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Limited evidence concerning optimal azole dosing regimens currently exists for antifungal prophylaxis in hemato-oncological pediatric patients.Hemato-oncological children receiving intravenous or oral isavuconazole or voriconazole for primary antifungal prophylaxis at IRCCS Azienda Ospedaliero-Universitaria of Bologna during November 2020 to October 2021 and undergoing CPA programs based on real-time therapeutic drug monitoring (TDM) were retrospectively analyzed. CPAs for isavuconazole and voriconazole and the number of dosage adjustments were collected. Normalized trough concentrations [(C min )/dose/kg] were calculated for both drugs at each TDM assessment, and the coefficient of variation was determined. The efficacy and safety of the drugs were evaluated.Sixteen hemato-oncological pediatric patients received azole prophylaxis (mean age and weight: 9.1 ± 4.9 years and 32.6 ± 16.0 kg; 6 isavuconazole and 10 voriconazole). Sixty and 89 CPAs were delivered as isavuconazole and voriconazole, respectively. Dosage adjustments were needed in 3.3% of cases for isavuconazole and 53.9% of cases for voriconazole ( P0.001). At first TDM, achievement of the desired target during standard dosing regimens was higher for isavuconazole (83.3%) than for voriconazole (10.0%; P = 0.008). Dispersion of normalized concentrations was higher for voriconazole (CV = 139.1% vs. CV = 79.4%). Elevation of ALT and aspartate aminotransferase levels between baseline and the third month was higher in patients receiving voriconazole (median, 28 vs. 90 U/L; P = 0.038, and 19 vs. 65.5 U/L; P = 0.002).Our findings suggest that there is limited variability in isavuconazole exposure in hemato-oncological pediatric patients receiving azole prophylaxis , resulting in a low need for CPA-guided dosage adjustments.

Fungal infections are rare in the general population but are an emerging cause of disease in immunosuppressed patients, especially solid organ transplant recipients. Here, we report the case of a female Caucasian liver transplant patient who developed pulmonary nocardiosis two months after an episode of liver rejection. At the time of lung nocardiosis, she was being treated with tacrolimus and corticosteroids and suffered from diffuse papular skin lesions. She was initially suspected of having a cutaneous nocardial infection but culture examination revealed the presence of a dematiaceous fungus; Alternaria alternata. The prompt identification of the fungus and administration of oral Voriconazole resolved the skin infection with complete remission.

Purpose This multicenter observational study was done to evaluate risk factors related to the development of BSI in patients admitted to ICU for COVID-19. Methods All patients with COVID-19 admitted in two COVID-19 dedicated ICUs in two different hospital between 02–2020 and 02–2021 were recruited. Result 537 patients were included of whom 265 (49.3%) experienced at least one BSI. Patients who developed bacteremia had a higher SOFA score [10 (8–12) vs 9 (7–10), p p p p p Conclusion A high SOFA score and a high Charlson score resulted associated with BSI’s development. Conversely, immunosuppressive therapy like steroids and tocilizumab, has no role in increasing the risk of bacteremia.

Objective The aim of our study was to build a predictive model able to stratify the risk of bacterial co-infection at hospitalization in patients with COVID-19. Methods Multicenter observational study of adult patients hospitalized from February to December 2020 with confirmed COVID-19 diagnosis. Endpoint was microbiologically documented bacterial co-infection diagnosed within 72 h from hospitalization. The cohort was randomly split into derivation and validation cohort. To investigate risk factors for co-infection univariable and multivariable logistic regression analyses were performed. Predictive risk score was obtained assigning a point value corresponding to β-coefficients to the variables in the multivariable model. ROC analysis in the validation cohort was used to estimate prediction accuracy. Results Overall, 1733 patients were analyzed: 61.4% males, median age 69 years (IQR 57–80), median Charlson 3 (IQR 2–6). Co-infection was diagnosed in 110 (6.3%) patients. Empirical antibiotics were started in 64.2 and 59.5% of patients with and without co-infection (p = 0.35). At multivariable analysis in the derivation cohort: WBC ≥ 7.7/mm3, PCT ≥ 0.2 ng/mL, and Charlson index ≥ 5 were risk factors for bacterial co-infection. A point was assigned to each variable obtaining a predictive score ranging from 0 to 5. In the validation cohort, ROC analysis showed AUC of 0.83 (95%CI 0.75–0.90). The optimal cut-point was ≥2 with sensitivity 70.0%, specificity 75.9%, positive predictive value 16.0% and negative predictive value 97.5%. According to individual risk score, patients were classified at low (point 0), intermediate (point 1), and high risk (point ≥ 2). CURB-65 ≥ 2 was further proposed to identify patients at intermediate risk who would benefit from early antibiotic coverage. Conclusions Our score may be useful in stratifying bacterial co-infection risk in COVID-19 hospitalized patients, optimizing diagnostic testing and antibiotic use.

