Invasive aspergillosis in liver transplant recipients in the current era.

Invasive aspergillosis (IA) is a rare but fatal disease among liver transplant recipients (LiTRs). We performed a multicenter 1:2 case-control study comparing LiTRs diagnosed with proven/probable IA and controls with no invasive fungal infection. We included 62 IA cases and 124 matched controls. Disseminated infection occurred only in 8 cases (13%). Twelve-week all-cause mortality of IA was 37%. In multivariate analyses, systemic antibiotic usage (adjusted odds ratio [aOR], 4.74; P = .03) and history of pneumonia (aOR, 48.7; P = .01) were identified as independent risk factors associated with the occurrence of IA. Moreover, reoperation (aOR, 5.99; P = .01), systemic antibiotic usage (aOR, 5.03; P = .04), and antimold prophylaxis (aOR, 11.9; P = .02) were identified as independent risk factors associated with the occurrence of early IA. Among IA cases, Aspergillus colonization (adjusted hazard ratio [aHR], 86.9; P < .001), intensive care unit stay (aHR, 3.67; P = .02), disseminated IA (aHR, 8.98; P < .001), and dialysis (aHR, 2.93; P = .001) were identified as independent risk factors associated with 12-week all-cause mortality, while recent receipt of tacrolimus (aHR, 0.11; P = .001) was protective. Mortality among LiTRs with IA remains high in the current era. The identified risk factors and protective factors may be useful for establishing robust targeted antimold prophylactic and appropriate treatment strategies against IA.

Burden and Management of Multi-Drug Resistant Organism Infections in Solid Organ Transplant Recipients Across the World: A Narrative Review.

Solid organ transplant (SOT) recipients are particularly susceptible to infections caused by multidrug-resistant organisms (MDRO) and are often the first to be affected by an emerging resistant pathogen. Unfortunately, their prevalence and impact on morbidity and mortality according to the type of graft is not systematically reported from high-as well as from low and middle-income countries (HIC and LMIC). Thus, epidemiology on MDRO in SOT recipients could be subjected to reporting bias. In addition, screening practices and diagnostic resources may vary between countries, as well as the availability of new drugs. In this review, we aimed to depict the burden of main Gram-negative MDRO in SOT patients across HIC and LMIC and to provide an overview of current diagnostic and therapeutic resources.

Survey on the approach to antibiotic prophylaxis in liver and kidney transplant recipients colonized with "difficult to treat" Gram-negative bacteria.

BACKGROUND: Performance of active screening for multidrug-resistant Gram-negative bacteria (MDR-GNB) and administration of targeted antibiotic prophylaxis (TAP) in colonized patients undergoing liver (LT) and/or kidney transplantation (KT) are controversial issues. METHODS: Self-administered electronic cross-sectional survey disseminated from January to February 2022. Questionnaire consisted of four parts: hospital/transplant program characteristics, standard screening and antibiotic prophylaxis, clinical vignettes asking for TAP in patients undergoing LT and KT with prior infection/colonization with four different MDR-GNB (extended-spectrum cephalosporin-resistant Enterobacterales [ESCR-E], carbapenem-resistant Enterobacterales [CRE], multidrug-resistant Pseudomonas aeruginosa [MDR-Pa], and carbapenem-resistant Acinetobacter baumannii [CRAb]). RESULTS: Fifty-five respondents participated from 14 countries, mostly infectious disease specialists (69%) with active transplant programs (>100 procedures/year for 34.5% KT and 23.6% LT), and heterogeneous local MDR-GNB prevalence from <15% (30.9%), 15%-30% (43.6%) to >30% (16.4%). The frequency of screening for ESCR-E, CRE, MDR-Pa, and CRAb was 22%, 54%, 17%, and 24% for LT, respectively, and 18%, 36%, 16%, and 11% for KT. Screening time-points were mainly at transplantation 100%, only one-third following transplantation. Screening was always based on rectal swab cultures (100%); multi-site sampling was reported in 40% of KT and 35% of LT. In LT clinical cases, 84%, 58%, 84%, and 40% of respondents reported TAP for prior infection/colonization with ESCR-E, CRE, MDR-Pa, and CRAb, respectively. In KT clinical cases, 55%, 39%, 87%, and 42% of respondents reported TAP use for prior infection/colonization with ESCR-E, CRE, MDR-Pa, and CRAb, respectively. CONCLUSION: There is a large heterogeneity in screening and management of MDR-GNB carriage in LT and KT.

