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As the at-risk population expands and new antifungal resistance patterns develop, it is critical to understand and recognize cutaneous manifestations of old and emerging fungal diseases. PURPOSE OF REVIEW The aim of this review is to provide an overview of the most frequent and emerging deep cutaneous fungal infections following either primary inoculation or secondary spread after haematogenous seeding in disseminated infections in different geographical areas. RECENT FINDINGS Fungal skin and soft tissue infections (SSTIs) encompass a variety of pathological conditions based on the site of the infection, route of acquisition of the pathogen, epidemiological setting and the virulence of the fungus in relation to the host. The approach to a patient suspected of having a fungal SSTI is complex and usually poses a major diagnostic challenge. The treatment approach should include attempts at immune reconstitution, targeted antifungal therapy and/or aggressive surgical debridement. SUMMARY Fungal SSTIs can be an important cause of morbidity and mortality in both immunocompromised and immunocompetent patients and are being reported with increasing frequency worldwide.

Resumen Introduccion y objetivos El objetivo del estudio fue determinar la prevalencia de patologia colorrectal en los pacientes con endocarditis infecciosa por Enterococcus faecalis (EIEF). Metodos Se realizo un estudio observacional, retrospectivo y multicentrico en 4 hospitales de referencia. Se incluyeron todos los episodios consecutivos de EIEF definitivas en adultos desde el momento en que se empezo a realizar una colonoscopia por protocolo en cada centro participante hasta octubre de 2018. Se recogieron los hallazgos endoscopicos de patologia colorrectal potencialmente causante de una bacteriemia. Resultados Se incluyeron 103 pacientes con EIEF; 83 (81%) eran varones, la edad mediana era 76 [rango intercuartilico, 67-82] anos, y la mediana del indice de Charlson ajustado por edad fue 5 [rango intercuartilico, 4-7]. El presunto origen de la infeccion fue desconocido en 63 (61%), urinario en 20 (19%), digestivo en 13 (13%), bacteriemia de cateter en 5 (5%), y otros en 2 (2%). En 78 (76%) pacientes se realizo una colonoscopia, y en 47 (60%) habia hallazgos endoscopicos que indicaban un potencial foco de bacteriemia. Treinta y nueve (83%) tenian una enfermedad colorrectal neoplasica, y 8 (17%) no neoplasica. De los 45 pacientes con puerta de entrada desconocida y colonoscopia, un posible origen gastrointestinal se identifico en 64%. En el subgrupo de 25 con foco de entrada conocido y colonoscopia, excluyendo aquellos con enfermedad colorrectal ya previamente diagnosticada, 44% tenian patologia colorrectal. Conclusiones Realizar una colonoscopia en la EIEF, sin tener en cuenta la puerta de entrada, puede ayudar a diagnosticar la enfermedad colorrectal en estos pacientes y evitar una nueva bacteriemia (y eventualmente endocarditis infecciosa) por el mismo u otro microorganismo.

Introduction The most serious COVID‐19 deriving from severe acute respiratory syndrome coronavirus 2 causes cytokine release storm and it is associated with worse outcomes. In COVID‐19 patients, Interleukin (IL)‐6 levels are significantly elevated. Blocking IL‐6 preliminary resulted in the improvement of this hyperinflammatory state. It is unknown which patients could require higher doses of tocilizumab to get out of the cytokine storm. Materials and Methods Twenty‐four patients affected by COVID‐19 pneumonia were included. All the patients underwent tocilizumab 8 mg/kg intravenously and were tested for serum IL‐6 24‐48 hours before and 12‐48 hours after tocilizumab infusion. Comparisons between survivors and non‐survivors were performed. Results Eighteen patients were discharged, while six patients died, with no clinical or laboratory differences between the two groups at baseline. IL‐6 was not different at baseline (p=0.41), while 24‐48h post‐tocilizumab IL‐6 serum levels were significantly higher in non‐survivors than in survivors [2398.5 (430.5‐9372) pg/mL vs 290.5 (58.5‐1305.5) pg/mL, p=0.022)]. Serum IL‐6 post‐tocilizumab showed a good predictive ability to discriminate survivors from non‐survivors (AUC 0.815 95%CI 0.63‐0.99, p=0.02). Conclusion Repeated measurement of serum level of IL‐6 early after tocilizumab may distinguish non‐survivors from survivors and support the choice of deeper targeting IL‐6 in COVID‐19 pneumonia. This article is protected by copyright. All rights reserved.

Antimicrobial resistance poses a substantial threat to global public health. The pursuit of new antibiotics has decreased and very few options have been investigated for the treatment of complicated multidrug-resistant Gram-negative (MDR-GN) infections in adult population and even less in pediatric patients. Ceftazidime-avibactam (CAZ-AVI) is novel cephalosporin/β-lactamase inhibitor (BL-BLI) combination with broad antibacterial spectrum. The aim of this review is to describe the current and future role CAZ-AVI in the pediatric population with suspected or confirmed MDR-GN infections.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Complicacions infeccioses; Càncer Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Complicaciones infecciosas; Cáncer Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Infectious complications; Cancer Background We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. Methods International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 h were included in the analysis of superinfections. Results 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa . Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. Conclusions Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized. This study was supported by the Spanish Plan Nacional de IDi 2013-2016, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, and the Spanish Network for Research in Infectious Diseases (REIPI grant: RD16/0016/0001). It was also co-financed by the European Development Regional Fund ‘A Way to Make Europe’, Operational Programme Smart Growth 2014-2020.

Introduction: Antimicrobial resistance poses a substantial threat to global public health since it decreases the probability of effectively treating an infection and increases the risk of morbidity and mortality.Areas covered: In this review, the authors discuss the advantages and disadvantages of classical and novel trial designs for evaluating novel antibiotics for infections due to multidrug-resistant organisms (MDRO). An inductive literature search was performed using different keywords pertinent to the reviewed topics.Expert opinion: The need for active, effective compounds has strengthened regulatory, academic, and industry cooperation, leading to the recent approval of some novel anti-MDRO agents, with other promising compounds being also in the late phase of clinical development. Nonetheless, some important issues regarding the design of clinical trials have gained importance that are peculiar for novel anti-MDRO agents and should be addressed for continuing to guarantee the availability of effective treatments in the future. Very importantly, concerted cooperation with regulatory agencies will always be needed for continuously discussing and refining the acceptable level of evidence to be pursued through non-conventional and/or innovative trial designs or development strategies. Failure to do so would seriously pose the risk of perpetuating the unmet need for effective anti-MDRO agents.

Summary Objectives bloodstream infections (BSI) due to multidrug-resistant (MDR) Acinetobacter baumannii (AB) have been increasingly observed among hospitalized patients. Methods prospective, observational study conducted among 12 large tertiary-care hospitals, across 7 Italian regions. From June 2017 to June 2018 all consecutive hospitalized patients with bacteremia due to MDR-AB were included and analyzed in the study. Results During the study period 281 episodes of BSI due to MDR-AB were observed: 98 (34.8%) episodes were classified as primary bacteremias, and 183 (65.2%) as secondary bacteremias; 177 (62.9%) of them were associated with septic shock. Overall, 14-day mortality was observed in 172 (61.2%) patients, while 30-day mortality in 207 (73.6%) patients. On multivariate analysis, previous surgery, continuous renal replacement therapy, inadequate source control of infection, and pneumonia were independently associated with higher risk of septic shock. Instead, septic shock and Charlson Comorbidity Index >3 were associated with 14-day mortality, while adequate source control of infection and combination therapy with survival. Finally, septic shock, previous surgery, and aminoglycoside-containing regimen were associated with 30-day mortality, while colistin-containing regimen with survival. Conclusions BSI caused by MDR-AB represents a difficult challenge for physicians, considering the high rates of septic shock and mortality associated with this infection.

