Search

Background: Fluconazole represents a common antifungal option for the treatment of Candida infections in liver transplant recipients. Although adequate antifungal exposure is known to correlate with favorable outcomes in patients with invasive candidiasis, therapeutic drug monitoring (TDM) of fluconazole is currently not recommended. Methods: We conducted a retrospective study including adult liver transplant recipients receiving fluconazole for invasive candidiasis and undergoing TDM. We assessed the correlation between clinical variables, fluconazole trough plasma levels (Cmin), and outcome. Results: Twenty‐seven patients (74% males; median age 57 years) were included. Abdominal candidiasis was the most frequent infection (56%). Median duration of fluconazole therapy was 17 days (IQR 9‐21). Fluconazole median Cmin was 11.0 mg/L (range 2.4‐30.6 mg/L). Five (19%) patients required TDM‐guided fluconazole dose increase. All‐cause in hospital mortality was 33%. Fluconazole Cmin >11 mg/L significantly correlated with clinical success (OR 8.78, 95% CI 1.13‐67.8, P = 0.04). Conclusions: Our study identified decreased fluconazole Cmin as a factor associated with negative outcomes in liver transplant recipients with Candida infection. TDM of fluconazole may be advisable in this patient population. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe.Methods: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU).Results: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis.Conclusions: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions. [ABSTRACT FROM AUTHOR]

• Overall, the etiology of vertebral osteomyelitis is obtained in less than 40% of cases. • UDIPROVE (UDIne PROtocol on VErtebral osteomyelitis) was applied in all cases. • Rigorous application of the protocol allowed the etiology to be obtained in 74% of cases. • Antimicrobial washout plus vertebral biopsy increased the rate of diagnosis. • The use of FDG-PET/CT was more reliable in the follow-up of infection than MRI. Vertebral osteomyelitis (VO) is a compelling clinical entity for clinicians because of its insidious and indolent course, which makes diagnosis difficult. All patients with a suspected diagnosis of VO were analyzed over an 8-year period (January 2009 to January 2017). The UDIPROVE protocol (UDIne PROtocol on VErtebral osteomyelitis) was applied in all cases. The primary endpoint was the performance of the UDIPROVE protocol to obtain the causal bacteria of infection. During the study period, 133 episodes of confirmed VO were observed. The etiology of infection was obtained in 73.6% of cases: 70.5% were gram-positive, 16.3% were gram-negative, and 13.2% were mycobacteria. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) showed that for tubercular VO, the median standard uptake value (SUV) was higher when compared with VO caused by other bacteria. Clinical cure at the end of therapy was reported in 85.7% of patients. Previous antimicrobial therapy and a delay of more than 5 days in performing biopsy were associated with an undiagnosed etiology of VO. Targeted antibacterial therapy and follow-up with FDG-PET/CT were associated with clinical cure at the end of therapy, while the involvement of more than two vertebrae and inadequate drainage were associated with failure. Rigorous application of the UDIPROVE protocol allowed the causative pathogens of VO to be obtained – at about twice the rate reported in the literature. The use of FDG-PET/CT for the follow-up of infection was more reliable when compared to magnetic resonance imaging (MRI). [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was to describe the characteristics of cirrhotic patients with candidemia and intra-abdominal candidiasis (IAC) and to evaluate the risk factors associated with 30-day mortality.Methods: A multicenter multinational retrospective study including all consecutive episodes of candidemia and IAC in adult patients with liver cirrhosis in 14 European hospitals during the period 2011-2013 was performed.Results: A total of 241 episodes (169 candidemia, 72 IAC) were included. Most Candida infections were acquired in hospital (208, 86.3%), mainly in the intensive care unit (ICU) (121, 50.2%). At clinical presentation, fever was seen in 60.6% of episodes (146/241) and septic shock in 34.9% (84/241). C. albicans was the most common species (found in 131 episodes, 54.4%), followed by C. glabrata (35, 14.5%) and C. parapsilosis (34, 14.1%). Overall, the 30-day mortality was 35.3%. Multivariable analysis identified candidemia (OR 2.2, 95% CI 1.2-4.5) and septic shock (OR 3.2, 95% CI 1.7-6) as independent factors associated with 30-day mortality. Adequate antifungal treatment (OR 0.4, 95% CI 0.3-0.9) was associated with survival benefit.Conclusions: A shift towards increasing prevalence of C. glabrata and C. parapsilosis species in patients with liver disease was documented. Candidemia and IAC were associated with significant mortality in cirrhotic patients. Thirty-day mortality was associated with candidemia and severe clinical presentation, whereas adequate antifungal treatment improved the prognosis. [ABSTRACT FROM AUTHOR]

