The use of C-reactive protein testing and antibiotic prescribing in Italy: A population-based study in primary care.

Testing serum C-reactive protein (CRP) levels can help determine whether there is a need for antibiotics and can limit prescribing of antibiotics for illnesses that are likely viral or non-infectious in origin. Using Health Search, an Italian primary care database, we identified all patients, aged 15 years or older, being registered in the period between 1 January 2000 and 31 December 2019 and newly diagnosed with upper respiratory tract infections (URTIs) or COPD- or asthma-related exacerbations. From the date of these diagnoses, patients were followed up until occurrence of antibiotic prescription (for these indications) up to 31 December 2019. The association between the CRP testing and the outcome was investigated using a nested case-control analysis. In a cohort of 469 684 patients being diagnosed for URTI (83%), COPD- (11%) and asthma (7%)-related exacerbations, 28 688 (6.11%) were prescribed with antibiotics because of the aforementioned indications. Of note, 98% of cases, nominally those prescribed with antibiotics, were not tested with CRP. However, those receiving antibiotics were more likely to have been previously tested for CRP than controls who did not receive antibiotics (833/28 601 [3%] and 4128/277 968 [1.5%]; OR 2.0 [95% CI: 1.8-2.1]). Our findings indicate that most of the antibiotic prescriptions for the investigated conditions were given without any prior CRP testing. A small minority of GPs did properly use CRP to determine whether antibiotics were needed. Further guidance is needed in Italy on the use of CRP in guiding antibiotic prescribing in primary care.

Time-varying association between herpes zoster infection and subsequent occurrence of stroke.

OBJECTIVES: The aim of this study was to investigate the shape of the time-varying relationship between herpes zoster infection, nominally shingles, and the occurrence of stroke. STUDY DESIGN: Retrospective cohort study. METHODS: Using the Italian Health Search Database, a cohort of patients aged ≥18 years who were registered between 2002 and 2021 was selected. In this cohort, a nested case-control analysis was used to model the time-varying distance (in months) between the dates of shingles and post-herpetic stroke, using a regression cubic spline, based on the odds of the occurrence of stroke compared with those without shingles. RESULTS: The dataset comprised 42,513 cases (51.1% males; mean age [stanndard deviation {SD}]: 71.0 [11.8] years) and 425,124 related controls (51.1% males; mean age [SD]: 70.9 [12] years). In the first 12 months following shingles diagnosis, a rapid increase in the risk of stroke was observed, reaching an odds ratio of 1.31 (95% confidence interval: 1.21-1.41); subsequently, there was some risk reduction and a new symmetric increase within the first 4.2 years of follow-up, thus shaping a bimodal distribution. Then, a new increase in the stroke risk was reported, although less steep, which was followed by a regular risk reduction (still 10% higher compared with those without shingles), resulting in a right-skewed relationship between the time from the shingles diagnosis and the occurrence of stroke. This association was no longer statistically significant 13.1 years after shingles diagnosis. CONCLUSIONS: This study demonstrated that the risk of post-herpetic stroke has a short- and long-term association according to a risk continuum relationship. These findings confirm the relevance of vaccination coverage for herpes zoster.

Reduced effectiveness among ß-lactam antibiotics: a population-based cohort study in primary care in Italy.

BACKGROUND: There are few data comparing the relative effectiveness of the individual ß-lactams. OBJECTIVES: To quantify the reduced effectiveness, defined as switching to a different antibiotic being prescribed for the same indication, among new users of ß-lactam antibiotics in primary care. METHODS: A retrospective cohort study was conducted using the Health Search Database, an Italian primary care data source. Patients newly prescribed with ß-lactams for a specific indication between 1 January 2013 and 31 December 2017 were identified. A switch to a different antibiotic for the same indication occurring during a 30day follow-up was the study outcome. Cox regression was adopted to assess the risk of switching between the different ß-lactams. RESULTS: Among 178 256 patients newly treated with ß-lactam antibiotics, 1172 (0.65%) switched to a different antibiotic. Amoxicillin/clavulanate (co-amoxiclav: n = 104 891) and amoxicillin (n = 21 699) were the most frequently prescribed ß-lactams. The other antibiotics showed significantly higher risk of switching when compared with co-amoxiclav for lower respiratory tract [e.g. ceftriaxone, hazard ratio (HR): 1.6, 95% CI: 1.2-2.0], dental [e.g. amoxicillin, HR: 4.2, 95% CI: 2.9-5.9], and middle ear infections [e.g. amoxicillin, HR: 1.8, 95% CI: 1.1-2.7]. The same results were gathered when parenteral formulations were excluded. CONCLUSIONS: The prevalence of reduced effectiveness of newly prescribed ß-lactam antibiotics was lower than 1%. Specifically, the rate of switch to another antibiotic, when it was prescribed to treat low respiratory tract, dental, and middle ear infections, was lower among users of co-amoxiclav than those prescribed with other ß-lactams.

