Issues in the management of invasive pulmonary aspergillosis in non-neutropenic patients in the intensive care unit: A role for isavuconazole

Background: Almost half of all cases of invasive aspergillosis (IA) occur in the intensive care unit (ICU), with mortality rates of 70\u201380% for probable or proven cases. IA has become a major concern among non-neutropenic patients in the ICU with chronic obstructive pulmonary disease (COPD) but although prompt, appropriate antifungal therapy is crucial, diagnosis in this situation is challenging. Criteria for a probable diagnosis in critically ill patients have been proposed to help to expedite therapy. Methods: A case of probable invasive pulmonary aspergillosis (IPA) in a non-neutropenic patient admitted to the ICU was used to illustrate potential issues in the diagnostic work-up and management of patients in this setting. Results: A non-neutropenic 69-year-old man with COPD receiving clomipramine was diagnosed in the ICU with probable invasive aspergillosis based on the presence of severe chronic obstructive pulmonary disease, suspected X-linked granulomatous disease, nodular infiltrates and galactogamman positivity on bronchoalveolar lavage (BAL) fluid. Voriconazole was unsuitable due to the patient's prolonged QT interval and risk of a drug\u2013drug interaction with clomipramine. Isavuconazole was initiated and the patient's condition improved. The three-month course of isavuconazole treatment was well-tolerated and resulted in compete recovery of the patient. Conclusions: Voriconazole is a standard first-line treatment for IA but intravenous therapy is associated with toxicity and the potential for drug\u2013drug interactions. Isavuconazole is another first-line therapy which was effective and safe in the management of this critically ill non-neutropenic patient with baseline QT prolongation and potential drug\u2013drug interactions with voriconazole

Emerging treatment options for acute bacterial skin and skin structure infections: Focus on intravenous delafloxacin

The increase in hospitalization due to acute bacterial skin and skin structure infections (ABSSSI) caused by resistant pathogens supports the need for new treatment options. Antimicrobial options for ABSSSI that provide broad-spectrum coverage, including gram-negative pathogens and multidrug-resistant gram-positive bacteria, such as methicillinresistant Staphylococcus aureus (MRSA), are limited. Delafloxacin is a novel fluoroquinolone available as intravenous and oral formulations and is characterized by an increased efficacy in acidic environments and activity on bacterial biofilm. Delafloxacin displays enhanced in vitro activity against MRSA, and enterococci, while maintaining efficacy against gram-negative pathogens and anaerobes. Delafloxacin has been studied for the treatment of ABSSSI and respiratory infections. Phase III studies have demonstrated noninferiority of delafloxacin compared to vancomycin, linezolid, tigecycline, and the combination of vancomycin plus aztreonam in the treatment of ABSSSI. Due to its favorable pharmacokinetic characteristics, the wide spectrum of action, and the potential for sequential therapy, delafloxacin represents a promising option in the empirical and targeted treatment of ABSSSI, both in hospital- and in community-based care

Impact of new treatment options for hepatitis c virus infection in liver transplantation

Liver transplant candidates and recipients with hepatitis C virus (HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens (e.g., pegylated-interferon plus ribavirin with or without first generation protease inhibitors, boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents (DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir, daclatasvir, and combination of other DAA. Possible interactions should be monitored, especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals

Antimicrobial treatment challenges in the era of carbapenem resistance

Infections due to carbapenem-resistant Gram-negative bacteria are burdened by high mortality and represent an urgent threat to address. Clinicians are currently at a dawn of a new era in which antibiotic resistance in Gram-negative bacilli is being dealt with by the availability of the first new antibiotics in this field for many years. Although new antibiotics have shown promising results in clinical trials, there is still uncertainty over whether their use will improve clinical outcomes in real world practice. Some observational studies have reported a survival benefit in carbapenem-resistant Enterobacteriaceae bloodstream infections using combination therapy, often including “old” antibiotics such as colistin, aminoglycosides, tigecycline, and carbapenems. These regimens, however, are linked to increased risk of antimicrobial resistance, and their efficacy has yet to be compared to new antimicrobial options. While awaiting more definitive evidence, antibiotic stewards need clear direction on how to optimize the use of old and novel antibiotic options. Furthermore, carbapenem-sparing regimens should be carefully considered as a potential tool to reduce selective antimicrobial pressure