Introduction: To promote judicious prescribing of methicillin-resistant Staphylococcus aureus (MRSA)-active therapy for skin and soft tissue infections (SSTI), we previously developed an MRSA risk assessment tool. The objective of this study was to validate this risk assessment tool internationally. Methods: A multicenter, prospective cohort study of adults with purulent SSTI was performed at seven international sites from July 2016 to March 2018. Patient MRSA risk scores were computed as follows: MRSA infection/colonization history (2 points); previous hospitalization, previous antibiotics, chronic kidney disease, intravenous drug use, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), diabetes with obesity (1 point each). Predictive performance of MRSA surveillance percentage, MRSA risk score, and estimated MRSA probability (surveillance percentage adjusted by risk score) were quantified using the area under the receiver operating characteristic curves (aROC) and compared. Performance characteristics of different risk score thresholds across varying baseline MRSA prevalence were examined. Results: Two hundred three patients were included. Common SSTI were wounds (28.6%), abscess (25.1%), and cellulitis with abscess (20.7%). Patients with higher risk scores were more likely to have MRSA (P < 0.001). The MRSA risk score aROC (95%CI) [0.748 (0.678–0.819)] was significantly greater than MRSA surveillance percentage [0.646 (0.569–0.722)] (P = 0.016). Estimated MRSA probability aROC [0.781 (0.716–0.845)] was significantly greater than surveillance percentage (P < 0.001) but not the risk score (P = 0.192). The estimated negative predictive value (NPV) of an MRSA score ≥ 1 (i.e., a score of 0) was greater than 90% when MRSA prevalence was 30% or less. Conclusion: The MRSA risk score and estimated MRSA probability were significantly more predictive of MRSA compared with surveillance percentage. An MRSA risk score of zero had high predictive value and could help avoid unnecessary empiric MRSA coverage in low-acuity patients. Further study, including impact of such risk assessment tools on prescribing patterns and outcomes are required before implementation. [ABSTRACT FROM AUTHOR]

Background Candida species are among the most frequent causative agents of health care–associated bloodstream infections, with mortality >40% in critically ill patients. Specific populations of critically ill patients may present peculiar risk factors related to their reason for intensive care unit admission. The primary objective of the present study was to assess the predictors of candidemia after open heart surgery. Methods This retrospective, matched case–control study was conducted in 8 Italian hospitals from 2009 to 2016. The primary study objective was to assess factors associated with the development of candidemia after open heart surgery. Results Overall, 222 patients (74 cases and 148 controls) were included in the study. Candidemia developed at a median time (interquartile range) of 23 (14–36) days after surgery. In multivariable analysis, independent predictors of candidemia were New York Heart Association class III or IV (odds ratio [OR], 23.81; 95% CI, 5.73–98.95; P  < .001), previous therapy with carbapenems (OR, 8.87; 95% CI, 2.57–30.67; P  = .001), and previous therapy with fluoroquinolones (OR, 5.73; 95% CI, 1.61–20.41; P  = .007). Crude 30-day mortality of candidemia was 53% (39/74). Septic shock was independently associated with mortality in the multivariable model (OR, 5.64; 95% CI, 1.91–16.63; P  = .002). No association between prolonged cardiopulmonary bypass time and candidemia was observed in this study. Conclusions Previous broad-spectrum antibiotic therapy and high NYHA class were independent predictors of candidemia in cardiac surgery patients with prolonged postoperative intensive care unit stay. [ABSTRACT FROM AUTHOR]

Objectives: To analyze risk factors for early and late mortality in individuals aged 75 and older with Staphylococcus aureus bacteremia (SAB) in Italy. Design: Four‐year retrospective observational study (January 2011‐December 2014). Setting: Two tertiary care university hospitals in Italy (Santa Maria Misericordia Hospital in Udine, Policlinico Universitario Agostino Gemelli in Rome). Participants: All adults consecutively admitted with SAB. Measurements: Clinical presentation, infection characteristics, and clinical outcomes of individuals aged 75 and older were compared with those of individuals younger than 75. Results: Three hundred thirty‐seven cases of SAB were diagnosed during the study period, 118 of which (35%) occurred in those aged 75 and older. Seven‐ (20.3% vs 9.2%) and 30‐day (35.7% vs 20.7%) mortality were significantly higher in elderly than younger adults. Clinical presentation with septic shock, adequacy of empiric antibiotic treatment, and liver cirrhosis were found to be predictors of 7‐day mortality in elderly adults with SAB. Risk factors independently associated with 30‐day mortality included isolation of methicillin‐resistant Staphylococcus aureus (MRSA) and not receiving an infectious disease consultation. Conclusion: Mortality is significantly higher in elderly than in younger adults with SAB, particularly in those presenting with septic shock, liver cirrhosis, or SAB due to MRSA. Additional risk factors for mortality included inappropriate empiric antibiotic treatment and not receiving an infectious disease consultation. [ABSTRACT FROM AUTHOR]