Introduction Previous series on the use of daptomycin in enterococcal infective endocarditis (EIE) have shown various outcomes, including higher mortality rates. We analyzed the effectiveness of high-dose daptomycin for the treatment of EIE. Methods We performed a prospective study from 2010 to 2018 in a referral center in patients with native (NVE) and prosthetic valve endocarditis (PVE) due to Enterococcus spp. The standard high-dose daptomycin at our institution is 10–12 mg/kg/day (CLCr > 30 ml/min). We compared the efficacy of a daptomycin-based regimen (DBR) versus daptomycin-sparing regimen (DSR) and daptomycin monotherapy versus combination therapy. Primary endpoints of the study were evaluation of risk factors associated with 30-day mortality and failure at end of therapy. Results We collected 43 EIE cases; 29 were NVE (67.4%). Overall, 16 (37.2%) were treated with DBR, mainly with combination regimens (11, 68.7%), in the majority of cases in association with ß-lactam (7, 43.7%). The mean administered dose of daptomycin was 10.125 mg/kg/day (range 8–12 mg/kg/day). Overall, patients treated with DBR compared with patients treated with DSR had no higher mortality rates and/or failure at end of therapy (6.2% vs. 22. 2%; P 0.41 and MICs 0.25–2 mg/l, 6.2% vs. 3.7%; P 1.0). In the sub-group of patients with NVE and PVE treated with DBR and DSR, no difference was found regarding the primary endpoints on the single or combined use of daptomycin. Conclusion Our findings suggest that high-dose daptomycin might be used as an alternative treatment regimen in EIE.

Introduction Tedizolid phosphate is an oxazolidinone approved for the treatment of acute bacterial skin and skin-structure infections (ABSSSIs) and active against methicillin-resistant Staphylococcus aureus. Aims The objective of this article was to review the evidence for the efficacy and safety of tedizolid phosphate for the treatment of ABSSSI. Evidence review Approval of tedizolid phosphate for the treatment of ABSSSI was based on the results of two phase III randomized controlled trials, ESTABLISH-1 (NCT01170221) and ESTABLISH-2 (NCT01421511), comparing 6-day once-daily tedizolid vs 10-day twice-daily linezolid. In ESTABLISH-1, noninferiority was met with early clinical response rates of 79.5% and 79.4% in tedizolid and linezolid groups, respectively (difference 0.1%, 95% CI -6.1% to 6.2%, with a 10% noninferiority margin). In ESTABLISH-2, noninferiority was met with 85% and 83% rates of early clinical response in tedizolid and linezolid groups, respectively (difference 2.6%, 95% CI -3.0% to 8.2%). Pooled data from ESTABLISH-1 and ESTABLISH-2 indicated a lower frequency of thrombocytopenia in tedizolid-treated than in linezolid-treated patients. Conclusion Tedizolid offers the option of an intravenous to oral switch, allows once-daily administration, and presents lower risk of myelotoxicity when a 6-day course is used for the treatment of ABSSSI. Greater economic cost associated with this antibiotic could be offset by its shorter treatment duration and possibility of oral administration in routine clinical practice, although either sponsored or nonsponsored postmarketing observational experience remains essential for ultimately confirming the effectiveness and tolerability of tedizolid outside clinical trials.

Polymicrobial bloodstream infections (pBSI) occurring in hematological patients are still poorly understood, and specific information are very limited. In this epidemiologic survey, we describe clinical characteristics and outcome of 125 consecutive pBSI occurred in oncohematological patients. Polymicrobial bloodstream infections (pBSI) were defined with the isolation of 2 or more bacteria from blood culture specimens obtained within 72 h. Over an 11-year period, we documented 500 bacterial bloodstream infections (BSI) in 4542 hospital admissions and 25% (125) of these were pBSI. Most common underlying hematological disease was acute myeloid leukemia and 89% of patients had severe neutropenia. Fifty pBSI (40%) occurred in patients undergoing a stem cell transplantation (SCT), mostly within 30 days from transplant (42/50–84%). Principal bacterial association was Gram-positive plus Gram-negative (57%). Resolution rate of pBSI was 82%, without differences between SCT and non-SCT cases. pBSI-related mortality was 15% (6% in SCT cases). Septic shock occurred in 16% of cases and septic shock–related mortality was 65% (75% in SCT cases and 63% in non-SCT cases; p = 0.6). Multidrug-resistant (MDR) bacteria were involved in 22% of pBSI and the MDR-pBSI–related mortality was significantly higher in SCT patients (p = 0.007). This observational study highlights that pBSI is not a rare bloodstream infectious complication in oncohematological patients. pBSI-related mortality is lower than 20%, but, if septic shock occurs, mortality reaches 65%. MDR bacteria were involved in 22% of cases and pBSI-MDR–related mortality was significantly higher in SCT patients.

We aimed to assess the attitude towards influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations among coronavirus disease 2019 (COVID-19) recovered patients. We performed a cross-sectional study consisting of a standardized telephone interview carried out between September and November 2020 targeting a cohort of adult in- and out-patients that had recovered from COVID-19 after the first wave (March–May 2020) at Udine Hospital (Italy). Overall, 599 people participated (320 female, median age 53 years) and most had experienced an acute COVID-19 with mild illness (409, 68.3%). The majority were hesitant or undecided towards influenza (327, 54.6%) and SARS-CoV-2 (353, 59.2%) vaccines. Older age, public work exposure, and previous 2019 flu shots were the main factors associated with a positive attitude toward both vaccinations (p &lt, 0.05). Being hospitalized during the acute COVID-19 phase was associated with the willingness to get a flu shot (94/272, 34.5%) but not SARS-CoV-2 vaccine (70/244, 28.7%). Vaccine hesitancy is diffuse and multifactorial also among COVID-19 recovered.

Purpose of review Poststernotomy mediastinitis (PSM) remains a serious infection and is significantly associated with high morbidity, short-term and long-term mortality. Gram-negative bacteria (GNB) are an underestimated cause of PSM, and there is little information on the risk factors, prevention, diagnosis and management of GNB PSM. Recent findings The pathogenesis of PSM is the result of a complex and multifactorial interplay between intraoperative wound contamination, host-related and surgical host factors but GNB are probably mostly translocated from other host site infections. GNB are frequent cause of PSM (18-38% of cases) and GNB PSM have shown to more frequently polymicrobial (20-44%). GNG PSM has shown to occur earlier than Gram-positive PSM. Early diagnosis is crucial to successful treatment. The management of PSM needs a combination of culture-directed antimicrobial therapy and an early extensive surgical debridement with either immediate or delayed closure of the sternal space. Antibiotic treatment choice and duration should be based on clinical evaluation, evolution of inflammatory markers, microbiological tests and imaging studies. Mortality has shown to be significantly higher with GNB PSM compared with other causes and the inappropriateness of initial antibiotic therapy may explain the worse outcome of GNB PSM. Summary GNB PSM is usually undervalued in the setting of PSM and have shown to be a frequent cause of inappropriate treatment with adverse prognostic potential. There is a need for efforts to improve knowledge to prevent and adequately treat GNB PSM.

