How to manage adult patients with malaria in the non-endemic setting.

BACKGROUND: The diagnosis and management of malaria in non-endemic countries presents a continuing challenge. Plasmodium falciparum, which is capable of rapidly inducing severe and life-threatening multiorgan disease, is the species most frequently diagnosed in Europe and North America. OBJECTIVES: To summarise the more relevant diagnostic findings and clinical features of malaria observed in non-endemic settings and to provide an update of the key management decision points using three illustrative clinical scenarios of uncomplicated and severe malaria. SOURCES: The discussion is based on a relevant literature search spanning the last 20 years. Recommendations are based on available clinical guidelines including those of the WHO, observational studies conducted in non-endemic settings, and, when available, extrapolation from randomised studies from malaria-endemic settings. CONTENT: The following topics are covered: diagnosis, including the use of molecular biology; clinical characteristics; management with a specific focus on complicated (severe) and uncomplicated malaria; and areas of resistance to available antimalarial drugs. IMPLICATIONS: Malaria imported to non-endemic settings, especially P. falciparum malaria, is sometimes initially overlooked and the delayed diagnosis is responsible for every year of preventable deaths. This review aims to raise awareness of malaria outside endemic countries and to provide clinicians with a practical guide for efficient diagnosis and targeted therapy for the different species involved.

Mismanagement of SARS-CoV-2 Infection Pre Hospitalisation during the Omicron Era: Antibiotics and Steroids Instead of Early Antivirals.

The aim of this study was to assess the prevalence of inappropriate treatment among hospitalised patients affected by SARS-CoV-2 infection before hospital admission during the Omicron era. This single-centre, retrospective observational study included all the patients hospitalised because of SARS-CoV-2 infection during three periods characterised by the Italian prevalence of an Omicron variant of concern: (1) January-May 2022 (BA.1-BA.2), (2) June-October 2022 (BA.5), and (3) November 2022-March 2023 (BQ.1-XBB). Inappropriate treatment was defined as pre-hospitalisation exposure to antibiotics and/or steroids in the absence of a documented bacterial infection or the need for steroid treatment of an underlying medical condition. A total of 931 subjects were hospitalised: 394 in period 1, 334 in period 2, and 203 in period 3. Of the 157 patients undergoing inappropriate treatment (16.9%), 142 (15.3%) received antibiotics and 52 (5.6%) steroids. The proportion of inappropriately treated patients significantly decreased over time, from 23.1% in period 1 to 11.7% in period 2 and 13.3% in period 3 (p < 0.001), and there was a parallel decrease in antibiotic (p < 0.001) and steroid treatment (p < 0.013). Only 13 subjects (1.4%) received early pre-hospitalisation treatment for SARS-CoV-2. A significant proportion of hospitalised COVID-19 patients were exposed to inappropriate treatment before hospital admission.

Impact of a Bundle of Interventions on Quality-of-Care Indicators for Staphylococcus aureus Bacteraemia: A Single-Centre, Quasi-Experimental, Before-After Study.

Staphylococcus aureus bacteraemia (SAB) is a life-threatening bloodstream infection. Improved adherence to quality-of-care indicators (QCIs) can significantly enhance patient outcomes. This quasi-experimental study evaluated the impact of a bundle of interventions on QCI adherence in adult patients with SAB. Additionally, a molecular rapid diagnostic test (mRDT) for S. aureus and methicillin resistance was introduced during weekdays. We compared pre-intervention (January-December 2022) and post-intervention (May 2023-April 2024) data on QCI adherence and time to appropriate treatment. A total of 56 and 40 SAB episodes were included in the pre- and post-intervention periods, respectively. Full QCI adherence significantly increased from 28.6% to 67.5% in the post-intervention period (p < 0.001). The mRDT diagnosed SAB in eight cases (26.6%), but the time to achieve appropriate target therapy did not improve in the post-intervention period (54 h (IQR 30-74) vs. 72 h (IQR 51-83), p = 0.131). The thirty-day mortality rate was comparable between the two periods (17.9% vs. 12.5%, p = 0.476). This study demonstrates that a bundle of interventions can substantially improve adherence to SAB management QCIs.

Breakthrough Acute HIV Infections among Pre-Exposure Prophylaxis Users with High Adherence: A Narrative Review.

