Risk factors for candidaemia in hospitalized patients with liver cirrhosis: a multicentre case-control-control study.

OBJECTIVES: The aim of this study was to evaluate the risk factors for candidaemia in patients with liver cirrhosis. METHODS: This was a case-control-control (1:2:2) study performed in four Italian tertiary centres from 2006 to 2015. Cases were patients with liver cirrhosis developing candidaemia. For every case of candidaemia we enrolled two additional patients undergoing blood cultures for suspected infection yielding isolation of a bacterial pathogen (control A) and two additional patients undergoing blood cultures for suspected infection yielding negative results (control B). Patients were matched according to age, sex and model for end stage liver disease at hospital admission. RESULTS: During the study period 90 cases, 180 controls A and 180 controls B were included. At multivariate analysis assessed by means of multinomial conditional regression models, factors independently associated with candidaemia were previous (<30 days) acute-on-chronic liver failure (relative risk ratio (RRR) 2.22 (95% confidence interval (CI) 1.09-4.54), p = 0.046), previous(<30 days) gastrointestinal endoscopy (RRR 2.38 (95% CI 1.19-4.78) p = 0.014), previous(<30 days) antibiotic treatment for at least 7 days (RRR 2.74 (95% CI 1.00-7.48), p = 0.049), presence of central venous catheter (RRR 2.77 (95% CI 1.26-6.09, p = 0.011), total parenteral nutrition (RRR 3.90 (95% CI 1.62-9.40), p = 0.002) at infection onset and length of in-hospital stay >15 days (RRR 4.63 (95% CI 2.11-10.18), p <0.001] Conversely, rifaximin treatment was associated with lower rate of candidaemia (RRR 0.38 (95% CI 0.19-0.77), p = 0.007). Multivariable analysis for 30-day mortality showed that patients with isolation of Candida spp. from blood cultures had worse outcome when compared with controls even though the difference did not reach a statistical significance (hazard ratio 1.64 (95% 0.97-2.75) p = 0.06). CONCLUSIONS: We identified previous antibiotic use, gastrointestinal endoscopy or acute-on-chronic liver failure and presence of central venous catheter especially for parenteral nutrition as independent factors associated with candidaemia. Surprisingly, chronic rifaximin use was a protective factor.

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. OBJECTIVES: To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer. IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.

Performance of existing definitions and tests for the diagnosis of invasive aspergillosis in critically ill, adult patients: A systematic review with qualitative evidence synthesis.

OBJECTIVES: To summarize the available evidence on the diagnostic performance for invasive aspergillosis (IA) in non-hematological, non-solid organ transplantation critically ill patients of the following: (i) existing definitions of IA (developed either for classical immunocompromised populations or for non-immunocompromised critically ill patients); (ii) laboratory tests; (iii) radiology tests. METHODS: A systematic review was performed by evaluating studies assessing the diagnostic performance for IA of a definition/s and/or laboratory/radiology test/s vs. a reference standard (histology) or a reference definition. RESULTS: Sufficient data for evaluating the performance of existing definitions and laboratory tests for the diagnosis of IA in critically ill patients is available only for invasive pulmonary aspergillosis. Against histology/autopsy as reference, the AspICU definition showed a promising diagnostic performance but based on small samples and applicable only to patients with positive respiratory cultures. Studies on laboratory tests consistently indicated a better diagnostic performance of bronchoalveolar lavage fluid (BALF) galactomannan (GM) than serum GM, and a suboptimal specificity of BALF and serum (1,3)-ß-D-glucan. CONCLUSIONS: Evidence stemming from this systematic review will guide the discussion for defining invasive aspergillosis within the FUNDICU project. The project aims to develop a standard set of definitions for invasive fungal diseases in critically ill, adult patients.

Rapid microbiological tests for bloodstream infections due to multidrug resistant Gram-negative bacteria: therapeutic implications.

BACKGROUND: Treating severe infections due to multidrug-resistant Gram-negative bacteria (MDR-GNB) is one of the most important challenges for clinicians worldwide, partly because resistance may remain unrecognized until identification of the causative agent and/or antimicrobial susceptibility testing (AST). Recently, some novel rapid test for identification and/or AST of MDR-GNB from positive blood cultures or the blood of patients with bloodstream infections (BSIs) have become available. OBJECTIVES: The objective of this narrative review is to discuss the advantages and limitations of different rapid tests for identification and/or AST of MDR-GNB from positive blood cultures or the blood of patients with BSI, as well as the available evidence on their possible role to improve therapeutic decisions and antimicrobial stewardship. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The present review is structured in the following way: (a) rapid tests on positive blood cultures; (b) rapid tests directly on whole blood; (c) therapeutic implications. IMPLICATIONS: Novel molecular and phenotypic rapid tests for identification and AST show the potential for favourably influencing patients' outcomes and results of antimicrobial stewardship interventions by reducing both the time to effective treatment and the misuse of antibiotics, although the interpretation about their impact on actual therapeutic decisions and patients' outcomes is still complex. Factors such as feasibility and personnel availability, as well as the detailed knowledge of the local microbiological epidemiology, need to be considered very carefully when implementing novel rapid tests in laboratory workflows and algorithms. Providing high-level, comparable evidence on the clinical impact of rapid identification and AST is becoming of paramount importance for MDR-GNB infections, since in the near future rapid identification of specific resistance mechanisms could be crucial for guiding rapid, effective, and targeted therapy against specific resistance mechanisms.

