Intravenous fosfomycin for treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: a multicenter clinical experience.

BACKGROUND: severe infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have been increasingly reported over the past few years. Many in vivo and in vitro studies suggest a possible role of intravenous fosfomycin for the treatment of CRAB infections. METHODS: this multicenter, retrospective study included patients treated with intravenous fosfomycin for severe infections caused by CRAB admitted consecutively from December 2017 to December 2022 in four Hospitals in Italy. The primary goal of the study was to evaluate the risk factors associated with 30-day mortality in the study population. A propensity score matched analysis was added to the model. RESULTS: during the study period, 102 patients with severe infection caused by CRAB treated with an intravenous fosfomycin-containing regimen were enrolled: ventilator-associated pneumonia (VAP) was diagnosed in 59% of patients, primary bacteremia in 22%, and CVC-related infection in 16%. All patients were treated with a regimen containing intravenous fosfomycin, mainly in combination with cefiderocol (n=54), colistin (n=48), and ampicillin/sulbactam (n=18). Forty-eight (47%) patients died within 30 days. Fifty-eight (57%) patients experienced a clinical therapeutic failure. Cox regression analysis showed that diabetes, primary bacteraemia, and a colistin-containing regimen were independently associated with 30-day mortality, whereas an adequate source control of infection, an early 24 h active in vitro therapy, and a cefiderocol-containing regimen were associated with survival. A colistin-based regimen, A. baumannii colonization and primary bacteremia were independently associated with clinical failure. Conversely, an adequate source control of infection, a cefiderocol-containing regimen, and an early 24 h active in vitro therapy were associated with clinical success. CONCLUSIONS: Our data showed different antibiotic regimens containing fosfomycin in combination treatment of severe infections caused by CRAB.

Midregional-proAdrenomedullin as a prognostic tool in sepsis and septic shock: A systematic review and meta-analysis.

BACKGROUND: Midregional-proAdrenomedullin (MR-proADM) has been recently proposed as a tool in patients with sepsis and septic shock. Our aim was to evaluate the prognostic role of MR-proADM in hospitalized patients with sepsis and septic shock. METHODS: PRISMA guideline was followed. MEDLINE and EMBASE were searched up to June 2023. Primary outcome was mean difference in MR-proADM among survivors and nonsurvivors, secondary outcome mean difference in MR-proADM according to infection severity and type. Risk of bias was evaluated using Newcastle-Ottawa scale for observational studies and Cochrane tool for randomized trials. Pooled mean differences (MD) with corresponding 95% confidence intervals (CIs) were calculated in a random-effects model. RESULTS: Twenty-four studies included 6730 adult patients (1208 nonsurvivors and 5522 survivors) and three studies included 195 paediatric patients (30 nonsurvivors and 165 survivors). A total of 10, 4 and 13 studies included, respectively, patients with sepsis (3602 patients), septic shock (386 patients) and a mixed population (2937 patients). Twenty-one studies included patients with different source of infection, three with pneumonia and one with a catheter-related infection. Most studies (n = 12) had a follow-up of 28 days. In adult cohort, pooled mean difference between nonsurvivors and survivors of MR-proADM was 2.55 mmol/L (95% CI: 1.95-3.15) with higher values in patients with septic shock (4.25 mmol/L; 95% CI, 2.23-6.26 mmol/L) than in patients with sepsis (1.77 mmol/L; 95% CI: 1.11-2.44 mmol/L). In paediatric cohort, pooled mean difference was 3.11 mmol/L (95% CI: -0.02-6.24 mmol/L). CONCLUSIONS: Higher values of MR-proADM are detectable in nonsurvivors adult and paediatric-hospitalized patients with sepsis or septic shock.

Clinical effectiveness of cefiderocol for the treatment of bloodstream infections due to carbapenem-resistant Acinetobacter baumannii during the COVID-19 era: a single center, observational study.

