Efficacy of bezlotoxumab in preventing the recurrence of Clostridioides difficile infection: an Italian multicenter cohort study.

OBJECTIVES: Bezlotoxumab (BEZ) is a promising tool for preventing the recurrence of Clostridioides difficile infection (rCDI). The aim of the study was to emulate, in a real-world setting, the MODIFY trials in a cohort of participants with multiple risk factors for rCDI treated with BEZ in addition to the standard of care (SoC) versus SoC alone. METHODS: A multicenter cohort study was conducted including 442 patients with Clostridioides difficile infection from 2018 to 2022, collected from 18 Italian centers. The main outcome was the 30-day occurrence of rCDI. The secondary outcomes were (i) all-cause mortality at 30 days (ii) and the composite outcome (30-day recurrence and/or all-cause death). RESULTS: rCDI at day 30 occurred in 54 (12%): 11 in the BEZ + SoC group and 43 treated with SoC alone (8% vs 14%, odds ratio [OR] = 0.58, 95% confidence interval [CI]: 0.31-1.09, P = 0.09). The difference between BEZ + SoC versus SoC was statistically significant after controlling for confounding factors (adjusted OR = 0.40, 95% CI: 018-0.88, P = 0.02) and even more using the composite outcome (adjusted OR = 0.35, 95% CI: 0.17-0.73, P = 0.005). CONCLUSION: Our study confirms the efficacy of BEZ + SoC for the prevention of rCDI and death in a real-world setting. BEZ should be routinely considered among participants at high risk of rCDI regardless of age, type of Clostridioides difficile infection therapy (vancomycin vs fidaxomicin), and number of risk factors.

How relevant is the HIV low level viremia and how is its management changing in the era of modern ART? A large cohort analysis.

BACKGROUND: It is still unclear what might be the best management of people living with HIV (PLWHIV) with low level viremia (LLV) despite being on antiretroviral treatment (ART). OBJECTIVES: Aim of our study is to describe the clinical management of PLWHIV with LLV followed in a large cohort. STUDY DESIGN: Retrospective cohort study. RESULTS: We included 1607 adult patients over a three-year period (2015-2017). Follow up continued until June, 30th 2019 or last available visit. We observed a low incidence of LLV (0.9 % in 2015, 0.7 % in 2016 and 0.4 % in 2017), with a total of 21 patients with persistent LLV (pLLV), i.e. two consecutive HIV-RNA determinations of 50-500 copies/ml after at least 4 months of viral suppression. Among them, 12 had low compliance to treatment. Genotype resistance test (GRT) was performed in 14 patients and demonstrated at least one resistance mutation in 85.7 %. We described three categories of patients with pLLV: i) those whose ART regimen was not adequate based on GRT; ii) those with presumed suboptimal drug exposure, consequence of low adherence and/or drug-drug interactions and iii) those in which pLLV remained unexplained. For the first two categories, optimization or intensification of ART regimen led to viral suppression in >80 % of patients. We observed only 2 (9.5 %) virological failures and 1 (4.8 %) persistence of LLV in patients who did not switch ART. CONCLUSIONS: In our cohort, the rate of LLV showed a decline in most recent years. Adherence and previous GRT should be carefully considered with the aim of further reducing the phenomenon.

A Global View to HBV Chronic Infection: Evolving Strategies for Diagnosis, Treatment and Prevention in Immunocompetent Individuals.

Hepatitis B Virus (HBV) is a significant public health challenge. Around 250 million people live with chronic HBV infection. With a global approach to this issue, we focus on new perspective in diagnosis, management and prevention of HBV chronic infection. Precise diagnosis of HBV status is crucial to guide patient management. Although available drugs reduce the risk of liver disease progression, they are not able to definitely eradicate HBV, and new therapeutic options are urgently needed. Thus, prevention of HBV infection is still the most effective strategy to achieve the control of the disease. Key aspects of prevention programs include surveillance of viral hepatitis, screening programs and immunization strategies. In spite of the high success rate of licensed HBV vaccines, a need for improved vaccine persists, especially in order to provide coverage of current non-responders.

Epidemiology of carbapenemase-producing Enterobacteriaceae in a pediatric hospital in a country with high endemicity.