Objectives To assess the prevalence of and factors associated with post-coronavirus disease 2019 (COVID-19) syndrome 6 months after the onset. Methods A bidirectional prospective study. Interviews investigated symptoms potentially associated with COVID-19 6 months after the disease onset of all consecutive adult inpatients and outpatients with COVID-19 attending Udine Hospital (Italy) from March to May 2020. IgG antibodies against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were also evaluated 6 months after the onset of symptoms, at the time of the interview. Results A total of 599 individuals were included (320 female, 53.4%; mean age 53 years, SD 15.8) and interviewed 187 days (22 SD) after onset. The prevalence of post-COVID-19 syndrome was 40.2% (241/599). The presence of IgG antibodies was significantly associated with the occurrence of post-COVID-19 syndrome (OR 2.56, 95% CI 1.48–4.38, p 0.001) and median SARS-CoV-2 IgG titres were significantly higher in patients with post-COVID-19 syndrome than in patients without symptoms (42.1, IQR 17.1–78.4 vs. 29.1, IQR 12.1–54.2 kAU/L, p 0.004). Female gender (OR 1.55, 95% CI 1.05–2.27), a proportional increase in the number of symptoms at the onset of COVID-19 (OR 1.81, 95% CI 1.59–2.05) and ICU admission OR 3.10, 95% CI 1.18–8.11) were all independent risk factors for post-COVID-19 syndrome. The same predictors also emerged in a subgroup of 231 patients with the serological follow-up available at the time of the interview alongside the proportional increase in anti-SARS-CoV-2 IgG (OR 1.01, 95% CI 1.00–1.02, p 0.04). Discussion Prospective follow-up could be offered to specific subgroups of COVID-10 patients, to identify typical symptoms and persistently high anti-SARS-CoV-2 IgG titres as a means of early detection of post-COVID-19 long-term sequelae.

Diagnòstic; Malalties fúngiques invasores; Pneumocystis Diagnóstico; Enfermedades fúngicas invasivas; Pneumocystis Diagnosis; Invasive fungal diseases; Pneumocystis The Fungal Infections Definitions in Intensive Care Unit (ICU) patients (FUNDICU) project aims to provide standard sets of definitions for invasive fungal diseases (IFDs) in critically ill, adult patients, including invasive aspergillosis (IA), invasive candidiasis (IC), Pneumocystis jirovecii pneumonia (PJP), and other non-IA, non-IC IFDs. The first step of the project was the conduction of separated systematic reviews of the characteristics and applicability to critically ill, adult patients outside classical populations at risk (hematology patients, solid organ transplant recipients) of available definitions and diagnostic tests for IFDs. We report here the results of two systematic reviews exploring the performance of available definitions and tests, for PJP and for other non-IA, non-IC IFDs. Starting from 2585 and 4584 records for PJP and other IFDs, respectively, 89 and 61 studies were deemed as eligible for full-text evaluation. However, only two studies for PJP and no studies for other IFDs met the FUNDICU protocol criteria for inclusion in qualitative synthesis. Currently, there is no sufficient solid data for directly evaluating the performance of existing definitions and laboratory tests for the diagnosis of PJP and other non-IA, non-IC IFDs in critically ill adult patients outside classical populations at risk. The present project did not require additional funding from routine research activities. Costs for open-access publications were covered by research funds of the main authors.

The aim of this study was to assess the long-term dynamics and factors associated with the serological response against the severe acute respiratory syndrome coronavirus 2 after primary infection. A prospective longitudinal study was conducted with monthly serological follow-up during the first 4 months, and then at 6, 8, and 10 months after the disease onset of all recovered adult in- and outpatients with coronavirus disease 2019 (COVID-19) attending Udine Hospital (Italy) during the first wave (from March to May 2020). A total of 546 individuals were included (289 female, mean age 53.1 years), mostly with mild COVID-19 (370, 68.3%). Patients were followed for a median of 302 days (interquartile range, 186 to 311). The overall seroconversion rate within 2 months was 32% for IgM and 90% for IgG. Seroreversion was observed in 90% of patients for IgM at 4 months and in 47% for IgG at 10 months. Older age, number of symptoms at acute onset, and severity of acute COVID-19 were all independent predictors of long-term immunity both for IgM (β, linear regression coefficient, 1.10, P = 0.001; β 5.15 P = 0.014; β 43.84 P = 0.021, respectively) and for IgG (β 1.43 P

Background: Little is known on the clinical relevance of the nutritional status and body composition of patients hospitalized with SARS-CoV-2 infection. The aim of our study was to assess the prevalence of malnutrition in patients with COVID-19 pneumonia using bioelectrical impedance vector analysis (BIVA), and to evaluate the relationship of their nutritional status with the severity and outcome of disease. Methods: Among 150 consecutive patients who were hospitalized with COVID-19 pneumonia, 37 (24.3%) were classified as malnourished by BIVA, and were followed-up for 60 days from admission. Outcome measures were differences in the need for invasive mechanical ventilation, in-hospital mortality, and the duration of hospital stay in survivors. Results: During 60 days of follow-up, 10 (27%) malnourished patients and 13 (12%) non-malnourished patients required invasive mechanical ventilation (p = 0.023), and 13 (35%) malnourished patients and 9 (8%) non-malnourished patients died (p &lt, 0.001). The average duration of the hospital stay in survivors was longer in patients with malnutrition (18.2 ± 15.7 vs. 13.2 ± 14.8 days, p &lt, 0.001). In survival analyses, mechanical ventilation free (log-rank 7.887, p = 0.050) and overall (log-rank 17.886, p &lt, 0.001) survival were significantly longer in non-malnourished than malnourished patients. The Cox proportional ratio showed that malnutrition was associated with an increased risk of mechanical ventilation (HR 4.375, p = 0.004) and death (HR 4.478, p = 0.004) after adjusting for major confounders such as age, sex, and BMI. Conclusions: Malnutrition diagnosed with BIVA was associated with worse outcomes in hospitalized patients with COVID-19 pneumonia.

Background A growing body of observational evidence supports the value of ceftazidime-avibactam (CAZ-AVI) in managing infections caused by carbapenem-resistant Enterobacteriaceae. Methods We retrospectively analyzed observational data on use and outcomes of CAZ-AVI therapy for infections caused by Klebsiella pneumoniae carbapenemase–producing K. pneumoniae (KPC-Kp) strains. Multivariate regression analysis was used to identify variables independently associated with 30-day mortality. Results were adjusted for propensity score for receipt of CAZ-AVI combination regimens versus CAZ-AVI monotherapy. Results The cohort comprised 577 adults with bloodstream infections (n = 391) or nonbacteremic infections involving mainly the urinary tract, lower respiratory tract, and intra-abdominal structures. All received treatment with CAZ-AVI alone (n = 165) or with ≥1 other active antimicrobials (n = 412). The all-cause mortality rate 30 days after infection onset was 25% (146/577). There was no significant difference in mortality between patients managed with CAZ-AVI alone and those treated with combination regimens (26.1% vs 25.0%, P = .79). In multivariate analysis, mortality was positively associated with presence at infection onset of septic shock (P = .002), neutropenia (P < .001), or an INCREMENT score ≥8 (P = .01); with lower respiratory tract infection (LRTI) (P = .04); and with CAZ-AVI dose adjustment for renal function (P = .01). Mortality was negatively associated with CAZ-AVI administration by prolonged infusion (P = .006). All associations remained significant after propensity score adjustment. Conclusions CAZ-AVI is an important option for treating serious KPC-Kp infections, even when used alone. Further study is needed to explore the drug’s seemingly more limited efficacy in LRTIs and potential survival benefits of prolonging CAZ-AVI infusions to ≥3 hours.