BACKGROUND: We assessed the clinical effectiveness of cefiderocol (CFDC) in comparison with colistin (COL) for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections (BSI). MATERIALS/METHODS: Retrospective cohort study including adults with CRAB-BSI. Outcomes were mortality, clinical cure and adverse events during therapy. The average treatment effect of CFDC compared to COL was weighted with the inverse-probability treatment weight (IPTW). RESULTS: Overall, 104 patients were included (50 CFDC, 54 COL), median age 66.5 years, median Charlson Comorbidity Index 5, septic shock in 33.6% of patients. Primary BSI accounted for 43.3% of cases, followed by ventilator-associated pneumonia (VAP) (26%), catheter-related BSI (20.2%) and hospital-acquired pneumonia (HAP) (9.6%). Although not significantly, mortality at all time points was lower for CFDC than COL, while clinical cure was higher in CFDC than COL (66% vs. 44.4%, p = 0.027). Adverse events were more frequent in COL than CFDC-group (38.8% vs. 10%, p < 0.0001), primarily attributed to acute kidney injury (AKI) in the COL group. Patients with bacteremic HAP/VAP treated with CFDC had a significant lower 30-d mortality and higher clinical cure than COL (p = 0.008 and p = 0.0008, respectively). Increment of CCI (p = 0.005), ICU (p = 0.025), SARS-CoV2 (p = 0.006) and ECMO (p < 0.0001) were independently associated with 30-d mortality, while receiving CFDC was not associated with survival. CONCLUSIONS: CFDC could represent an effective and safe treatment option for CRAB BSI, especially in patients with bacteremic HAP/VAP and frail patients where the risk of acute renal failure during therapy should be avoided.

Risk factors for COVID-19 associated pulmonary aspergillosis and outcomes in patients with acute respiratory failure in a respiratory sub-intensive care unit.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) is burdened by high mortality. Data are lacking about non-ICU patients. Aims of this study were to: (i) assess the incidence and prevalence of CAPA in a respiratory sub-intensive care unit, (ii) evaluate its risk factors and (iii) impact on in-hospital mortality. Secondary aims were to: (i) assess factors associated to mortality, and (ii) evaluate significant features in hematological patients. MATERIALS AND METHODS: This was a single-center, retrospective study of COVID-19 patients with acute respiratory failure. A cohort of CAPA patients was compared to a non-CAPA cohort. Among patients with CAPA, a cohort of hematological patients was further compared to another of non-hematological patients. RESULTS: Three hundred fifty patients were included in the study. Median P/F ratio at the admission to sub-intensive unit was 225 mmHg (IQR 155-314). 55 (15.7%) developed CAPA (incidence of 5.5%). Eighteen had probable CAPA (37.3%), 37 (67.3%) possible CAPA and none proven CAPA. Diagnosis of CAPA occurred at a median of 17 days (IQR 12-31) from SARS-CoV-2 infection. Independent risk factors for CAPA were hematological malignancy [OR 1.74 (95%CI 0.75-4.37), p = 0.0003], lymphocytopenia [OR 2.29 (95%CI 1.12-4.86), p = 0.02], and COPD [OR 2.74 (95%CI 1.19-5.08), p = 0.014]. Mortality rate was higher in CAPA cohort (61.8% vs 22.7%, p < 0.0001). CAPA resulted an independent risk factor for in-hospital mortality [OR 2.92 (95%CI 1.47-5.89), p = 0.0024]. Among CAPA patients, age > 65 years resulted a predictor of mortality [OR 5.09 (95% CI 1.20-26.92), p = 0.035]. No differences were observed in hematological cohort. CONCLUSION: CAPA is a life-threatening condition with high mortality rates. It should be promptly suspected, especially in case of hematological malignancy, COPD and lymphocytopenia.

Biofilm-Related Infections in Healthcare: Moving towards New Horizons.

In this Special Issue, titled "Biofilm-Related Infections in Healthcare", we have reported considerable progress in understanding the physiology and pathology of biofilms [...].

Adjunctive immunotherapeutic agents in patients with sepsis and septic shock: a multidisciplinary consensus of 23.

BACKGROUND: In the last decades, several adjunctive treatments have been proposed to reduce mortality in septic shock patients. Unfortunately, mortality due to sepsis and septic shock remains elevated and NO trials evaluating adjunctive therapies were able to demonstrate any clear benefit. In light of the lack of evidence and conflicting results from previous studies, in this multidisciplinary consensus, the authors considered the rational, recent investigations and potential clinical benefits of targeted adjunctive therapies. METHODS: A panel of multidisciplinary experts defined clinical phenotypes, treatments and outcomes of greater interest in the field of adjunctive therapies for sepsis and septic shock. After an extensive systematic literature review, the appropriateness of each treatment for each clinical phenotype was determined using the modified RAND/UCLA appropriateness method. RESULTS: The consensus identified two distinct clinical phenotypes: patients with overwhelming shock and patients with immune paralysis. Six different adjunctive treatments were considered the most frequently used and promising: (i) corticosteroids, (ii) blood purification, (iii) immunoglobulins, (iv) granulocyte/monocyte colony-stimulating factor and (v) specific immune therapy (i.e. interferon-gamma, IL7 and AntiPD1). Agreement was achieved in 70% of the 25 clinical questions. CONCLUSIONS: Although clinical evidence is lacking, adjunctive therapies are often employed in the treatment of sepsis. To address this gap in knowledge, a panel of national experts has provided a structured consensus on the appropriate use of these treatments in clinical practice.

