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Introduzione Survey intersocietaria SICP-SIMIT-FADOI-SIMG La febbre in un contesto clinico di fine vita Peculiarità dei principali setting di cura Principali quadri sindromici nei pazienti a fine vita e indicazioni terapeutiche Antibiotici in infusione continua endovena o per via sottocutanea Bibliografia

Enterococci commonly cause nosocomial bloodstream infections (BSIs), and the global incidence of vancomycin-resistant enterococci (VRE) BSIs is rising. This study aimed to assess the risk factors for enterococcal BSIs and 30-day mortality, stratified by Enterococcus species, vancomycin resistance, and treatment appropriateness. We conducted a retrospective cohort study (2014–2021) including all hospitalized adult patients with at least one blood culture positive for Enterococcus faecalis or Enterococcus faecium. We included 584 patients with enterococcal BSI: 93 were attributed to vancomycin-resistant E. faecium. The overall 30-day mortality was 27.5%; higher in cases of BSI due to vancomycin-resistant E. faecium (36.6%) and vancomycin-sensitive E. faecium (31.8%) compared to E. faecalis BSIs (23.2%) (p = 0.016). This result was confirmed by multivariable Cox analysis. Independent predictors of increased mortality included the PITT score, complicated bacteremia, and age (HR = 1.269, p < 0.001; HR = 1.818, p < 0.001; HR = 1.022, p = 0.005, respectively). Conversely, male gender, consultation with infectious disease (ID) specialists, and appropriate treatment were associated with reduced mortality (HR = 0.666, p = 0.014; HR = 0.504, p < 0.001; HR = 0.682, p = 0.026, respectively). In conclusion, vancomycin-resistant E. faecium bacteremia is independently associated with a higher risk of 30-day mortality.

Effective treatment of infectious diseases requires prompt and accurate bacterial identification and tailored antimicrobial treatments. Traditional culture methods are considered the gold standard, but their effectiveness diminishes for fastidious and hard-to-grow microorganisms. In recent years, molecular diagnostic tools such as 16S rRNA gene next-generation sequencing (16S NGS) have gained popularity in the field. We analysed data from samples submitted for 16S NGS between July 2022 and July 2023 at the Department of Advanced Translational Microbiology in Trieste, Italy. The study included samples submitted for both culture-based identification and 16S NGS. Conventional media were used for culture, and bacterial identification was performed using MALDI-TOF mass spectrometry. The V3 region of the 16S rRNA gene was sequenced using the Ion PGM platform. Among the 123 samples submitted, drainage fluids (38%) and blood (23%) were the most common, with requests predominantly from the Infectious Diseases (31.7%) and Orthopedic (21.13%) Units. In samples collected from patients with confirmed infections, 16S NGS demonstrated diagnostic utility in over 60% of cases, either by confirming culture results in 21% or providing enhanced detection in 40% of instances. Among the 71 patients who had received antibiotic therapies before sampling (mean 2.3 prior antibiotic days), pre-sampling antibiotic consumption did not significantly affect the sensitivity of 16S NGS. In routine microbiology laboratories, combining 16S NGS with culture method enhances the sensitivity of microbiological diagnostics, even when sampling is conducted during antibiotic therapy.

Infections caused by KPC-producing K. pneumoniae continue to pose a significant clinical challenge due to their emerging resistance to new antimicrobials. We investigated the association between two drugs whose roles have been repurposed against multidrug-resistant bacteria: fosfomycin and temocillin. Temocillin exhibits unusual stability against KPC enzymes, while fosfomycin acts as a potent “synergizer”. We conducted in vitro antimicrobial activity studies on 100 clinical isolates of KPC-producing K. pneumoniae using a combination of fosfomycin and temocillin. The results demonstrated synergistic activity in 91% of the isolates. Subsequently, we assessed the effect on Galleria mellonella larvae using five genetically different KPC-Kp isolates. The addition of fosfomycin to temocillin increased larvae survival from 73 to 97% (+Δ 32%; isolate 1), from 93 to 100% (+Δ 7%; isolate 2), from 63 to 86% (+Δ 36%; isolate 3), from 63 to 90% (+Δ 42%; isolate 4), and from 93 to 97% (+Δ 4%; isolate 10). Among the temocillin-resistant KPC-producing K. pneumoniae isolates (24 isolates), the addition of fosfomycin reduced temocillin MIC values below the resistance breakpoint in all isolates except one. Temocillin combined with fosfomycin emerges as a promising combination against KPC-producing K. pneumoniae, warranting further clinical evaluation.

In the present study, we analyzed the genome of two S. enterica strains TS1 and TS2 from stool and blood cultures, respectively, and one strain of C. freundii TS3, isolated from a single hospitalized patient with acute myeloid leukemia. The S. enterica Goldcoast ST358 (O:8 (C2-C3) serogroup), sequenced by the MiSeq Illumina system, showed the presence of β-lactamase genes (blaVIM-1, blaSHV-12 and blaOXA-10), aadA1, ant(2″)-Ia, aac(6′)-Iaa, aac(6′)-Ib3, aac(6′)-Ib-cr, qnrVC6, parC(T57S), and several incompatibility plasmids. A wide variety of insertion sequences (ISs) and transposon elements were identified. In C. freundii TS3, these were the blaVIM-1, blaCMY-150, and blaSHV-12, aadA1, aac(6′)-Ib3, aac(6′)-Ib-cr, mph(A), sul1, dfrA14, ARR-2, qnrVC6, and qnrB38. IncA plasmid isolated from E.coli/K12 transconjugant and C. freundii exhibited a sequence identity >99.9%. The transfer of IncA plasmid was evaluated by conjugation experiments.