Pre-exposure prophylaxis (PrEP) is a pivotal intervention among HIV prevention strategies. We aimed to narratively revise the topic of HIV acute infection in the setting of PrEP exposure with a focus on diagnostic options, clinical features, and future PrEP perspectives, with a particular focus on users with high adherence to PrEP. We searched the main databases (PubMed, Embase, and Scopus) with the keywords "PrEP" or "Pre-Exposure Prophylaxis" and "HIV" or "PLWH" and "breakthrough" or "acute infection" or "primary infection". We included all randomized clinical trials and non-experimental studies (both case reports and observational studies) ever published. In the present narrative review, we revise the diagnostic challenges related to HIV diagnosis in the setting of PrEP and the clinical characteristics and symptoms of breakthrough infections. We discuss the management of acute HIV infection during PrEP and the new challenges that arise from the use of long-acting drugs for PrEP. Our review underlines that although extremely rare, HIV seroconversions are still possible during PrEP, even in a context of high adherence. Efforts to promptly identify these events must be included in the PrEP follow-up in order to minimize the chance of overlooked HIV breakthrough infections and thus exposure to suboptimal concentrations of antiretrovirals.

Hospital-Based Influenza and Pneumococcal Vaccination for Cancer Patients on Active Treatment and Their Family Members during the COVID-19 Pandemic in Italy: A Single-Center Experience.

In patients with cancer, tumor- and treatment-induced immunosuppression are responsible for a four-fold increase in morbidity and mortality caused by influenza and invasive Streptococcus pneumoniae infections compared to the general population. The main oncology societies strongly recommend vaccination in patients with cancer to prevent these infections. However, vaccine hesitancy is a main concern in this population. The aim of this study was to assess the feasibility of in-hospital vaccination for patients under anticancer treatment and their family members (FMs) against influenza and pneumococcal infections during the COVID-19 pandemic in order to increase vaccine coverage. This was a single-center, prospective, observational study conducted at the Department of Oncology of Luigi Sacco University Hospital (Milan, Italy) between October 2020 and April 2021. The main primary outcome was the incidence of influenza-like illness (ILI) and pneumococcal infections. The main secondary outcome was safety. A total of 341 subjects were enrolled, including 194 patients with cancer and 147 FMs. The incidence of ILI was higher among patients than among FMs (9% vs. 2.7%, OR 3.92, p = 0.02). Moreover, two subjects were diagnosed with pneumococcal pneumonia. The most frequent vaccine-related AEs were pain in the injection site (31%) and fatigue (8.7%). In conclusion, this hospital-based vaccination strategy was feasible during the COVID-19 pandemic, representing a potential model to maximize vaccine coverage during a public health emergency.

Outcomes and Predictors of Mortality in Patients With KPC-Kp Infections Treated With Meropenem Vaborbactam: An Observational Multicenter Study.

Background: Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam. Methods: We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least ≥24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality. Results: The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index ≥ 3, dialysis, concomitant COVID-19, and INCREMENT score ≥ 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy. Conclusions: Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy.

Major Bleeding Events in Hospitalized COVID-19 Patients: A Retrospective Observational Study.

Thromboprophylaxis/anticoagulation treatment is often required in hospitalized COVID-19 patients. We aimed to estimate the prevalence of major bleeding events in hospitalized COVID-19 patients. This was a retrospective observational study including all COVID-19 hospitalized patients ≥18 years of age at one reference center in northern Italy. The crude prevalence (between February 2020-2022) of major bleeding events was estimated as the number of major bleeding episodes divided by patients at risk. Uni- and multivariable Cox models were built to assess factors potentially associated with major bleeding events. Twenty-nine (0.98%) out of 2,945 COVID-19 patients experienced a major bleeding event [prevalence of 0.55% (95%CI 0.37-0.79)], of which five were fatal. Patients who experienced a major bleeding event were older [78 years (72-84 IQR) vs. 67 years (55-78 IQR), p-value < 0.001] and more frequently exposed to anti-aggregating therapy (44.8% vs. 20.0%, p-value 0.002) when compared to those who did not. In the multivariable Cox model, age [per 1 year more AHR 1.05 (CI95% 1.02-1.09)] was independently associated with an increased risk of major bleeding events. A strict monitoring of older hospitalized COVID-19 patients is warranted due to the risk of major bleeding events.

Laryngeal Leishmaniasis: A Neglected, Emerging Disease in Northern Italy.

