Clinical and Radiological Features of Pneumocystis jirovecii Pneumonia in Children: A Case Series.

BACKGROUND: Pneumocytis jirovecii pneumonia (PJP) has high mortality rates in immunocompromised children, even though routine prophylaxis has decreased in incidence. The aim of this case series is to present the radiological and clinical pathway of PJP in a pediatric population. DESCRIPTION OF CASES: All PJP cases in non-HIV/AIDS patients diagnosed at Istituto Giannina Gaslini Pediatric Hospital in Genoa (Italy) from January 2012 until October 2022 were retrospectively evaluated. Nine cases were identified (median age: 8.3 years), and of these, 6/9 underwent prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX; five once-a-week schedules and one three times-a-week schedule), while 3/9 did not receive this. PJP was diagnosed by real-time PCR for P. jirovecii-DNA in respiratory specimens in 7/9 cases and two consecutive positive detections of ß-d-glucan (BDG) in the serum in 2/9 cases. Most patients (6/8) had a CT scan with features suggestive of PJP, while one patient did not undergo a scan. All patients were treated with TMP/SMX after a median time from symptoms onset of 3 days. In 7/9 cases, empirical TMP/SMX treatment was initiated after clinical suspicion and radiological evidence and later confirmed by microbiological data. Clinical improvement with the resolution of respiratory failure and 30-day survival included 100% of the study population. DISCUSSION: Due to the difficulty in obtaining biopsy specimens, PJP diagnosis is usually considered probable in most cases. Moreover, the severity of the clinical presentation often leads physicians to start TMP/SMX treatment empirically. BDG proved to be a useful tool for diagnosis, and CT showed good accuracy in identifying typical patterns. In our center, single-day/week prophylaxis was ineffective in high-risk patients; the three-day/week schedule would, therefore, seem preferable and, in any case, should be started promptly in all patients who have an indication of pneumonia.

Whipple Disease Presenting as Isolated Transverse Myelitis with Permanent Neurological Damage in a Patient with Systemic Lupus Erythematosus: A Case Report of a Difficult Diagnosis with a Literature Review.

We describe an atypical case of Whipple disease exclusively involving the spinal cord in an adolescent receiving immunosuppressive therapy for systemic lupus erythematosus. The diagnosis was particularly difficult since lupus and Whipple disease can present similar clinical features and the patient's prolonged contact with sewage was initially not mentioned. A literature review of the clinical, imaging, diagnostic, and therapeutic challenges of Whipple disease is also performed.

Clinical course and peculiarities of Parechovirus and Enterovirus central nervous system infections in newborns: a single-center experience.

Parechovirus (HpEV) and Enterovirus (EV) infections in children mostly have a mild course but are particularly fearsome in newborns in whom they may cause aseptic meningitis, encephalitis, and myocarditis. Our study aimed to describe the clinical presentations and peculiarities of CNS infection by HpEV and EV in neonates. This is a single-center retrospective study at Istituto Gaslini, Genoa, Italy. Infants aged ≤ 30 days with a CSF RTq-PCR positive for EV or HpEV from January 1, 2022, to December 1, 2023, were enrolled. Each patient's record included demographic data, blood and CSF tests, brain MRI, therapies, length of stay, ICU admission, complications, and mortality. The two groups were compared to identify any differences and similarities. Twenty-five patients (15 EV and 10 HpEV) with a median age of 15 days were included. EV patients had a more frequent history of prematurity/neonatal respiratory distress syndrome (p = 0.021), more respiratory symptoms on admission (p = 0.012), and higher C-reactive protein (CRP) levels (p = 0.027), whereas ferritin values were significantly increased in HpEV patients (p = 0.001). Eight patients had a pathological brain MRI, equally distributed between the two groups. Three EV patients developed myocarditis and one HpEV necrotizing enterocolitis with HLH-like. No deaths occurred.  Conclusion: EV and HpEV CNS infections are not easily distinguishable by clinical features. In both cases, brain MRI abnormalities are not uncommon, and a severe course of the disease is possible. Hyper-ferritinemia may represent an additional diagnostic clue for HpEV infection, and its monitoring is recommended to intercept HLH early and initiate immunomodulatory treatment. Larger studies are needed to confirm our findings. What is Known: • Parechovirus and Enteroviruses are the most common viral pathogens responsible for sepsis and meningoencephalitis in neonates and young infants. • The clinical course and distinguishing features of Parechovirus and Enterovirus central nervous system infections are not well described. What is New: • Severe disease course, brain MRI abnormalities, and complications are not uncommon in newborns with Parechovirus and Enteroviruses central nervous system infections. • Hyper-ferritinemia may represent an additional diagnostic clue for Parechovirus infection and its monitoring is recommended.