Low serum albumin (SA) correlates with mortality in critically ill patients, including those with COVID-19. We aimed to identify SA thresholds to predict the risk of longer hospital stay, severe respiratory failure, and death in hospitalized adult patients with COVID-19 pneumonia. A prospective longitudinal study was conducted at the Infectious Diseases Unit of Trieste University Hospital (Italy) between March 2020 and June 2021. The evaluated outcomes were: (1) need of invasive mechanical ventilation (IMV); (2) length of hospital stay (LOS); and (3) 90-day mortality rate. We enrolled 864 patients. Hypoalbuminemia (p < 0.001). The optimal SA cutoff predicting the need of IMV was 3.17 g/dL (AUC 0.688; 95% CI: 0.618–0.759; p < 0.001) and this threshold appeared as an independent risk factor for the risk of IMV in multivariate Cox regression analysis. The median LOS was 12 days and a higher SA was predictive for a shorter LOS (p < 0.001). The overall 90-day mortality rate was 15%. SA was significantly lower in patients who died within 90 days from hospital admission (3.1 g/dL; IQR 2.8–3.4; p < 0.001) as compared to those who survived (3.4 g/dL; IQR 3.1–3.7). The optimal SA threshold predicting high risk of 90-day mortality was 3.23 g/dL (AUC 0.678; 95% CI: 0.629–0.734; p < 0.001). In a multivariate Cox regression analysis, SA of

We aimed to determine whether neck circumference predicts mortality among hospitalized COVID-19 patients with respiratory failure. We performed a prospective multicenter (Italy and Brasil) study carried out from March to December 2020 on 440 hospitalized COVID-19 patients with respiratory failure. Baseline neck circumference was measured. The study outcome was 30- and 60-days mortality. Female and male participants were classified as “large neck” when exceeding fourth-quartile. Patients had a median age of 65 years (IQR 54–76), 68% were male. One-quarter of patients presented with grade-1 or higher obesity. The median neck circumference was 40 cm (IQR 38–43): 38 cm (IQR 36–40) for female and 41 cm (IQR 39–44) for male subjects. “Large neck” patients had a significantly higher prevalence of hypertension (63 vs. 48%), diabetes (33 vs. 19%), obesity (26 vs. 14%), and elevated C-reactive protein (CRP) (98 vs. 88%). The cumulative mortality rate was 13.1% (n = 52) and 15.9% (n = 63) at 30 and 60 days, respectively. After adjusting for age, BMI, relevant comorbidities, and high C-reactive protein to albumin ratio, “large neck” patients showed a significantly increased risk of death at 30- (adjusted HR 2.50; 95% CI 1.18–5.29; p = 0.017) and 60-days (adjusted HR 2.26; 95% CI 1.14–4.46; p = 0.019). Neck circumference is easy to collect and provides additional prognostic information to BMI. Among hospitalized COVID-19 patients with respiratory failure, those with large neck phenotype had a more than double risk of death at 30 and 60 days.

Purpose: The aim of this observational study was to highlight high resolution CT scan characteristics of COVID-19-associated pulmonary aspergillosis (CAPA) with a focus on the detection of de-novo appeared or evolved bronchiectasis. Methods: From March 2020 to May 2021, we enrolled 350 consecutive mechanically ventilated ICU patients with COVID-19. Patients with CAPA and at least one chest CT scan performed within 15 days from the diagnosis were included. Two radiologists were asked to identify typical and atypical signs of COVID-19 pneumonia. Bronchiectasis locations were described and a modified Reiff score was calculated, as severity score. A total of 19 CAPA patients (median age 71.0, Interquartile range (IQR) 62.5–75.0; male 16, 84.2%) were included. Results: According to the 2020 ECMM/ISHAM criteria, 18 patients had probable CAPA and one had proven CAPA. The median time between hospital admission and CT scan was 21 days (IQR 14.5–25.0). The incidence of bronchiectasis in the study population was 57.9% (n = 11). Tubular bronchiectasis was detected in 10 patients and were scored as follows: three patients had a score of 1, three patients had a score of score 2, one patient had a score of 5 and four patients had a score of 6. Eight patients had a previous CT scan (performed at hospital admission), among them: 5 patients developed de-novo bronchiectasis, while 2 patients demonstrated a volumetric increase of bronchiectasis. At the 6-months follow-up, the mortality rate for patients with CAPA was >60%. Conclusion: the radiologic detection of de-novo appearance or volumetric increase of bronchiectasis in COVID-19 should lead clinicians to search for fungal superinfections.