In vivo emergence of cefiderocol and ceftazidime/avibactam cross-resistance in KPC-producing Klebsiella pneumoniae following ceftazidime/avibactam -based therapies.

We described the emergence of ceftazidime/avibactam and cefiderocol cross-resistance in patients with KPC-producing Klebsiella pneumoniae infections. All strains with ceftazidime/avibactam and cefiderocol cross-resistance showed point mutations on KPC Ω-loop. Taken together, our results indicate that prolonged exposure to ceftazidime/avibactam can confer cross-resistance to ceftazidime/avibactam and cefiderocol.

Real-Time TDM-Guided Optimal Joint PK/PD Target Attainment of Continuous Infusion Piperacillin-Tazobactam Monotherapy Is an Effective Carbapenem-Sparing Strategy for Treating Non-Severe ESBL-Producing Enterobacterales Secondary Bloodstream Infections: Findings from a Prospective Pilot Study.

(1) Objectives: To assess the impact of optimal joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) piperacillin-tazobactam monotherapy on the microbiological outcome of documented ESBL-producing Enterobacterlaes secondary bloodstream infections (BSIs). (2) Methods: Patients hospitalized in the period January 2022-October 2023, having a documented secondary BSI caused by ESBL-producing Enterobacterales, and being eligible for definitive targeted CI piperacillin-tazobactam monotherapy according to specific pre-defined inclusion criteria (i.e., absence of septic shock at onset; favorable clinical evolution in the first 48 h after starting treatment; low-intermediate risk primary infection source) were prospectively enrolled. A real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program was adopted for optimizing (PK/PD) target attainment of CI piperacillin-tazobactam monotherapy. Steady-state plasma concentrations (Css) of both piperacillin and tazobactam were measured, and the free fractions (f) were calculated based on theoretical protein binding. The joint PK/PD target attainment was considered optimal whenever the piperacillin fCss/MIC ratio was >4 and the tazobactam fCss/target concentration (CT) ratio was >1 (quasi-optimal or suboptimal if only one or neither of the two thresholds were achieved, respectively). Univariate analysis was carried out for assessing variables potentially associated with failure in achieving the optimal joint PK/PD target of piperacillin-tazobactam and microbiological eradication. (3) Results: Overall, 35 patients (median age 79 years; male 51.4%) were prospectively included. Secondary BSIs resulted from urinary tract infections as a primary source in 77.2% of cases. The joint PK/PD target attainment was optimal in as many as 97.1% of patients (34/35). Microbiological eradication occurred in 91.4% of cases (32/35). Attaining the quasi-optimal/suboptimal joint PK/PD target of CI piperacillin-tazobactam showed a trend toward a higher risk of microbiological failure (33.3% vs. 0.0%; p = 0.08) (4) Conclusions: Real-time TDM-guided optimal joint PK/PD target attainment of CI piperacillin-tazobactam monotherapy may represent a valuable and effective carbapenem-sparing strategy when dealing with non-severe ESBL-producing Enterobacterales secondary BSIs.

Impact of a multidisciplinary management team on clinical outcome in ICU patients affected by Gram-negative bloodstream infections: a pre-post quasi-experimental study.