Background COVID-19 has caused considerable morbidity and mortality worldwide and cardiac involvement has been reported during infection. The short-term cardiac outcome in survivors of COVID-19 is not known. Objective To examine the heart of patients who survived COVID-19 and to compare the cardiac outcome between patients who recovered from mild-to-moderate or severe illness. Methods With use of ECG and echocardiography, we examined the heart of 105 patients who had been hospitalized with COVID-19 and were consecutively recruited after hospital discharge while attending follow-up visits. Survivors of COVID-19 were compared with 105 matched controls. We also compared the cardiac outcome and lung ultrasound scan between COVID-19 patients who had mild-to-moderate or severe illness. Results Cardiac data were collected a median of 41 days from the first detection of COVID-19. Symptoms were present in a low percentage of patients. In comparison with matched controls, no considerable structural or functional differences were observed in the heart of survivors of COVID-19. Lung ultrasound scan detected significantly greater residual pulmonary involvement in COVID-19 patients who had recovered from severe than mild-to-moderate illness. No significant differences were detected in ECG tracings nor were found in the left and right ventricular function of patients who had recovered from mild-to-moderate or severe illness. Conclusions In a short-term follow-up, no abnormalities were identified in the heart of survivors of COVID-19, nor cardiac differences were detected between patients who had different severity of illness. With the limitations of a cross-sectional study, these findings suggest that patients who recover from COVID-19 do not have considerable cardiac sequelae. Graphic abstract

Highlights • There is an urgent need for markers of prognosis in COVID-19. • Higher inflammatory markers best select tocilizumab treatment. • The ward based tocilizumab group showed better responses and less infections than ICU tocilizumab group. • The former group may be the best for evaluating the impact of anti-cytokine therapy in COVID-19. • The known poor risk factors for COVID-19 infection were present in the TOCI treated rather than in the good prognosis standard of care group., Objective Approximately 5% of patients with coronavirus disease 2019 (COVID-19) develop a life-threatening pneumonia that often occurs in the setting of increased inflammation or “cytokine storm”. Anti-cytokine treatments are being evaluated but optimal patient selection remains unclear, and the aim of our study is to address this point. Methods Between February 29 to April 6, 2020, 111 consecutive hospitalized patients with COVID-19 pneumonia were evaluated in a single centre retrospective study. Patients were divided in two groups: 42 severe cases (TOCI) with adverse prognostic features including raised CRP and IL-6 levels, who underwent anti-cytokine treatments, mostly tocilizumab, and 69 standard of care patients (SOC). Results In the TOCI group, all received anti-viral therapy and 40% also received glucocorticoids. In TOCI, 62% of cases were ventilated and there were 3 deaths (17.8 ± 10.6 days, mean follow up) with 7/26 cases remaining on ventilators, without improvement, and 17/26 developed bacterial superinfection. One fatality occurred in the 15 TOCI cases treated on noninvasive ventilation and 1 serious bacterial superinfection. Of the 69 cases in SOC, there was no fatalities and no bacterial complications. The TOCI group had higher baseline CRP and IL-6 elevations (p

Background Malaria still represents a major health threat, in terms of both morbidity and mortality. Complications of malaria present a diversified clinical spectrum, with neurological involvement leading to the most serious related-conditions. The authors recently encountered a case of a 60-year old Italian man presenting with confusion, language disturbances and Parkinson-like syndrome 3 weeks after complete remission from severe Plasmodium falciparum cerebral malaria. Chemical and microbiological analysis revealed aseptic meningitis, diffuse encephalitis and abnormal immune-activation. Re-infection and recrudescence of infection were excluded. Further analysis excluded paraneoplastic and autoimmune causes of encephalitis. A diagnosis of Post-Malaria Neurological Syndrome (PMNS) was finally formulated and successfully treated with high dose of steroids. Methods A systematic research of current literature related to PMNS was performed. Results 151 cases of PMNS were included, the majority of which occurred after severe P. falciparum infections. Four main clinical pattern were identified: 37% of the cases presented as “classical” PMNS, 36% presented as delayed cerebellar ataxia (DCA), 18% resembled acute inflammatory demyelinating polyneuropathy (AIDP), and 8% presented as acute disseminated encephalomyelitis (ADEM)-like form. Differentiation between different forms was not always simple, as clinical and radiological findings frequently overlap. Overall, in almost all of the tested cases, cerebrospinal fluid was found pathological; EEG revealed nonspecific encephalopathy in 30% of classical PMNS and 67% ADEM; imaging tests were found abnormal in 92% of ADEM-like forms. Pathogenesis remains unclear. An autoimmune mechanism is the most corroborated pathogenic hypothesis. Overall, the majority of PMNS cases revert without specific treatment. In most severe forms, high dose steroids, intravenous immunoglobulins, and plasmapheresis have been shown to improve symptoms. Conclusions PMNS is a disabling complication of malaria. The overall incidence is not known, due to frequent misdiagnosis and under-reporting. Pathogenesis is not also fully understood, but rapid response to immune-modulating treatment along with similarities to auto-immune neurological disease, strongly support a dysregulated immunological genesis of this condition. The lack of randomized controlled studies regarding therapeutic approaches is a major unmet need in this setting. A systematic collection of all the PMNS cases would be desirable, in order to increase awareness of this rare condition and to prospectively investigate the most appropriate management.

Objectives Our aim was to analyze the prevalence of multidrug-resistant bacterial infections in lung transplant donors and to evaluate its influence on donor-derived bacterial infections. Methods We conducted a retrospective study of adult patients who underwent lung transplantation (2013–2016) at our hospital. Donor-derived bacterial infection was defined as the isolation of the same bacteria with identical antibiotic susceptibility patterns in the recipient and the perioperative cultures from the donor during the first month posttransplantation. We utilized a preventive antibiotic strategy adapted to the bacteria identified in donor cultures using systemic and nebulized antibiotics. Results 252 lung transplant recipients and 243 donors were included. In 138/243 (56.8%) donors, one bacterial species was isolated from at least one sample; graft colonization (118/243; 48.6%), blood cultures (5/243; 2.1%) and the contamination of preservation fluids (56/243; 23%). Multidrug-resistant bacteria were isolated from 12/243 (4.9%) donors; four Enterobacterales, four Stenotrophomonas maltophilia, three Pseudomonas aeruginosa and one methicillin-resistant Staphylococcus aureus. There was no transmission of these multidrug-resistant bacteria. Donor-derived infections, primarily tracheobronchitis due to non-MDR bacteria, were diagnosed in 7/253 (2.9%) recipients, with good clinical outcomes. Conclusions The lungs of donors colonized with multidrug-resistant bacteria may be safely used when recipients receive prompt tailored antibiotic treatment.

Background Invasive fungal infections (IFIs) represent a global issue and affect various patient populations. In recent years, resistant fungal isolates showing increased azole or echinocandin MICs have been reported, and their potential clinical impact has been investigated. Aims To provide an update on the epidemiology of resistance among fungi (e.g., Candida spp., Aspergillus spp., and Cryptococcus spp.) and to offer a critical appraisal of the relevant literature regarding the impact of MICs on clinical outcome in patients with IFI. Sources PubMed search with relevant keywords along with a personal collection of relevant publications. Content Although antifungal resistance has been associated with a poorer response to antifungal therapy in various studies, other factors such as comorbidities, septic shock and source of infection appear to be key determinants affecting the clinical outcome of patients with IFI. Implications Future international collaborative studies are required to tease out the relative contribution of in vitro antifungal resistance on patient outcomes, thus enabling the optimization of IFI management.