Post-coronavirus disease 2019 (post-COVID-19) condition, previously referred to as long COVID, includes a post-acute syndrome defined by the presence of non-specific symptoms occurring usually 3 months from the onset of the acute phase and lasting at least 2 months. Patients with chronic lymphocytic leukemia (CLL) represent a high-risk population for COVID-19. Moreover, the response to SARS-CoV-2 vaccination is often absent or inadequate. The introduction of monoclonal antibodies (mAbs) in the treatment landscape of COVID-19 allowed to reduce hospitalization and mortality in mild–moderate SARS-CoV-2 infection, but limited data are available in hematological patients. We here report the effective use of casirivimab/imdevimab (CI) in the treatment of two CLL patients with persistent infection and post-COVID-19 condition. Full genome sequencing of viral RNA from nasopharyngeal swabs was performed at the time of COVID-19 diagnosis and before the administration of CI. Both patients experienced persistent SARS-CoV-2 infection with no seroconversion for 8 and 7 months, respectively, associated with COVID symptoms. In both cases after the infusion of CI, we observed a rapid negativization of the nasal swabs, the resolution of post-COVID-19 condition, and the development of both the IgG against the trimeric spike protein and the receptor-binding domain (RBD) of the spike protein. The analysis of the viral genome in the period elapsed from the time of COVID-19 diagnosis and the administration of mAbs showed the development of new mutations, especially in the S gene. The genome variations observed during the time suggest a role of persistent SARS-CoV-2 infection as a possible source for the development of viral variants. The effects observed in these two patients appeared strongly related to passive immunity conferred by CI treatment permitting SARS-CoV-2 clearance and resolution of post-COVID-19 condition. On these grounds, passive anti-SARS-CoV-2 antibody treatment may represent as a possible therapeutic option in some patients with persistent SARS-CoV-2 infection.

Background. Several drugs which are easy to administer in outpatient settings have been authorized and endorsed for high-risk COVID-19 patients with mild–moderate disease to prevent hospital admission and death, complementing COVID-19 vaccines. However, the evidence on the efficacy of COVID-19 antivirals during the Omicron wave is scanty or conflicting. Methods. This retrospective controlled study investigated the efficacy of Molnupiravir or Nirmatrelvir/Ritonavir (Paxlovid®) or Sotrovimab against standard of care (controls) on three different endpoints among 386 high-risk COVID-19 outpatients: hospital admission at 30 days; death at 30 days; and time between COVID-19 diagnosis and first negative swab test result. Multivariable logistic regression was employed to investigate the determinants of hospitalization due to COVID-19-associated pneumonia, whereas time to first negative swab test result was investigated by means of multinomial logistic analysis as well as Cox regression analysis. Results. Only 11 patients (overall rate of 2.8%) developed severe COVID-19-associated pneumonia requiring admission to hospital: 8 controls (7.2%); 2 patients on Nirmatrelvir/Ritonavir (2.0%); and 1 on Sotrovimab (1.8%). No patient on Molnupiravir was institutionalized. Compared to controls, hospitalization was less likely for patients on Nirmatrelvir/Ritonavir (aOR = 0.16; 95% CI: 0.03; 0.89) or Molnupiravir (omitted estimate); drug efficacy was 84% for Nirmatrelvir/Ritonavir against 100% for Molnupiravir. Only two patients died of COVID-19 (rate of 0.5%), both were controls, one (a woman aged 96 years) was unvaccinated and the other (a woman aged 72 years) had adequate vaccination status. At Cox regression analysis, the negativization rate was significantly higher in patients treated with both antivirals—Nirmatrelvir/Ritonavir (aHR = 1.68; 95% CI: 1.25; 2.26) or Molnupiravir (aHR = 1.45; 95% CI: 1.08; 1.94). However, COVID-19 vaccination with three (aHR = 2.03; 95% CI: 1.51; 2.73) or four (aHR = 2.48; 95% CI: 1.32; 4.68) doses had a slightly stronger effect size on viral clearance. In contrast, the negativization rate reduced significantly in patients who were immune-depressed (aHR = 0.70; 95% CI: 0.52; 0.93) or those with a Charlson index ≥5 (aHR = 0.63; 0.41; 0.95) or those who had started the respective treatment course 3+ days after COVID-19 diagnosis (aOR = 0.56; 95% CI: 0.38; 0.82). Likewise, at internal analysis (excluding patients on standard of care), patients on Molnupiravir (aHR = 1.74; 95% CI: 1.21; 2.50) or Nirmatrelvir/Ritonavir (aHR = 1.96; 95% CI: 1.32; 2.93) were more likely to turn negative earlier than those on Sotrovimab (reference category). Nonetheless, three (aHR = 1.91; 95% CI: 1.33; 2.74) or four (aHR = 2.20; 95% CI: 1.06; 4.59) doses of COVID-19 vaccine were again associated with a faster negativization rate. Again, the negativization rate was significantly lower if treatment started 3+ days after COVID-19 diagnosis (aHR = 0.54; 95% CI: 0.32; 0.92). Conclusions. Molnupiravir, Nirmatrelvir/Ritonavir, and Sotrovimab were all effective in preventing hospital admission and/or mortality attributable to COVID-19. However, hospitalizations also decreased with higher number of doses of COVID-19 vaccines. Although they are effective against severe disease and mortality, the prescription of COVID-19 antivirals should be carefully scrutinized by double opinion, not only to contain health care costs but also to reduce the risk of generating resistant SARS-CoV-2 strains. Only 64.7% of patients were in fact immunized with 3+ doses of COVID-19 vaccines in the present study. High-risk patients should prioritize COVID-19 vaccination, which is a more cost-effective approach than antivirals against severe SARS-CoV-2 pneumonia. Likewise, although both antivirals, especially Nirmatrelvir/Ritonavir, were more likely than standard of care and Sotrovimab to reduce viral shedding time (VST) in high-risk SARS-CoV-2 patients, vaccination had an independent and stronger effect on viral clearance. However, the effect of antivirals or COVID-19 vaccination on VST should be considered a secondary benefit. Indeed, recommending Nirmatrelvir/Ritonavir in order to control VST in high-risk COVID-19 patients is rather questionable since other cheap, large spectrum and harmless nasal disinfectants such as hypertonic saline solutions are available on the market with proven efficacy in containing VST.

