Personalized infection prevention and control: a concept whose time has arrived.

Personalized medicine has been progressively implemented in several diagnostic and therapeutic patients' algorithms, based on the common assumption that tailoring interventions, practices, and/or therapies to individual patients' clinical, biological, epidemiological, and genetic characteristics would optimize their effectiveness and reduce adverse effects. The potential benefit of the precision medicine approach has been recently considered for possible implementation in the field of infection prevention and control. The commentary explores available evidence and assesses possible future scenarios where, through advanced modeling approaches, we would be able to provide personalized prediction algorithms identifying at-risk patients who deserve the implementation of tailored preventive measures.

Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort.

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials. Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

Exploring the Use of Monoclonal Antibodies and Antiviral Therapies for Early Treatment of COVID-19 Outpatients in a Real-World Setting: A Nationwide Study from England and Italy.

BACKGROUND: Real-world data on early treatment of coronavirus disease 2019 (COVID-19) outpatients with newly approved therapies are sparse. AIM: To explore the pattern of use of monoclonal antibodies (mAbs)/antiviral therapies approved for early COVID-19 treatment in non-hospitalized patients from England and Italy from December 2021 to October 2022. METHODS: Public national dashboards on weekly mAb/antiviral use and/or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnoses from the Italian Medicines Agency, the Italian National Institute of Health, National Health Service in England and the UK Government were explored. Prevalence of antiviral use in outpatients during the entire study period and every two weeks was calculated, as a whole and by class and compounds. An interrupted time-series (ITS) analysis was carried out to assess the impact of predominant SARS-CoV-2 variants over time on the prevalence of use of mAbs/antivirals in England and Italy. RESULTS: Overall, 77,469 and 195,604 doses of mAbs/antivirals were respectively administered to a total of 10,630,903 (7.3 per 1000) and 18,168,365 (10.8 per 1000) patients diagnosed with SARS-CoV-2 infection in England and Italy. Prevalence of use every two weeks increased from 0.07% to 3.1% in England and 0.9% to 2.3% in Italy during the study period. Regarding individual compounds, sotrovimab (prevalence of use, 1.6%) and nirmatrelvir/ritonavir (1.6%) in England, and nirmatrelvir/ritonavir (1.7%) and molnupiravir (0.5%) in Italy, reported the highest prevalence during a 2-week period. In the ITS analysis, the transition from Delta to Omicron variant predominance was associated with a significant increase in the use of sotrovimab, molnupiravir, remdesivir and nirmatrelvir/ritonavir in both England and Italy, with a reduction of other marketed mAbs. The extent of the increase was higher in England than in Italy for all these drugs except for nirmatrelvir/ritonavir. CONCLUSIONS: In this dual nationwide study, the prevalence of use of mAbs/antivirals against SARS-CoV-2 for early outpatients' treatment increased slowly up to 2.0-3.0% of all patients diagnosed with SARS-CoV-2 infection in both England and Italy from December 2021 to October 2022. The trend of individual drug use varied in relation to predominant SARS-CoV-2 variants with some differences across countries. In line with scientific societies' guidelines, nirmatrelvir/ritonavir was the most frequently prescribed antiviral in both countries in the most recent period.

Mycoplasma genitalium antibiotic resistance-associated mutations in genital and extragenital samples from men-who-have-sex-with-men attending a STI clinic in Verona, Italy.