Carbapenemase-producing Enterobacteriaceae represent an increasing global threat worldwide and Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) has become one of the most important contemporary pathogens, especially in endemic areas. Risk stratification and rapid diagnostics laboratory workflows are of paramount importance and indication for therapy of KPC-KP infection must be individualized according to the baseline characteristics of the patient and severity of infection. The optimal treatment of infection because of KPC-KP organisms is uncertain and antibiotic options are limited. The knowledge of the patient’s pathophysiology, infection site, and application of the pharmacokinetic/pharmacodynamic principles on the basis of minimum inhibitory concentration (MIC) has progressively gained major relevance. Combination therapies including high-dose meropenem, colistin, fosfomycin, tigecycline, and aminoglycosides are widely used, with suboptimal results. In the past few years, new antimicrobials targeting KPC-KP have been developed and are now at various stages of clinical research. However, their optimal use should be guaranteed in the long term for delaying, as much as possible, the emergence of resistance. Strict infection control measures remain necessary. The aim of this review is to discuss the challenges in the management and treatment of patients with infections because KPC-KP and provide an expert opinion.

Mycobacterium chimaera infections have been associated with contamination of a heater–cooler unit used during cardiopulmonary bypass procedures since 2006. Mycobacterium chimaera is a slow-growing non-tuberculous mycobacterium responsible for an infection, which is difficult to treat and has often a devastating course. Until now, M. chimaera infection has been shown to occur up to 8 years after operation. We report a patient presenting with an aortic pseudoaneurysm who developed M. chimaera infection 12 years after repair of an acute type A aortic dissection with graft replacement of the ascending aorta and stent-grafting of the arch. As far as we know, this is the case with the longest incubation period of M. chimaera infection. The present experience indicates that all patients who underwent open heart procedures since 2006 with such heater–cooler unit model should be closely followed up regardless of time of index surgery.

The 2018 West Nile Virus (WNV) season in Europe was characterized by an extremely high infection rate and an exceptionally higher burden when compared to previous seasons. Overall, there was a 10.9-fold increase in incidence in Italy, with 577 human cases, 230 WNV neuroinvasive diseases (WNNV) and 42 WNV-attributed deaths. Methods: in this paper we retrospectively reported the neurological presentation of 7 patients admitted to University Hospital of Udine with a diagnosis of WNNV, especially focusing on two patients who presented with atypical severe brain stem involvement. Conclusions: the atypical features of some of these forms highlight the necessity to stay vigilant and suspect the diagnosis when confronted with neurological symptoms. We strongly encourage clinicians to consider WNNV in patients presenting with unexplained neurological symptoms in mild climate-areas at risk.

Contains fulltext : 229471.pdf (Publisher’s version ) (Closed access) 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)-β-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.

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 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.

Background The relationship between community-acquired respiratory viruses (CARVs) and chronic lung allograft dysfunction (CLAD) in lung transplant recipients is still controversial. Methods We performed a prospective cohort study (2009–2014) in all consecutive adult patients (≥18 years) undergoing lung transplantation in the Hospital Universitari Vall d’Hebron (Barcelona, Spain). We systematically collected nasopharyngeal swabs from asymptomatic patients during seasonal changes, from patients with upper respiratory tract infectious disease, lower respiratory tract infectious disease (LRTID), or acute rejection. Nasopharyngeal swabs were analyzed by multiplex polymerase chain reaction. Primary outcome was to evaluate the potential association of CARVs and development of CLAD. Time-dependent Cox regression models were performed to identify the independent risk factors for CLAD. Results Overall, 98 patients (67 bilateral lung transplant recipients; 63.3% male; mean age, 49.9 years) were included. Mean postoperative follow-up was 3.4 years (interquartile range [IQR], 2.5–4.0 years). Thirty-eight lung transplant recipients (38.8%) developed CLAD, in a median time of 20.4 months (IQR, 12–30.4 months). In time-controlled multivariate analysis, CARV-LRTID (hazard ratio [HR], 3.00 [95% confidence interval {CI}, 1.52–5.91]; P = .002), acute rejection (HR, 2.97 [95% CI, 1.51–5.83]; P = .002), and cytomegalovirus pneumonitis (HR, 3.76 [95% CI, 1.23–11.49]; P = .02) were independent risk factors associated with developing CLAD. Conclusions Lung transplant recipients with CARVs in the lower respiratory tract are at increased risk to develop CLAD., “Community-acquired respiratory viruses (CARVs) lower respiratory tract infection” should be better than viral lower respiratory tract infection. It should be: CARVs lower respiratory tract infection, acute rejection and cytomegalovirus pneumonitis were independently associated with chronic lung allograft dysfunction.

The increase of skin and soft tissue infections (SSTIs) represents a major concern both in community and in the hospital setting. Staphylococcus aureus is the most frequently isolated pathogen, and the rise in infections due to methicillin-resistant Staphylococcus aureus (MRSA) has been associated with inadequate antibiotic treatment and increased morbidity.A number of new antimicrobials with activity against drug-resistant Gram-positive pathogens, including MRSA, have been recently approved for the treatment of SSTIs. New lipoglycopeptides, in particular dalbavancin, are long-acting antibiotics with potential for infrequent administration, offering the possibility for outpatient treatment and early hospital discharge.Dalbavancin is a new lipoglycopeptide showing high activity against Gram-positive bacteria, including drug-resistant strains. Dalbavancin presents a distinctive pharmacokinetic profile with a terminal prolonged half-life of approximately 14 days. This characteristic allows once-weekly dosing interval, avoiding the need for daily dosing and offering an advantage over other compounds for potential use in the outpatient setting or to promote early hospital discharge. Dalbavancin has a favorable adverse effect profile and appears to be a promising new alternative for treatment of SSTIs. We have reviewed the pharmacokinetic properties of dalbavancin and the clinical evidence for its use in complicated SSTIs and other potential applications.