Leishmaniasis represents an emerging public health issue in Mediterranean countries. The incidence of this condition has progressively risen in Northern Italy due to the growing number of immunocompromised people and probably due to climate changes. We hereby describe a case of relapsing laryngeal leishmaniasis in a female immunocompetent patient, presenting as aspecific chronic laryngitis. She was affected by severe asthma treated by inhaled steroid therapy, likely responsible for the parasite's diffusion through a locus minori resistentiae. The aspecific clinical presentation led to a delayed diagnosis and the lack of guidelines for the treatment caused multiple relapses. Biopsies of laryngeal lesions in the follow-up were performed by operative flexible videolaryngoscopy, thus avoiding general anesthesia and reducing associated healthcare costs. The aim of this report is to underline the diagnostic and therapeutic challenges that patients with this condition face and to present what is, to the best of our knowledge, the first application of prophylactic aerosolized pentamidine for relapsing laryngeal leishmaniasis.

Evaluation of analytical performance of the STANDARDTM M10 MPX/OPX assay for the simultaneous DNA detection and clade attribution of Monkeypox virus.

Monkeypox virus (MPXV) infection confirmation needs reliable polymerase chain reaction (PCR) assays; in addition, viral clade attribution is a key factor in containment measures, considering a more severe syndrome in clade I and the possibility of simultaneous circulation. This study evaluates the performance of all-in-one STANDARD M10 MPX/OPX (SD BIOSENSOR, South Korea - M10). Frozen samples from 205 subjects were selected and stratified according to routine test results (RealStar® Orthopoxvirus PCR Kit 1.0, Altona DIAGNOTICS, Germany - RS; RS-1): in detail, 100 negative skin lesions (SL) and 200 positive samples at the variable stage of infection were analysed. Positive samples were retested with RS (RS-2). Positive and Negative Percent Agreements (PPA, NPA) were calculated. The median (IQR) Ct values of RS and M10 (OPXV target) assays were highly similar. The PPA of M10 compared to RS-1 was 89.5% considering system interpretation, and 96.0% when the operator classified results as positive if any target was detected; NPA was 100%. Comparing the RS-2 run and M10, an overall concordance of 95.3% between assays was found; however, considering operator interpretation, M10 returned more positive results than RS-2. The occurrence of False-Negative results was likely associated with the influence of thawing on low viral concentration; no False-Positive tests were observed. All samples collected at the time of Mpox diagnosis were positive and M10 correctly attributed the clade (West-Africa/II). The M10 MPX/OPX assay demonstrated high reliability in confirming MPXV infection and clade attribution.

The WHO fungal priority pathogens list: a crucial reappraisal to review the prioritisation.

In October, 2022, WHO published the first fungal priority pathogen list, which categorised 19 fungal entities into three priority groups (critical, high, and medium), for prioritisation of research efforts. The final ranking was determined via multiple criteria decision analysis, considering both research and development needs and perceived public health importance. In this Personal View, we discuss the positioning of the fungal pathogens, namely, Mucorales, Candida spp, Histoplasma spp, Coccidioides and Paracoccidioides spp, Fusarium spp, eumycetoma causative agents, Talaromyces marneffei, and Pneumocystis jirovecii, while expressing concerns about potential disparities between the WHO fungal priority pathogen list ranking and the actual disease burden associated with these pathogens. Finally, we propose a revised prioritisation list that also considers the regional disparities in the burden of fungal diseases.

Prognostic Significance of NLR and PLR in COVID-19: A Multi-Cohort Validation Study.

INTRODUCTION: Recent studies have highlighted the prognostic value of easily accessible inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) for predicting severe outcomes in patients affected by Coronavirus disease 2019 (COVID-19). Our study validates NLR and PLR cut-off values from a prior cohort at IRCCS Policlinico San Matteo (OSM) of Pavia, Italy, across two new cohorts from different hospitals. This aims to enhance the generalizability of these prognostic indicators. METHODS: In this retrospective cohort study, conducted at Milan's Ospedale Luigi Sacco (OLS) and IRCCS Ospedale Maggiore Policlinico (OMP) hospitals, we assess the predictive capacity of NLR and PLR for three main outcomes-non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) usage, invasive ventilation (IV), and death-in patients with COVID-19 at admission. For each outcome, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were computed separately for male and female cohorts. Distinct NLR and PLR cut-off values were used for men (7.00, 7.29, 7.00 for NLR; 239.22, 248.00, 250.39 for PLR) and women (6.36, 7.00, 6.28 for NLR; 233.00, 246.45, 241.54 for PLR), retrieved from the first cohort at OSM. RESULTS: A total of 3599 patients were included in our study, 1842 from OLS and 1757 from OMP. OLS and OMP sensitivity values for both NLR and PLR (NLR: 24-67%, PLR: 40-64%) were inferior to specificity values (NLR: 64-76%, PLR: 55-72%). Additionally, PPVs generally remained lower (< 63%), while NPVs consistently surpassed 68% for PLR and 72% for NLR. Finally, both PLR and NLR exhibited consistently higher NPVs for more severe outcomes (> 82%) compared to NPVs for CPAP/NIV. CONCLUSIONS: Consistent findings across diverse patient populations validate the reliability and applicability of NLR and PLR cut-off values. High NPVs emphasize their role in identifying individuals less likely to experience severe outcomes. These markers not only aid in risk stratification but also guide resource allocation in emergencies or limited-resource situations.