Objective: To investigate the rate of and the risk factors for breakthrough-IFI (b-IFI) after orthotopic liver transplantation (OLT) according to the new definition proposed by Mycoses-Study-Group-Education-and-Research-Consortium (MSG-ERC) and the European-Confederation-of-Medical-Mycology (ECMM). Methods: Multicenter prospective study of adult patients who underwent OLT at three Italian hospitals, from January 2015 to December 2018. Targeted antifungal prophylaxis (TAP) protocol was developed and shared among participating centers. Follow-up was 1-year after OLT. B-IFI was defined as infection occurring during exposure to antifungal prophylaxis. Risk factors for b-IFI were analyzed among patients exposed to prophylaxis by univariable analysis. Results: We enrolled 485 OLT patients. Overall compliance to TAP protocol was 64.3%, 220 patients received antifungal prophylaxis, 172 according to TAP protocol. Twenty-nine patients were diagnosed of IFI within 1year after OLT. Of them, 11 presented with b-IFI within 17 (IQR 11-33) and 16 (IQR 4-30) days from OLT and from antifungal onset, respectively. Then out of 11 patients with b-IFI were classified as having high risk of IFI and were receiving anti-mould prophylaxis, nine with echinocandins and one with polyenes. Comparison of patients with and without b-IFI showed significant differences for prior Candida colonization, need of renal replacement therapy after OLT, re-operation, and CMV infection (whole blood CMV-DNA >100000 copies/mL). Although non-significant, a higher rate of b-IFI in patients on echinocandins was observed (8.2% vs 1.8%, P=.06). Conclusions: We observed 5% of b-IFI among OLT patients exposed to antifungal prophylaxis. The impact of echinocandins on b-IFI risk in this setting should be further explored.

Background: High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with initial SARS-CoV-2 infection. Methods: Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial performed in outpatients in Italy. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; participants under dialysis; severe medical condition with prognosis < 6 months; warfarin treatment; antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned according to a randomized permuted block procedure to one of the following arms with allocation ratio 1:1:1: placebo (arm A); single dose ivermectin 600 μg/kg plus placebo for 5 days (arm B); single dose ivermectin 1200 μg/kg for 5 days (arm C). The pharmacist prepared the treatment according to the randomization list and on the basis of the participant’s weight. Primary outcomes: serious adverse drug reactions (SADR) and change of viral load at Day 7. The protocol was registered with ClinicalTrials.gov , NCT04438850. Findings. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively). Interpretation: High- dose ivermectin demonstrated safe, but did not prove efficacy to reduce viral load. Trial Registration: The protocol was registered with ClinicalTrials.gov , NCT04438850. Funding: The trial was partly funded by the Italian Ministry of Health. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the national Ethics Committee of INMI – Spallanzani in Rome that is competent for all COVID-19 trials in Italy (resolution 139/2020 of 28th May, 2020), and by the Italian drug agency AIFA (resolution 136BIS/2020 of 18th May, 2020).