Management of KPC-producing Klebsiella pneumoniae infections.

BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) has become one of the most important contemporary pathogens, especially in endemic areas. AIMS: To provide practical suggestion for physicians dealing with the management of KPC-KP infections in critically ill patients, based on expert opinions. SOURCES: PubMed search for relevant publications related to the management of KPC-KP infections. CONTENTS: A panel of experts developed a list of 12 questions to be addressed. In view of the current lack of high-level evidence, they were asked to provide answers on the bases of their knowledge and experience in the field. The panel identified several key aspects to be addressed when dealing with KPC-KP in critically ill patients (preventing colonization in the patient, preventing infection in the colonized patient and colonization of his or her contacts, reducing mortality in the infected patient by rapidly diagnosing the causative agent and promptly adopting the best therapeutic strategy) and provided related suggestions that were based on the available observational literature and the experience of panel members. IMPLICATIONS: Diagnostic technologies could speed up the diagnosis of KPC-KP infections. Combination treatment should be preferred to monotherapy in cases of severe infections. For non-critically ill patients without severe infections, results from randomized clinical trials are needed for ultimately weighing benefits and costs of using combinations rather than monotherapy. Multifaceted infection control interventions are needed to decrease the rates of colonization and cross-transmission of KPC-KP.

Regional point prevalence study of healthcare-associated infections and antimicrobial use in acute care hospitals in Liguria, Italy.

BACKGROUND: Given the importance of monitoring healthcare-associated infections (HCAIs) and the consumption of antibiotics, a regional point prevalence survey was conducted in Liguria between March and April 2016. AIM: To measure the overall prevalence of HCAI and describe the use of antibiotics in all public hospitals. METHODS: Data on risk factors and use of antibiotics were collected for each hospitalized patient. To define the variables significantly associated with HCAI, univariate and multivariate analyses were conducted. Standardized infection ratio and standardized antimicrobial use ratio were measured for each participating hospital. FINDINGS: A total of 3647 patients were enrolled. In all, 429 HCAIs were diagnosed in 376 patients, giving a prevalence of HCAI of 10.3%. Respiratory tract (21.7%) and urinary tract (20%) were the most frequent sites of infection. High rates of meticillin-resistant Staphylococcus aureus (47.4%) and Enterobacteriaceae resistant to carbapenems (26.3%) were isolated. Forty-six percent of patients received at least one antibiotic. Combinations of penicillins including ß-lactamase inhibitors (24.1%) were the most widely used; the main indication (46.7%) was the treatment of a community-acquired infection. CONCLUSION: There was an increase in HCAI prevalence compared to a similar survey conducted in 2007; however, the performance of overlapping investigations will enable more reliable considerations. Nevertheless, data on antimicrobial resistance and use of antibiotics are consistent with the national trend. Despite methodological limitations, prevalence studies are useful to monitor HCAI over time and encourage greater awareness of the problem by all stakeholders.

Previous bloodstream infections due to other pathogens as predictors of carbapenem-resistant Klebsiella pneumoniae bacteraemia in colonized patients: results from a retrospective multicentre study.

INTRODUCTION: the purpose of this retrospective multicenter study was to assess whether the risk of developing bloodstream infections (BSI) due to carbapenem-resistant Klebsiella pneumoniae (CRKP) in colonized patients is influenced by the occurrence of BSI due to other pathogens. METHODS: from January 2012 to March 2014, all patients with at least one rectal swab positive for CRKP and at least 30 days of previous hospital stay were included in the study. The primary outcome measure was CRKP BSI, defined as a time-to-event endpoint. The role of potential predictors was evaluated through univariable and multivariable Cox regression analyses, considering previous BSI as a time-dependent variable. RESULTS: during the study period, 353 patients met the inclusion criteria. Thirty-seven developed a CRKP BSI (11%). A higher incidence of CRKP BSI was observed in presence rather than in absence of previous BSI. In the final multivariable model of risk factors for CRKP BSI, multisite colonization (hazard ratio [HR] 13.73, 95% confidence intervals [CI] 3.29-57.32, p < 0.001), ICU stay (HR 3.14, 95% CI 1.19-8.31, p = 0.021), and previous BSI (p = 0.026, with the overall effect being mainly due to Enterococcus spp. BSI vs absence of BSI, HR 6.62, 95% CI 2.11-20.79) were associated with the development of CRKP BSI, while an inverse association was observed for age (HR 0.98, 95% CI 0.95-1.00, p = 0.027). CONCLUSIONS: previous BSI due to other pathogens were associated with an increased risk of CRKP BSI that was independent of other factors in colonized patients with prolonged hospital exposure.