BACKGROUND: Bloodstream infections (BSIs) by Gram-negative pathogens play a major role in intensive care patients, both in terms of prevalence and severity, especially if multi-drug resistant pathogens are involved. Early appropriate antibiotic therapy is therefore a cornerstone in the management of these patients, and growing evidence shows that implementation of a multidisciplinary team may improve patients' outcomes. Our aim was to evaluate the clinical and microbiological impact of the application of a multidisciplinary team on critically ill patients. METHODS: Pre-post study enrolling critically ill patients with Gram negative bloodstream infection in intensive care unit. In the pre-intervention phase (from January until December 2018) patients were managed with infectious disease consultation on demand, in the post-intervention phase (from January until December 2022) patients were managed with a daily evaluation by a multidisciplinary team composed of intensivist, infectious disease physician, clinical pharmacologist and microbiologist. RESULTS: Overall, 135 patients were enrolled during the study period, of them 67 (49.6%) in the pre-intervention phase and 68 (50.4%) in the post-intervention phase. Median age was 67 (58-75) years, sex male was 31.9%. Septic shock, the need for continuous renal replacement therapy and mechanical ventilation at BSI onset were similar in both groups, no difference of multidrug-resistant organisms (MDRO) prevalence was observed. In the post-phase, empirical administration of carbapenems decreased significantly (40.3% vs. 62.7%, p = 0.02) with an increase of appropriate empirical therapy (86.9% vs. 55.2%, p < 0.001) and a decrease of overall antibiotic treatment (12 vs. 16 days, p < 0.001). Despite no differences in delta SOFA and all-cause 30-day mortality, a significant decrease in microbiological failure (10.3% vs. 29.9%, p = 0.005) and a new-onset 30-day MDRO colonization (8.3% vs. 36.6%, p < 0.001) in the post-phase was reported. At multivariable analysis adjusted for main covariates, the institution of a multidisciplinary management team (MMT) was found to be protective both for new MDRO colonization [OR 0.17, 95%CI(0.05-0.67)] and microbiological failure [OR 0.37, 95%CI (0.14-0.98)]. CONCLUSIONS: The institution of a MMT allowed for an optimization of antimicrobial treatments, reflecting to a significant decrease in new MDRO colonization and microbiological failure among critically ill patients.

Mollaret's Meningitis due to Herpes Simplex Virus 2: A Case Report and Review of the Literature.

Mollaret's meningitis is a rare neurological disorder characterized by recurrent episodes of aseptic lymphocytic meningitis, often associated with herpes simplex virus 2 (HSV-2) infection. We report the case of a 39 y.o. Italian woman who experienced four episodes of aseptic lymphocytic meningitis between 2004 and 2023, diagnosed as Mollaret's meningitis. In each episode, the patient presented with fever, severe headache and photophobia. In two episodes cutaneous vesicles in the left gluteal area preceding meningitis symptoms were also reported. A diagnostic evaluation included a physical-chemical analysis and a real-time PCR of the cerebrospinal fluid (CSF). The CSF presented pleocytosis with lymphocytic predominance and a positive HSV-2 load, with a peak of 1234 copies/mL. The patient was treated successfully with acyclovir, and the symptoms resolved without neurological sequelae. This case highlights the importance of comprehensive diagnostic testing and vigilant monitoring to manage Mollaret's syndrome effectively.

Gut microbiome dynamics and Enterobacterales infection in liver transplant recipients: A prospective observational study.