First imported case of Candida auris infection in Milan, Italy: genomic characterisation.

PURPOSE: Candida auris, an emerging multidrug-resistant yeast, has been reported worldwide. In Italy, the first case was reported in 2019. We describe the first case of C. auris, imported from Greece, in Milan, using whole genome sequencing to characterise mutations associated with antifungal resistance. CASE PRESENTATION: On October 2022 an 80-year-old Italian man was hospitalised in Greece. In the absence of clinical improvement, the patient was transferred to our hospital, in Italy, where blood culture resulted positive for C. auris. Despite therapy, the patient died of septic shock. In a phylogenetic analysis the genome was assigned to Clade I with strains from Kenya, United Arab Emirates and India. D1/D2 region resulted identical to a Greek strain, as for many other strains from different World regions, highlighting the diffusion of this strain. CONCLUSION: Importation of C. auris from abroad has been previously described. We report the first case of C. auris imported into Italy from Greece, according to phylogenetic analysis. This case reinforces the need for monitoring critically ill hospitalised patients also for fungi and addresses the need for the standardisation of susceptibility testing and strategies for diagnosis and therapy.

Early administration of nirmatrelvir/ritonavir leads to faster negative SARS-CoV-2 nasal swabs than monoclonal antibodies in COVID 19 patients at high-risk for severe disease.

PURPOSE: Besides the well-established efficacy in preventing severe COVID-19, the impact of early treatments, namely antivirals and monoclonal antibodies (mAbs), on the time length to negativization of SARS-CoV-2 nasal swabs is still unclear. The aim of this study was to compare the efficacy of different early treatments in reducing the SARS-CoV-2 viral shedding, identifying a single drug that might potentially lead to a more rapid negativization of SARS-CoV-2 nasal swab. METHODS: This was a single-centre, retrospective, observational study conducted at Ospedale Luigi Sacco in Milan. Data of high-risk COVID-19 patients who received early treatments between 23 December 2021 and March 2023 were extracted. The comparison across treatments was conducted using the Kruskall-Wallis test for continuous variables. Dunn's test with Bonferroni adjustment was performed for post-hoc comparisons of days to negativization. Secondly, a negative binomial regression adjusted for age, sex, number of comorbidities, immunosuppression, and SARS-CoV-2 vaccination status was implemented. RESULTS: Data from 428 patients receiving early treatments were collected. The majority were treated with Nirmatrelvir/Ritonavir and were affected by SARS-CoV-2 Omicron infection with BA.2 sublineage. The median length time to SARS-CoV-2 nasal swab negativization was 9 days [IQR 7-13 days]. We found that Nirmatrelvir/Ritonavir determined a significant decrease of the length time to SARS-CoV-2 nasal swab negativization compared to mAbs (p = 0.003), but not compared to Remdesivir (p = 0.147) and Molnupiravir (p = 0.156). CONCLUSION: Our findings highlight the importance of promptly treating high-risk COVID-19 patients with Nirmatrelvir/Ritonavir, as it also contributes to achieving a faster time to negative SARS-CoV-2 nasal swabs.

Consensus definitions in imported human schistosomiasis: a GeoSentinel and TropNet Delphi study.

Terminology in schistosomiasis is not harmonised, generating misunderstanding in data interpretation and clinical descriptions. This study aimed to achieve consensus on definitions of clinical aspects of schistosomiasis in migrants and returning travellers. We applied the Delphi method. Experts from institutions affiliated with GeoSentinel and TropNet, identified through clinical and scientific criteria, were invited to participate. Five external reviewers revised and pilot-tested the statements. Statements focusing on the definitions of acute or chronic; possible, probable, or confirmed; active; and complicated schistosomiasis were managed through REDCap and replies managed in a blinded manner. Round 1 mapped the definitions used by experts; subsequent rounds were done to reach consensus, or quantify disagreement, on the proposed statements. Data were analysed with percentages, medians, and IQRs of a 5-point Likert scale. The study was terminated on the basis of consensus or stability-related and time-related criteria. 28 clinicians and scientists met the criteria for experts. 25 (89%) of 28 experts replied to Round 1, 18 (64%) of 28 to Round 2, 19 (68%) of 28 to Round 3, and 21 (75%) of 28 to at least two rounds. High-level consensus (79-100% agreement and IQRs ≤1) was reached for all definitions. Consensus definitions will foster harmonised scientific and clinical communication and support future research and development of management guidelines for schistosomiasis.