Objectives: The aim of this study was to evaluate the risk factors for candidaemia in patients with liver cirrhosis. Methods: This was a case–control–control (1:2:2) study performed in four Italian tertiary centres from 2006 to 2015. Cases were patients with liver cirrhosis developing candidaemia. For every case of candidaemia we enrolled two additional patients undergoing blood cultures for suspected infection yielding isolation of a bacterial pathogen (control A) and two additional patients undergoing blood cultures for suspected infection yielding negative results (control B). Patients were matched according to age, sex and model for end stage liver disease at hospital admission. Results: During the study period 90 cases, 180 controls A and 180 controls B were included. At multivariate analysis assessed by means of multinomial conditional regression models, factors independently associated with candidaemia were previous (15 days (RRR 4.63 (95% CI 2.11–10.18), p

Objectives: We aimed to develop and validate a risk score to predict severe respiratory failure (SRF) among patients hospitalized with coronavirus disease-2019 (COVID-19). Methods: We performed a multicentre cohort study among hospitalized (>24 hours) patients diagnosed with COVID-19 from 22 February to 3 April 2020, at 11 Italian hospitals. Patients were divided into derivation and validation cohorts according to random sorting of hospitals. SRF was assessed from admission to hospital discharge and was defined as: SpO2 30 breaths/min or respiratory distress. Multivariable logistic regression models were built to identify predictors of SRF, β-coefficients were used to develop a risk score. Trial Registration NCT04316949. Results: We analysed 1113 patients (644 derivation, 469 validation cohort). Mean (±SD) age was 65.7 (±15) years, 704 (63.3%) were male. SRF occurred in 189/644 (29%) and 187/469 (40%) patients in the derivation and validation cohorts, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort assessed at hospitalization were age ≥70 years (OR 2.74; 95% CI 1.66–4.50), obesity (OR 4.62; 95% CI 2.78–7.70), body temperature ≥38°C (OR 1.73; 95% CI 1.30–2.29), respiratory rate ≥22 breaths/min (OR 3.75; 95% CI 2.01–7.01), lymphocytes ≤900 cells/mm3 (OR 2.69; 95% CI 1.60–4.51), creatinine ≥1 mg/dL (OR 2.38; 95% CI 1.59–3.56), C-reactive protein ≥10 mg/dL (OR 5.91; 95% CI 4.88–7.17) and lactate dehydrogenase ≥350 IU/L (OR 2.39; 95% CI 1.11–5.11). Assigning points to each variable, an individual risk score (PREDI-CO score) was obtained. Area under the receiver-operator curve was 0.89 (0.86–0.92). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 71.6% (65%–79%), 89.1% (86%–92%), 74% (67%–80%) and 89% (85%–91%), respectively. PREDI-CO score showed similar prognostic ability in the validation cohort: area under the receiver-operator curve 0.85 (0.81–0.88). At a score of >3, sensitivity, specificity, and positive and negative predictive values were 80% (73%–85%), 76% (70%–81%), 69% (60%–74%) and 85% (80%–89%), respectively. Conclusion: PREDI-CO score can be useful to allocate resources and prioritize treatments during the COVID-19 pandemic.

Background Serum bactericidal titres (SBTs) were widely used in the 1970s and 1980s to monitor antimicrobial therapy but are now seldom recommended. It is the only laboratory test that integrates drug pharmacodynamics, host pharmacokinetics and synergistic or antagonistic interactions of antimicrobial combinations into a single index of antimicrobial activity. We hypothesized that SBTs could play a renewed role in monitoring antibiotic treatment of multidrug-resistant Gram-negative infections. However, the last critical appraisal of the test was published over 30 years ago. Objectives This narrative review provides an updated assessment of the SBT test and its methodological limitations. We performed a diagnostic meta-analysis to estimate the value of SBTs for predicting clinical failure or death during antibiotic treatment. Sources A comprehensive literature search of PubMed including all English publications was performed in December 2019 using the Medical Subject Headings (MeSH search terms “serum”, “bactericidal”, “inhibitory”, “titre”, “monitoring”, “anti-infective agents” “antimicrobial therapy” and “therapeutic drug monitoring”). Content Although standardized methods for performing SBTs were approved in 1999, the test remains labour intensive, and results may not be available until 72 hr. However, the use of non-culture-based endpoints (i.e. spectrophotometric or fluorescent) may shorten test time to 24 hr. Despite considerable heterogeneity in published studies, a meta-analysis of 11 evaluable studies published from 1974 to 2007 indicated a critical SBT result (peak SBT ≤1:8 or trough ≤1:2) is associated with a diagnostic odds ratio for clinical failure during antibiotic treatment of 12.27 (95% confidence interval 5.28–28.54) and a 5.32 (95% 1.32–21.42) odds of death. Implications SBTs have prognostic value for identifying patients at high risk for antibiotic treatment failure, but the slow turnaround time of the current test limits its clinical utility. Standardization of a more rapid SBT testing method is needed.