Background & Aims: The aim of this study was to investigate gut microbiome (GM) dynamics in relation to carbapenem-resistant Enterobacterales (CRE) colonization, CRE infection, and non-CRE infection development within 2 months after liver transplant (LT). Methods: A single-center, prospective study was performed in patients undergoing LT from November 2018 to January 2020. The GM was profiled through 16S rRNA amplicon sequencing of a rectal swab taken on the day of transplantation, and fecal samples were collected weekly until 1 month after LT. A subset of samples was subjected to shotgun metagenomics, including resistome dynamics. The primary endpoint was to explore changes in the GM in the following groups: (1) CRE carriers developing CRE infection (CRE_I); (2) CRE carriers not developing infection (CRE_UI); (3) non-CRE carriers developing microbial infection (INF); and (4) non-CRE carriers not developing infection (NEG). Results: Overall, 97 patients were enrolled, and 91 provided fecal samples. Of these, five, nine, 22, and 55 patients were classified as CRE_I, CRE_UI, INF, and NEG, respectively. CRE_I patients showed an immediate and sustained post-LT decrease in alpha diversity, with depletion of the GM structure and gradual over-representation of Klebsiella and Enterococcus. The proportions of Klebsiella were significantly higher in CRE_I patients than in NEG patients even before LT, serving as an early marker of subsequent CRE infection. CRE_UI patients had a more stable and diverse GM, whose compositional dynamics tended to overlap with those of NEG patients. Conclusions: GM profiling before LT could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis. Impact and implications: Little is known about the temporal dynamics of gut microbiome (GM) in liver transplant recipients associated with carbapenem-resistant Enterobacterales (CRE) colonization and infection. The GM structure and functionality of patients colonized with CRE and developing infection appeared to be distinct compared with CRE carriers without infection or patients with other microbial infection or no infection and CRE colonization. Higher proportions of antimicrobial-resistant pathogens and poor representation of bacteria and metabolic pathways capable of promoting overall host health were observed in CRE carriers who developed infection, even before liver transplant. Therefore, pretransplant GM profiling could improve patient stratification and risk prediction and guide early GM-based intervention strategies to reduce infectious complications and improve overall prognosis.

SARS-CoV-2 mRNA vaccination and short-term changes in viral load and CD4/CD8 T-cell counts in people living with HIV.

OBJECTIVES: To investigate whether SARS-CoV-2 messenger RNA (mRNA) vaccination has an impact on HIV-related viro-immunological parameters. METHODS: People with HIV (PWH) in the VAXICONA-ORCHESTRA cohort who received one or more doses of SARS-CoV-2 mRNA vaccine and for whom paired measures of immuno-virological markers (viral load, clusters of differentiation [CD]4, and CD8 count 1 month before and after a vaccine dose [VD]) were available were included. Paired t-test and generalized estimating equation linear regression analyses were used to study changes over ± 1 month around the VD. Subgroup analyses were performed. RESULTS: A total of 510 PWH were enrolled: the median age was 55 years (interquartile range 46-60 years), the CD4 and CD8 count were 489 (287-719) and 790 (59-1104) cells/mm3, respectively, and 81% received three VDs. After a median of 28 (3-53) days from VD, CD4 count increased by +15 cells/mm3 (SD ± 129.7, P = 0.001) and CD8 by +12 (±250.5, P = 0.199) and the viral load decreased by -0.11 log10 (±0.88, P = 0.001). Similar results were observed after restricting the analysis to viro-suppressed PWH, with CD4 ≤200/mm3, more than 6 months of antiretroviral therapy before VD and after excluding previous COVID-19. CONCLUSIONS: A small significant increase in CD4 count and a negligible drop in HIV RNA were observed. Our findings are consistent with the hypothesis that SARS-CoV-2 mRNA vaccine can prime CD4 T spike-specific cells, even in the more immuno-compromised PWH.

ESCMID/EUCIC clinical guidelines on preoperative decolonization and targeted prophylaxis in patients colonized by multidrug-resistant Gram-positive bacteria before surgery.