Simultaneous post-neurosurgical ventriculitis and bacteraemia by two different strains of KPC-producing K. pneumoniae successfully treated with meropenem/vaborbactam and high dose of fosfomycin.

OBJECTIVE: A case of post-neurosurgical ventriculitis caused by a KPC-producing Klebsiella pneumoniae (KPC-Kp) with a ceftazidime/avibactam-resistant, meropenem-susceptible phenotype is reported. METHODS AND RESULTS: The patient had a concomitant bloodstream infection with a wild-type KPC-Kp with a ceftazidime/avibactam-susceptible, meropenem-resistant phenotype. Prolonged treatment with intravenous fosfomycin and meropenem/vaborbactam achieved clinical success. Therapeutic drug monitoring performed during the first days of treatment showed for the first time that vaborbactam efficiently penetrates cerebrospinal fluid. In contrast, meropenem was undetectable in cerebrospinal fluid at each sampling, suggesting that additional doses of meropenem may be required to appropriately prescribe meropenem/vaborbactam for central nervous system infections. Plasma and cerebrospinal fluid levels of fosfomycin were adequate, confirming the potential of this agent possibly even in the fight against multidrug-resistant organisms. CONCLUSIONS: This case highlights the need for therapeutic drug monitoring as a crucial tool for optimizing treatment in complicated cases where the pharmacokinetic behaviour of antibiotics is difficult to predict.

Immunogenicity and reactogenicity of modified vaccinia Ankara pre-exposure vaccination against mpox according to previous smallpox vaccine exposure and HIV infection: prospective cohort study.