ABSTRACT: Objectives: Ceftazidime/avibactam (CAZ-AVI), approved in 2015, is an important first-line option for Klebsiella pneumoniae carbapenemase-producing Enterobacterales (KPC-E). Although still uncommon, resistance to CAZ-AVI has emerged and may represent a serious cause of concern. Methods: We performed a systematic literature review of clinical and microbiological features of infections and colonisations by CAZ-AVI-resistant KPC-E, focused on the in vivo emergence of CAZ-AVI resistance in different clinical scenarios. Results: Twenty-three papers were retrieved accounting for 42 patients and 57 isolates, mostly belonging to K. pneumoniae ST258 harbouring D179Y substitution in the KPC enzyme. The USA, Greece and Italy accounted for 80% of cases. In one-third of isolates resistance was not associated with previous CAZ-AVI exposure. Moreover, 20% of the strains were colistin-resistant and 80% were extended-spectrum β-lactamase (ESBL)-producers. The majority of infected patients had severe underlying diseases (39% cancer, 22% solid-organ transplantation) and 37% died. The abdomen, lung and blood were the most involved infection sites. Infections by CAZ-AVI-resistant strains were mainly treated with combination therapy (85% of cases), with meropenem being the most common (65%) followed by tigecycline (30%), gentamicin (25%), colistin (25%) and fosfomycin (10%). Despite the emergence of resistance, 35% of patients received CAZ-AVI. Conclusion: Taken together, these data highlight the need for prompt susceptibility testing including CAZ-AVI for Enterobacterales, at least in critical areas. Resistance to CAZ-AVI is an urgent issue to monitor in order to improve both empirical and targeted CAZ-AVI use as well as the management of patients with infections caused by CAZ-AVI-resistant strains.

Candida lipolytica is an uncommon Candida species causing invasive fungemia. This yeast is mainly associated with the colonisation of intravascular catheters, complicated intra-abdominal infections, and infections in the paediatric population. Here, we report a case of C. lipolytica bloodstream infection in a 53-year-old man. He was admitted for an alcohol withdrawal syndrome and mild COVID-19. Among the primary risk factors for candidemia, only the use of broad-spectrum antimicrobials was reported. The empiric treatment was commenced with caspofungin and then targeted with intravenous fluconazole. Infective endocarditis was ruled out using echocardiography, and PET/TC was negative for other deep-seated foci of fungal infection. The patient was discharged after blood culture clearance and clinical healing. To the best of our knowledge, this is the first case of C. lipolytica candidemia in a patient with COVID-19 and alcohol use disorder. We performed a systematic review of bloodstream infections caused by C. lipolytica. Clinicians should be aware of the possibility of C. lipolytica bloodstream infections in patients with alcohol use disorder, especially in a COVID-19 setting.

Abstract Clostridioides difficile infection (CDI) and recurrent CDI (rCDI) remain associated with a reduction in the patients’ quality of life and with increased healthcare costs. Bezlotoxumab is a monoclonal antibody against toxin B of C. difficile, approved for prevention of rCDI. In this narrative review, we briefly discuss the pathophysiology of CDI and the mechanism of action of bezlotoxumab, as well as the available evidence from investigational and observational studies in terms of efficacy, effectiveness, and safety of bezlotoxumab for the prevention of rCDI. Overall, bezlotoxumab has proved efficacious in reducing the burden of rCDI, thereby providing clinicians with an important novel strategy to achieve sustained cure. Nonetheless, experiences outside randomized controlled trials (RCTs) remain scant, and mostly represented by case series without a control group. Along with the conduction of RCTs to directly compare bezlotoxumab with faecal microbiota transplantation (or to precisely evaluate the role of their combined use), further widening our post-marketing experience remains paramount to firmly guide the use of bezlotoxumab outside RCTs, and to clearly identify those real-life settings where its preventive benefits can be exploited most.

