Clinical evaluation of guidelines and therapeutic approaches in multi drug-resistant urinary tract infections

Antibiotic resistance represents a real health emergency worldwide, mostly due to the lack of new antibiotics active against multidrug-resistant Enterobacteriaceae. Considering the global epidemiological situation in several infections, including urinary tract infections (UTIs), some antibiotics, such as fluoroquinolones and trimethoprim/sulphamethoxazole, can no longer be used for empiric treatment due to high resistance rates. However, some old antibiotics maintain high microbiological activity against UTI pathogens: according to many recent guidelines, fosfomycin trometamol, nitrofurantoin and pivmecillinam are recommended for the first-line treatment of uncomplicated UTIs. This article provides an overview of the therapeutic management of UTIs, especially uncomplicated and recurrent cystitis, as well as complicated UTIs such as catheter-related UTIs, and UTIs in males, post-menopausal women and diabetic patients, based on the main international guidelines

Anti-SARS-CoV-2 Receptor-Binding Domain Total Antibodies Response in Seropositive and Seronegative Healthcare Workers Undergoing COVID-19 mRNA BNT162b2 Vaccination

Background: This study monitored total anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) RBD (receptor-binding domain) antibodies levels in a large population of healthcare workers undergoing mRNA COVID-19 vaccination. Methods. The study population consisted of employees of Pederzoli Hospital of Peschiera del Garda (Verona, Italy), who underwent voluntary vaccination with two doses of COVID-19 mRNA BNT162b2 (Comirnaty; Pfizer Inc). Venous blood was drawn immediately before the first vaccine dose, as well as 21 days (immediately before second vaccine dose) and 50 days afterwards. Humoral response was assessed with Roche Elecsys Anti-SARS-CoV-2 S total antibodies, on Roche Cobas 6000 (Roche Diagnostics). Results: The final study population consisted of 925 subjects (mean age, 44 \ub1 13 years; 457 women), 206 (22.3%) anti-SARS-CoV-2 baseline seropositive. The increase of total anti-SARS-CoV-2 RBD antibodies levels 21 days after the first vaccine dose was ~3 orders of magnitude higher in seropositive than in seronegative individuals (11782 vs. 42 U/mL; p < 0.001). Total anti-SARS-CoV-2 RBD antibodies levels further increased by over 30-fold after the second vaccine dose in baseline seronegative subjects, while such increase was only ~1.3-fold in baseline seropositive subjects. In multivariate analysis, total anti-SARS-CoV-2 RBD antibodies level was inversely associated with age after both vaccine doses and male sex after the second vaccine dose in baseline seronegative subjects, while baseline antibodies value significantly predicted immune response after both vaccine doses in baseline seropositive recipients. Conclusion: Significant difference exists in post-mRNA COVID-19 vaccine immune response in baseline seronegative and seropositive subjects, which seems dependent on age and sex in seronegative subjects, as well as on baseline anti-SARS-CoV-2 antibodies level in seropositive patients

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria

Clinical management of severe infections caused by carbapenem-resistant Gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations.

OBJECTIVES: Optimal treatment of carbapenem-resistant Gram-negative (CR-GNB) infections is uncertain due to the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. METHODS: A 36-items-questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball-sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. RESULTS: 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in High-Income-Countries vs 59% (194/283) in Upper-Medium-Income-Countries and 30% (118/196) in Lower-Middle-Income-Countries/Lower-Income-Countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of 'combination therapy' with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) of in vitro-synergism. CONCLUSIONS: Management of CR-GNB infections is far from being standardized. Strategic public health focussed randomised controlled trials are urgently required to inform evidence-based treatment guidelines

Clinical assessment of the Roche SARS-CoV-2 rapid antigen test

Objectives: Novel point-of-care antigen assays present a promising opportunity for rapid screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. The purpose of this study was the clinical assessment of the new Roche SARS-CoV-2 Rapid Antigen Test. Methods: The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test was evaluated vs. a reverse transcription polymerase chain reaction (RT-PCR) laboratory-based assay (Seegene AllplexTM2019-nCoV) in nasopharyngeal swabs collected from a series of consecutive patients referred for SARS-CoV-2 diagnostics to the Pederzoli Hospital (Peschiera del Garda, Verona, Italy) over a 2-week period. Results: The final study population consisted of 321 consecutive patients (mean age, 46 years and IQR, 32-56 years; 181 women, 56.4%), with 149/321 (46.4%) positive for SARS-CoV-2 RNA via the Seegene AllplexTM2019-nCoV Assay, and 109/321 (34.0%) positive with Roche SARS-CoV-2 Rapid Antigen Test, respectively. The overall accuracy of Roche SARS-CoV-2 Rapid Antigen Test compared to molecular testing was 86.9%, with 72.5% sensitivity and 99.4% specificity. Progressive decline in performance was observed as cycle threshold (Ct) values of different SARS-CoV-2 gene targets increased. The sensitivity was found to range between 97-100% in clinical samples with Ct values <25, between 50-81% in those with Ct values between 25 and <30, but low as 12-18% in samples with Ct values between 30 and <37. Conclusions: The clinical performance of Roche SARS-CoV-2 Rapid Antigen Test is excellent in nasopharyngeal swabs with Ct values <25, which makes it a reliable screening test in patients with high viral load. However, mass community screening would require the use of more sensitive techniques