Background: Pre-exposure vaccination with MVA-BN has been widely used against mpox to contain the 2022 outbreak. Many countries have defined prioritized strategies, administering a single dose to those historically vaccinated for smallpox, to achieve quickly adequate coverage in front of low supplies. Using epidemiological models, real-life effectiveness was estimated at approximately 36%-86%, but no clinical trials were performed. Few data on MVA-BN immunogenicity are currently available, and there are no established correlates of protection. Immunological response in PLWH in the context of the 2022 outbreak was also poorly described. Methods: Blood samples were collected from participants eligible for pre-exposure MVA-BN vaccination before (T1) receiving a full course of vaccine (single-dose for vaccine-experienced or smallpox-primed and two-dose for smallpox vaccine-naïve or smallpox non-primed) and one month after the last dose (T2 and T3, respectively). MPXV-specific IgGs were measured by in-house immunofluorescence assay, using 1:20 as screening dilution, MPXV-specific nAbs by 50% plaque reduction neutralization test (PRNT50, starting dilution 1:10), and IFN-γ-producing specific T cells to MVA-BN vaccine, by ELISpot assay. Paired or unpaired t-test and Wilcoxon or Mann-Whitney test were used to analyse IgG and nAbs, and T-cell response, as appropriate. The probability of IgG and nAb response in vaccine-experienced vs. vaccine-naïve was estimated in participants not reactive at T1. The McNemar test was used to evaluate vaccination's effect on humoral response both overall and by smallpox vaccination history. In participants who were not reactive at T1, the proportion of becoming responders one month after full-cycle completion by exposure groups was compared by logistic regression and then analysed by HIV status strata (interaction test). The response was also examined in continuous, and the Average Treatment Effect (ATE) of the difference from baseline to schedule completion according to previous smallpox vaccination was estimated after weighting for HIV using a linear regression model. Self-reports of adverse effects following immunization (AEFIs) were prospectively collected after the first MVA-BN dose (T1). Systemic (S-AEFIs: fatigue, myalgia, headache, GI effects, chills) and local (L-AEFIs: redness, swelling, pain) AEFIs were graded as absent (grade 0), mild (1), moderate (2), or severe (3). The maximum level of severity for S-AEFIs and L-AEFIs ever experienced over the 30 days post-dose by vaccination exposure groups were analysed using a univariable multinomial logistic regression model and after adjusting for HIV status; for each of the symptoms, we also compared the mean duration by exposure group using an unpaired t-test. Findings: Among the 164 participants included, 90 (54.8%) were smallpox vaccine-experienced. Median age was 49 years (IQR 41-55). Among the 76 (46%) PLWH, 76% had a CD4 count >500 cells/µL. There was evidence that both the IgG and nAbs titers increased after administration of the MVA-BN vaccine. However, there was no evidence for a difference in the potential mean change in humoral response from baseline to the completion of a full cycle when comparing primed vs. non-primed participants. Similarly, there was no evidence for a difference in the seroconversion rate after full cycle vaccination in the subset of participants not reactive for nAbs at T1 (p = 1.00 by Fisher's exact test). In this same analysis and for the nAbs outcome, there was some evidence of negative effect modification by HIV (interaction p-value = 0.17) as primed people living with HIV (PLWH) showed a lower probability of seroconversion vs. non-primed, and the opposite was seen in PLWoH. When evaluating the response in continuous, we observed an increase in T-cell response after MVA-BN vaccination in both primed and non-primed. There was evidence for a larger increase when using the 2-dose vs. one-dose strategy with a mean difference of -2.01 log2 (p ≤ 0.0001), after controlling for HIV. No evidence for a difference in the risk of developing any AEFIs of any grade were observed by exposure group, except for the lower risk of grade 2 (moderate) fatigue, induration and local pain which was lower in primed vs. non-primed [OR 0.26 (0.08-0.92), p = 0.037; OR 0.30 (0.10-0.88), p = 0.029 and OR 0.19 (0.05-0.73), p = 0.015, respectively]. No evidence for a difference in symptom duration was also detected between the groups. Interpretation: The evaluation of the humoral and cellular response one month after the completion of the vaccination cycle suggested that MVA-BN is immunogenic and that the administration of a two-dose schedule is preferable regardless of the previous smallpox vaccination history, especially in PLWH, to maximize nAbs response. MVA-BN was safe as well tolerated, with grade 2 reactogenicity higher after the first administration in vaccine-naïve than in vaccine-experienced individuals, but with no evidence for a difference in the duration of these adverse effects. Further studies are needed to evaluate the long-term duration of immunity and to establish specific correlates of protection. Funding: The study was supported by the National Institute for Infectious Disease Lazzaro Spallanzani IRCCS "Advanced grant 5 × 1000, 2021" and by the Italian Ministry of Health "Ricerca Corrente Linea 2".

Association of piperacillin/tazobactam MIC and mortality in a cohort of ceftriaxone-resistant Escherichia coli bloodstream infections treated with piperacillin/tazobactam and carbapenems: a multicentric propensity score-weighted observational cohort study.

OBJECTIVES: To assess the impact of piperacillin/tazobactam MICs on in-hospital 30 day mortality in patients with third-generation cephalosporin-resistant Escherichia coli bloodstream infection treated with piperacillin/tazobactam, compared with those treated with carbapenems. METHODS: A multicentre retrospective cohort study was conducted in three large academic hospitals in Italy between 2018 and 2022. The study population comprised patients with monomicrobial third-generation cephalosporin-resistant E. coli bloodstream infection, who received either piperacillin/tazobactam or carbapenem therapy within 48 h of blood culture collection. The primary outcome was in-hospital 30 day all-cause mortality. A propensity score was used to estimate the likelihood of receiving empirical piperacillin/tazobactam treatment. Cox regression models were performed to ascertain risk factors independently associated with in-hospital 30 day mortality. RESULTS: Of the 412 consecutive patients included in the study, 51% received empirical therapy with piperacillin/tazobactam, while 49% received carbapenem therapy. In the propensity-adjusted multiple Cox model, the Pitt bacteraemia score [HR 1.38 (95% CI, 0.85-2.16)] and piperacillin/tazobactam MICs of 8 mg/L [HR 2.35 (95% CI, 1.35-3.95)] and ≥16 mg/L [HR 3.69 (95% CI, 1.86-6.91)] were significantly associated with increased in-hospital 30 day mortality, while the empirical use of piperacillin/tazobactam was not found to predict in-hospital 30 day mortality [HR 1.38 (95% CI, 0.85-2.16)]. CONCLUSIONS: Piperacillin/tazobactam use might not be associated with increased mortality in treating third-generation cephalosporin-resistant E. coli bloodstream infections when the MIC is <8 mg/L.