Background: Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-associated coronavirus disease-2019 (COVID-19) is spreading worldwide challenging healthcare resources. To provide the best possible care for patients, efficient prognosis is needed. Methods: We performed a multicentre cohort study to develop and validate a risk score for severe respiratory failure (SRF) among hospitalized patients diagnosed with COVID-19. Study population included all adult patients with RT-PCR on nasopharyngeal swab positive for SARS-CoV-2, hospitalized from February 22 to April 3 2020, at 11 hospitals from four Italian Regions. Exclusion criteria were early ( 30bpm, or respiratory distress. Findings: Of the 1265 included patients, 1044 patients were analyzed, (581 derivation, 463 validation cohort). Mean age was 65.7±15 years, 661 (63·3%) were male. SRF rates were 29% and 38% in derivation and validation cohort, respectively. At multivariate analysis, risk factors for SRF in the derivation cohort were age ≥70 years, obesity, body temperature ≥38°C, RR ≥22bpm, lymphocytes ≤900/mm3, creatinine ≥ 1 mg/dl, C-reactive protein ≥10mg/dl, and lactate dehydrogenase ≥350IU/L at hospitalization. Area under receiver-operator curve (AUROC) was 0·90 (95%CI 0.86-0.93). Assigning points to each variable an individual risk score (PREDICO score) was obtained. At risk score of >3, sensitivity, specificity, positive and negative predictive values were 71·6% (64-78), 89·1% (85-92), 72·9% (65-79), and 88·4% (85-91), respectively; positive and negative likelihood ratios were 6·56 (95% CI 4·9-8·77) and 0·31 (95%CI 0·25-0·40), respectively. PREDICO score showed similar prognostic ability in the validation cohort: AUROC 0·80 (0·74-0·88). Interpretation: Using eight variables, easy to obtain at hospitalization, patients with COVID-19 could be classified according to their probability of developing SRF during hospitalization. PREDICO score can be useful to allocate resources and prioritize treatments during COVID-19 pandemic. Trial Registration: NCT04316949. Funding Statement: None. Declaration of Interests: Authors state no conflict of interest related to the content of the present study. Ethics Approval Statement: The study was approved by the Ethic Committee of the promoting center (Comitato Etico Indipendente di Area Vasta Emilia Centro, n. 283/2020/Oss/AOUBo).