Dynamics of viral DNA shedding and culture viral DNA positivity in different clinical samples collected during the 2022 mpox outbreak in Lombardy, Italy.

BACKGROUND: Mpox virus (MPXV) has recently spread outside of sub-Saharan Africa. This large multicentre study was conducted in Lombardy, the most densely populated Italian region accounting for more than 40% of Italian cases. The present study aims to: i) evaluate the presence and the shedding duration of MPXV DNA in different body compartments correlating the MPXV viability with the time to onset of symptoms; ii) provide evidence of MPXV persistence in different body compartment as a source of infection and iii) characterize the MPXV evolution by whole genome sequencing (WGS) during the outbreak occurred in Italy. MATERIAL AND METHODS: The study included 353 patients with a laboratory-confirmed diagnosis of MPXV infection screened in several clinical specimens in the period May 24th - September 1st, 2022. Viral isolation was attempted from different biological matrices and complete genome sequencing was performed for 61 MPXV strains. RESULTS: MPXV DNA detection was more frequent in the skin (94.4%) with the longest median time of viral clearance (16 days). The actively-replicating virus in cell culture was obtained for 123/377 (32.6%) samples with a significant higher viral quantity on isolation positive samples (20 vs 31, p < 0.001). The phylogenetic analysis highlighted the high genetic identity of the MPXV strains collected, both globally and within the Lombardy region. CONCLUSION: Skin lesion is gold standard material and the high viral load and the actively-replicating virus observed in genital sites confirms that sexual contact plays a key role in the viral transmission.

Rilpivirine and cabotegravir trough concentrations in people with HIV on long-term treatment with long-acting injectable antiretrovirals.

OBJECTIVE: Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment. METHODS: Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated. RESULTS: Sixty-seven PWH were identified. LAI treatment duration was 216 ±â€Š80 weeks (range 32-320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; P < 0.05). No differences were found in rilpivirine (160 ±â€Š118 versus 189 ±â€Š81 ng/mL; P = 0.430) and cabotegravir (1758 ±â€Š807 versus 1969 ±â€Š802 ng/mL; P = 0.416) trough concentrations in males (n = 55) versus females (n = 12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index >30 kg/m2 (n = 9) versus non-obese participants (1916 ±â€Š905 versus 1606 ±â€Š576 ng/mL; P = 0.131). Three out of the 67 PWH had at least one drug concentration <4×PA-IC90: 100% of PWH had undetectable HIV viral load. CONCLUSIONS: At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included.

Management of Polypharmacy and Potential Drug-Drug Interactions in Patients with Pulmonary Aspergillosis: A 2-Year Study of a Multidisciplinary Outpatient Clinic.

Pulmonary aspergillosis mainly affects elderly patients, patients with pulmonary complications, patients with hematological malignancies, organ transplant recipients, or critically ill patients. Co-morbidities may result in a high rate of polypharmacy and a high risk of potential drug-drug interaction (pDDI)-related antifungal azoles, which are perpetrators of several pharmacokinetic- and pharmacodynamic-driven pDDIs. Here, we report the results of the first 2-year study of an outpatient clinic focusing on the management of therapies in patients with pulmonary aspergillosis. All patients who underwent an outpatient visit from May 2021 to May 2023 were included in this retrospective analysis. A total of 34 patients who were given an azole as an antifungal treatment (53% voriconazole, 41% isavuconazole, and 6% itraconazole) were included. Overall, 172 pDDIs were identified and classified as red- (8%), orange- (74%), or yellow-flag (18%) combinations. We suggested handling polypharmacy in those patients using specific diagnostic and pharmacologic interventions. As expected, red-flag pDDIs involved mainly voriconazole as a perpetrator (71%). However, nearly 30% of red-flag pDDIs were not related to antifungal therapy. These findings highlight the importance of conducting an overall assessment of the pharmacologic burden and the key role played by a multidisciplinary team for the optimization of therapies in patients with pulmonary aspergillosis.