Scarce data are available about immune cell frequencies in HIV-positive recipients of liver transplant. Alterations in immune subsets can lead to persistent immune activation and disease progression or reduced HIV-specific responses. In liver transplantation, impaired immune tolerance can lead to organ rejection. HIV-positive subjects with undetectable HIVRNA and CD4 > 100/mm3 were included. Control groups were non-transplanted HIV-positive patients with similar immunovirological parameters and healthy subjects. B cells (memory, transitional, and mature subsets), T cells (effector TH1, nonclassic TH1, TH17, TH1/17; T regulatory naïve and effector subsets and CD8+ T regulatory cells), and NK cells (CD56dim and CD56bright subsets) were analyzed by flow cytometry. A total of 56 patients, including 14 HIV-positive transplant recipients (HIV-LT), 14 HIV-positive controls, and 28 healthy controls were included. Median age of HIV-LT patients was 54.9 years with median time from transplant of 7.6 years. Eleven (79%) were HIV/HCV coinfected. Compared to nontransplanted patients, HIV-LT displayed significantly increased frequency of T CD8+ cells, lower percentage of T CD4+ cell, and lower number of nonclassic TH1, TH1/17 cells and naïve T CD4+ regulatory cells (Tregs). Healthy controls showed increased numbers of B cell subsets and decreased percentage of T effector subpopulations compared to HIV-LT. Compared to HIV-positive patients, healthy controls had higher B cells, NK cells, CD4+ T cells, naïve CD4+ Tregs but lower CD8+ T cells, effector Tregs, CD8+ Tregs, and all T effector cell subsets. Immune cell subpopulations potentially associated with HIV progression and organ rejection were detected in HIV-positive transplant recipients. We confirmed altered frequencies of B, T, and NK cell populations in HIV-positive liver transplant recipients compared to healthy controls. The imbalance among immune cell subsets deserves further studies to identify markers of transplant outcome and potential therapeutic targets. • Limited data are available about immune profiles in HIV-positive recipients of liver transplant (HIV-LT) • Healthy controls showed increased numbers of B cell subsets and decreased T effector subpopulations compared to HIV-LT. • Altered frequencies of B, T, and NK cell populations were shown in HIV-LT compared to healthy controls. • Knowledge of immune cell proportions may help stratify HIV-LT requiring additional monitoring after transplantation [ABSTRACT FROM AUTHOR]

Introduction: Intra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10-30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU., Methods: We performed a case-control study in 26 European ICUs during the period January 2015-December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study., Results: During the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65-72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98-21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73-25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04-17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32-10.52, p = 0.01) were independently associated with IAC., Conclusions: Gastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment., (© 2022. The Author(s).)

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration-time curve (AUC 24 h )/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus ) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (C trough ) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of C trough < 1.0 mg/L was around 1%, and that of C trough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

The authors present the case of a critically ill morbidly obese patient (body mass index, 51.2 kg/m) who suffered from methicillin-resistant Staphylococcus epidermidis, and Candida albicans bloodstream infections. Initial treatment with caspofungin and daptomycin was deemed inappropriate, because blood cultures remained positive for both isolates after 14 days. The clinical pharmacological consultant suggested adding fluconazole and ceftobiprole to the ongoing antimicrobial therapy, and starting a real-time therapeutic drug monitoring program of daptomycin, ceftobiprole, and fluconazole, aimed at optimizing plasma exposures. Punctual minimum inhibitory concentration knowledge on the clinical isolates allowed attainment of the desired pharmacodynamic efficacy targets. Within few days, the patient greatly improved, as blood cultures became negative, and the inflammatory markers decreased to near normal values. This is a proof-of-concept of the importance of a therapeutic drug monitoring-based multidisciplinary approach in the proper management of complex antimicrobial therapy in special populations.

Objective: To assess the added value of serial 2-deoxy-2-[18F]fluoro-D-glucose (FDG) uptake analysis in predicting clinical response to treatment in infectious spondylodiscitis (IS). We sought to analyze changes in quantitative FDG-PET/CT parameters among patients with clinical response or treatment failure and to compare the sensitivity and specificity of serial FDG-PET/CT and MRI in predicting treatment response in IS., Materials and Methods: This retrospective study consisted of 68 FDG-PET/CT examinations in 34 patients performed before and after at least 2 weeks of antibiotic treatment. Serial MRI scans were available in 32 (94%) patients before and after treatment. FDG-avid lesions were quantified as maximum standardized uptake value (SUV max ), partial-volume corrected lesion metabolic volume (LMV), and partial-volume corrected lesion metabolic activity (LMA)., Results: All FDG-PET/CT parameters significantly decreased in patients with clinical improvement (31/34, 91%, P < 0.001), while patients with disease progression did not show FDG-PET/CT improvement. FDG uptake decrease was similar between patients undergoing early assessment (< 6 weeks) compared with those performing FDG-PET/CT after 6 weeks of treatment. SUV max , LMV, and LMA decrease over time was 39.0%, 97.4%, and 97.1%, respectively. In predicting clinical responses, SUV max reduction > 15% and > 25% showed 94% and 89% sensitivity and 67% and 100% specificity compared with 37% and 50% of MRI, respectively. Low degree of agreement with clinical response was shown for MRI compared with FDG-PET/CT parameters using the Cohen kappa coefficient., Conclusions: FDG-PET/CT monitoring is a valuable tool to predict clinical response to treatment in IS and has greater sensitivity and specificity compared with MRI.