Objectives KPC-producing Klebsiella pneumoniae (KPC-Kp) represent a serious problem worldwide. Herein, we describe the evolution of ceftazidime/avibactam resistance by sequencing longitudinal clinical isolates from a patient with KPC-Kp bloodstream infection undergoing ceftazidime/avibactam treatment. Methods WGS was performed on one ceftazidime/avibactam-susceptible KPC-Kp (BOT-CA-S) and two phenotypically different ceftazidime/avibactam-resistant KPC-Kp with low (BOT-CA-R) and high (BOT-EMO) carbapenem MICs. The population diversity was assessed by the frequency of allele mutations and population analysis profiles (PAPs). Results Phylogenetic analysis demonstrated clonal relatedness of the KPC-Kp isolates, all belonging to the clone ST1519. The D179Y mutation in blaKPC-3 was detected in both of the ceftazidime/avibactam-resistant KPC-Kp, whereas it was absent in the ceftazidime/avibactam-susceptible isolate. The mutation emerged independently in the two ceftazidime/avibactam-resistant isolates and was associated with a significant reduction in carbapenem MICs in BOT-CA-R, but not in BOT-EMO. WGS analysis revealed that the frequency of the D179Y mutation was 96.32% and 51.05% in BOT-CA-R and BOT-EMO, respectively. PAP results demonstrated that carbapenem resistance in BOT-EMO was due to the coexistence of mixed subpopulations harbouring WT and mutated blaKPC-3. A bacterial subpopulation with high ceftazidime/avibactam resistance for BOT-EMO KPC-Kp showed low carbapenem MICs, whereas a subpopulation with high meropenem resistance had a low MIC of ceftazidime/avibactam. Conclusions Our analysis indicates that mixed subpopulations of ceftazidime/avibactam-resistant KPC-Kp emerge after ceftazidime/avibactam treatment. The evolution of different subpopulations that are highly resistant to ceftazidime/avibactam likely contributes to treatment failure, thereby highlighting the need for combination treatment strategies to limit selection of ceftazidime/avibactam-resistant KPC-Kp subpopulations.

Combination therapies are frequently used in the treatment of multidrug-resistant Klebsiella pneumoniae infection without consensus regarding which combination is the most effective. We compared bactericidal titres from sera collected from critically ill patients receiving meropenem plus tigecycline (n= 5), meropenem plus colistin (n= 5), or meropenem, colistin and tigecycline (n= 5) against K. pneumoniae isolates that included ESBL-producing (n= 7) and KPC-producing strains (n= 14) with varying sensitivity patterns to colistin and tigecycline. Meropenem concentrations (Cmin) were measured in all samples by LC-MS/MS, and indexed to respective pathogen MICs to explore differences in patterns of bactericidal activity for two versus three drug combination regimens. All combination regimens achieved higher SBTs against ESBL (median reciprocal titre 128, IQR 32–256) versus KPC (4, IQR 2–32) strains. Sera from patients treated with meropenem-colistin yielded higher median SBTs (256, IQR 64–512) than either meropenem-tigecycline (32, IQR 8–256; P' 0.001). The addition of tigecycline was associated with a lower probability of achieving a reciprocal SBT above 8 when meropenem concentrations were below the MIC (P= 0.04). Although the clinical significance is unknown, sera from patients receiving tigecycline-based combination regimens produce lower serum bactericidal titres against ESBL or KPC-producing K. pneumoniae. SBTs may represent a useful complimentary endpoint for comparing pharmacodynamics of combinations regimens for MDR Enterobacteriaceae.

Objective To investigate the impact of colonization with carbapenemase-producing Enterobacteriaceae (CPE) on the CPE infection risk after liver transplantation (LT). Methods Prospective cohort study of all adult patients undergoing LT at our centre over an 8-year period (2010–2017). Individuals were screened for CPE colonization by rectal swabs at inclusion onto the waiting list, immediately before LT and weekly after LT until hospital discharge. Asymptomatic carriers did not receive decolonization, anti-CPE prophylaxis or pre-emptive antibiotic therapy. Participants were followed up for 1 year after LT. Results We analysed 553 individuals who underwent a first LT, 38 were colonized with CPE at LT and 104 acquired colonization after LT. CPE colonization rates at LT and acquired after LT increased significantly over the study period: incidence rate ratios (IRR) 1.21 (95% CI 1.05–1.39) and 1.17 (95% CI 1.07–1.27), respectively. Overall, 57 patients developed CPE infection within a median of 31 (interquartile range 11–115) days after LT, with an incidence of 3.05 cases per 10 000 LT-recipient-days and a non-significant increase over the study period (IRR 1.11, 95% CI 0.98–1.26). In multivariable analysis, CPE colonization at LT (hazard ratio (HR) 18.50, 95% CI 6.76–50.54) and CPE colonization acquired after LT (HR 16.89, 95% CI 6.95–41.00) were the strongest risk factors for CPE infection, along with combined transplant (HR 2.60, 95% CI 1.20–5.59), higher Model for End-Stage Liver Disease at the time of LT (HR 1.03, 95% CI 1.00–1.07), prolonged mechanical ventilation (HR 2.63, 95% CI 1.48–4.67), re-intervention (HR 2.16, 95% CI 1.21–3.84) and rejection (HR 2.81, 95% CI 1.52–5.21). Conclusions CPE colonization at LT or acquired after LT were the strongest predictors of CPE infection. Prevention strategies focused on LT candidates and recipients colonized with CPE should be investigated.

