The Role for Tocilizumab in COVID-19 Patients: Reflections on Monza Cohort Data.

The severe acute respiratory syndrome coronavirus 2 pandemic has dominated the global health scenario from the beginning of 2020 and still represents a major health emergency. Cytokine inhibitors as tocilizumab have been used to treat COVID-19 severe pneumonia with conflicting results. We performed a retrospective study whose results can contribute to the general overview regarding the role of these agents in severe COVID-19 pneumonia, suggesting an interesting, even not statistically significant evidence of the effectiveness of tocilizumab treatment in this disease and sow a seed of reflection about their use in future waves of pandemic. We compared two cohorts of patients treated with local standard of care and with tocilizumab in the experimental one. With a median follow-up of 92 days, deaths were 6 and 16 in the tocilizumab and the standard of care group, respectively. With a longer follow-up than previous studies, a trend in difference with regards to mortality of the groups was observed.

De-Escalation and Discontinuation of Empirical Antibiotic Treatment in a Cohort of Allogeneic Hematopoietic Stem Cell Transplantation Recipients during the Pre-Engraftment Period.

To investigate rates and outcomes of antibiotic de-escalation during pre-engraftment neutropenia in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. 110 consecutive HSCTs performed between January 2013 and March 2014 were analyzed. De-escalation was defined as narrowing the spectrum of antibiotic treatment either within (early) or after 96 hours (late) from starting antibiotics. Discontinuation, considered a form of de-escalation, was defined as stopping antibiotics before engraftment. De-escalation failure was defined as restarting/escalating antibiotics within 96 hours after de-escalation. Predictors of de-escalation were analyzed. Among 102 patients who started antibiotics and were included, 68 (67%) received monotherapy (mainly piperacillin-tazobactam, n = 58), whereas 34 (33%) received combination therapy (mainly meropenem plus glycopeptide, n = 24). Median duration of neutropenia was 17 days. Bloodstream infections (BSIs) were diagnosed in 28 patients (20%). Early de-escalation rate was 25.5% (n = 26) and mostly consisted of reducing the spectrum of ß-lactams (n = 11, 42%). In comparison with theoretical scenario of continuing therapy until engraftment, the median savings in terms of antibiotic days were 10 for meropenem, 8 for piperacillin-tazobactam, and 7 for vancomycin. Failure rate of early de-escalation was 15% (4/26). Late de-escalation rate was 30.4% (n = 31) and failure rate 19% (6/31). The rate of de-escalation any time before engraftment was 55.9% (n = 57), including discontinuation in 33 patients (32%). Death at day 60 after HSCT occurred in 3 patients who never underwent de-escalation. Acute myeloid disease and BSIs were independent predictors of early de-escalation. De-escalation, including discontinuation, is feasible and safe in pre-engraftment neutropenia after allogeneic HSCT.

Pharmacokinetic/pharmacodynamic parameters for treatment optimization of infection due to antibiotic resistant bacteria: a summary for practical purposes in children and adults.

In the last years, there has been a tremendous increase in the incidence of bacterial infections due to resistant strains, especially multi-drug resistant Gram-negative bacilli. In Europe, a north to south and a west to east gradient was noticed, with more than one third of the K. pneumonia isolates being resistant to carbapenems in few countries. New antibiotics are lacking and, as a consequence, pharmacokinetic/pharmacodynamic parameters, normalized to pathogen minimal inhibitory concentration, are used with increased frequency to treat infections due to difficult-to-treat pathogens. These parameters are available at least for the adult population, but sparse in many different publications. This review wants to provide a comprehensive and 'easy to read' text for everyday practice, briefly summarizing the presently available knowledge on pharmacokinetic/pharmacodynamic parameters (normalized for minimal inhibitory concentration values) of different class drugs, that can be applied for an effective antibacterial treatment infections due to antibiotic-resistant pathogens.

Durability of Second Antiretroviral Regimens in the Italian Cohort Naive Antiretrovirals Foundation Study and Factors Associated with Discontinuation.

The study was designed to investigate the median duration of second antiretroviral regimens and factors associated with early discontinuation in HIV patients who switched with an undetectable viral load. We conducted a retrospective analysis of the Italian Cohort Naive Antiretrovirals Foundation Study (ICONA), which collects data throughout the country. Patients who started first antiretroviral therapy (ART) after January 1, 2008 in any center involved in this cohort and then switched to a second regimen were included in the study. Second ART failure was described as two HIV-RNA >200 copies/mL or the discontinuation of any drug. Statistical analysis was performed utilizing Kaplan-Meier curves and Cox regression model. The study population included 835 patients and the median duration of first ART regimens was 16 months with HIV-RNA undetectable for 13 months. The main causes of switch to second ART regimens were toxicity (42.5%) and simplification (37.5%). The switch mostly involved the third drug (63.5%) and almost one third of the population received a single-tablet regimen (STR) as second treatment (30.6%). The median duration of second ART regimens was 9.2 months and the probabilities of treatment discontinuation at 12, 24, and 36 months were 21%, 35%, and 48.2%, respectively. STR formulations had a protective effect against second ART discontinuation. Almost half of our population needed a third regimen within 3 years, but STR could improve second ART durability.