Personalized machine learning approach to predict candidemia in medical wards.

PURPOSE: Candidemia is a highly lethal infection; several scores have been developed to assist the diagnosis process and recently different models have been proposed. Aim of this work was to assess predictive performance of a Random Forest (RF) algorithm for early detection of candidemia in the internal medical wards (IMWs). METHODS: A set of 42 potential predictors was acquired in a sample of 295 patients (male: 142, age: 72 ± 15 years; candidemia: 157/295; bacteremia: 138/295). Using tenfold cross-validation, a RF algorithm was compared with a classic stepwise multivariable logistic regression model; discriminative performance was assessed by C-statistics, sensitivity and specificity, while calibration was evaluated by Hosmer-Lemeshow test. RESULTS: The best tuned RF algorithm demonstrated excellent discrimination (C-statistics = 0.874 ± 0.003, sensitivity = 84.24% ± 0.67%, specificity = 91% ± 2.63%) and calibration (Hosmer-Lemeshow statistics = 12.779 ± 1.369, p = 0.120), markedly greater than the ones guaranteed by the classic stepwise logistic regression (C-statistics = 0.829 ± 0.011, sensitivity = 80.21% ± 1.67%, specificity = 84.81% ± 2.68%; Hosmer-Lemeshow statistics = 38.182 ± 15.983, p < 0.001). In addition, RF suggests a major role of in-hospital antibiotic treatment with microbioma highly impacting antimicrobials (MHIA) that are found as a fundamental risk of candidemia, further enhanced by TPN. When in-hospital MHIA therapy is not performed, PICC is the dominant risk factor for candidemia, again enhanced by TPN. When PICC is not used and MHIA therapy is not performed, the risk of candidemia is minimum, slightly increased by in-hospital antibiotic therapy. CONCLUSION: RF accurately estimates the risk of candidemia in patients admitted to IMWs. Machine learning technique might help to identify patients at high risk of candidemia, reduce the delay in empirical treatment and improve appropriateness in antifungal prescription.

Efficacy of Ceftazidime-Avibactam Salvage Therapy in Patients With Infections Caused by Klebsiella pneumoniae Carbapenemase-producing K. pneumoniae.

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.

A prediction rule for early recognition of patients with candidemia in Internal Medicine: results from an Italian, multicentric, case-control study.

PURPOSE: Increasing prevalence of candidemia in Internal Medicine wards (IMWs) has been reported in recent years, but risk factors for candida bloodstream infection in patients admitted to IMW may differ from those known in other settings. The aim of this study was to identify risk factors and define a prediction rule for the early recognition of the risk of candidemia in IMW inpatients. METHODS: This was a multicentric, retrospective, observational case-control study on non-neutropenic patients with candidemia admitted to IMWs of four large Italian Hospitals. Each eligible patient with candidemia (case) was matched to a control with bacteremia. Stepwise logistic regression analyses were performed. RESULTS: Overall, 300 patients (150 cases and 150 controls) were enrolled. The following factors were associated with an increased risk of candidemia and weighted to build a score: total parenteral nutrition (OR 2.45, p = 0.008; 1 point); central venous catheter (OR 2.19, p = 0.031; 1 point); peripherally inserted central catheter (OR 5.63, p < 0.0001; 3 points), antibiotic treatment prior (OR 2.06; p = 0.059; 1 point) and during hospitalization (OR2.38, p = 0.033; 1 point); neurological disability (OR 2.25, p = 0.01; 1 point); and previous hospitalization within 3 months (OR 1.56, p = 0.163; 1 point). At ROC curve analysis, a final score ≥ 4 showed 84% sensitivity, 76% specificity, and 80% accuracy in predicting the risk of candidemia. CONCLUSIONS: The proposed scoring system showed to be a simple and highly performing tool in distinguishing bloodstream infections due to Candida and bacteria in patients admitted to IMW. The proposed rule might help to reduce delay in empirical treatment and improve appropriateness in antifungal prescription in septic patients.