Clinical and therapeutic aspects of candidemia: A five year single centre study

B ackground Candida is an important cause of bloodstream infections (BSI) in nosocomial settings causing significant mortality and morbidity. This study was performed to evaluate contemporary epidemiology, species distribution, antifungal susceptibility and outcome of candida BSI in an Italian hospital. Methods All consecutive patients who developed candidemia at Santa Maria della Misericordia University Hospital (Italy) between January 2009 and June 2014 were enrolled in the study. Results A total of 204 episodes of candidemia were identified during the study period with an incidence of 0.79 episodes/1000 admissions. C. albicans was isolated in 60.3% of cases, followed by C. parapsilosis (16.7%), C. glabrata (11.8%) and C. tropicalis (6.4%). Of all Candida BSI, 124 (60.8 %) occurred in patients admitted to IMW, 31/204 (15.2 %) in ICUs, 33/204 (16.2%) in surgical units and 16/204 (7.8%) in Hematology/Oncology wards. Overall, 47% of patients died within 30 days from the onset of candidemia. C. parapsilosis and C. glabrata candidemia were associated with the lowest mortality rate (36%), while patients with C. tropicalis BSI had the highest mortality rate (58.3%). Lower mortality rates were detected in patients receiving therapy within 48 hours from the time of execution of the blood cultures (57,1% vs 38,9%, P <0.05). At multivariate analysis, steroids treatment (OR= 0.27, p=0.005) and CVC removal (OR=3.77, p=0.014) were independently associated with lower and higher survival probability, respectively. Candidemia in patients with peripherally inserted central catheters (PICC) showed to be associated with higher mortality in comparison with central venous catheters (CVC, Short catheters and Portacath) and no CVC use. For each point increase of APACHE III score, survival probability decreased of 2%. Caspofungin (OR=3.45, p=0.015) and Amphothericin B lipid formulation (OR=15.26, p=0.033) were independently associated with higher survival probability compared with no treatment

Is first-line antimicrobial therapy still adequate to treat MRSA in the ICU? A report from a highly endemic country

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Long-term morbidity and mortality following bloodstream infection: a systematic literature review

Bloodstream infection results in significant short-term morbidity and mortality. No literature review has studied the long-term outcome following a bloodstream infection. This PROSPERO registered systematic review evaluated studies, which measured the association of a bloodstream infection with long-term morbidity and mortality.Databases were systematically searched for studies of adult patients reporting morbidity and/or mortality one year or more following a bloodstream infection in comparison to a matched cohort without a bloodstream infection.Ten observational studies were included in the final analysis. Five studies assessed only mortality, two assessed morbidity and mortality and three studies assessed morbidity only. The one year mortality ranged from between 8 and 48% for patients with bloodstream infection. The pooled risk ratio of death at one year was significantly higher for patients with bloodstream infection when compared to the matched cohort (RR 4.04 [95% CI 1.84-8.87]).Bloodstream infection was associated with poor long-term outcome measured at one year when compared to matched controls. More evidence is needed to determine if this association is causative

In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol

ObjectiveThere is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria.Methods and analysisThis protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE's risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias.DisseminationThis systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals.PROSPERO registration numberCRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104)

Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: systematic review and meta-analysis

Background: Carbapenem-resistant Gram-negative bacteria are recognized as a cause of difficult-to-treat infections associated with high mortality. Objectives: To perform a systematic review of currently available data on distribution, characteristics and outcome associated with carbapenem-resistant bloodstream infections in adult neutropenic patients. Methods: Included studies were identified through Medline, Embase and Cochrane databases between January 1995 and April 2016. Random effect meta-analysis was used to quantify the association between carbapenem resistance and mortality and between carbapenem exposure and resistance. Results: A total of 30 studies from 21 countries were included. Overall carbapenem resistance varied from 2% to 53% (median 9%) among studies. Infections due to carbapenem-resistant Pseudomonas spp. were reported in 18 (60%) studies showing high median resistance rates (44% of all carbapenem-resistant Gram-negatives and 19% of Pseudomonas isolates). Resistance of Enterobacteriaceae was less commonly reported and bloodstream infections due to carbapenem-resistant Klebsiella spp. were mainly documented from endemic areas (Greece, Italy, Israel). Carbapenem resistance in Acinetobacter spp. was reported in 9 (30%) studies (median resistance 58% of Acinetobacter isolates). Mortality rates ranged from 33% to 71% (median 50%) in patients with carbapenem-resistant infections. Carbapenemresistance appeared to correlate with mortality (OR 4.89, 95% CI 3.30-7.26) and previous exposure to carbapenems (OR 4.63, 95% CI 3.08-6.96). Conclusions: Carbapenem resistance represents a threat to neutropenic patients. In this group, resistance is likely promoted by previous carbapenem use and leads to high mortality rates. The knowledge of resistance patterns is crucial and can direct clinicians in the use of alternatives to carbapenem-based regimens