Background: Mycoplasma genitalium (MG) is one of the most warning emerging sexually transmitted pathogens also due to its ability in developing resistance to antibiotics. MG causes different conditions ranging from asymptomatic infections to acute mucous inflammation. Resistance-guided therapy has demonstrated the best cure rates and macrolide resistance testing is recommended in many international guidelines. However, diagnostic and resistance testing can only be based on molecular methods, and the gap between genotypic resistance and microbiological clearance has not been fully evaluated yet. This study aims at finding mutations associated with MG antibiotic resistance and investigating the relationship with microbiological clearance amongst MSM. Methods: From 2017 to 2021, genital (urine) and extragenital (pharyngeal and anorectal swabs) biological specimens were provided by men-who-have-sex-with-men (MSM) attending the STI clinic of the Infectious Disease Unit at the Verona University Hospital, Verona, Italy. A total of 1040 MSM were evaluated and 107 samples from 96 subjects resulted positive for MG. Among the MG-positive samples, all those available for further analysis (n=47) were considered for detection of mutations known to be associated with macrolide and quinolone resistance. 23S rRNA, gyrA and parC genes were analyzed by Sanger sequencing and Allplex™ MG and AziR Assay (Seegene). Results: A total of 96/1040 (9.2%) subjects tested positive for MG in at least one anatomical site. MG was detected in 107 specimens: 33 urine samples, 72 rectal swabs and 2 pharyngeal swabs. Among them, 47 samples from 42 MSM were available for investigating the presence of mutations associated with macrolide and quinolone resistance: 30/47 (63.8%) showed mutations in 23S rRNA while 10/47 (21.3%) in parC or gyrA genes. All patients with positive Test of Cure (ToC) after first-line treatment with azithromycin (n=15) were infected with 23S rRNA-mutated MG strains. All patients undergoing second-line moxifloxacin treatment (n=13) resulted negative at ToC, even those carrying MG strains with mutations in parC gene (n=6). Conclusion: Our observations confirm that mutations in 23S rRNA gene are associated with azithromycin treatment failure and that mutations in parC gene alone are not always associated with phenotypic resistance to moxifloxacin. This reinforces the importance of macrolide resistance testing to guide the treatment and reduce antibiotic pressure on MG strains.

Diagnostic Accuracy of a Rapid SARS-CoV-2 Antigen Test Among People Experiencing Homelessness: A Prospective Cohort and Implementation Study.

INTRODUCTION: Detection strategies in vulnerable populations such as people experiencing homelessness (PEH) need to be explored to promptly recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks. This study investigated the diagnostic accuracy of a rapid SARS-CoV-2 Ag test in PEH during two pandemic waves compared with gold standard real-time multiplex reverse transcription polymerase chain reaction (rtRT-PCR). METHODS: All PEH ≥ 18 years requesting residence at the available shelters in Verona, Italy, across two cold-weather emergency periods (November 2020-May 2021 and December 2021-April 2022) were prospectively screened for SARS-CoV-2 infection by means of a naso-pharyingeal swab. A lateral flow immunochromatographic assay (Biocredit® COVID-19 Ag) was used as antigen-detecting rapid diagnostic test (Ag-RDT). The rtRT-PCR was performed with Allplex™ SARS-CoV-2 assay kit (Seegene). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated as measures for diagnostic accuracy. RESULTS: Overall, 503 participants were enrolled during the two intervention periods for a total of 732 paired swabs collected: 541 swabs in the first period and 191 in the second. No significant differences in demographic and infection-related characteristics were observed in tested subjects in the study periods, except for the rate of previous infection (0.8% versus 8%; p < 0.001) and vaccination (6% versus 73%; p < 0.001). The prevalence of SARS-CoV-2 in the cohort was 8% (58/732 swabs positive with rtRT-PCR). Seventeen swabs were collected from symptomatic patients (7%). Among them, the concordance between rtRT-PCR and Ag-RDT was 100%, 7 (41.2%) positive and 10 negative pairs. The overall sensitivity of Ag-RDT was 63.8% (95% CI 60.3-67.3) and specificity was 99.8% (95% CI 99.6-100). PPV and NPV were 97.5% and 96.8%, respectively. Sensitivity and specificity did not change substantially across the two periods (65.1% and 99.8% in 2020-2021 vs. 60% and 100% in 2021-2022). CONCLUSIONS: A periodic Ag-RDT-based screening approach for PEH at point of care could guide preventive measures, including prompt isolation, without referral to hospital-based laboratories for molecular test confirmation in case of positive detection even in individuals asymptomatic for COVID-19. This could help reduce the risk of outbreaks in shelter facilities.

Host immunological responses facilitate development of SARS-CoV-2 mutations in patients receiving monoclonal antibody treatments.