Efficacy and safety of abacavir/lamivudine with raltegravir in treatment-experienced and treatment-na\uefve patients with HIV-1 infection: an observational, retrospective, multi-centre study

Raltegravir (RAL) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults living with human immunodeficiency virus (HIV), due to its high virological efficacy and good tolerability profile. To date, limited data are available on the use of RAL with abacavir/lamivudine (ABC/3TC). We investigated retrospectively 62 HIV-1 infected patients managed by three Italian Infectious Diseases Outpatient Departments, including 57 treatment-experienced patients and 5 treatment-na\uefve patients, treated with ABC/3TC plus RAL. In all five na\uefve patients (100%), virological suppression was achieved and maintained , while 55 experienced patients (96.5%) maintained viral suppression at the most recent review. In the treatment-experienced patients, we observed a significant decrease in triglyceride levels (p\u2009<\u20090.01), while liver transaminases, renal function and cholesterol levels remained substantially stable. In the 34 treatment-experienced patients who switched from a protease inhibitor (PI)-based regimen, we observed a significant improvement of total cholesterol (p=0.03) and triglyceride (p\u2009<\u20090.01) levels. No significant alterations were found on renal and liver function and serum lipid profile of treatment-na\uefve patients. Despite the small number of participants, results support the efficacy and safety of ABC/3TC plus RAL, either in treatment-na\uefve or treatment-experienced patients

Monoclonal gammopathy in SARS-CoV-2 infection

A 90-years-old woman, was referred to our center for dyspnea in January 2022 after testing positive for SARS-CoV-2 infection. The patient completed the COVID 19 vaccination cycle (I and II dose) in October 2021. At the time of hospital admission, chest high resolution computed tomography (HRCT) revealed bilateral ground-glass opacities compatible with interstitial pneumonia. Blood tests revealed abnormal values of lymphocytes (0.7×109/L, r.i. 1.5-4.5), iron (33 µg/dL, r.i. 50-145) C reactive protein (CRP; 28.1 mg/L, r.v. &lt;5.0) and erythrocyte sedimentation rate (ESR; 79 mm/h, r.v. &lt;37). Two weeks after hospital discharge, an unprecedented alteration of the electrophoretic pattern was found during routine serum protein electrophoresis (SPEP), showing a monoclonal peak in the γ region. The patient had no previous evidence of monoclonal gammopathy on previous exams (SPEP was normal in January 2022). This finding underlines the need to focus more on immune hyperactivation in patients with COVID-19 as well as the prognostic role of these abnormalities for improving patient management

Anti-spike S1 IgA, anti-spike trimeric IgG, and anti-spike RBD IgG response after BNT162b2 COVID-19 mRNA vaccination in healthcare workers

Background: Most studies on immune response after coronavirus disease 2019 (COVID-19) vaccination focused on serum IgG antibodies and cell-mediated immunity, discounting the role of anti-SARS-CoV-2 neutralizing IgA antibodies in preventing viral infection. This study was aimed to quantify serum IgG and IgA neutralizing antibodies after mRNA COVID-19 vaccination in baseline SARS-CoV-2 seronegative healthcare workers. Methods: The study population consisted of 181 SARSCoV-2 seronegative healthcare workers (median age 42 years, 59.7% women), receiving two doses of Pfizer COVID-19 vaccine BNT162b2 (Comirnaty). Serum samples were collected before receiving the first vaccine dose, 21 days (before the second vaccine dose) and 50 days afterwards. We then measured anti-spike trimeric IgG (Liaison XL, DiaSorin), anti-spike receptor binding domain (RBD) IgG (Access 2, Beckman Coulter) and anti-spike S1 subunit IgA (ELISA, Euroimmun). Results were presented as median and interquartile range (IQR). Results: Vaccine administration elicited all anti-SARS-CoV-2 antibodies measured. Thirty days after the second vaccine dose, 100% positivization occurred for anti-spike trimeric IgG and anti-spike RBD IgG, whilst 1.7% subjects remained anti-spike S1 IgA negative. The overall increase of antibodies level ratio over baseline after the second vaccine dose was 576.1 (IQR, 360.7–867.8) for anti-spike trimeric IgG, 1426.0 (IQR, 742.0–2698.6) for anti-spike RBD IgG, and 20.2 (IQR, 12.5–32.1) for anti-spike S1 IgA. Significant inverse association was found between age and overall increase of anti-spike trimeric IgG (r=-0.24; p=0.001) and anti-spike S1 IgA (r=-0.16; p=0.028), but not with anti-spike RBD IgG (r=-0.05; p=0.497). Conclusions: mRNA COVID-19 vaccination elicits sustained serum levels of anti-spike trimeric IgG and anti-spike RBD IgG, while also modestly but significantly increasing those of anti-spike S1 IgA