SCOPE: The aim of these guidelines is to provide recommendations on decolonization and perioperative antibiotic prophylaxis (PAP) in multidrug-resistant Gram-positive bacteria (MDR-GPB) adult carriers before inpatient surgery. METHODS: These European Society of Clinical Microbiology and Infectious Diseases (ESCMID)/European Committee on Infection Control (EUCIC) guidelines were developed following the systematic review of published studies targeting methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), methicillin-resistant coagulase-negative staphylococci (MR-CoNS) and pan-drug-resistant (PDR)-GPB. Critical outcomes were the occurrence of surgical site infections (SSIs) caused by the colonizing MDR-GPB and SSIs-attributable mortality. Important outcomes included the occurrence of SSIs caused by any pathogen, hospital-acquired infections, all-cause mortality, and adverse events associated with the interventions, including resistance development to the agents used and incidence of Clostridioides difficile infections. The last search of all databases was performed on November 1st, 2023. The level of evidence and strength of each recommendation were defined according to the GRADE approach. Consensus of a multidisciplinary expert panel was reached for the final list of recommendations. Antimicrobial stewardship considerations were included. RECOMMENDATIONS: The guideline panel reviewed the impact of decolonization, targeted PAP, and combined interventions (e.g., decolonization and targeted PAP) on the risk of SSIs and other outcomes in MDR-GPB carriers, according to the type of bacteria and type of surgery. We recommend screening for S. aureus (SA) before high-risk operations, such as cardiothoracic and orthopedic surgery. Decolonization with intranasal mupirocin with or without chlorhexidine bathing is recommended in patients colonized with SA before cardiothoracic and orthopedic surgery and suggested in other surgeries. Addition of vancomycin to standard prophylaxis is suggested for MRSA carriers in cardiothoracic surgery, orthopedic surgery, and neurosurgery. Combined interventions (e.g., decolonization and targeted prophylaxis) are suggested in MRSA carriers undergoing cardiothoracic and orthopedic surgery. No recommendation could be made regarding screening, decolonization, and targeted prophylaxis for VRE due to the lack of data. No evidence was retrieved for MR-CoNS and PDR-GPB. Careful consideration of the laboratory workload and involvement of antimicrobial stewardship as well as infection control teams are warranted before implementing screening procedures or performing changes in PAP policy. Future research should focus on novel decolonizing techniques, on the monitoring of resistance to decolonizing agents and PAP regimens, and on standardized combined interventions in high-quality studies.

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.

Outcomes and Predictors of Mortality in Patients With KPC-Kp Infections Treated With Meropenem Vaborbactam: An Observational Multicenter Study.

Background: Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam. Methods: We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least ≥24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality. Results: The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index ≥ 3, dialysis, concomitant COVID-19, and INCREMENT score ≥ 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy. Conclusions: Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy.

Management of intra-abdominal infections: recommendations by the Italian council for the optimization of antimicrobial use.

Intra-abdominal infections (IAIs) are common surgical emergencies and are an important cause of morbidity and mortality in hospital settings, particularly if poorly managed. The cornerstones of effective IAIs management include early diagnosis, adequate source control, appropriate antimicrobial therapy, and early physiologic stabilization using intravenous fluids and vasopressor agents in critically ill patients. Adequate empiric antimicrobial therapy in patients with IAIs is of paramount importance because inappropriate antimicrobial therapy is associated with poor outcomes. Optimizing antimicrobial prescriptions improves treatment effectiveness, increases patients' safety, and minimizes the risk of opportunistic infections (such as Clostridioides difficile) and antimicrobial resistance selection. The growing emergence of multi-drug resistant organisms has caused an impending crisis with alarming implications, especially regarding Gram-negative bacteria. The Multidisciplinary and Intersociety Italian Council for the Optimization of Antimicrobial Use promoted a consensus conference on the antimicrobial management of IAIs, including emergency medicine specialists, radiologists, surgeons, intensivists, infectious disease specialists, clinical pharmacologists, hospital pharmacists, microbiologists and public health specialists. Relevant clinical questions were constructed by the Organizational Committee in order to investigate the topic. The expert panel produced recommendation statements based on the best scientific evidence from PubMed and EMBASE Library and experts' opinions. The statements were planned and graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence. On November 10, 2023, the experts met in Mestre (Italy) to debate the statements. After the approval of the statements, the expert panel met via email and virtual meetings to prepare and revise the definitive document. This document represents the executive summary of the consensus conference and comprises three sections. The first section focuses on the general principles of diagnosis and treatment of IAIs. The second section provides twenty-three evidence-based recommendations for the antimicrobial therapy of IAIs. The third section presents eight clinical diagnostic-therapeutic pathways for the most common IAIs. The document has been endorsed by the Italian Society of Surgery.