Lower sensitivity of serum (1,3)-ß-d-glucan for the diagnosis of candidaemia due to Candida parapsilosis.

The aim of this study was to evaluate the sensitivity and the levels of 1,3-ß-d-glucan (BDG) among patients with candidaemia due to different Candida species. Retrospective study of all patients who had a single-species candidaemia and BDG testing performed within 48 h from the onset of candidaemia during 2009-2015 was performed. Factors influencing the sensitivity of BDG, including the presence of a central venous catheter, antifungal therapy and Candida species, were analysed in univariate and multivariate models. In all, 107 patients with the following Candida distribution were included: 46 (43%) Candida albicans, 37 (35%) Candida parapsilosis, and 24 (22%) other species. BDG sensitivity and levels were the highest in C. albicans candidaemia and lowest for C. parapsilosis (respectively, 72% and 410 pg/mL for C. albicans, 41% and 39 pg/mL for C. parapsilosis, and 63% and 149 pg/mL for other species; p 0.015 and p 0.003). In multivariate analysis, Candida species (parapsilosis versus others) was the only factor influencing the sensitivity of BDG (OR 0.3, 95% CI 0.1-0.7, p 0.006). The sensitivity of BDG in candidaemia seems highly dependent on the fungal species, with the lowest being for C. parapsilosis.

Increasing incidence of Clostridium difficile infections: results from a 5-year retrospective study in a large teaching hospital in the Italian region with the oldest population.

Limited information is available on the incidence of Clostridium difficile infections (CDIs) in Italian hospitals. In this study, we assessed the changes in the incidence of CDI over a 5-year period in a teaching hospital in Liguria, the Italian region with the oldest population. Secondary endpoints were the development of severe CDI and 30-day mortality. The annual incidence of CDI/10000 patient-days significantly increased from 0·54 in 2010 to 3·04 in 2014 (χ 2 for trend, P < 0·001). The median age of patients with CDI was 81 years. As many as 81% and 89% of these patients had comorbid conditions and previous exposure to antibiotics, respectively. In the multivariate analysis of risk factors for severe CDI, previous therapy with histamine 2 blockers and low serum albumin were associated with severe CDI, while diabetes appeared to be protective. In the multivariate model of risk factors for 30-day mortality, high leukocyte count, low serum albumin, and increased serum creatinine were unfavourably associated with outcome. Strict adherence to infection control measures was of utmost importance to counteract the increasing incidence of CDI in our hospital, particularly because of the advanced age of the patients and their very high frequency of chronic conditions and use of antibiotics, which readily predispose them to the development of CDI.

Risk factors for bloodstream infections due to colistin-resistant KPC-producing Klebsiella pneumoniae: results from a multicenter case-control-control study.

The increasing prevalence of colistin resistance (ColR) Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (Kp) is a matter of concern because of its unfavourable impact on mortality of KPC-Kp bloodstream infections (BSI) and the shortage of alternative therapeutic options. A matched case-control-control analysis was conducted. The primary study end point was to assess risk factors for ColR KPC-Kp BSI. The secondary end point was to describe mortality and clinical characteristics of these infections. To assess risk factors for ColR, 142 patients with ColR KPC-Kp BSI were compared to two controls groups: 284 controls without infections caused by KPC-Kp (control group A) and 284 controls with colistin-susceptible (ColS) KPC-Kp BSI (control group B). In the first multivariate analysis (cases vs. group A), previous colistin therapy, previous KPC-Kp colonization, ≥3 previous hospitalizations, Charlson score ≥3 and neutropenia were found to be associated with the development of ColR KPC-Kp BSI. In the second multivariate analysis (cases vs. group B), only previous colistin therapy, previous KPC-Kp colonization and Charlson score ≥3 were associated with ColR. Overall, ColR among KPC-Kp blood isolates increased more than threefold during the 4.5-year study period, and 30-day mortality of ColR KPC-Kp BSI was as high as 51%. Strict rules for the use of colistin are mandatory to staunch the dissemination of ColR in KPC-Kp-endemic hospitals.

Initial serum (1,3)-ß-D-glucan as a predictor of mortality in proven candidaemia: findings from a retrospective study in two teaching hospitals in Italy and Brazil.