Reduce susceptibility to cefiderocol in gram negative bacteria in children: Is hope already lost before it's even arrived?

BACKGROUND: In last years the diffusion of carbapenem resistance in Gram-negative bacteria (CR-GNB) is increasing worldwide, mainly due to the expression of carbapenemases. Cefiderocol has molecular characteristics that ideally confers activity against all CR-GNB, but resistant strains have already been identified. We describe cefiderocol susceptibility profile among multi-drug resistant Gram-negative isolated from pediatric patients. METHODS: Prospective, single pediatric center study, 1st January 2020-15th June 2023. All GNB carbapenemases producers or phenotypically carbapenem-resistant isolated in the study period were tested for cefiderocol susceptibility. Clinical and microbiological data were collected. A descriptive analysis was performed, comparing the groups of cefiderocol-resistant vs. cefiderocol-susceptible Enterobacterales and non-fermenting Gram-negative bacteria (NF-GNB). RESULTS: Forty-seven GNB were tested for cefiderocol susceptibility; 38% were cefiderocol-resistant: 16/30 (52%) among Enterobacterales and 2/17 (12%) among NF-GNB. None of the patients were previously exposed to cefiderocol. Looking at Enterobacterales, resistance to ceftazidime/avibactam was higher among cefiderocol-resistant vs. cefiderocol-susceptible strains (62% vs 36%, respectively), as MBL expression (67% vs. 36%, respectively). Too few NF-GNB were cefiderocol-resistance to draw any conclusion. No difference in ICU admission and mortality was identified comparing cefiderocol-resistant vs. susceptible strains. Patients colonized/infected by cefiderocol-resistant strains had been previously hospitalized more frequently. CONCLUSION: In our cohort cefiderocol resistance was mostly registered among Enterobacterales, and especially among MBL producers' strains (that were alongside resistant to ceftazidime/avibactam). This could be explained by the known possible cross resistance mechanism among ceftazidime/avibactam and cefiderocol. Also, correlation of cefiderocol-resistance with previous hospitalization could be associated with horizontal resistance transmission. Looking at our data, we believe that cefiderocol should be use cautiously, especially empirically and in monotherapy, due to the high resistance rate.

Dose optimization and target attainment of vancomycin in children.

Vancomycin is a glycopeptide antibiotic that has been adopted in clinical practice to treat gram-positive infections for more than 70 years. Despite vancomycin's long history of therapeutic use, optimal dose adjustments and pharmacokinetic/pharmacodynamic (PK/PD) target attainment in children are still under debate. Therapeutic drug monitoring (TDM) has been widely integrated into pediatric clinical practice to maximize efficacy and safety of vancomycin treatment. Area under the curve (AUC)-guided TDM has been recently recommended instead of trough-only TDM to ensure PK/PD target attainment of AUC0-24h/minimal inhibitory concentration (MIC) > 400 to 600 and minimize acute kidney injury risk. Bayesian forecasting in pediatric patients allows estimation of population PK to accurately predict individual vancomycin concentrations over time, and consequently total vancomycin exposure. AUC-guided TDM for vancomycin, preferably with Bayesian forecasting, is therefore suggested for all pediatric age groups and special pediatric populations. In this review we aim to analyze the current literature on the pediatric use of vancomycin and summarize the current knowledge on dosing optimization for target attainment in special patient populations.

Application of the Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the empiric antibiotic treatment of febrile neutropenia in oncological paediatric patients: experience from two paediatric hospitals in Northern Italy.

BACKGROUND: Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. METHODS: We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. RESULTS: We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin-tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin-tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. CONCLUSIONS: The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Therapeutic drug monitoring of glycopeptide antimicrobials: An overview of liquid chromatography-tandem mass spectrometry methods.