BackgroundThe role of host immunity in emergence of evasive SARS-CoV-2 Spike mutations under therapeutic monoclonal antibody (mAb) pressure remains to be explored.MethodsIn a prospective, observational, monocentric ORCHESTRA cohort study, conducted between March 2021 and November 2022, mild-to-moderately ill COVID-19 patients (n = 204) receiving bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were longitudinally studied over 28 days for viral loads, de novo Spike mutations, mAb kinetics, seroneutralization against infecting variants of concern, and T cell immunity. Additionally, a machine learning-based circulating immune-related biomarker (CIB) profile predictive of evasive Spike mutations was constructed and confirmed in an independent data set (n = 19) that included patients receiving sotrovimab or tixagevimab/cilgavimab.ResultsPatients treated with various mAbs developed evasive Spike mutations with remarkable speed and high specificity to the targeted mAb-binding sites. Immunocompromised patients receiving mAb therapy not only continued to display significantly higher viral loads, but also showed higher likelihood of developing de novo Spike mutations. Development of escape mutants also strongly correlated with neutralizing capacity of the therapeutic mAbs and T cell immunity, suggesting immune pressure as an important driver of escape mutations. Lastly, we showed that an antiinflammatory and healing-promoting host milieu facilitates Spike mutations, where 4 CIBs identified patients at high risk of developing escape mutations against therapeutic mAbs with high accuracy.ConclusionsOur data demonstrate that host-driven immune and nonimmune responses are essential for development of mutant SARS-CoV-2. These data also support point-of-care decision making in reducing the risk of mAb treatment failure and improving mitigation strategies for possible dissemination of escape SARS-CoV-2 mutants.FundingThe ORCHESTRA project/European Union's Horizon 2020 research and innovation program.

Exploratory data on the clinical efficacy of monoclonal antibodies against SARS-CoV-2 Omicron variant of concern.

Background: Recent in-vitro data have shown that the activity of monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies according to the variant of concern (VOC). No studies have compared the clinical efficacy of different mAbs against Omicron VOC. Methods: The MANTICO trial is a non-inferiority randomised controlled trial comparing the clinical efficacy of early treatments with bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab in outpatients aged 50 or older with mild-to-moderate SARS-CoV-2 infection. As the patient enrolment was interrupted for possible futility after the onset of the Omicron wave, the analysis was performed according to the SARS-CoV-2 VOC. The primary outcome was coronavirus disease 2019 (COVID-19) progression (hospitalisation, need of supplemental oxygen therapy, or death through day 14). Secondary outcomes included the time to symptom resolution, assessed using the product-limit method. Kaplan-Meier estimator and Cox proportional hazard model were used to assess the association with predictors. Log rank test was used to compare survival functions. Results: Overall, 319 patients were included. Among 141 patients infected with Delta, no COVID-19 progression was recorded, and the time to symptom resolution did not differ significantly between treatment groups (Log-rank Chi-square 0.22, p 0.90). Among 170 patients infected with Omicron (80.6% BA.1 and 19.4% BA.1.1), two COVID-19 progressions were recorded, both in the bamlanivimab/etesevimab group, and the median time to symptom resolution was 5 days shorter in the sotrovimab group compared with the bamlanivimab/etesevimab and casirivimab/imdevimab groups (HR 0.53 and HR 0.45, 95% CI 0.36-0.77 and 95% CI 0.30-0.67, p<0.01). Conclusions: Our data suggest that, among adult outpatients with mild-to-moderate SARS-CoV-2 infection due to Omicron BA.1 and BA.1.1, early treatment with sotrovimab reduces the time to recovery compared with casirivimab/imdevimab and bamlanivimab/etesevimab. In the same population, early treatment with casirivimab/imdevimab may maintain a role in preventing COVID-19 progression. The generalisability of trial results is substantially limited by the early discontinuation of the trial and firm conclusions cannot be drawn. Funding: This trial was funded by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA). The VOC identification was funded by the ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic) project, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement number 101016167. Clinical trial number: NCT05205759.

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections: The ORCHESTRA Prospective Cohort Study.

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p < 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05-0.27, p < 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08-5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03-1.08, p < 0.001), and male gender (aOR:1.97, 95%CI: 1.04-3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p < 0.001) in immunocompromised and elderly patients >75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.

Clinical efficacy of different monoclonal antibody regimens among non-hospitalised patients with mild to moderate COVID-19 at high risk for disease progression: a prospective cohort study.