Purpose. Obesity is a risk factor for severe coronavirus disease 2019 (COVID-19). Circulating adipokines have been associated with inflammatory burden and amplified or dysregulated immune responses. This study aimed to evaluate the discriminatory ability of adipokines to identify COVID-19 pneumonia and to assess disease severity. Methods. We conducted an observational case-control study, with a prospective design, and recruited patients with diagnosis of COVID-19 pneumonia (n = 48) and healthy controls (n = 36), who were matched by age, sex, and BMI. Leptin, adiponectin, IL-6, and TNF-α were measured by ELISA. Results. Patients with COVID-19 pneumonia had higher levels of leptin, lower adiponectin/leptin (Adpn/Lep) ratio, and higher expression of IL-6. Leptin had an acceptable discriminatory accuracy for COVID-19 pneumonia in patients with BMI >30 (AUC 0.74 [0.58, 0.90]) with a cutoff of 7852 pg/mL and it was associated with maximum respiratory support. By contrast, Adpn/Lep had an excellent discriminatory accuracy for COVID-19 pneumonia in patients with BMI 2.23) in lean patients is consistent with a state of good health, which decreases in case of inflammatory states, ranging from adipose tissue dysfunction with low-grade inflammation to COVID-19 pneumonia.

Therapeutic options for infections caused by vancomycin-resistant enterococci are currently suboptimal. Combination regimens where fosfomycin is used alongside existing treatments are emerging given the proven synergistic potential and PK/PD properties. In the studies presented here, we tested five vanA and five vanB clinical isolates of Enterococcus faecium using a combination of oritavancin + fosfomycin both in vitro (checkerboard, time killing) and in vivo (Galleria mellonella). The combination of oritavancin and fosfomycin increased drug susceptibility, showing a synergistic effect in 80% of isolates and an additive effect in the remaining isolates. The combination restored fosfomycin susceptibility in 85% of fosfomycin-resistant isolates. Time killing on four selected isolates demonstrated that the combination of oritavancin and fosfomycin provided a CFU/mL reduction > 2 log10 compared with the most effective drug alone and prevented the bacterial regrowth seen after 8–24 h at sub-inhibitory drug concentrations. In addition, the combination was also tested in a biofilm assay with two isolates, and a strong synergistic effect was observed in one isolate and an additive effect in the other. Finally, we demonstrated in vivo (Galleria mellonella) a higher survival rate of the larvae treated with the combination therapy compared to monotherapy (fosfomycin or oritavancin alone). Our study provides preclinical evidence to support trials combining oritavancin and fosfomycin for VRE BSI in humans, even when biofilm is involved.

The presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been recently demonstrated in the sputum or saliva, suggesting how the shedding of viral RNA outlasts the end of symptoms. Recent data from transcriptome analysis show that the oral cavity mucosa harbors high levels of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2), highlighting its role as a double-edged sword for SARS-CoV-2 body entrance or interpersonal transmission. Here, we studied the oral microbiota structure and inflammatory profile of 26 naive severe coronavirus disease 2019 (COVID-19) patients and 15 controls by 16S rRNA V2 automated targeted sequencing and magnetic bead-based multiplex immunoassays, respectively. A significant diminution in species richness was observed in COVID-19 patients, along with a marked difference in beta-diversity. Species such as Prevotella salivae and Veillonella infantium were distinctive for COVID-19 patients, while Neisseria perflava and Rothia mucilaginosa were predominant in controls. Interestingly, these two groups of oral species oppositely clustered within the bacterial network, defining two distinct Species Interacting Groups (SIGs). COVID-19-related pro-inflammatory cytokines were found in both oral and serum samples, along with a specific bacterial consortium able to counteract them. We introduced a new parameter, named CytoCOV, able to predict COVID-19 susceptibility for an unknown subject at 71% of power with an Area Under Curve (AUC) equal to 0.995. This pilot study evidenced a distinctive oral microbiota composition in COVID-19 subjects, with a definite structural network in relation to secreted cytokines. Our results would be usable in clinics against COVID-19, using bacterial consortia as biomarkers or to reduce local inflammation.

Abstract 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

The pathogenicity of group A Streptococcus (GAS) is mediated by direct bacterial invasivity and toxin-associated damage. Among the extracellular products, the exotoxin streptolysin O (SLO) is produced by almost all GAS strains. SLO is a pore forming toxin (PFT) hemolitically active and extremely toxic in vivo. Recent evidence suggests that human serum albumin (HSA), the most abundant protein in plasma, is a player in the innate immunity “orchestra.” We previously demonstrated that HSA acts as a physiological buffer, partially neutralizing Clostridioides difficile toxins that reach the bloodstream after being produced in the colon. Here, we report the in vitro and ex vivo capability of HSA to neutralize the cytotoxic and hemolytic effects of SLO. HSA binds SLO with high affinity at a non-conventional site located in domain II, which was previously reported to interact also with C. difficile toxins. HSA:SLO recognition protects HEp-2 and A549 cells from cytotoxic effects and cell membrane permeabilization induced by SLO. Moreover, HSA inhibits the SLO-dependent hemolytic effect in red blood cells isolated from healthy human donors. The recognition of SLO by HSA may have a significant protective role in human serum and sustains the emerging hypothesis that HSA is an important constituent of the innate immunity system.

Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information.

Reactivation of herpes simplex virus type 1 (HSV-1) has been described in critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. In the present two-center retrospective experience, we primarily aimed to assess the cumulative risk of HSV-1 reactivation detected on bronchoalveolar fluid (BALF) samples in invasively ventilated COVID-19 patients with worsening respiratory function. The secondary objectives were the identification of predictors for HSV-1 reactivation and the assessment of its possible prognostic impact. Overall, 41 patients met the study inclusion criteria, and 12/41 patients developed HSV-1 reactivation (29%). No independent predictors of HSV-1 reactivation were identified in the present study. No association was found between HSV-1 reactivation and mortality. Eleven out of 12 patients with HSV-1 reactivation received antiviral therapy with intravenous acyclovir. In conclusion, HSV-1 reactivation is frequently detected in intubated patients with COVID-19. An antiviral treatment in COVID-19 patients with HSV-1 reactivation and worsening respiratory function might be considered.

Studies suggest that the incidence of coinfections in patients with the coronavirus disease 2019 (COVID-19) is low, but a large number of patients receive antimicrobials during hospitalisation. This may fuel a rise in antimicrobial resistance (AMR). We conducted a multicentre point-prevalence survey in seven tertiary university hospitals (in medical wards and intensive care units) in Croatia, Italy, Serbia and Slovenia. Of 988 COVID-19 patients, 521 were receiving antibiotics and/or antifungals (52.7%; range across hospitals: 32.9–85.6%) on the day of the study. Differences between hospitals were statistically significant (χ2 (6, N = 988) = 192.57, p < 0.001). The majority of patients received antibiotics and/or antifungals within 48 h of admission (323/521, 62%; range across hospitals: 17.4–100%), their most common use was empirical (79.4% of prescriptions), and pneumonia was the main indication for starting the treatment (three-quarters of prescriptions). The majority of antibiotics prescribed (69.9%) belonged to the “Watch” group of the World Health Organization AWaRe classification. The pattern of antimicrobial use differed across hospitals. The data show that early empiric use of broad-spectrum antibiotics is common in COVID-19 patients, and that the pattern of antimicrobial use varies across hospitals. Judicious use of antimicrobials is warranted to prevent an increase in AMR.

Acetylsalicylic acid (ASA) is one of the most commonly used drugs in the world. It derives from the extract of white willow bark, whose therapeutic potential was known in Egypt since 1534 BC. ASA’s pharmacological effects are historically considered secondary to its anti-inflammatory, platelet-inhibiting properties; however, human studies demonstrating a pro-inflammatory effect of ASA exist. It is likely that we are aware of only part of ASA’s mechanisms of action; moreover, the clinical effect is largely dependent on dosages. During the past few decades, evidence of the anti-infective properties of ASA has emerged. We performed a review of such research in order to provide a comprehensive overview of ASA and viral, bacterial, fungal and parasitic infections, as well as ASA’s antibiofilm properties.

C.difficile infection (CDI) is not a merely “gut-confined” disease as toxemia could drive the development of CDI-related extra-intestinal effects. These effects could explain the high CDI-associated mortality, not just justified by diarrhea and dehydration. Here, the extra-intestinal effects of toxin A (TcdA) and B (TcdB) produced by C. difficile have been studied in vivo using the zebrafish embryo model. Noteworthy, protective properties of human serum albumin (HSA) towards toxins-induced extra-intestinal effects were also addressed. Zebrafish embryos were treated with TcdA, TcdB and/or HSA at 24 h post-fertilization. Embryos were analyzed for 48 h after treatment to check vital signs and morphological changes. Markers related to cardio-vascular damage and inflammation were evaluated by Real-Time quantitative PCR and/or western blotting. Both toxins induced cardiovascular damage in zebrafish embryos by different mechanisms: (i) direct toxicity (i.e., pericardial edema, cardiac chambers enlargement, endothelial alteration); (ii) increased hormonal production and release (i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)), (iii) alteration of the vascular system through the increase of the vascular endothelial growth factor (VEGF-A) levels, as well as of its receptors, (iv) pro-inflammatory response through high cytokines production (i.e., CXCL8, IL1B, IL6 and TNFα) and (v) cell-mediated damage due to the increase in neutrophils number. In addition to cardiovascular damage, we observe skin alteration and inflammation. Finally, our data indicate a protective effect of HSA toward the toxins induced extra-intestinal effects. Together, our findings can serve as a starting point for humans’ studies to substantiate and understand the extra-intestinal effects observed in CDI patients.

Background: Patients with coronavirus infectious disease 2019 (COVID-19) and gastrointestinal symptoms showed increased values of fecal calprotectin (FC). Additionally, bowel abnormalities were a common finding during abdominal imaging of individuals with COVID-19 despite being asymptomatic. The current pilot study aims at evaluating FC concentrations in patients without gastrointestinal symptoms. Methods: we enrolled 25 consecutive inpatients with COVID-19 pneumonia, who were admitted without gastrointestinal symptoms and a previous history of inflammatory bowel disease. Results: At admission, 21 patients showed increased FC with median values of 116 (87.5; 243.5) mg/kg despite absent gastrointestinal symptoms. We found a strong positive correlation between FC and D-Dimer (r = 0.745, p < 0.0001). Two patients developed bowel perforation. Conclusion: our findings may change the current understanding of COVID-19 intestinal-related disease pathogenesis, shedding new light on the potential role of thrombosis and the consequent hypoxic intestinal damage.