BACKGROUND: Little is known about epidemiology of carbapenemase-producing Enterobacteriaceae (CPE) in children. Aim of this study was to describe CPE epidemiology in a tertiary care pediatric hospital in Italy that admits patients coming from geographic areas with high diffusion of CPE. METHODS: Prospective evaluation of the proportion and rates per 100,000 hospital discharges (D) or hospitalization-days (HD) of invasive infections due to CPE from 2013 to 2017 and of CPE infections and colonizations from 2014 to 2017. Disease-preventing strategies comprised patients' screening at admission, pre-emptive contact isolation precautions pending cultures results, and bundles for prevention of healthcare associated infections. RESULTS: From 2013 to 2017 CPE represented 3.5% of all invasive infections due to Enterobacteriaceae, with rates ranging 7.30-14.33 for D and 1.03-2.06 for HD, without major changes over time. On the contrary, overall rates of isolates increased from 83.03 to 191.34 for D and from 12.21 to 28.35 for HD. The intra-hospital diffusion consisted of 2 small outbreaks without invasive diseases in 2014-2015, and sporadic, not epidemiologically-related cases in 2016-2017. Globally, Escherichia coli and Klebsiella pneumoniae represented 64% of identified CPE, while 70% of carbapenemases identified were metallo-beta-lactamases (VIM or NDM), with changes over time. CONCLUSIONS: In our center metallo-beta lactamases were the most frequently identified carbapenemases in Enterobacteriaceae and E. coli and K. pneumoniae the most frequently isolated pathogens carrying these enzymes. A proactive management strategy was effective in containing in-hospital spreading.

Improvement of lipid profile after switching from efavirenz or ritonavir-boosted protease inhibitors to rilpivirine or once-daily integrase inhibitors: results from a large observational cohort study (SCOLTA).

BACKGROUND: Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen. METHODS: We analyzed data from SCOLTA prospective database. All patients with HIV-RNA < 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV). Total cholesterol (TC), TC/HDL ratio, LDL-cholesterol (LDL) and triglycerides (TG) were compared at baseline, six months and one year. Comparisons among groups were performed by a general linear model. RESULTS: Four hundred and ninety patients were enrolled, 24.9% female, mean age 47.3 years (±10.1). According to ART switch, 11.4% were classified in group EFV-DTG, 3.9% in EFV-EVG, 23.9% in EFV-RPV, 17.6% in PI/r-DTG, 17.8% in PI/r-EVG, and 25.5% in PI/r-RPV. After adjusted analysis, TC significantly decreased in all groups but EFV-EVG, TC/HDL in all but EFV-DTG and EFV-EVG, while the reduction of TG was significant only in switches to RPV (EFV-RPV and PI/r-RPV). The one year decrease of TC, TC/HDL, LDL and TG was higher in patients with higher baseline levels of the same variable (p < .0001 for all). CONCLUSIONS: In SCOLTA, all switches from PI/r regimens gave advantages on lipid profile, while stopping EFV had consistently favorable lipid effects only if replaced by RPV.

Epidemiology of Infectious Complications During Extracorporeal Membrane Oxygenation in Children: A Single-Center Experience in 46 Runs.

BACKGROUND: Infections represent a severe complication of extracorporeal membrane oxygenation (ECMO). Aim of the present study was to describe the epidemiology of infections acquired during ECMO in a tertiary care children's hospital. METHODS: Retrospective analysis of clinical records of patients undergoing ECMO between January 2009 and December 2016. For each patient, data were collected on clinical characteristics, modality of ECMO support, site and etiology of documented infections, survival within 1 week after ECMO weaning and/or at pediatric intensive care unit discharge. These data were employed to evaluate overall infection prevalence, infection rate expressed as episodes/1000 days of support and cumulative risk estimates of infections occurring during ECMO. RESULTS: During the study period, a total of 46 ECMO procedures were performed. The overall prevalence of documented infections was 33%, with an infection rate of 27.22 and a cumulative risk of 55%. Bloodstream infection represented the most frequently documented (53%), followed by pneumonia (40%). Coagulase-negative staphylococci and Pseudomonas aeruginosa prevailed as isolated pathogens. Overall survival was 59%, and 46% among those developing infections during ECMO. CONCLUSIONS: ECMO is a procedure at high risk for infections. Our data, limited to 1 center, represent a recent benchmark for further investigations.

Predictors of attrition from care at 2 years in a prospective cohort of HIV-infected adults in Tigray, Ethiopia.