Correction to: Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy.

A technical error led to incorrect rendering of the author group in this article. The correct authorship is as follows: Daniele Roberto Giacobbe1, Valerio Del Bono1, Malgorzata Mikulska1, Giulia Gustinetti1, Anna Marchese2, Federica Mina3, Alessio Signori4, Andrea Orsi5, Fulvio Rudello6, Cristiano Alicino5, Beatrice Bonalumi3, Alessandra Morando7, Giancarlo Icardi5, Sabrina Beltramini3, Claudio Viscoli1; On behalf of the San Martino Antimicrobial Stewardship Group.

Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy.

BACKGROUND: The overuse of antimicrobials favors the dissemination of antimicrobial resistance, as well as invasive fungal diseases and Clostridium difficile infections (CDI). In this study, we assessed the impact of a mixed educational and semi-restrictive antimicrobial stewardship (AMS) project in a large teaching hospital in Italy. METHODS: The AMS project was conducted from May 2014 to April 2016. It consisted of two initiatives in two consecutive periods: (1) educational activities; (2) semi-restrictive control of antimicrobial prescribing through a computerized software. The primary endpoint was consumption of antibacterials and antifungals. Secondary endpoints were incidence of CDI, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI, and Candida BSI. RESULTS: During the study period, a statistically significant reduction in consumption was observed for antibacterials (-1.45 defined daily doses (DDD)/1000 patient-days monthly, 95% confidence intervals [CI] -2.38 to -0.52, p 0.004), mainly driven by reductions in the use of fluoroquinolones, third/fourth generation cephalosporins, and carbapenems. No decrease in consumption of antifungals was observed (-0.04 DDD/1000 patient-days monthly, 95% CI -0.34 to +0.25, p 0.750). A statistically significant trend towards reduction was observed for incidence of CRKP BSI (incidence rate ratio 0.96, 95% CI 0.92-0.99, p 0.013). No statistically significant variations in trends were observed for CDI, MRSA BSI, and Candida BSI. CONCLUSIONS: The mixed AMS project was effective in reducing the use of major antibacterials and the incidence of CRKP BSI. Further research is needed to assess the extent of long-term benefits of semi-restrictive approaches.

Sepsis by Pasteurella multocida in an Elderly Immunocompetent Patient after a Cat Bite.

Pasteurella multocida colonizes animal scratches and bites. This bacterium was described to cause sepsis or endocarditis mainly in immunocompromised patients. We report the case of a 92-year-old woman presenting at the Emergency Department with coma and fever a week after the bite of her cat. The cat bite was misdiagnosed at admission partly due to an underestimation of this event by the patient's relatives. An inflamed area localized at perimalleolar skin of the right leg was detected. Laboratory biomarkers of inflammation were elevated. The cerebral computed tomography (CT) scan with angiographic sequences showed a complete occlusion of right intracranial vertebral artery. Total body CT scan and abdominal echocardiography were negative for foci of infection. Three consecutive blood cultures were positive for Pasteurella multocida. A diagnosis of sepsis by Pasteurella multocida was made, and the patient recovered after a specific antimicrobial treatment. In order to confirm the animal transmission, the cat saliva was cultured and found positive for Pasteurella multocida with a similar antibiotic sensitivity to that isolated from the patient. In conclusion, the case of a patient with coma and fever after a cat bite was presented. The transmission of pathogens from pets has to be carefully considered as an important route of infection in immunocompetent patients.

Bloodstream infections in neutropenic cancer patients: A practical update.

Bloodstream infections (BSI) are among the most frequent complications in neutropenic cancer patients and, if caused by Gram-negative rods, are associated with high mortality. Thus, fever during neutropenia warrants prompt empirical antibiotic therapy which should be active against the most frequent Gram-negatives. In the last decade, there has been a worldwide increase in multidrug resistant (MDR) strains. In these cases, the traditional choices such as oral therapy, ceftazidime, cefepime, piperacillin-tazobactam, or even carbapenems, might be ineffective. Therefore novel de-escalation approach has been proposed for patients who are at high risk for infections due to MDR bacteria. It consists of starting antibiotics which cover the most probable resistant strain but it is narrowed down after 72 hours if no MDR pathogen is isolated. With increasing bacterial resistance, the benefit of fluoroquinolone prophylaxis during prolonged neutropenia remains to be confirmed. Antibiotic stewardship and infection control programs are mandatory in every cancer center.