Fosfomycin is being increasingly prescribed for multidrug-resistant bacterial infections. In patients with systemic involvement, intravenous fosfomycin is usually administered as a partner drug, as part of an antibiotic regimen. Hence, the knowledge of fosfomycin pharmacodynamic interactions (synergistic, additive, indifferent and antagonistic effect) is fundamental for a proper clinical management of severe bacterial infections. We performed a systematic review to point out fosfomycin’s synergistic properties, when administered with other antibiotics, in order to help clinicians to maximize drug efficacy optimizing its use in clinical practice. Interactions were more frequently additive or indifferent (65.4%). Synergism accounted for 33.7% of total interactions, while antagonism occurred sporadically (0.9%). Clinically significant synergistic interactions were mostly distributed in combination with penicillins (51%), carbapenems (43%), chloramphenicol (39%) and cephalosporins (33%) in Enterobactaerales; with linezolid (74%), tetracyclines (72%) and daptomycin (56%) in Staphylococcus aureus; with chloramphenicol (53%), aminoglycosides (43%) and cephalosporins (36%) against Pseudomonas aeruginosa; with daptomycin (97%) in Enterococcus spp. and with sulbactam (75%) and penicillins (60%) and in Acinetobacter spp. fosfomycin-based antibiotic associations benefit from increase in the bactericidal effect and prevention of antimicrobial resistances. Taken together, the presence of synergistic interactions and the nearly total absence of antagonisms, make fosfomycin a good partner drug in clinical practice.

This study aims to assess the peripheral blood cell count “signature” of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) to discriminate promptly between COronaVIrus Disease 19 (COVID-19) and community-acquired pneumonia (CAP). We designed a retrospective case-control study, enrolling 525 patients (283 COVID-19 and 242 with CAP). All patients had a fever and at least one of the following signs: cough, chest pain, or dyspnea. We excluded patients treated with immunosuppressants, steroids, or affected by diseases known to modify blood cell count. COVID-19 patients showed a significant reduction in white blood cells (neutrophils, lymphocytes, monocytes, eosinophils) and platelets. We studied these parameters univariately, combined the significant ones in a multivariate model (AUROC 0.86, Nagelkerke PSEUDO-R2 0.5, Hosmer–Lemeshow p-value 0.9) and examined its discriminative performance in an internally-randomized validation cohort (AUROC 0.84). The cut-off selected according to Youden’s Index (−0.13) showed a sensitivity of 84% and a specificity of 72% in the training cohort, and a sensitivity of 88% and a specificity of 73% in the validation cohort. In addition, we determined the probability of having COVID-19 pneumonia for each Model for possible Early COvid-19 Recognition (MECOR) Score value. In conclusion, our model could provide a simple, rapid, and cheap tool for prompt COVID-19 diagnostic triage in patients with CAP. The actual effectiveness should be evaluated in further, prospective studies also involving COVID-19 patients with negative nasopharyngeal swabs.

“Antimicrobial stewardship” is a strategy that promotes the responsible use of antimicrobials. The objective of this paper is to focus on consolidated and more recent improvements in clinical strategies that should be adopted in hospitalized patients to ameliorate their infectious diseases’ outcome and to reduce the antibiotic resistance risk through judicious use of antibiotics. We present 13 common clinical scenarios, the respective suggested interventions and the explanations of the supporting evidence, in order to help clinicians in their decision-making process. Strategies including the choice of antibiotic and dose optimization, antibiotic spectrum narrowing (de-escalation), shortening of duration, shift to oral route or outpatient parenteral antibiotic (including elastomeric pumps), and biomarkers are described and discussed.

Despite the availability of a safe and effective vaccine, in 2018, around 350,000 measles cases were reported worldwide, which resulted in an estimate of 142,300 deaths from measles. Additionally, in 2017, global measles cases spiked, causing the death of 110,000 people, mostly children under the age of 5 years and immunocompromised adults. The increase in measles incidence is caused by the ongoing reduction of vaccination coverage. This event has triggered public and scientific interest. For this reason, we reviewed the pathophysiology of measles infection, focusing on mechanisms by which the virus spreads systemically through the host organism. By reaching the lymphocytes from the airways through a “trojan horse” strategy, measles induces an immunosuppression status. H and F glycoproteins, both expressed in the envelope, ensure attachment of the virus to host cells and spreading from one cell to another by binding to several receptors, as described in detail. The severity of the disease depends both on the age and underlying conditions of patients as well as the social and health context in which epidemics spread, and is often burdened by sequelae and complications that may occur several years after infection. Particular attention was paid to special groups that are more susceptible to severe or atypical measles. An overview of microbiology, symptoms, diagnosis, prevention, and treatment completes and enriches the review.