Nocardia infection over 5 years (2011-2015) in an Italian tertiary care hospital.

This study was conducted reviewing clinical records of 14 patients affected by nocardiosis over 5 years in a tertiary care hospital. Nocardia abscessus was responsible for one third of infections, deviating significantly from the results reported by other epidemiological investigations and highlighting the key role of molecular identification tests. Indeed, a precise identification of species is crucial for the determination of antibiotic sensitivity patterns and, consequently, for the choice of antibiotic treatment. Noteworthy, 40% of isolates of N. abscessus (formerly N. asteroides complex) showed resistance to carbapenems, which are usually recommended for empirical therapy.

Preoperative surveillance rectal swab is associated with an increased risk of infectious complications in pancreaticoduodenectomy and directs antimicrobial prophylaxis: an antibiotic stewardship strategy?

BACKGROUND: Despite improvements in the perioperative care, the morbidity rate after pancreaticoduodenectomy (PD) is still higher than 50%. The aim of this study was twofold: first, to assess the correlation between preoperative rectal swab (RS) and intraoperative bile cultures; to examine the impact of RS isolates on postoperative course after PD. METHODS: An observational study was conducted analyzing all consecutive PD performed from January 2015 to July 2016. Based on the positivity/negativity of preoperative RS for multi-drug resistant bacteria, two groups of patients were identified (RS+ vs. RS-) and then compared. RESULTS: Three hundred thirty-eight patients were considered for the analysis. RS culture showed a perfect correlation (species and phenotypic antibiotic susceptibility pattern) with bile culture in 157 patients (86.7%). Fifty patients (14.8%) had a RS+. Preoperative biliary drain (PBD) was the single independent preoperative risk factor associated to RS+ (p = 0.021, OR = 2.6, 95% CI = 1.5-11.7). Infective complications (IC) and mortality were independently correlated to RS+ (p = 0.013, OR = 2.9, 95% CI = 1.3-6.7; p = 0.009 OR = 3.4, 95% CI = 1.8-14.9, respectively). CONCLUSIONS: Preoperative surveillance RS-culture's positivity correlates to biliary colonization that occurs after PBD. IC and mortality after PD are associated with RS+. Preoperative RS can direct antibiotic prophylaxis to reduce morbidity and mortality after PD.

Nosocomial candidemia in patients admitted to medicine wards compared to other wards: a multicentre study.

PURPOSE: Risk factors for nosocomial candidemia, severity of sepsis, treatment, and outcome were compared between patients admitted to medicine wards and those to surgical and intensive care units (ICUs). METHODS: Data were retrospectively collected from patients belonging to six referral hospitals in Italy between January 2011 and December 2013. Risk factors for 30-day mortality were evaluated in the whole patient population. RESULTS: A total of 686 patients (mean age 70 ± 15 years) with candidemia were included. 367 (53.5 %) patients were in medicine wards, and 319 in surgery and ICUs. Host-related risk factors for candidemia were more common in medicine patients whereas healthcare-related factors in surgery/ICU patients. These patients showed severe sepsis and septic shock more commonly (71.7 %) than medicine patients (59.9 %) (p 0.003). The latter underwent central venous catheter (CVC) removal and adequate antifungal therapy less frequently than surgery/ICU patients. 149 (40.6 %) patients died with candidemia in medicine wards and 69 (21.6 %) in other wards (p < 0.001). Overall, the 30-day mortality was 36.3 %. At multivariate analysis, independent risk factors for death were aging, higher Charlson score, severe sepsis and septic shock, and no antifungal therapy, while major surgery and CVC removal were associated with higher probability of survival. CONCLUSIONS: The burden of risk factors for candidemia was different between medicine patients and those in other wards. Despite the lower severity of candidemia in medicine patients, their mortality turned out to be higher than in surgery or ICU patients. Awareness of the best management of candidemia should be pursued, especially in medicine wards.

CFTR Inhibitors Display In Vitro Antiviral Activity against SARS-CoV-2.