Genetic mapping identifies Homer1 as a developmental modifier of attention.

Attention is required for most higher-order cognitive functions. Prior studies have revealed functional roles for the prefrontal cortex and its extended circuits to enabling attention, but the underlying molecular processes and their impacts on cellular and circuit function remain poorly understood. To develop insights, we here took an unbiased forward genetics approach to identify single genes of large effect on attention. We studied 200 genetically diverse mice on measures of pre-attentive processing and through genetic mapping identified a small locus on chromosome 13 (95%CI: 92.22-94.09 Mb) driving substantial variation (19%) in this trait. Further characterization of the locus revealed a causative gene, Homer1, encoding a synaptic protein, where down-regulation of its short isoforms in prefrontal cortex (PFC) during early postnatal development led to improvements in multiple measures of attention in the adult. Subsequent mechanistic studies revealed that prefrontal Homer1 down-regulation is associated with GABAergic receptor up-regulation in those same cells. This enhanced inhibitory influence, together with dynamic neuromodulatory coupling, led to strikingly low PFC activity at baseline periods of the task but targeted elevations at cue onset, predicting short-latency correct choices. Notably high-Homer1, low-attentional performers, exhibited uniformly elevated PFC activity throughout the task. We thus identify a single gene of large effect on attention - Homer1 - and find that it improves prefrontal inhibitory tone and signal-to-noise (SNR) to enhance attentional performance. A therapeutic strategy focused on reducing prefrontal activity and increasing SNR, rather than uniformly elevating PFC activity, may complement the use of stimulants to improve attention.

Did the updated Duke criteria missed Erysipelothrix rhusiopathiae from the list of typical microorganisms causing infective endocarditis?

Infectious endocarditis is a severe condition still characterized by a high morbidity and mortality rate. An early diagnosis may positively impact the outcome, so we need our diagnostic tools to match with the ever-changing epidemiologic and microbiologic landscape of infectious diseases. We read with great interest the update to the Modified Duke Criteria for the diagnosis of Infectious Endocarditis recently proposed by the International Society for Cardiovascular Infectious Diseases and decided to propose the addition of Erysipelothrix rhusiopathiae to the list of typical microorganisms causing Endocarditis. This pathogen is widespread distributed in the world, has a zoonotic origin, harbors virulence factors and a multidrug resistance phenotype. Moreover, its retrieval from blood seems to have an important correlation with the presence of Endocarditis. The inclusion of E. rhusiopathiae in the list of typical microorganisms may represent a further refinement of the Modified Duke Criteria, which represent a fundamental tool in the management of patients with suspected endocarditis.

New Antimicrobials and New Therapy Strategies for Endocarditis: Weapons That Should Be Defended.

The overall low-quality evidence concerning the clinical benefits of different antibiotic regimens for the treatment of infective endocarditis (IE), which has made it difficult to strongly support or reject any regimen of antibiotic therapy, has led to a discrepancy between the available guidelines and clinical practice. In this complex scenario, very recently published guidelines have attempted to fill this gap. Indeed, in recent years several antimicrobials have entered the market, including ceftobiprole, ceftaroline, and the long-acting lipoglycopeptides dalbavancin and oritavancin. Despite being approved for different indications, real-world data on their use for the treatment of IE, alone or in combination, has accumulated over time. Furthermore, an old antibiotic, fosfomycin, has gained renewed interest for the treatment of complicated infections such as IE. In this narrative review, we focused on new antimicrobials and therapeutic strategies that we believe may provide important contributions to the advancement of Gram-positive IE treatment, providing a summary of the current in vitro, in vivo, and clinical evidence supporting their use in clinical practice.

Genotypic Evolution of Klebsiella pneumoniae Sequence Type 512 during Ceftazidime/Avibactam, Meropenem/Vaborbactam, and Cefiderocol Treatment, Italy.