Background: Experience in real clinical practice with ceftazidime-avibactam for the treatment of serious infections due to gram−negative bacteria (GNB) other than carbapenem-resistant Enterobacterales (CRE) is very limited. Methods: We carried out a retrospective multicenter study of patients hospitalized in 13 Italian hospitals who received ≥72 h of ceftazidime-avibactam for GNB other than CRE to assess the rates of clinical success, resistance development, and occurrence of adverse events. Results: Ceftazidime-avibactam was used to treat 41 patients with GNB infections other than CRE. Median age was 62 years and 68% of them were male. The main causative agents were P. aeruginosa (33/41; 80.5%) and extended spectrum beta lactamase (ESBL)-producing Enterobacterales (4/41, 9.8%). Four patients had polymicrobial infections. All strains were susceptible to ceftazidime-avibactam. The most common primary infection was nosocomial pneumonia (n = 20; 48.8%), primary bacteremia (n = 7; 17.1%), intra-abdominal infection (n = 4; 9.8%), and bone infection (n = 4; 9.8%). Ceftazidime-avibactam was mainly administered as a combination treatment (n = 33; 80.5%) and the median length of therapy was 13 days. Clinical success at the end of the follow-up period was 90.5%, and the only risk factor for treatment failure at multivariate analysis was receiving continuous renal replacement therapy during ceftazidime-avibactam. There was no association between clinical failures and type of primary infection, microbiological isolates, and monotherapy with ceftazidime-avibactam. Only one patient experienced recurrent infection 5 days after the end of treatment. Development of resistance to ceftazidime-avibactam was not detected in any case during the whole follow-up period. No adverse events related to ceftazidime-avibactam were observed in the study population. Conclusions: Ceftazidime-avibactam may be a valuable therapeutic option for serious infections due to GNB other than CRE.

We report the first case of multiple brain abscesses caused by Nocardia paucivorans in a patient suffering from multiple myeloma on treatment with lenalidomide and dexamethasone. Nocardia paucivorans is a recently described species of the genus Nocardia, which is supposed to have a heightened neurotropism in cases of disseminated infection. Although nocardiosis itself is an uncommon infectious complication in multiple myeloma so far, nocardial brain abscess should be added to the spectrum of adverse effects due to this novel chemotherapy regimen.

Objectives: To evaluate burden and predictors of HSV pneumonia among immunocompromised patients not undergoing invasive mechanical ventilation according to a tailored diagnostic algorithm.Methods: This prospective, observational study included immunocompromised adults with pneumonia non-responding to empirical antibiotic therapy. Bronchoalveolar lavage (BAL) specimens were cultured for bacteria, mycobacteria and fungi. Real-time PCR for Herpesviruses and other microorganisms were performed on BAL and other specimens. Cytological examination of BAL samples was carried out for identification of intranuclear inclusion bodies and immunohistochemical staining for HSV.Results: We enrolled 45 patients (mean age 64.6 years) from January 2015 to June 2016. Nineteen (42.2%) cases tested positive for HSV-1 PCR on BAL. According to our definitions, 11 (24.4%) patients had HSV-1 pneumonia with viral loads ranging between 103 copies/mL and 107 copies/mL. HSV-1 positive throat swab (OR 85.2, 95% CI 5.83-1245.1, P < 0.001) and solid organ transplant (SOT) (OR 53.3, 95% CI 1.37-2072.8, P < 0.03) as underlying condition were found to be independently associated with HSV pneumonia by multivariable analysis.Conclusions: HSV pneumonia turned out to be relatively common and should be investigated especially in individuals with HSV positive throat swab and SOT. Interventional studies are needed to assess the real clinical impact of HSV pneumonia in immunocompromised patients. [ABSTRACT FROM AUTHOR]

Background Echinocandins are recommended as firstline therapy in patients with candidemia. However, there is debate on their efficacy in survival outcomes. The aim of this study is to evaluate whether the choice of initial antifungal therapy improves mortality in patients with candidemia in relation to the presence of septic shock. Methods Patients with candidemia hospitalized in internal medicine wards of 5 tertiary care centers were included in the study (December 2012–December 2014). Patient characteristics, therapeutic interventions, and outcome were reviewed. Propensity score (PS) was used as a covariate of the multivariate analysis to perform a stratified analysis according to PS quartiles and to match patients receiving "echinocandins" or "azoles." Results Overall, 439 patients with candidemia were included in the study. A total of 172 (39.2%) patients had septic shock. Thirty-day mortality was significantly higher in patients with septic shock (45.3%) compared with those without septic shock (31.5%; P =.003). Among patients with septic shock, the use of echinocandins in the first 48 hours, compared with azoles, did not affect 30-day mortality in the PS-adjusted Cox regression analysis (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.37–1.59; P =.48), the PS-stratified analysis, or the logistic regression model in matched cohorts (adjusted HR, 0.92; 95% CI, 0.51–1.63; P =.77). Conclusions Echinocandin therapy seems not to improve the outcome of non–intensive care unit patients with septic shock due to candidemia. These findings support the urgent need of further studies in this patient population. [ABSTRACT FROM AUTHOR]