INTRODUCTION: Ethiopia has experienced rapid expansion of antiretroviral therapy (ART). However, as long-term retention in ART therapy is key for ART effectiveness, determinants of attrition need to be identified so appropriate interventions can be designed. METHODS: We used data from the 'Cohort of African people Starting Antiretroviral therapy' (CASA) project, a prospective study of a cohort of HIV-infected patients who started ART in seven health facilities (HFs). We analysed the data of patients who had started first-line ART between January 2013 and December 2014. The Kaplan-Meier method was used to estimate the probability of retention at different time points. The Cox proportional hazards model was used to identify factors associated with attrition. RESULTS: A total of 1198 patients were included in the study. Kaplan-Meier estimates of retention in care were 83.9%, 82.1% and 79.8% at 12, 18 and 24 months after starting ART, respectively. Attrition was mainly due to loss to follow-up, transferred-out patients and documented mortality. A multivariate Cox proportional hazard model showed that male sex, CD4 count <200 cells/µL and the type of HF were significantly associated with attrition. CONCLUSIONS: The observed attrition differences according to gender suggest that separate interventions designed for women and men should be explored. Moreover, innovative strategies to increase HIV testing should be supported to avoid CD4 levels falling too low, a factor significantly associated with higher attrition in our study. Finally, specific studies to analyse the reasons for different levels of attrition among HFs are required.

Epidemiology of invasive fungal diseases in children with solid tumours undergoing autologous haematopoietic stem cell transplantation: a 10-year experience in a tertiary Italian centre.

The objective of the study was to determine the incidence of invasive fungal disease (IFD) in children undergoing autologous haematopoietic stem cell transplantation (auHSCT) for solid tumours (ST). Retrospective study on auHSCT was performed in children with ST (January 2006-December 2015). Data on the number of patient-days at risk (pdr) during the first 30 and 90 days after auHSCT and cases of proven/probable IFDs were collected. Infection rate (IR, episodes/1000 pdr) and proportions and cumulative risk (CR) of IFD were evaluated. In 186 patients, 270 auHSCT were performed, for a total of 8327 pdr during the first 30 days and 24 366 up to day 90. Median age was 5 years (interquartile range 2;8), 63% were male. At day 30, seven procedures were complicated by IFD, with an IR of 0.84 (95% CI 0.66-1.02) and aCR of 2.6% (95% CI 1.4-5.4) at 18 days after HSCT. Within day 90, two further IFDs were detected with an IR of 0.37 (95% CI -0.49 to 1.23) and a CR of 3.3% (95% CI 1.7-6.3) at day 69. Children undergoing auHSCT for ST have a low incidence of IFDs in the first 90 days after the procedure.

Good tolerability of high dose colistin-based therapy in patients with haematological malignancies.

PURPOSE: Colistin is usually the only drug fully active against multi-drug resistant Gram-negative bacteria, but its nephrotoxicity might limit its use. Recent pharmacokinetic/pharmacodynamic data suggest that high dose of colistin, preceded by a loading dose, are needed to maximize its antibacterial effect. The aim of this study was to determine the safety of high doses colistin, in haematology population. METHODS: A retrospective review of haematology patients who received high dose colistin-based therapy in years 2011-2016 was performed. Nephrotoxicity was assessed using RIFLE criteria. RESULTS: Thirty patients who received 38 courses of colistin were included in the study. Colistin was always administered together with other antibiotics. Colistin was well tolerated, with one case of neurological toxicity and one of cutaneous reaction. There were 22 (58%) treatment cycles without any nephrotoxicity, even though during 16 of these cycles other nephrotoxic drugs were administered. Severe (injury or failure) renal toxicity occurred during 6 (16%) treatment courses, requiring colistin discontinuation in 2 patients and colistin dose reduction in 1. Poorer renal function at baseline and younger age were the only variables associated with increased renal toxicity (p = 0.011 and p = 0.031, respectively). Overall mortality was 18% (7/38) and 29% (11/38) at 7 and 30 days after the treatment onset. CONCLUSIONS: In adult haematology population, high dose colistin therapy is safe and efficacious, despite high frequency of concomitant nephrotoxic treatment.

HIV-1 RNA quantification in CRF02_AG HIV-1 infection: too easy to make mistakes.

The number of patients newly infected by HIV-1 non-B subtypes and circulating recombinant forms (CRFs) is increasing worldwide, including in the western countries. We report on a primary HIV-1 infection in a Caucasian patient. A routine quantitative assay (Nuclisens EasyQ HIV-1 2.0, BioMérieux SA) showed 6,700 HIV-1 RNA copies/ml. A combined antiretroviral therapy (cART) consistent with low baseline HIV-1 RNA was started. Few days later, the analysis performed with REGA HIV-1 Subtyping Tool - Version 3.0 attributed the HIV-1 sequence to the CRF02_AG recombinant form. Therefore, a second real-time PCR assay was performed, using the Versant HIV-1 RNA 1.0 Assay (kPCR) (Siemens HealthCare Diagnostics) which revealed a HIV-1 RNA of 230,000 copies/ml. Consequently, the ongoing cART was potentiated. This case suggests that the wide genetic variability of HIV-1 subtypes may affect the capability of the commonly used assays to detect and accurately quantify HIV-1 RNA in non-B subtypes and CRFs. In presence of CRFs different commercial HIV-1 RNA tests should be performed to find the most reliable for viral load quantification at the diagnosis, because it influences the choice of cART, and during the follow-up. Indeed, international guidelines for HIV-1 infection management suggest to monitor patient' HIV-RNA with the same assay over the course of treatment. As different commercial tests can be performed in the same laboratory with considerable difficulty, the laboratory should select an assay that is suitable not only for the more prevalent strain, but also for less frequent ones that, nevertheless, can occur. Then, knowing and investigating the spread of non-B strains has essential clinical and laboratory implications.