In February 2022, a critically ill patient colonized with a carbapenem-resistant K. pneumoniae producing KPC-3 and VIM-1 carbapenemases was hospitalized for SARS-CoV-2 in the intensive care unit of Policlinico Umberto I hospital in Rome, Italy. During 95 days of hospitalization, ceftazidime/avibactam, meropenem/vaborbactam, and cefiderocol were administered consecutively to treat 3 respiratory tract infections sustained by different bacterial agents. Those therapies altered the resistome of K. pneumoniae sequence type 512 colonizing or infecting the patient during the hospitalization period. In vivo evolution of the K. pneumoniae sequence type 512 resistome occurred through plasmid loss, outer membrane porin alteration, and a nonsense mutation in the cirA siderophore gene, resulting in high levels of cefiderocol resistance. Cross-selection can occur between K. pneumoniae and treatments prescribed for other infective agents. K. pneumoniae can stably colonize a patient, and antimicrobial-selective pressure can promote progressive K. pneumoniae resistome evolution, indicating a substantial public health threat.

Risk factors for carbapenem-resistant Acinetobacter baumannii (CRAB) bloodstream infections and related mortality in critically ill patients with CRAB colonization.

Background: Among MDR bacteria, carbapenem-resistant Acinetobacter baumannii (CRAB) is a major concern due to the limited therapeutic options. During the COVID-19 pandemic, a worrying increase in the spread of CRAB infections was reported. Objectives: The study assessed the risk factors for CRAB bloodstream infection (BSI) in patients admitted to the ICU with CRAB colonization, and the related mortality risk factors. Methods: We conducted a single-centre, observational, prospective study; all consecutive patients with CRAB colonization admitted to the ICU of a tertiary hospital in Rome from January 2021 to September 2022 were included in the study. Univariate and multivariate analyses were performed to investigate BSI and mortality risk factors. Results: Overall, 129 patients were included in the study; 57 (44%) out of these developed BSI. In our study population, at the multivariable analysis the Charlson comorbidity index (CCI) (P = 0.026), COVID-19 (P < 0.001), multisite colonization (P = 0.016) and the need for mechanical ventilation (P = 0.024) were risk factors independently associated with BSI development. Furthermore, age (P = 0.026), CCI (P < 0.001), septic shock (P = 0.001) and Pitt score (P < 0.001) were independently associated with mortality in the BSI patients. Instead, early appropriate therapy (P = 0.002) and clinical improvement within 72 h (P = 0.011) were shown to be protective factors. Conclusions: In critically ill patients colonized by CRAB, higher CCI, multisite colonization and the need for mechanical ventilation were identified as risk factors for BSI onset. These predictors could be useful to identify patients at highest risk of BSI.

Acinetobacter baumannii in the critically ill: complex infections get complicated.

Acinetobacter baumannii is increasingly associated with various epidemics, representing a serious concern due to the broad level of antimicrobial resistance and clinical manifestations. During the last decades, A. baumannii has emerged as a major pathogen in vulnerable and critically ill patients. Bacteremia, pneumonia, urinary tract, and skin and soft tissue infections are the most common presentations of A. baumannii, with attributable mortality rates approaching 35%. Carbapenems have been considered the first choice to treat A. baumannii infections. However, due to the widespread prevalence of carbapenem-resistant A. baumannii (CRAB), colistin represents the main therapeutic option, while the role of the new siderophore cephalosporin cefiderocol still needs to be ascertained. Furthermore, high clinical failure rates have been reported for colistin monotherapy when used to treat CRAB infections. Thus, the most effective antibiotic combination remains disputed. In addition to its ability to develop antibiotic resistance, A. baumannii is also known to form biofilm on medical devices, including central venous catheters or endotracheal tubes. Thus, the worrisome spread of biofilm-producing strains in multidrug-resistant populations of A. baumannii poses a significant treatment challenge. This review provides an updated account of antimicrobial resistance patterns and biofilm-mediated tolerance in A. baumannii infections with a special focus on fragile and critically ill patients.

Invasive Candida infection: epidemiology, clinical and therapeutic aspects of an evolving disease and the role of rezafungin.

