. However, severe drinkers were more likely to interrupt ART. Efforts on ART continuation should be especially implemented in individuals reporting high alcohol consumption.

Outcome of smoking cessation counselling of HIV‐positive persons by HIV care physicians

Smoking is the most prevalent modifiable risk factor for cardiovascular diseases among HIV‐positive persons. We assessed the effect on smoking cessation of training HIV care physicians in counselling.

The J-Curve in HIV: Low and Moderate Alcohol Intake Predicts Mortality but Not the Occurrence of Major Cardiovascular Events.

Objectives:In HIV-negative populations, light-to-moderate alcohol consumption is associated with a lower cardiovascular morbidity and mortality than alcohol abstention. Whether the same holds true for HIV-infected individuals has not been evaluated in detail. Design:Cohort study. Methods:Adults on antiretroviral therapy in the Swiss HIV Cohort Study with follow-up after August 2005 were included. We categorized alcohol consumption into: abstention or very low (<1 g/d), low (1–9 g/d), moderate (10–29 g/d in women and 10–39 g/d in men), and high alcohol intake. Cox proportional hazards models were used to describe the association between alcohol consumption and cardiovascular disease-free survival (combined endpoint), cardiovascular disease events (CADE) and overall survival. Baseline and time-updated risk factors for CADE were included in the models. Results:Among 9741 individuals included, there were 788 events of major CADE or death during 46,719 patient-years of follow-up, corresponding to an incidence of 1.69 events/100 person-years. Follow-up according to alcohol consumption level was 51% no or very low, 20% low, 23% moderate, and 6% high intake. As compared with no or very low alcohol intake, low (hazard ratio 0.79, 95% confidence interval 0.63 to 0.98) and moderate alcohol intakes (0.78, 0.64 to 0.95) were associated with a lower incidence of the combined endpoint. There was no significant association between alcohol consumption and CADE. Conclusions:Compared with no or very low alcohol consumption, low and moderate intake associated with a better CADE-free survival. However, this result was mainly driven by mortality and the specific impact of drinking patterns and type of alcoholic beverage on this outcome remains to be determined.

Discontinuation of empirical antibiotic therapy in neutropenic leukaemia patients with fever of unknown origin is ethical

[Orasch, C.; Marchetti, O.] Univ Lausanne Hosp, CHUV, Dept Med, Infect Dis Serv, Lausanne, Switzerland. [Averbuch, D.; Engelhard, D.] Hadassah Hebrew Univ, Med Ctr, Pediat Infect Dis Unit, Jerusalem, Israel. [Mikulska, M.; Viscoli, C.] Univ Genova DISSAL, IRCCS San Martino IST, Div Infect Dis, Genoa, Italy. [Cordonnier, C.] Henri Mondor Hosp, AP HP, Dept Hematol, Paris, France. [Cordonnier, C.] Univ Paris Est Creteil, Paris, France. [Livermore, D. M.] Univ East Angila, Norwich Med Sch, Norwich, Norfolk, England. [Gyssens, I. C.] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, NL-6525 ED Nijmegen, Netherlands. [Gyssens, I. C.] Canisius Wilhelmina Hosp, Dept Med Microbiol & Infect Dis, Nijmegen, Netherlands. [Gyssens, I. C.] Hasselt Univ, Hasselt, Belgium. [Klyasova, G.] Natl Res Ctr Hematol, Moscow, Russia. [Kern, W.] Univ Freiburg, Univ Hosp, Ctr Infect Dis & Travel Med, Dept Med, D-79106 Freiburg, Germany. [Akova, M.] Hacettepe Univ, Sch Med, Dept Infect Dis, Ankara, Turkey.

Daptomycin-Associated Eosinophilic Pneumonia in Two Patients with Prosthetic Joint Infection

BACKGROUND Daptomycin is used increasingly to treat prosthetic joint infection (PJI). A possible side effect of this drug is eosinophilic pneumonia. We describe two patients with PJI treated with daptomycin who had this side effect with different clinical presentations. METHODS Case reports and review of the literature. RESULTS The first case was a 64-year-old male who received daptomycin as a part of the treatment for PJI caused by methicillin-resistant Staphylococcus epidermidis (MRSE). He developed fever without other symptoms; bronchoalveolar lavage (BAL) revealed eosinophils. The second was a 61-year-old male who also used daptomycin as part of the treatment of PJI caused by MRSE and developed severe lung symptoms. Bronchoalveolar lavage and pleural fluid showed an increased number of eosinophils. CONCLUSION Daptomycin-induced pneumonia can present with a wide range of symptoms, from fever alone to severe lung symptoms. Surgeons should be aware of this possible side effect when prescribing daptomycin.

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-&agr; rs1800629, hazard ratio = 4.31; 95% CI, 1.85–10.1; p= 0.0007; &bgr;-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-&agr; 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-&agr; 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.