Introduction Fungal infections are a significant and increasing public health problem worldwide, that range in severity from mild superficial infections that affect a large proportion of the otherwise healthy population to life-threatening invasive diseases limited mostly to vulnerable immunosuppressed patients (1). Patients that are at risk for fungal infections, those hospitalised with serious underlying diseases, such as those with HIV infection, haemato-oncological malignancies, recipients of immunosuppressive therapies, solid-organ or hematopoietic stem cell transplant (HSCT) recipients (2). The incidence of fungaemia is growing and has dramatically increased within the past two decades. Such infections have been attributed to the common practice of prolonged hospitalisation of highly susceptible patients receiving advanced medical treatment; such conditions render patients more susceptible to invasive fungal infections (3,4)The populations of patients at risk have expanded to include those with usually multiple underlying medical conditions, such as diabetes mellitus, chronic obstructive pulmonary diseases and those receiving corticosteroids (3,4) The current number of fungal infections occurring each year in Italy is not known. The aim of this work was to estimate the burden of fungal infections in Italy, a country, with a population of 61 millions. As invasive fungal infections are not reportable, exact data are not available. For this reason, we have taken different approaches to explore the current number of invasive fungal infections. First, we have estimated fungal infections based on populations at risk, with data from published Italian or international cohort studies and clinical trials.Material and methodsThe burden of serious fungal infections was estimated for general healthy population and for specific at-risk groups, including patients affected by HIV infection, respiratory diseases (COPD, asthma and tuberculosis), solid organ or hematologic malignancy and critical illness.Demographic data regarding Italian population were obtained from the Italian National Statistical Institute (ISTAT) (5).Data on the HIV/AIDS population were obtained from the Epicentro-National Institute of Health (Istituto Superiore di Sanità-ISS) (6) and recent published data estimating adult HIV prevalence in Italy (7).Tuberculosis statistics were taken from the Epicentro-National Institute of Health (ISS) (6) and World Health Organization (WHO) reports (8). COPD and asthma prevalence in Italy were obtained from the Health Examination Survey (OEC/HES) 2008-2012(9).Solid organ cancer and haematological diseases cases were taken from Associazione Italiana Oncologia Medica (AIOM) (10) and Associazione Italiana dei Registri Tumori (AIRTUM) reports (11).Country’s profile, populations and rates required to calculate burden of serious fungal infections are reported in Table 1.We conducted an extensive literature review and published epidemiology papers reporting fungal infections incidence and/or prevalence in Italy were identified.Where no national data existed, authors reviewed data from published single-center or multicentre trials and from public health institutions in Italy. Moreover, in selected cases, when Italian data were not available, we calculated Italian fungal burden based on fungal infection incidence in other European countries. RESULTSCountry profile Italy is a country with an estimated population of 61 million people, represented by adults ( 14 years) in up to 85% of cases. Of the general population, approximately 13 million (22%) are older than 65 years. Chronic obstructive pulmonary disease prevalence has been estimated in 3.5-5% in men and 2.3 - 3.3% in women overall among adult population, with the large majority of patients in classified as GOLD stage I. The number of HIV-infected patients ranged between 114.000 and 156.000 people, with approximately 84% of patients receiving ARV (7). Solid organ cancer prevalence is 3.037.127 cases, accounting for approximately 5% of overall population (11). The exact prevalence of patients with hematological malignancies is not available, but an estimated number of 31.300 new diagnosis per year, mainly represented by non-Hodgkin lymphoma and acute leukemia has been reported in Italian registries (11). The number of autologous and allogeneic HSCTs is available at the registry of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) and accounted in 2016 for 2905 and 1796 transplants, respectively (www.gitmo.it). Country’s profile, populations and rates required to calculate burden of serious fungal infections are reported in Table 1. Prevalence rates previously reported used to estimate the burden of serious fungal infections are reported in Table 2.

The epidemiology of respiratory viruses (RVs) in lung transplant recipients (LTRs) and the relationship of RVs to lung function, acute rejection (AR) and opportunistic infections in these patients are not well known. We performed a prospective cohort study (2009–2014) by collecting nasopharyngeal swabs (NPSs) from asymptomatic LTRs during seasonal changes and from LTRs with upper respiratory tract infectious disease (URTID), lower respiratory tract infectious disease (LRTID) and AR. NPSs were analyzed by multiplex polymerase chain reaction. Overall, 1094 NPSs were collected from 98 patients with a 23.6% positivity rate and mean follow‐up of 3.4 years (interquartile range 2.5–4.0 years). Approximately half of URTIDs (47 of 97, 48.5%) and tracheobronchitis cases (22 of 56, 39.3%) were caused by picornavirus, whereas pneumonia was caused mainly by paramyxovirus (four of nine, 44.4%) and influenza (two of nine, 22.2%). In LTRs with LRTID, lung function changed significantly at 1 mo (p = 0.03) and 3 mo (p = 0.04). In a nested case–control analysis, AR was associated with RVs (hazard ratio [HR] 6.54), Pseudomonas aeruginosa was associated with LRTID (HR 8.54), and cytomegalovirus (CMV) replication or disease was associated with URTID (HR 2.53) in the previous 3 mo. There was no association between RVs and Aspergillus spp. colonization or infection (HR 0.71). In conclusion, we documented a high incidence of RV infections in LTRs. LRTID produced significant lung function abnormalities. Associations were observed between AR and RVs, between P. aeruginosa colonization or infection and LRTID, and between CMV replication or disease and URTID., A large prospective study of the epidemiology of respiratory viruses in lung transplant recipients using molecular assays demonstrates a very high incidence of respiratory viral infection and an association between respiratory virus infectious diseases, immediate allograft dysfunction, and the development of acute rejection and opportunistic infection.

This study aimed to characterise UTIs caused by Pseudomonas aeruginosa in hospitalised adults and to identify risk factors for infections caused by multidrug-resistant (MDR) strains. A retrospective case-case-control study was conducted in two Italian teaching hospitals. Totally, 242 monomicrobial P. aeruginosa UTIs were analysed; 65 (26.9%) were caused by MDR strains. Clinical treatment failure at 72 h in 215 patients receiving empirical therapy was more frequent in MDR versus non-MDR cases [35/59 (59.3%) vs. 55/156 (35.3%); P = 0.001], particularly when a β-lactam/β-lactamase inhibitor or fluoroquinolone was initially prescribed. By Day 7 (when all regimens were consistent with antimicrobial susceptibility results), treatment failure rates were similar [MDR 15/65 (23.1%) vs. non-MDR 25/177 (14.1%); P = 0.09]. In-hospital mortality rates remained low in both groups [6/65 (9.2%) vs. 22/177 (12.4%); P = 0.49], but median hospital stay for MDR cases was longer (48 vs. 22 days; P ≤ 0.001). Models for predicting MDR and non-MDR P. aeruginosa UTIs displayed good discriminatory power. Presence of ≥3 risk factors for MDR P. aeruginosa UTI was associated with an OR for this outcome of 7.44 (95% CI 3.24-17.57; P0.001; specificity 91%, accuracy 75%). The model for predicting non-MDR P. aeruginosa UTI displayed similar accuracy (74%) with a risk factor burden threshold of ≥2 (OR = 7.02, 95% CI 4.61-10.70; P0.001). Risk factor assessment can identify UTIs in hospitalised patients likely to be caused by MDR P. aeruginosa, thereby facilitating targeted infection control and timelier effective treatment.

Contains fulltext : 206779.pdf (Publisher’s version ) (Open Access) 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.

Introduction and objectives The aim of this study was to determine the prevalence of colorectal disease in Enterococcus faecalis infective endocarditis (EFIE) patients. Methods An observational, retrospective, multicenter study was performed at 4 referral centers. From the moment that a colonoscopy was systematically performed in EFIE in each participating hospital until October 2018, we included all consecutive episodes of definite EFIE in adult patients. The outcome was an endoscopic finding of colorectal disease potentially causing bacteremia. Results A total of 103 patients with EFIE were included; 83 (81%) were male, the median age was 76 [interquartile range 67-82] years, and the median age-adjusted Charlson comorbidity index was 5 [interquartile range 4-7]. The presumed sources of infection were unknown in 63 (61%), urinary in 20 (19%), gastrointestinal in 13 (13%), catheter-related bacteremia in 5 (5%), and others in 2 (2%). Seventy-eight patients (76%) underwent a colonoscopy, and 47 (60%) had endoscopic findings indicating a potential source of bacteremia. Thirty-nine patients (83%) had a colorectal neoplastic disease, and 8 (7%) a nonneoplastic disease. Of the 45 with an unknown portal of entry who underwent a colonoscopy, gastrointestinal origin was identified in 64%. In the subgroup of 25 patients with a known source of infection and a colonoscopy, excluding those with previously diagnosed colorectal disease, 44% had colorectal disease. Conclusions Performing a colonoscopy in all EFIE patients, irrespective of the presumed source of infection, could be helpful to diagnose colorectal disease in these patients and to avoid a new bacteremia episode (and eventually infective endocarditis) by the same or a different microorganism.