Therapeutic drug monitoring (TDM) is a critical clinical tool used to optimize the safety and effectiveness of drugs by measuring their concentration in biological fluids. These fluids are primarily plasma or blood. TDM, together with real-time dosage adjustment, contributes highly to the successful management of glycopeptide antimicrobial therapies. Understanding pharmacokinetic/pharmacodynamic (PK/PD) properties is vital for optimizing antimicrobial therapies, as the efficacy of these therapies depends on both the exposure of the patient to the drug (PK) and pharmacodynamic (PD) parameters such as the in vitro estimated minimum drug concentration that inhibits bacterial growth (MIC). Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is widely recognized as the gold standard for measuring small molecules, such as antibiotics. This review provides a comprehensive overview of LC-MS/MS methods available for TDM of glycopeptide antibiotics, including vancomycin, teicoplanin, dalbavancin, oritavancin, and telavancin.

Real-Life Vancomycin Therapeutic Drug Monitoring in Coagulase-Negative Staphylococcal Bacteremia in Neonatal and Pediatric Intensive Care Unit: Are We Underestimating Augmented Renal Clearance?

Bloodstream infections (BSI) from coagulase-negative-staphylococci (CoNS) are among the most frequent healthcare-related infections. Their treatment involves the use of vancomycin, a molecule whose optimal pharmacokinetic/pharmacodynamic (PK/PD) target for efficacy and safety is an area-under-curve/minimum inhibitory concentration (AUC/MIC) ratio ≥ 400 with AUC < 600. BSIs from CoNS in pediatric and neonatal intensive care unit that occurred at the Gaslini Institute over five years were evaluated to investigate the efficacy of vancomycin therapy in terms of achieving the desired PK/PD target and determining whether any variables interfere with the achievement of this target. AUC/MIC ≥ 400 with AUC < 600 at 48 and 72 h after therapy initiation was achieved in only 21% of the neonatal population and 25% of the pediatric population. In the pediatric population, an inverse correlation emerged between estimated glomerular filtration rate (eGFR) and achieved AUC levels. Median eGFR at 72 h was significantly higher (expression of hyperfiltration) in events with AUC < 400, compared with those with AUC ≥ 400 (p < 0.001). A cut-off value of eGFR in the first 72 h has been identified (145 mL/min/1.73 m2), beyond which it is extremely unlikely to achieve an AUC ≥ 400, and therefore a higher dose or a different antibiotic should be chosen.

Clinical and Microbiological Characteristics of Deep Neck Abscesses in Pediatrics: Analysis of a Case Series from a 3rd Level Pediatric Hospital.

As there is currently no consensus on managing deep neck infections in pediatric populations, we report a case series from a large pediatric hospital. Clinical data of patients discharged from Istituto Gaslini-Children's Hospital from January 2014 to June 2020 with peritonsillar, parapharyngeal, or retropharyngeal abscess diagnoses were collected. A total of 59 patients were identified. Patients underwent surgical drainage in 47% of cases. Streptococcus mitis/oralis was the most isolated pathogen. Surgically treated patients did have larger abscesses compared to others, but there were no differences in the duration of hospitalization. Children who received NSAIDs at home had significant delays in diagnosis (median 4 vs. 1.5 days, p = 0.008). In our experience, clinical presentation of DNIs is often evocative, but evaluation should include imaging with CT/MRI. Surgery is effective in larger abscesses, allowing for etiological diagnosis with consequent antibiotic adjusting. From an anamnestic point of view, home medications such as NSAIDs could delay diagnosis.

Sirolimus Restores Erythropoiesis and Controls Immune Dysregulation in a Child With Cartilage-Hair Hypoplasia: A Case Report.

Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.

Epidemiology of Antibiotic Resistant Pathogens in Pediatric Urinary Tract Infections as a Tool to Develop a Prediction Model for Early Detection of Drug-Specific Resistance.

Antibiotic resistance is an increasing problem, especially in children with urinary tract infections. Rates of drug-specific resistant pathogens were reported, and an easy prediction model to guide the clinical decision-making process for antibiotic treatment was proposed. Data on microbiological isolation from urinoculture, between January 2007−December 2018 at Istituto Gaslini, Italy, in patients aged <19 years were extracted. Logistic regression-based prediction scores were calculated. Discrimination was determined by the area under the receiver operating characteristic curve; calibration was assessed by the Hosmer and Lemeshow test and the Spiegelhalterz test. A total of 9449 bacterial strains were isolated in 6207 patients; 27.2% were <6 months old at the first episode. Enterobacteriales (Escherichia coli and other Enterobacteriales) accounted for 80.4% of all isolates. Amoxicillin-clavulanate (AMC) and cefixime (CFI) Enterobacteriales resistance was 32.8% and 13.7%, respectively, and remained quite stable among the different age groups. On the contrary, resistance to ciprofloxacin (CIP) (overall 9.6%) and cotrimoxazole (SXT) (overall 28%) increased with age. After multivariable analysis, resistance to AMC/CFI could be predicted by the following: sex; age at sampling; department of admission; previous number of bacterial pathogens isolated. Resistance to CIP/SXT could be predicted by the same factors, excluding sex. The models achieved very good calibration but moderate discrimination performance. Specific antibiotic resistance among Enterobacteriales could be predicted using the proposed scoring system to guide empirical antibiotic choice. Further studies are needed to validate this tool.