A retrospective study was conducted to assess the role of initial serum (1,3)-ß-d-glucan (BDG) values in predicting mortality in proven candidaemia. The study was conducted in two large teaching hospitals in Italy and Brazil. From January 2009 to June 2014, all patients with proven candidaemia who underwent a BDG test within 96 hours before or after the first positive blood culture were included in the study. The primary end point was 28-day mortality, with the role of initial BDG being assessed by univariate and multivariate analyses. A total of 104 patients met the inclusion criteria. Overall, the crude 28-day mortality was 30% (31/104). In the final multivariate model, an initial BDG of >287 pg/mL (odds ratio (OR) 4.40, 95% confidence interval (CI) 1.56-12.39, p 0.005), haemodialysis (OR 4.33, 95% CI 1.24-15.17, p 0.022) and a Pitt score of ≥ 2 (OR 4.10, 95% CI 1.24-13.54, p 0.021) were significant predictors of 28-day mortality. The >287 pg/mL cutoff predicted 28-day mortality with 65% sensitivity and 70% specificity. Centre of enrolment (p for interaction 0.012), haemodialysis (p for interaction 0.062) and timing of BDG test of more than 24 hours before or after the positive culture (p for interaction 0.143) appeared to interact with BDG's ability to predict mortality. Although not statistically significant, the last two of these interactions might partially explain why BDG's ability to predict mortality was present only in the Italian cohort.

Insights on common vaccinations in HIV-infection: efficacy and safety.

HIV-infected patients are at increased risk for both vaccine-preventable diseases and their complications, with mortality rates higher than in non-HIV-infected individuals. Consequently, international guidelines generally recommend inactivated vaccines in HIV-patients, even if HIV-related immunodeficiency may impair efficacy; live vaccines are usually not recommended in these patients because of safety concerns. The aim of this short article is to review current knowledge about both efficacy and safety of vaccines in HIV-infected individuals.

Risk factors and mortality of healthcare-associated and community-acquired Staphylococcus aureus bacteraemia.

Staphylococcus aureus bacteraemia (SAB) is a leading cause of mortality and morbidity in both nosocomial and community settings. The objective of the study is to explore epidemiological characteristics and predisposing risk factors associated with healthcare-associated (HCA) and community-acquired (CA) SAB, and to evaluate any differences in mortality and efficacy of initial antimicrobial therapy on treatment outcome. We conducted a two-part analysis. First, a triple case-control study in which groups of HCA SAB with onset ≥ 48 h after hospital admission (HCA ≥ 48 h), HCA SAB with onset <48 h of hospital admission (HCA <48 h), and CA SAB were compared with controls. Second, a cohort study including all patients with SAB was performed to identify factors associated with in-hospital mortality. SAB was diagnosed in 165 patients over the study period (January 2007 to December 2007). Five variables were independently associated with HCA ≥ 48 h SAB: presence of central venous catheter, solid tumour, chronic renal failure, previous hospitalization and previous antibiotic therapy. Significant risk factors for HCA <48 h SAB were: Charlson Comorbidity Index ≥ 3, previous hospitalization, living in long-term care facilities and corticosteroid therapy. Factors independently associated with CA SAB were: diabetes mellitus, HIV infection and chronic live disease. Patients with HCA <48 h SAB were significantly more likely to receive initial inadequate antimicrobial treatment than patients with CA or HCA ≥ 48 h SAB (44.8% versus 33.3% and 31.5%, respectively). Logistic-regression analysis identified three variables as independent predictors of mortality: presentation with septic shock, infection with methicillin-resistant S. aureus, and initial inadequate antimicrobial treatment. More than half of patients with SAB have MRSA strains and presentation with septic shock, and inappropriate empirical therapy was associated with increased mortality.

New approaches for empiric therapy in Gram-positive sepsis.

Nosocomial bloodstream infections (BSIs) have become an important cause of morbidity and mortality, particularly in intensive care units (ICUs). Gram-positive organisms are the prevalent causes of antibiotic-resistant BSI, especially Staphylococcus aureus, coagulase-negative staphylococci and enterococci. In recent years, several reports have shown an increase in antimicrobial resistance among Gram-positive bacteria isolated from patients in ICUs. In this context, methicillin-resistant Staphylococcus aureus (MRSA) is a major problem. In the ICU more than 50% of S. aureus isolates in Europe are resistant to methicillin. Although vancomycin became the drug of choice for MRSA and is still widely used for this indication, many studies suggest that when vancomycin MIC values are at the high end of the susceptibility range, vancomycin is less effective against MRSA. High MRSA prevalence combined with the widespread use of vancomycin for empirical Gram-positive coverage may lead to changes in patient outcomes. Here we describe the microbiological, pharmacological and clinical characteristics of three new antibacterials helpful in severe infections in ICU patients: linezolid, tigecycline and daptomycin. These new drugs have some limitations, and the possibility developing resistance is real. Knowledge of both old and new antibacterials is necessary to utilize them most effectively.