Several reports have indicated that SARS-CoV-2 infection displays unexpected mild clinical manifestations in people with cystic fibrosis (pwCF), suggesting that CFTR expression and function may be involved in the SARS-CoV-2 life cycle. To evaluate the possible association of CFTR activity with SARS-CoV-2 replication, we tested the antiviral activity of two well-known CFTR inhibitors (IOWH-032 and PPQ-102) in wild type (WT)-CFTR bronchial cells. SARS-CoV-2 replication was inhibited by IOWH-032 treatment, with an IC50 of 4.52 µM, and by PPQ-102, with an IC50 of 15.92 µM. We confirmed this antiviral effect on primary cells (MucilAirTM wt-CFTR) using 10 µM IOWH-032. According to our results, CFTR inhibition can effectively tackle SARS-CoV-2 infection, suggesting that CFTR expression and function might play an important role in SARS-CoV-2 replication, revealing new perspectives on the mechanisms governing SARS-CoV-2 infection in both normal and CF individuals, as well as leading to potential novel treatments.

CFTR Modulation Reduces SARS-CoV-2 Infection in Human Bronchial Epithelial Cells.

People with cystic fibrosis should be considered at increased risk of developing severe symptoms of COVID-19. Strikingly, a broad array of evidence shows reduced spread of SARS-CoV-2 in these subjects, suggesting a potential role for CFTR in the regulation of SARS-CoV-2 infection/replication. Here, we analyzed SARS-CoV-2 replication in wild-type and CFTR-modified human bronchial epithelial cell lines and primary cells to investigate SARS-CoV-2 infection in people with cystic fibrosis. Both immortalized and primary human bronchial epithelial cells expressing wt or F508del-CFTR along with CRISPR/Cas9 CFTR-ablated clones were infected with SARS-CoV-2 and samples were harvested before and from 24 to 72 h post-infection. CFTR function was also inhibited in wt-CFTR cells with the CFTR-specific inhibitor IOWH-032 and partially restored in F508del-CFTR cells with a combination of CFTR modulators (VX-661+VX-445). Viral load was evaluated by real-time RT-PCR in both supernatant and cell extracts, and ACE-2 expression was analyzed by both western blotting and flow cytometry. SARS-CoV-2 replication was reduced in CFTR-modified bronchial cells compared with wild-type cell lines. No major difference in ACE-2 expression was detected before infection between wild-type and CFTR-modified cells, while a higher expression in wild-type compared to CFTR-modified cells was detectable at 72 h post-infection. Furthermore, inhibition of CFTR channel function elicited significant inhibition of viral replication in cells with wt-CFTR, and correction of CFTR function in F508del-CFTR cells increased the release of SARS-CoV-2 viral particles. Our study provides evidence that CFTR expression/function is involved in the regulation of SARS-CoV-2 replication, thus providing novel insights into the role of CFTR in SARS-CoV-2 infection and the development of therapeutic strategies for COVID-19.

Progressive multifocal leukoencephalopathy in an HIV patient receiving successful long-term HAART.

Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immunosuppression and described mainly in highly active antiretroviral therapy (HAART)-naïve patients with a low lymphocyte CD4+ count. In the last years, some cases of PML have been described in HIV patients with a higher CD4+ count shortly after initiation of HAART and in association with the immune reconstitution inflammatory syndrome (IRIS). We report on a rare case of PML, not IRIS associated, that occurred in a HIV-positive patient with a lymphocyte CD4+ count greater than 700/µl and with an undetectable HIV viral load resulting from a long-term HAART. We describe the pathological and the ultrastructural features of the brain lesion. This case confirms that a severe immunosuppression or an IRIS is not required for the development of PML in HIV positives. The diagnosis of PML should always be considered in patients with consistent neurological symptoms, even with a high lymphocyte CD4+ level and a full viral suppression resulting from a long-term HAART.

Assessment of SARS-CoV-2 IgG and IgM antibody detection with a lateral flow immunoassay test.