Risk Factors for Intra-Abdominal Candidiasis in Intensive Care Units: Results from EUCANDICU Study.

INTRODUCTION: Intra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10-30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU. METHODS: We performed a case-control study in 26 European ICUs during the period January 2015-December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study. RESULTS: During the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65-72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98-21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73-25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04-17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32-10.52, p = 0.01) were independently associated with IAC. CONCLUSIONS: Gastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment.

Contact tracing, use of surgical masks, hand hygiene and social distancing represent a bundle of effective measures to control SARS-CoV-2 spreading among healthcare workers in a paediatric hospital.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent of pandemic coronavirus disease 2019 (COVID 19) Protection from virus exposure in children's hospital is a pivotal aspect of SARS-COV-2 pandemic control. Healthcare workers (HCW) could play an important role in viral infection in-hospital spread. Infection control measures were thus implemented to protect fragile patients and healthcare workers.We retrospectively described a HCW infectionscase-series due to SARS-CoV-2 from February 24th to July 31stat the IRCCS Istituto Giannina Gaslini. Seven separate cases of SARS-CoV-2 infection were observed among healthcare workers, with a total of 395 contacts, and 23 (6%) secondary case. A program of contact tracing and quarantine of SARS-CoV-2 positive HCW, screening of asymptomatic HCW, use of surgical masks, hand hygiene, social distancing and use of PPE in COVID-19 cases assistance prevented the spread of the virus to patients and blocked the diffusion within the hospital.

Impact of rotavirus vaccine in reducing hospitalization rates in pediatric patients: a single center experience in Italy.

Rotavirus is a major cause of acute gastroenteritis in children under 5 years of age, with severe illness occurring in 30-40% of cases. In Italian region of Liguria, vaccination with a two-dose human attenuated vaccine was introduced in 2013. We conducted a retrospective study to assess the impact of rotavirus vaccine on hospitalizations for rotavirus-related gastroenteritis (RVGE) at the IRCCS Istituto Giannina Gaslini. Every hospitalization due to laboratory-confirmed RVGE and acute gastroenteritis of unknown origin (AGUO) in patients aged 0-14 years in the period 2008-2019 were anonymously extracted. Vaccine coverage were obtained from the regional vaccination registry. The results were divided in 2008-2012 (before RV vaccine) and 2013-2019 (after) periods. From 2008 to 2012, there was a continuous reduction of AGUO hospitalizations while RVGE increased. Since 2013, a reduction in hospitalization rate was observed for RVGE with a sharp decrease from 17.81 per 10.000 children in 2012 to 0.79 per 10,000 in 2019, parallel with the ascending values of RV vaccination coverage that increased from 36.3% in 2013 to 63.9% in 2019. A significant negative correlation was found between the proportions of vaccinated newborns and RVGE rates (p = .012). Intussusception-related hospitalization did not show substantial modifications. We confirm vaccination as a safe practice that has a significant impact in pediatric hospitalization rates.

First Case of Candida auris Colonization in a Preterm, Extremely Low-Birth-Weight Newborn after Vaginal Delivery.

Candida auris is a multidrug-resistant, difficult-to-eradicate pathogen that can colonize patients and health-care environments and cause severe infections and nosocomial outbreaks, especially in intensive care units. We observed an extremely low-birth-weight (800 g), preterm neonate born from vaginal delivery from a C. auris colonized mother, who was colonized by C. auris within a few hours after birth. We could not discriminate whether the colonization route was the birth canal or the intensive care unit environment. The infant died on her third day of life because of complications related to prematurity, without signs or symptoms of infections. In contexts with high rates of C.auris colonization, antifungal prophylaxis in low-birth-weight, preterm neonates with micafungin should be considered over fluconazole due to the C. auris resistance profile, at least until its presence is excluded.