Background Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

Background Targeted antifungal prophylaxis against Candida species or against Candida species and Aspergillus species, according to individual patient risk factors (RFs), is recommended by experts. However, recent studies have reported fluconazole is as effective as broader spectrum antifungals for preventing invasive fungal infection (IFI) after liver transplantation (LT). Methods We performed a retrospective cohort study of all adult patients who underwent LT at our 1420-bed tertiary teaching hospital, from June 2010 to December 2014, to assess the rate and etiology of IFI within 100 days after LT, to investigate the compliance with targeted prophylaxis, and to analyze risk factors for developing IFI. Results In total, 303 patients underwent LT. Patients were classified as having low (no RFs), intermediate (1 RF for invasive candidiasis [IC]), and high risk (1 RF for invasive aspergillosis [IA] or ≥2 RFs for IC) for IFI in 20%, 30%, and 50% of cases, respectively. A total of 139 patients received antifungal prophylaxis: 98 with a mold-active drug and 41 with fluconazole. Overall adherence to targeted prophylaxis was 53%. Nineteen patients (6.3%) developed IFI: 7 IC and 12 IA. Multivariate Cox regression analysis, adjusted for median model for end-stage liver disease score at LT, stratification risk group, and adherence to targeted prophylaxis, showed that graft dysfunction, renal replacement therapy, and prophylaxis with fluconazole were independent risk factors for IFI. Seven of the 9 patients who received fluconazole prophylaxis and developed IFI were classified as having high risk for IFI, and 6 developed IA. Conclusion Recommended stratification is accurate for predicting patients at very high risk for IFI, who should receive prophylaxis with a mold-active drug.

Objectives The aim of this study was to evaluate the incidence of ceftazidime/avibactam resistance among Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) strains isolated from patients with bloodstream infection. Methods We collected 120 carbapenemase producing Enterobacteriaceae (CPE) strains from unique patients hospitalized in two Italian hospitals between January 2018 to February 2019. Strains were phenotypically characterized for the type of carbapenemase production and susceptibility to ceftazidime/avibactam. Ceftazidime/avibactam-resistant strains were characterized by whole-genome sequencing. Results During the study period, we characterized 105 (87.5%) KPC producers among a total of 120 CPE strains. Ceftazidime/avibactam resistance was found in three KPC-Kp strains isolated from patients with no history of previous ceftazidime/avibactam-based treatment. Of note, two out of three ceftazidime–avibactam-resistant KPC-Kp were also resistant to meropenem/vaborbactam. Genomic characterization showed that a ceftazidime/avibactam-resistant KPC-Kp harboured a mixed population with D179Y mutated KPC-2, while the other two ceftazidime–avibactam-resistant KPC-Kp possessed non-functional ompK35-ompK37 and mutated ompK36 porins associated with higher copy number of blaKPC gene. Conclusions Our results showed that incidence of ceftazidime/avibactam resistance emerged in KCP-Kp strains independently from previous antimicrobial exposure. Resistance to ceftazidime/avibactam was associated with mutations within the blaKPC gene or porin deficiency associated with higher blaKPC copy number and is also related to the meropenem/vaborbactam resistance.