The dramatic impact of SARS-CoV-2 infection on the worldwide public health has elicited the rapid assessment of molecular and serological diagnostic methods. Notwithstanding the diagnosis of SARS-CoV-2 infection is based on molecular biology approaches including multiplex or singleplex real time RT-PCR, there is a real need for affordable and rapid serological methods to support diagnostics, and surveillance of infection spreading. In this study, we performed a diagnostic accuracy analysis of COVID-19 IgG/IgM rapid test cassette lateral flow immunoassay test (LFIA) assay. To do so, we analyzed different cohorts of blood samples obtained from 151 SARS-CoV-2 RT-PCR assay positive patients (group 1) and 51 SARS-CoV-2 RT-PCR assay negative patients (group 2) in terms of sensitivity, specificity, PPV, NPV and likelihood ratios. In addition, we challenged LFIA with plasma from 99 patients stored during 2015-2017 period. Our results showed that this LFIA detected SARS-CoV-2 IgM and/or IgG in 103 out of 151 (68.21%) samples of group 1, whereas no IgM and/or IgG detection was displayed both in the group 2 and in pre-pandemic samples. Interestingly, IgM and/or IgG positivity was detected in 86 out of 94 (91.49%) group 1 samples collected after 10 days from symptoms onset whereas only 17 out of 57 of group 1 samples obtained before day 10 were positive to SARS-CoV-2 specific antibodies. We also compared the performance of this LFIA test with respect to other four different LFIA assays in 40 serum samples from multiplex RT-PCR positive individuals. Within the limits of the study size, the results demonstrated that COVID-19 IgG/IgM rapid test cassette LFIA assay displayed valid performance in IgM and IgG detection when compared with the other four LFIA assays. Hence, this approach might be considered as an alternative point-of-care procedure for SARS-CoV-2 serological investigation.

Cross-Immunization Against Respiratory Coronaviruses May Protect Children From SARS-CoV2: More Than a Simple Hypothesis?

In January 2020, a new coronavirus was identified as responsible for a pandemic acute respiratory syndrome. The virus demonstrated a high infectious capability and not-neglectable mortality in humans. However, similarly to previous SARS and MERS, the new disease COVID-19 caused by SARS-CoV-2 seemed to relatively spare children and younger adults. Some hypotheses have been proposed to explain the phenomenon, including lower ACE2 expression in children, cross-immunization from measles/rubella/mumps and BCG-vaccination, as well as the integrity of respiratory mucosa. Herein, we hypothesize that an additional mechanism might contribute to children's relative protection from SARS-CoV-2, the cross-immunization conferred by previous exposures to other common respiratory coronaviruses. To support our hypothesis, we show a statistically significant similarity in genomic and protein sequences, including epitopes for B- and T-cell immunity, of SARS-CoV-2 and the other beta coronaviruses. Since these coronaviruses are highly diffused across pediatric populations, cross-reactive immunity might reasonably induce an at least partial protection from SARS-CoV-2 in children.

[Efficacy and safety of TAM-sparing antiretroviral regimens in naïve HIV-positive patients]. / Efficacia e sicurezza dei regimi TAM-sparing in pazienti naïve con infezione da HIV.

To assess the potency, efficacy and toxicity of abacavir/lamivudine (ABC/3TC) versus tenfovir/emcitrabine (TDF/FTC) with efavirenz (EFV) in naive patients with HIV infection a prospective observational study was carried out to evaluate immunovirological parameters every three months and metabolic parameters every six months. In all, 21 patients were enrolled (10 on ABC/3TC and 11 on TDF/FTC). Fisher's test revealed no statistically significant difference between the two arms in terms of immunological recovery and control of viral replication. For metabolic parameters at week 48 no statistically significant differences were noted between the two arms. The two ABC/3TC and TDF/FTC backbones showed the same potency; ABC had a more negative impact on metabolic parameters without statistical power.

[Principles and application protocols in the treatment of intra-abdominal infections]. / Terapia: principi e protocolli applicativi per il trattamento delle infezioni intraddominali.

Antimicrobial therapy of intra-abdominal infection should consider its aetiology, which is generally polymicrobial, and its location with the aim of selecting the most suitable antimicrobial agents not only according to its spectrum but also to its pharmacokinetics profile Currently, both monotherapy and association therapy can be used, thanks the availability of newer drugs characterized by a wide range of antimicrobial activity both against aerobes and anaerobes. Antibiotic choice and duration therapy vary also according to the infection severity .

Multidrug-resistant Combined Infections in a Liver Transplanted Patient: Case Report.

We report a case of successfully treated multiple liver abscesses in a liver-transplanted patient, sustained by combined multidrug-resistant infections. Two months after a liver transplant, a computed tomography scan revealed the presence of multiple abscesses in the liver graft. Blood cultures and abscessual liver fluid were both positive for acquired colistin- and carbapenem- resistant Klebsiella pneumoniae and an extended-spectrum of beta-lactamases-producing Enterobacter aerogenes. The treatment strategy consisted of different prolonged antimicrobial combinations and draining of the abscesses with complete recovery of the liver lesions.