Multidrug-resistant bacteria in hematology patients: emerging threats.

Multidrug-resistant (MDR) bacteria, particularly Gram negatives, such as Enterobacteriaceae resistant to third-generation cephalosporins or carbapenems and MDR Pseudomonas aeruginosa, are increasingly frequent in hematology patients. The prevalence of different resistant species varies significantly between centers. Thus, the knowledge of local epidemiology is mandatory for deciding the most appr-opriate management protocols. In the era of increasing antibiotic resistance, empirical therapy of febrile neutropenia should be individualized. A de-escalation approach is recommended in case of severe clinical presentation in patients who are at high risk for infection with a resistant strain. Targeted therapy of an MDR Gram negative usually calls for a combination treatment, although no large randomized trials exist in this setting. Infection control measures are the cornerstone of limiting the spread of MDR pathogens in hematology units.

Bloodstream infections in HIV-infected patients.

In the combined antiretroviral therapy era, HIV-infected patients remain a vulnerable population for the onset of bloodstream infections (BSI). Worldwide, nontyphoid salmonellae, Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus and coagulase negative staphylococci are the most important pathogens. Intravenous catheter associated infection, skin-soft tissue infection and endocarditis are associated with Gram-positive bacteremia. Among the Gram-negative, nontyphoidal Salmonella have been previously correlated to sepsis. Other causes of BSI in HIV-infected patients are mycobacteria and fungi. Mycobacteria constitute a major cause of BSI in limited resource countries. Fungal BSI are not frequent and among them Cryptococcus neoformans is the most common life-threatening infection. The degree of immunosuppression remains the key prognostic factor leading to the development of BSI.

Potential role of raltegravir-based therapy to induce rapid viral decay in highly viraemic HIV-infected neonates.

We report safety and tolerability of raltegravir (RAL) as a forth HIV agent in two highly viraemic newborns. Raltegravir (6 mg/kg) was given orally twice daily. The other antiretrovirals were assumed according to standard dose for newborns. The first baby was born at week 36. An antiretroviral therapy consisting of zidovudine, lamivudine, and lopinavir/ritonavir was started 96 hour after delivery. Raltegravir was added at hour 120, being plasma HIV-1 RNA above 10×10(6) copies/ml. HIV RNA declined to 5·000 copies/ml at day 30. The second baby was born at week 40. He was started on zidovudine, lamivudine, and nevirapine at day 0, while RAL was added at day 3. Plasma HIV-1 RNA declined from 6·6×10(6) at birth to 52 copies/ml at day 28. RAL tolerability was good in both patients, one with gamma-glutamyltransferase increase, which normalized after RAL discontinuation. Raltegravir-based four drug regimen may be effective and well tolerated in highly viraemic HIV neonates up to 4 weeks.

Trend of eGFR in an Italian cohort of mother-to-child HIV-infected patients exposed to tenofovir for at least 2 years.

UNLABELLED: The aim of this study is to describe longitudinal changes in estimated glomerular filtration rate (eGFR) in a cohort of mother-to-child HIV-infected adolescents exposed to tenofovir dixoproxil fumarate (TDF) for at least 2 years. We retrospectively examined eGFR at starting TDF (T0), at 24 months (T2) and at the final assessment (T3). Twenty-nine patients were studied. The mean duration of TDF exposure was 67 months (24-123). At baseline, the mean eGFR was 152 ml/min/1.73 m(2) (105-227, SD, 33). There was a significant decrease of eGFR from a mean of 152 ml/min/1.73 m(2) (SD, 33) at T0 to 140 ml/min/1.73 m(2) (SD, 33) at T2 and 123 ml/min/1.73 m(2) (SD, 14) at T3. The decrease of eGFR was significant, with ΔGFR (T3-T0) of -29 ml/min/1.73 m(2) (SD, 30; p < 0.0001) and a mean ΔGFR per year of -6 and ml/min/1.73 m(2) (SD, 8). CONCLUSION: We noted a long-term decline in eGFR in this small cohort of mother-to-child HIV-infected adolescents receiving TDF-containing cART, even if the lack of a control group and the small sample size are major limitations.