Pharmacokinetics and pharmacodynamics of antibiotics in cystic fibrosis: a narrative review.

Cystic fibrosis affects several organs, predisposing patients to severe bacterial respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus. Cystic fibrosis is also associated with a wide spectrum of pathological changes that can significantly affect the absorption, distribution, metabolism, and/or elimination of several drugs, including antibacterial agents. Therefore, awareness of the pharmacokinetic derangements in patients with cystic fibrosis is mandatory for the optimisation of antibiotic therapy. This review discusses the basic principles of pharmacokinetics and the pathophysiology of the pharmacokinetics changes associated with cystic fibrosis; it also provides an update of available data for the most widely used antibiotics. Evidence accumulated in the last few years has clearly shown that a significant number of cystic fibrosis patients treated with conventional dosing schemes have sub-therapeutic antibiotic concentrations, increasing their risk of therapeutic failure and/or the emergence of resistant pathogens. Some proposals to optimise antibiotic therapies in this clinical setting based on therapeutic drug monitoring are also discussed.

Procalcitonin and Early Postoperative Infection After Pediatric Cardiopulmonary Bypass Surgery.

OBJECTIVES: Systemic inflammation and bacterial infections are critical occurrences after pediatric cardiac surgery. Elevated white blood cell count and C-reactive protein cannot discriminate between these two conditions in the early postoperative period. The aim of this study was to understand whether procalcitonin (PCT) values within 48 hours of surgery could be a useful marker of postoperative infection. DESIGN: Retrospective observational study. SETTING: The study was performed in a teaching hospital. PARTICIPANTS: All patients ≤six years of age. INTERVENTIONS: Cardiac surgery on cardiopulmonary bypass from January 1, 2017 to January 1, 2020. MEASUREMENT AND MAIN RESULTS: PCT, white blood cell count, and C-reactive protein values were measured at intensive care unit admission and at 24 and 48 hours after surgery. All positive cultures in the first seven days after surgery were recorded. Out of 177 consecutive patients, 22 (12%) developed infections. PCT at 48 hours after surgery was the only laboratory predictor of infections in the first seven days after surgery (p = 0.02). Receiver operating curve analyses on PCT values at 48 hours identified an optimal cut-off value of 1.85 ng/mL in the overall population. Area under the curve was 0.63, sensitivity 63%, and specificity 69%. CONCLUSIONS: In light of this preliminary result, the clinical relevance and predictive accuracy of PCT are promising in patients with increasing values of PCT but need to be confirmed in a larger sample.

Antibiotic Resistant Bloodstream Infections in Pediatric Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant: Factors Associated with Development of Resistance, Intensive Care Admission and Mortality.

Bloodstream infections (BSI) are a severe complication of antineoplastic chemotherapy or hematopoietic stem cell transplantation (HSCT), especially in the presence of antibiotic resistance (AR). A multinational, multicenter retrospective study in patients aged ≤ 18 years, treated with chemotherapy or HSCT from 2015 to 2017 was implemented to analyze AR among non-common skin commensals BSI. Risk factors associated with AR, intensive care unit (ICU) admission and mortality were analyzed by multilevel mixed effects or standard logistic regressions. A total of 1291 BSIs with 1379 strains were reported in 1031 patients. Among Gram-negatives more than 20% were resistant to ceftazidime, cefepime, piperacillin-tazobactam and ciprofloxacin while 9% was resistant to meropenem. Methicillin-resistance was observed in 17% of S. aureus and vancomycin resistance in 40% of E. faecium. Previous exposure to antibiotics, especially to carbapenems, was significantly associated with resistant Gram-negative BSI while previous colonization with methicillin-resistant S. aureus was associated with BSI due to this pathogen. Hematological malignancies, neutropenia and Gram-negatives resistant to >3 antibiotics were significantly associated with higher risk of ICU admission. Underlying disease in relapse/progression, previous exposure to antibiotics, and need of ICU admission were significantly associated with mortality. Center-level variation showed a greater impact on AR, while patient-level variation had more effect on ICU admission and mortality. Previous exposure to antibiotics or colonization by resistant pathogens can be the cause of AR BSI. Resistant Gram-negatives are significantly associated with ICU admission and mortality, with a significant role for the treating center too. The significant evidence of center-level variations on AR, ICU admission and mortality, stress the need for careful local antibiotic stewardship and infection control programs.