Seroprevalence and vaccination coverage of vaccine-preventable diseases in perinatally HIV-1-infected patients.

BACKGROUND: Even in the era of highly active antiretroviral therapy (HAART), HIV-infected subjects are at higher risk of complications from vaccine-preventable diseases than those uninfected. The current international guidelines strongly recommend that these patients should receive all the routine childhood vaccinations. Although these children represent an appropriate target for immunization, the available data indicate suboptimal coverage rates. METHODS: To evaluate seroprotection/seropositivity rates and vaccination coverage against the common vaccine-preventable diseases, all patients with vertically transmitted HIV-1 infection who attended San Martino Hospital were enrolled. Blood samples were collected for testing antibodies against diphtheria, tetanus, hepatitis A and B viruses by Enzyme-Linked ImmunoSorbent Assay and polioviruses by microneutralization test. In order to assess immunization coverage, retrospectively was recorded the vaccination history collecting data from Regional Immunization Database. RESULTS: A total of 39 perinatally HIV-1 infected patients were included in the study. At the time of serum was obtained, the mean age was 18,1 years (range: 6-28). The median CD4+ T-lymphocyte count was 702 cells/mm(3) (2-1476 cells/mm(3)). Twenty-nine (74.4%) patients were found with HIV RNA load < 50 copies/mL. The proportion of subjects with protective anti-tetanus and anti-HBs were 43.6% and 30.8%, respectively. Seroprotection rates about 20% against rubella and measles were found, less than 20% against all the other antigens investigated. In particular, all patients resulted susceptible to mumps. High immunization rates were observed for polio and HBV (100% and 92.3%, respectively) and suboptimal for diphtheria-tetanus (84.6%). For the other recommended vaccines the rates were generally low. None of the patients received varicella vaccine doses. CONCLUSIONS: As in the HAART era the vertically acquired HIV infection has become a chronic treatable disease, the vaccine-induced long-term protection plays an increasingly significant role; despite good initial response to primary vaccination, subsequent decline and loss of detectable antibodies may be prevented by additional strategies for booster doses of vaccines in adolescents and young adults.

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.

Efficacy and safety of darunavir/ritonavir plus etravirine dual regimen in antiretroviral therapy-experienced patients: a multicenter clinical experience.

OBJECTIVES: To assess the outcome of a dual regimen combining darunavir/ritonavir plus etravirine in a cohort of antiretroviral therapy (ART)-experienced patients. METHODS: A retrospective analysis was performed on all ART-experienced patients starting a darunavir/ritonavir plus etravirine regimen at the 3 clinics. Patients were stratified according to HIV RNA detectability (≥ 40 copies/mL) at baseline. Two efficacy endpoints were evaluated by Kaplan-Meier and Cox multivariable models: virological failure (confirmed HIV RNA ≥ 40 copies/mL after 6 months) and therapeutic failure (including virological failure and treatment discontinuation for any reason). RESULTS: Sixty-eight patients were included in the study. They had a median of 10.8 years on ART and 5 previous ART regimens; 61.3% showed primary protease inhibitor (PI) mutations and 70% showed previous non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure. HIV RNA was detectable in 34 (50%) patients. The median observation period was 21 (interquartile range [IQR], 11.9-25.1) months. After 24 months, 75.1% of the patients were still on the study regimen and 88.8% remained free from virological failure. Although a higher therapeutic failure rate was reported in patients with detectable viremia at baseline, only the immunological status revealed an independent predictive role. No differences in virological failure were observed according to HIV RNA detectability at baseline; a higher number of previous ART regimens was the only predictor. Discontinuation due to adverse events occurred in 5.9%. CONCLUSIONS: Darunavir/ritonavir plus etravirine regimen proved virological efficacy and safety in heavily pretreated patients with a high rate of virological success, even in patients who switched during virological failure.

Which patients have greatest need for elvitegravir/cobicistat/ emtricitabine/tenofovirDF-based therapy?

Elvitegravir/cobicistat/emtricitabine/tenofovirDF (EVG/COBI/FTC/TDF) is the new single-tablet, fixed-dose formulation containing an integrase strand transfer inhibitor recently approved as antiretroviral treatment. In this paper we analysed its use and advantages in naïve and experienced HIV-infected patients and we focused on special populations in which EVG/COBI/FTC/TDF could be a suitable option. Furthermore the manuscript reports the recent patent of EVG which may have an influence on the management of HIV-infected patients in the next future.