The role of combination therapy in the treatment of severe infections caused by carbapenem resistant gram-negatives: a systematic review of clinical studies

Abstract Background Effective treatment of sepsis due to carbapenem-resistant Gram-negative bacteria (CR-GNB) remains a challenge for clinicians worldwide. In recent years, the combination of antibiotics has become the preferred treatment strategy for CR-GNB infection. However, robust evidence to support this approach is lacking. This systematic review aimed at critically evaluating all available antibiotic options for CR-GNB sepsis with particular focus on combination. Methods We systematically searched published literature from January 1945 until December 2018 for observational comparative and non-comparative studies and randomized trials examining any antibiotic option for CR-GNB. Studies were included if reporting microbiologically-confirmed infection caused by Acinetobacter baumannii, Enterobacteriaceae/Klebsiella spp., or Pseudomonas aeruginosa, reporting at least one of the study outcomes, and definitive antibiotic treatment. Carbapenem-resistance was defined as phenotypically-detected in vitro resistance to at least one of the following carbapenems: doripenem, ertapenem, imipenem, meropenem. Each antibiotic regimen was classified as “defined” when at least the molecular class(es) composing the regimen was detailed. Primary outcomes were 30-day and attributable mortality. Bayesian network meta-analysis (NMA) approach was selected for quantitative synthesis to explore feasibility of pooling data on antibiotic regimens. Results A total of 6306 records were retrieved and 134 studies including 11,546 patients were included: 54 studies were on Acinetobacter, 52 on Enterobacteriaceae/Klebsiella, 21 on mixed Gram-negative, and 7 on Pseudomonas. Nine (7%) were RCTs; 19 prospective cohorts (14%), 89 (66%) retrospective, and 17 (13%) case series. Forty-one studies (31%) were multicentric. Qualitative synthesis showed an heterogeneous and scattered reporting of key-clinical and microbiological variables across studies. Ninety-two distinct antibiotic regimens were identified with 47 of them (51%, 5863 patients) not reporting any details on numbers, type, dosage and in vitro activity of the included antibiotic molecules. The NMAs could not be performed for any of the selected outcome given the presence of too many disconnected components. Conclusion The existing evidence is insufficient to allowing for the formulation of any evidence-based therapeutic recommendation for CR-GNB sepsis. Future studies must provide a standardized definition of antibiotic regimen to drive recommendations for using combination of antibiotics that can be reliably applied to clinical practice

Assessment of humoral and cellular immunity after bivalent BNT162b2 vaccination and potential association with reactogenicity

Objectives: This study investigated the feasibility and clinical value of using a novel, automated and high-throughput SARS-CoV-2 Interferon Gamma Release Assay (IGRA), combined with total anti-SARS-CoV-2 antibodies assessment, for evaluating the immune response after bivalent BNT162b2 vaccination. Methods: A cohort of healthcare workers, who already underwent primary vaccination and boosting with monovalent BNT162b2 vaccine, received a booster dose of the new BNT162b2 bivalent formulation. Blood samples were taken immediately before vaccination (T0) and 1 month afterwards (T1). Humoral and cellular immunity were assayed with Roche Elecsys Anti-SARS-CoV-2 and Roche Elecsys IGRA SARS-CoV-2, respectively. Results: The study population consisted of 51 subjects (median age: 43 years; 51% females). Total anti-SARS-CoV-2 antibodies and IGRA SARS-CoV-2 values increased at T1 from 9,050 to 25,000 BAU/mL (p&lt;0.001), and from 0.44 to 0.78 IU/mL (p=0.385), accounting for median increase of 2.0 and 1.6 folds, respectively. Increased T1 values of total anti-SARS-CoV-2 antibodies and IGRA SARS-CoV-2 were recorded in 100% and 68.6% subjects, respectively. In those with baseline values below the median, post-vaccine levels displayed larger increases of 3.3 and 5.1 folds for anti-SARS-CoV-2 total antibodies and IGRA SARS-CoV-2, respectively. The variation of total anti-SARS-CoV-2 antibodies was inversely associated with their T0 values (r=-0.97; p&lt;0.001), whilst that of IGRA SARS-CoV-2 was inversely associated with its T0 value (r=-0.58; p&lt;0.001). No other signifcant associations were found with demographical or clinical variables, including side effects. Conclusions: The bivalent BNT162b2 vaccine booster enhances humoral and cellular immunity against SARS-CoV-2, especially in recipients with lower baseline biological protection