The treatment of multidrug-resistant Gram-negative bacteria (MDR-GNB) infections in critically ill patients presents many challenges. Since an effective treatment should be administered as soon as possible, resistance to many antimicrobial classes almost invariably reduces the probability of adequate empirical coverage, with possible unfavorable consequences. In this light, readily available patient's medical history and updated information about the local microbiological epidemiology remain critical for defining the baseline risk of MDR-GNB infections and firmly guiding empirical treatment choices, with the aim of avoiding both undertreatment and overtreatment. Rapid diagnostics and efficient laboratory workflows are also of paramount importance both for anticipating diagnosis and for rapidly narrowing the antimicrobial spectrum, with de-escalation purposes and in line with antimicrobial stewardship principles. Carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii are being reported with increasing frequencies worldwide, although with important variability across regions, hospitals and even single wards. In the past few years, new treatment options, such as ceftazidime/avibactam, meropenem/vaborbactam, ceftolozane/tazobactam, plazomicin, and eravacycline have become available, and others will become soon, which have provided some much-awaited resources for effectively counteracting severe infections due to these organisms. However, their optimal use should be guaranteed in the long term, for delaying as much as possible the emergence and diffusion of resistance to novel agents. Despite important progresses, pharmacokinetic/pharmacodynamic optimization of dosages and treatment duration in critically ill patients has still some areas of uncertainty requiring further study, that should take into account also resistance selection as a major endpoint. Treatment of severe MDR-GNB infections in critically ill patients in the near future will require an expert and complex clinical reasoning, of course taking into account the peculiar characteristics of the target population, but also the need for adequate empirical coverage and the more and more specific enzyme-level activity of novel antimicrobials with respect to the different resistance mechanisms of MDR-GNB.

Objectives: To evaluate scoring systems that have been created to predict the risk of death post-surgery in infective endocarditis (IE). Design: Eight scores - (1) The Society of Thoracic Surgery (STS) risk score for IE, (2) De Feo score, (3) PALSUSE score (prosthetic valve, age ≥70, large intracardiac destruction, Staphylococcus spp, urgent surgery, sex [female], EuroSCORE ≥10), (4) ANCLA score (anemia, New York Heart Association class IV, critical state, large intracardiac destruction, surgery of thoracic aorta), (5) Risk-Endocarditis Score (RISK-E), (6) score for heart valve or prosthesis IE (EndoSCORE), and (7,8) Association pour l'Étude et la Prévention de l'Endocadite Infectieuse (AEPEI) score I and II - were evaluated in 324 (mean age, 61.8 ± 14.6 years) consecutive patients having IE and undergoing cardiac operation (1999-2018, Regione Autonoma Friuli-Venezia Giulia, Italy). Results: There were 45 (13.9%) in-hospital deaths. Despite many differences on the number and the type of variables, all the investigated scores showed good goodness-of-fit (Hosmer-Lemeshow test, p ≥.28). For five scores, accuracy of prediction (receiver-operating characteristic curve analysis) was good (ANCLA score) or fair (STS risk score for IE, PALSUSE score, AEPEI score I and II). When compared one-to-one (Hanley-McNeil method), accuracy of prediction of ANCLA score was higher than all of other risk scores except for AEPEI score I (p = .077). Conclusions: Five of eight scores that were evaluated in this study showed satisfactory performance in predicting in-hospital mortality following surgery for IE. The ANCLA score should be preferred.

Acute bacterial skin and skin-structure infections (ABSSSI) may develop in both in-patients and out-patients, possibly with a severe clinical presentation. Since most phase 3 randomized clinical trials have shown non-inferiority in efficacy across different agents, considerations regarding their different safety profiles inevitably play a crucial role in the everyday choice about which of them should be employed for the treatment of ABSSSI.In this review, the authors discuss the safety profile of different treatment options for ABSSSI.The spread of methicillin-resistant

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) infections represent a leading cause of infection-related morbidity and mortality worldwide. There has been a welcome increase in the number of agents available for the treatment of MRSA infection over the last decade and several clinical trials are currently investigating the role of new experimental strategies.Areas covered: The purpose of this manuscript is to review the efficacy and safety of recently approved anti-MRSA molecules as well as some newer agents currently under investigation with a specific focus on the potential role of these drugs in everyday clinical practice.Expert opinion: Many new drugs with an activity against MRSA have been recently approved or are in an advanced stage of development. All these compounds represent promising options to enhance our antibiotic armamentarium. However, data regarding the use of these new compounds in real-life terms are limited and their best placement in therapy and in terms of optimization of medical resources and balance of cost-effectiveness requires further investigation.

To the Editor: The interesting and timely paper by Cain et al.1, in press in the Journal of Cardiac Surgery , provides important details concerning the devastating consequences of Mycobacterium chimaera (MC ) infection. In their patient extreme fragility of the mediastinal tissues was observed after repair of an acute aortic dissection; during follow-up multiple reoperations were required to treat recurrent dehiscence of the aortic grafts. Despite repeat explantation of foreign materials infection persisted with mediastinitis and eventual systemic diffusion with fatal outcome.MC infection after open cardiac surgery using cardiopulmonary bypass has been recently reported as a clinical outbreak worldwide and identified as originating by contaminated water in heater-cooler units2. Current experience shows that MC causes a slow-growing and extremely difficult to treat infection with an incubation period which has been recently demonstrated to be as long as >12 years3.We have recently treated a patient, quite similar to that reported by Cain et al.1, who presented with a pseudoaneurysm of the distal suture line twelve years after repair of type A aortic dissection4. At first operation replacement of the ascending aorta and hemiarch using of a Djumbodis®dissection system (Saint Come-Chirurgie, Marseille, France) was performed. At reoperation extremely fragile tissues were noted and, after removing the metallic stent, the aortic arch was replaced with a frozen elephant trunk technique. Cultures of the excised material grewMC . In this case we hypothesized that the stent played an important role in the onset of infection for at least 2 reasons: presence of foreign material in the blood stream and injury to the aortic wall by the edges of the stent. The case described by Cain et al.1 also supports our belief that extreme fragility of the aortic tissues caused by MB was a further important factor in the occurrence of this complication.Interestingly, a delayed diagnosis occurred in both cases; this most likely played a critical role in favouring development of extra‐cardiac manifestations of the disease, in reducing the effectiveness of antibiotic therapy due to immunologic impairment and causing a negative outcome in both patients.MB infection may have different locations ranging from single-organ to systemic manifestations5. When it involves the mediastinum and particularly the major vascular structures often results in life-threatening complications despite proper antimycobacterial treatment. An early diagnosis, even with significantly extended surveillance, appears extremely difficult due to slow-growing and long incubation period of MB .Although no specific guidelines are so far available, intra-operative prevention with improvement of setting and development of heater-cooler units is mandatory and should be based on specific recommendations5.

Saprochaete species infection is a rare fungal disease reported so far only in immunocompromised patients. We describe the first case of aortitis caused by Saprochaete capitata, presenting as ascending aorta aneurysm, with secondary endophthalmitis in an immunocompetent patient. Infection by Saprochaete capitata is potentially fatal, with a mortality ranging from 50% to 90% of cases. In the present case aortic aneurysm caused by Saprochaete capitata aortitis was successfully treated by the combination of accurate diagnosis with surgical and specific antifungal therapy.