INTRODUCTION: Invasive Candida Infections (ICIs) have undergone a series of significant epidemiological, pathophysiological, and clinical changes during the last decades, with a shift toward non-albicans species, an increase in the rate of exogenous infections and clinical manifestations ranging from candidemia to an array of highly invasive and life-threatening clinical syndromes. The long-acting echinocandin rezafungin exhibits potent in-vitro activity against most wild-type and azole-resistant Candida spp. including C.auris. AREAS COVERED: The following topics regarding candidemia only and ICIs were reviewed and addressed: i) pathogenesis; ii) epidemiology and temporal evolution of Candida species; iii) clinical approach; iv) potential role of the novel long-acting rezafungin in the treatment of ICIs. EXPERT OPINION: Authors' expert opinion focused on considering the potential role of rezafungin in the evolving context of ICIs. Rezafungin, which combines a potent in-vitro activity against Candida species, including azole-resistant strains and C.auris, with a low likelihood of drug-drug interactions and a good safety profile, may revolutionize the treatment of candidemia/ICI. Indeed, it may shorten the length of hospital stays when clinical conditions allow and extend outpatient access to treatment of invasive candidiasis, especially when prolonged treatment duration is expected.

Clinical Characteristics and Outcome of Ceftazidime/Avibactam-Resistant Klebsiella pneumoniae Carbapenemase-Producing Klebsiella pneumoniae Infections: A Retrospective, Observational, 2-Center Clinical Study.

Background: Recently, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) with resistance to ceftazidime/avibactam (CZA-R) has been described, including KPC variants that restore carbapenem susceptibility. The aim of the study was to analyze the clinical characteristics and outcomes of infections caused by CZA-R KPC-Kp. Methods: From 2019 to 2021, a retrospective 2-center study including patients with infections due to CZA-R KPC-Kp hospitalized at 2 academic hospitals in Rome was conducted. Demographic and clinical characteristics were collected. Principal outcome was 30-day all-cause mortality. Statistical analyses were performed with Stata-IC17 software. Results: Overall, 59 patients were included (mean age, 64.4 ± 14.6 years; mean Charlson comorbidity index score, 4.5 ± 2.7). Thirty-four patients (57.6%) had infections caused by CZA-R and meropenem (MEM)-susceptible strains. A previous CZA therapy was observed in 40 patients (67.8%), mostly in patients with MEM-susceptible KPC variant (79.4% vs 52%, P = .026). Primary bacteremia was observed in 28.8%, followed by urinary tract infections and pneumonia. At infection onset, septic shock was present in 15 subjects (25.4%). After adjustment for confounders, only the presence of septic shock was independently associated with mortality (P = .006). Conclusions: Infections due to CZA-R KPC-Kp often occur in patients who had previously received CZA, especially in the presence of strains susceptible to MEM. Nevertheless, one-third of patients had never received CZA before KPC-Kp CZA-R. Since the major driver for mortality was infection severity, understanding the optimal therapy in patients with KPC-Kp CZA-R infections is of crucial importance.

Endothelial dysfunction, oxidative stress and low-grade endotoxemia in COVID-19 patients hospitalised in medical wards.

BACKGROUND: Endothelial dysfunction, assessed by flow-mediated dilation (FMD), is related to poor prognosis in patients with COVID-19 pneumonia (CP). In this study, we explored the interplay among FMD, NADPH oxidase type 2 (NOX-2) and lipopolysaccharides (LPS) in hospitalised patients with CP, community acquired pneumonia (CAP) and controls (CT). METHODS: We enrolled 20 consecutive patients with CP, 20 hospitalised patients with CAP and 20 CT matched for sex, age, and main cardiovascular risk factors. In all subjects we performed FMD and collected blood samples to analyse markers of oxidative stress (soluble Nox2-derived peptide (sNOX2-dp), hydrogen peroxide breakdown activity (HBA), nitric oxide (NO), hydrogen peroxide (H2O2)), inflammation (TNF-α and IL-6), LPS and zonulin levels. RESULTS: Compared with controls, CP had significant higher values of LPS, sNOX-2-dp, H2O2,TNF-α, IL-6 and zonulin; conversely FMD, HBA and NO bioavailability were significantly lower in CP. Compared to CAP patients, CP had significantly higher levels of sNOX2-dp, H2O2, TNF-α, IL-6, LPS, zonulin and lower HBA. Simple linear regression analysis showed that FMD inversely correlated with sNOX2-dp, H2O2, TNF-α, IL-6, LPS and zonulin; conversely FMD was directly correlated with NO bioavailability and HBA. Multiple linear regression analysis highlighted LPS as the only predictor of FMD. CONCLUSION: This study shows that patients with COVID-19 have low-grade endotoxemia that could activate NOX-2, generating increased oxidative stress and endothelial dysfunction.