This study aimed to compare the clinical progression of COVID-19 in high-risk outpatients treated with the monoclonal antibodies (mAb) bamlanivimab, bamlanivimab-etesevimab and casirivimab-imdevimab. This is an observational, multi-centre, prospective study conducted from 18 March to 15 July 2021 in eight Italian tertiary-care hospitals including mild-to-moderate COVID-19 outpatients receiving bamlanivimab (700 mg), bamlanivimab-etesevimab (700-1400 mg) or casirivimab-imdevimab (1200-1200 mg). All patients were at high risk of COVID-19 progression according to Italian Medicines Agency definitions. In a patient subgroup, SARS-CoV-2 variant and anti-SARS-CoV-2 serology were analysed at baseline. Factors associated with 28-day all-cause hospitalisation were identified using multivariable multilevel logistic regression (MMLR) and summarised with adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 635 outpatients received mAb: 161 (25.4%) bamlanivimab, 396 (62.4%) bamlanivimab-etesevimab and 78 (12.2%) casirivimab-imdevimab. Ninety-five (15%) patients received full or partial SARS-CoV-2 vaccination. The B.1.1.7 (Alpha) variant was detected in 99% of patients. Baseline serology showed no significant differences among the three mAb regimen groups. Twenty-eight-day all-cause hospitalisation was 11.3%, with a significantly higher proportion (p 0.001) in the bamlanivimab group (18.6%), compared to the bamlanivimab-etesevimab (10.1%) and casirivimab-imdevimab (2.6%) groups. On MMLR, aORs for 28-day all-cause hospitalisation were significantly lower in patients receiving bamlanivimab-etesevimab (aOR 0.51, 95% CI 0.30-0.88 p 0.015) and casirivimab-imdevimab (aOR 0.14, 95% CI 0.03-0.61, p 0.009) compared to those receiving bamlanivimab. No patients with a history of vaccination were hospitalised. The study suggests differences in clinical outcomes among the first available mAb regimens for treating high-risk COVID-19 outpatients. Randomised trials are needed to compare efficacy of mAb combination regimens in high-risk populations and according to circulating variants.

A Disseminated Mycobacterium Abscessus Infection in a Patient Affected by Pulmonary Graft versus Host Disease: Case Report with a Revision of Literature.

Mycobacterium abscessus complex, hereinafter Mab, is a taxonomic group of rapidly growing, nontuberculous mycobacteria (NTM). Despite major advances in understanding virulence, pathogenicity and mechanism of antibiotic resistance, Mab remains a significant cause of pulmonary and extra-pulmonary disease. Herein, we describe a disseminated, macrolide-resistant, Mab subspecies abscessus infection occurring in a severely immune-compromised 34-year-old allotransplanted female patient affected by pulmonary chronic graft versus host disease (cGVHD). The infection was characterized by hematogenous spread, and besides lungs, it involved skin, and soft tissues, resulting in a highly debilitating, painful, and finally fatal disease. Our case describes the severe impact of Mab infections in the setting of allogeneic hematopoietic stem cells transplant (alloHSCT) and related complications. It also highlights the unmet need of preventive and surveillance measures together with the urgency of developing effective vaccines and drugs against emerging NTM. The scarce literature regarding Mab infections in alloHSCT patients is also reviewed.

The antimicrobial resistance travel tool, an interactive evidence-based educational tool to limit antimicrobial resistance spread.

BACKGROUND: International travel has been recognized as a risk factor contributing to the spread of antimicrobial resistance (AMR). However, tools focused on AMR in the context of international travel and designed to guide decision-making are limited. We aimed at developing an evidence-based educational tool targeting both healthcare professionals (HCPs) and international travellers to help prevent the spread of AMR. METHODS: A literature review on 12 antimicrobial-resistant bacteria (ARB) listed as critical and high tiers in the WHO Pathogen Priority List covering four key areas was carried out: AMR surveillance data; epidemiological studies reporting ARB prevalence data on carriage in returning travellers; guidance documents reporting indications on screening for ARB in returning travellers and recommendations for ARB prevention for the public. The evidence, catalogued at country-level, provided the content for a series of visualizations that allow assessment of the risk of AMR acquisition through travel. RESULTS: Up to January 2021, the database includes data on: (i) AMR surveillance for 2.018.241 isolates from 86 countries; (ii) ARB prevalence of carriage from 11.679 international travellers and (iii) 15 guidance documents published by major public health agencies. The evidence allowed the development of a consultation scheme for the evaluation of risk factors, prevalence of carriage, proportion and recommendations for screening of AMR. For the public, pre-travel practical measures to minimize the risk of transmission were framed. CONCLUSIONS: This easy-to-use, annually updated, freely accessible AMR travel tool (https://epi-net.eu/travel-tool/overview/), is the first of its kind to be developed. For HCPs, it can provide a valuable resource for teaching and a repository that facilitates a stepwise assessment of the risk of AMR spread and strengthen implementation of optimized infection control measures. Similarly, for travellers, the tool has the potential to raise awareness of AMR and outlines preventive measures that reduce the risk of AMR acquisition and spread.