Describe the risk factors and discuss the management of multidrug-resistant (MDR) bacteria responsible for pneumonia among critically ill patients, including methicillin-resistant Staphylococcus aureus, extended spectrum beta-lactamase-producing Enterobactericeae, carbapenem-resistant Enterobactericeae, multidrug resistant Pseudomonas aeruginosa, and Acinetobacter baumannii.Multiple factors have been associated with infections because of MDR bacteria, including prolonged hospital stay, presence of invasive devices, mechanical ventilation, colonization with resistant pathogens, and use of broad-spectrum antibiotics. Management of these infections includes the prompt use of appropriate antimicrobial therapy, implementation of antimicrobial stewardship protocols, and targeted active microbiology surveillance. Combination therapy and novel molecules have been used for the treatment of severe infections caused by resistant bacteria.The exponential increase of antimicrobial resistance among virulent pathogens currently represents one of the main challenges for clinicians in the intensive care unit. Knowledge of the local epidemiology, patient risk stratification, and infection-control policies remain key elements for the management of MDR infections. Results from clinical trials on new molecules are largely awaited.

Ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) bacteria represents a global emerging problem. Delayed prescription of an adequate treatment for VAP has been associated with higher morbidity and mortality. New molecules have been developed to face the need of compounds that are active against resistant Gram-positive and Gram-negative pathogens. The aim of this review is to summarize the current scenario of new therapeutic options for the treatment of VAP.A number of new antibiotics with activity against MDR have been recently approved for the treatment of VAP, and other agents are under investigation. In this review, the authors summarize the current therapeutic options for the treatment of VAP that showed promising implications for clinical practice, including new compounds belonging to old antibiotic classes (e.g., ceftolozane/tazobactam, ceftazidime/avibactam meropenem/vaborbactam, imipenem/relebactam, tedizolid, cefiderocol, eravacycline, and plazomicin) and novel chemical classes, such as murepavadin. Nebulized antibiotics that are currently in development for the treatment of pneumonia in mechanically ventilated patients are also presented.Newly approved and investigational drugs for the treatment of VAP are expected to offer many advantages for the management of patients with respiratory infections caused by MDR. Promising characteristics of new compounds include high activity against both methicillin-resistant Staphylococcus aureus and MDR Gram-negative bacteria and a favorable safety profile.

PURPOSE OF REVIEW Skin and soft tissue infections prevalence is increasing and represent a frequent cause of hospital admission. New guidelines have become available in order to better define these infections and their response to antimicrobial treatment. Gram-positive bacteria, in particular Staphylococcus aureus, remain the most frequently isolated pathogens in skin and soft tissue infections. To treat complicated forms and infections caused by drug-resistant bacteria, hospital admission and administration of intravenous antibiotics are often required, impacting on healthcare costs and patients' morbidity. RECENT FINDINGS New therapeutic options offer efficacy against drug-resistant Gram-positive bacteria as well as potential to favor early patients' discharge, including the possibility for intravenous to oral switch and infrequent drug administration because of prolonged drug half-life. Although data from real-world studies on new antimicrobials is awaited, clinicians need clear direction on how to optimize the treatment of skin and soft tissue infections in order to avoid prolonged hospitalizations and extra costs. Early assessment of patient's clinical conditions and response to treatment appear useful in order to facilitate patients' discharge. SUMMARY We have reported the evidence for early intravenous to oral switch and early hospital discharge for patients with skin and soft tissue infections. New therapeutic options that represent promising tools in promoting an optimized management of these infections have also been reviewed.

Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections. SSTIs are a frequent clinical problem in surgical departments. In order to clarify key issues in the management of SSTIs, a task force of experts met in Bertinoro, Italy, on June 28, 2018, for a specialist multidisciplinary consensus conference under the auspices of the World Society of Emergency Surgery (WSES) and the Surgical Infection Society Europe (SIS-E). The multifaceted nature of these infections has led to a collaboration among general and emergency surgeons, intensivists, and infectious disease specialists, who have shared these clinical practice recommendations.

Background: Ceftolozane/tazobactam (C/T) is a novel antibiotic with enhanced microbiological activity against multidrug-resistant (MDR) gram-negative bacteria, including MDR Pseudomonas aeruginosa. Case report: Five months after left ventricular assist device (LVAD) implantation, a 49-year old man developed fever and blood culture was positive for MDR P. aeruginosa, susceptible only to aminoglycosides, ciprofloxacin and colistin. A diagnosis of LVAD-related infection was made based on persistent bacteremia associated with moderate 18 F-fluorodeoxyglucose positron emission tomography/CT uptake in the left ventricular apex. Disk diffusion testing for C/T was performed (MIC 2 μg/mL) and intravenous antibiotic therapy with C/T and amikacin was started, with clinical and microbiological response. Initial conservative management with 6 weeks of systemic antibiotic therapy was attempted, but the patient relapsed one month after antibiotic discontinuation. Priority for transplantation was given and after 4 weeks of antibiotic therapy (C/T + amikacin), LVAD removal and heart transplant were performed, with no infection relapse. Conclusions: We reported the first off-label use of C/T in the management of MDR P. aeruginosa LVAD infection as a bridge to heart transplant. C/T has shown potent anti-pseudomonal activity and good safety profile making this drug as a good candidate for suppressive strategy in intravascular device-associated bloodstream infections caused by MDR P. aeruginosa.

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n-LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization. We performed an observational study including consecutive LTR recipients (2003-2013) undergoing n-LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow-up 2.56 years; IQR 1.01-4.65). Fifty-three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person-time incidence rates of Aspergillus spp. colonization and infection decreased (2003-2008, 0.19; 2009-2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003-2008, 38.1% vs 2009-2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28-41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long-term administration of prophylaxis with n-LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection.

β-Lactam/β-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-β-lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients., We thank the ESGBIS and the ESGICH study groups for supporting the study. This study was supported by Ministerio de Economía y Competitividad, Instituto de Salud Carlos III—cofinanced by European Development Regional Fund “A way to achieve Europe” EDRF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015).

Invasive aspergillosis (IA) is a serious opportunistic infection, which has increasingly been recognized as an emerging disease of non-neutropenic patients. In this group of patients, the diagnosis of IA can be challenging owing to the lack of specificity of symptoms, the difficulty in discriminating colonization from infection, and the lower sensitivity of microbiological and radiological tests compared with immunocompromised patients. The aim of this article is to present to clinicians a critical review on the management of IA in non-neutropenic patients.

The isolation of multi-drug-resistant gram-negative (MDRGN) pathogens has progressively increased worldwide and has been associated with important delays in the prescription of an adequate antibiotic treatment, resulting in increased mortality rates. Patient's stratification for MDRGN infections to optimize the prescription of an adequate empiric antimicrobial regimen is crucial. Areas covered: This article covers MDRGN epidemiology, with a specific focus on risk factors for harbouring infections sustained by extended-spectrum-Beta-lactamase (ESBL), carbapenem resistant Enterobacteriacae (CRE), MDR Pseudomonas aeruginosa and MDR Acinetobacter baumanii. Moreover, we will propose an algorithm for the choice of empiric treatment when a MDRGN infection is suspected. Expert commentary: Although in clinical practice, a patient's stratification represents a challenge, whenever a MDRGN pathogen is suspected broad-spectrum, combination empiric treatment should be promptly started, looking for a balance between the prescription of an adequate empiric treatment and the risk of resistance selection.