Background Data about the optimal management of immunosuppressive therapy in liver transplant (LT) recipients with bloodstream infection (BSI) are missing. We aimed to describe the management of immunosuppressive therapy at diagnosis of BSI in LT recipients and to assess its impact on 28-day mortality. Methods We performed a single-center retrospective study of all LT recipients diagnosed with BSI, over 10-year period. Multivariate Cox regression analysis of risk factors for all cause 28-day mortality was adjusted for the propensity score of being managed with "any reduction" in immunosuppressive therapy at the diagnosis of BSI. Results We identified 209 episodes of BSI in 157 LT recipients: 107 (68%) male, median age 54 (IQR 48-63) years. "Any reduction" was made in 90 (43%) cases including: dosage reduction of ≥1 immunosuppressive drug in 31 (15%), discontinuation of ≥1 immunosuppressive drug in 28 (13%), both dosage reduction and discontinuation in 13 (6%), complete withdrawal of immunosuppressive therapy in 18 (9%) cases. All-cause 28-day mortality rate was 13.4%, varying from 22% to 7% (P = .002) in cases with and without "any reduction". Cox regression showed septic shock (aHR 3.15, P = .007) and "any reduction" (aHR 2.50, P = .02) as independent risk factors for all-cause 28-day mortality, while Escherichia coli (aHR 0.38, P = .03) and source control (aHR 0.43, P = .04) were protective factors. The final model did not change after the introduction of the propensity score for "any reduction". Conclusions Any reduction in the immunosuppressive therapy was common and was associated with worse outcome in LT recipients developing BSI.

Improved understanding of risk factors associated with carbapenem-resistant-Klebsiella pneumoniae (CR-KP) infection after liver transplantation (LT) can aid development of effective preventive strategies. We performed a prospective cohort study of all adult patients undergoing LT at our hospital during 30-month period to define risk factors associated with CR-KP infection. All patients were screened for CR-KP carriage by rectal swabs before and after LT. No therapy was administered to decolonize or treat asymptomatic CR-KP carriers. All patients were monitored up to 180 days after LT. Of 237 transplant patients screened, 41 were identified as CR-KP carriers (11 at LT, 30 after LT), and 20 developed CR-KP infection (18 bloodstream-infection, 2 pneumonia) a median of 41.5 days after LT. CR-KP infection rates among patients non-colonized, colonized at LT, and colonized after LT were 2%, 18.2% and 46.7% (p 48 h; HCV recurrence, and colonization at any time with CR-KP. Based on these four variables, we developed a risk score that effectively discriminated patients at low versus higher risk for CR-KP infection (AUC 0.93, 95% CI 0.86-1.00, p < 0.001). Our results may help to design preventive strategies for LT recipients in CR-KP endemic areas.

ESGBIS/BICHROME Study Group: C. Campoli, G. Siccardi, S. Ambretti, A. Stallmach, M. Venditti, C. Lucidi, S. Ludovisi, M. De Cueto, M. D. Navarro, E. Lopez Cortes, E. Bouza, M. Valerio, A. Eworo, R. Losito, M. Senzolo, E. Nadal, A. Ottobrelli, M. Varguvic, C. Badia, G. Borgia, I. Gentile, A. R. Buonomo, E. Boumis, A. Beteta-Lopez, A. Rianda, G. Taliani, S. Grieco., [Objectives] To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance., [Methods] Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model., [Results] We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure–SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29–18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93–5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28–1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73–4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48–4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12–0.73; p 0.008)., [Conclusions] MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients.

The incidence of C. difficile infections (CDI) in the elderly continues to rise and infection is associated with increased morbidity and mortality when compared to those affected in younger age-groups. Immunosenescence may be a contributory factor yet the exact immune responses that may protect against CDI are incompletely understood. Increased exposure to antibiotics, frequent and/or prolonged hospital admissions and residing in long-term care facilities provide multiple opportunities for host and pathogen to coincide. This review explores the epidemiology, diagnostic parameters and management of the spectrum of disease in the geriatric population. Deaths attributed to CDI are most common in the elderly population and are a major contributor to gastroenteritis-associated mortality in many countries. The elderly represent an at-risk population from this pathogen and efforts must be directed to preventing infection and optimising treatment in this group.