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 bacteria (CR-GNB) infections is uncertain because of 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-item 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: A total of 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of the 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 versus 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) requiring in vitro synergism. CONCLUSIONS: Management of CR-GNB infections is far from being standardized. Strategic public health focused randomized controlled trials are urgently required to inform evidence-based treatment guidelines.

Assessment of COVID-19 progression on day 5 from symptoms onset.

BACKGROUND: A major limitation of current predictive prognostic models in patients with COVID-19 is the heterogeneity of population in terms of disease stage and duration. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression in hospitalized patients with COVID-19. METHODS: Prospective cohort study on hospitalized adult patients with COVID-19. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day 5, 10, and 15 from symptoms onset. COVID-19 progression was defined as in-hospital death and/or transfer to ICU and/or respiratory failure (PaO2/FiO2 ratio < 200) within day-11 of symptoms onset. Multivariate regression was performed to identify predictors of COVID-19 progression. A model assessed at day-5 of symptoms onset including male sex, age > 65 years, dyspnoea, cardiovascular disease, and at least three abnormal laboratory parameters among CRP (> 80 U/L), ALT (> 40 U/L), NLR (> 4.5), LDH (> 250 U/L), and CK (> 80 U/L) was proposed. Discrimination power was assessed by computing area under the receiver operating characteristic (AUC) values. RESULTS: A total of 235 patients with COVID-19 were prospectively included in a 3-month period. The majority of patients were male (148, 63%) and the mean age was 71 (SD 15.9). One hundred and ninety patients (81%) suffered from at least one underlying illness, most frequently cardiovascular disease (47%), neurological/psychiatric disorders (35%), and diabetes (21%). Among them 88 (37%) experienced COVID-19 progression. The proposed model showed an AUC of 0.73 (95% CI 0.66-0.81) for predicting disease progression by day-11. CONCLUSION: An easy-to-use panel of laboratory/clinical parameters computed at day-5 of symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 of symptoms onset could facilitate clinicians' decision making. The model can also play a role as a tool to increase homogeneity of population in clinical trials on COVID-19 treatment in hospitalized patients.

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

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.

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, 0.35 < ES < 0.75; 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.

Impact of implementing a non-restrictive antibiotic stewardship program in an emergency department: a four-year quasi-experimental prospective study.

Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS), Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients' group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients' group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.

In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol.

OBJECTIVE: There is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria. METHODS AND ANALYSIS: This protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE's risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias. DISSEMINATION: This systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104).

Gross national income and antibiotic resistance in invasive isolates: analysis of the top-ranked antibiotic-resistant bacteria on the 2017 WHO priority list.

OBJECTIVES: To assess the association between country income status and national prevalence of invasive infections caused by the top-ranked bacteria on the WHO priority list: carbapenem-resistant (CR) Acinetobacter spp., Klebsiella spp. and Pseudomonas aeruginosa; third-generation cephalosporin-resistant (3GCR) Escherichia coli and Klebsiella spp.; and MRSA and vancomycin-resistant Enterococcus faecium (VR E. faecium). METHODS: Active surveillance systems providing yearly prevalence data from 2012 onwards for the selected bacteria were included. The gross national income (GNI) per capita was used as the indicator for income status of each country and was log transformed to account for non-linearity. The association between antibiotic prevalence data and GNI per capita was investigated individually for each bacterium through linear regression. RESULTS: Surveillance data were available from 67 countries: 38 (57%) were high income, 16 (24%) upper-middle income, 11 (16%) lower-middle income and two (3%) low income countries. The regression showed significant inverse association (P<0.0001) between resistance prevalence of invasive infections and GNI per capita. The highest rate of increase per unit decrease in log GNI per capita was observed in 3GCR Klebsiella spp. (22.5%, 95% CI 18.2%-26.7%), CR Acinetobacter spp. (19.2% 95% CI 11.3%-27.1%) and 3GCR E. coli (15.3%, 95% CI 11.6%-19.1%). The rate of increase per unit decrease in log GNI per capita was lower in MRSA (9.5%, 95% CI 5.2%-13.7%). CONCLUSIONS: The prevalence of invasive infections caused by the WHO top-ranked antibiotic-resistant bacteria is inversely associated with GNI per capita at the global level. Public health interventions designed to limit the burden of antimicrobial resistance should also consider determinants of poverty and inequality, especially in lower-middle income and low income countries.