Synergistic properties of linezolid against Enterococcus spp. isolates: a systematic review from in vitro studies.

PURPOSE: Vancomycin-resistant enterococci (VRE) are a leading cause of hospital-acquired infections with limited therapeutic options. Combination of at least two antimicrobials is a possible strategy to obtain rapid and sustained bactericidal effects and overcome the emergence of resistance. We revised the literature on linezolid synergistic properties from in vitro studies to assess its activity in combination with molecules belonging to other antibiotic classes against Enterococcus spp. METHODS: We performed a systematic review of the literature from three peer-reviewed databases including papers evaluating linezolid synergistic properties in vitro against Enterococcus spp. isolates. RESULTS: We included 206 Enterococcus spp. isolates (92 E. faecalis, 90 E. faecium, 2 E. gallinarum, 3 E. casseliflavus, 19 Enterococcus spp.) from 24 studies. When an isolate was tested with different combinations, each combination was considered independently for further analysis. The most frequent interaction was indifferent effect (247/343, 72% of total interactions). The highest synergism rates were observed when linezolid was tested in combination with rifampin (10/49, 20.4% of interactions) and fosfomycin (16/84, 19.0%, of interactions). Antagonistic effect accounted for 7/343 (2.0%) of total interactions. CONCLUSION: Our study reported overall limited synergistic in vitro properties of linezolid with other antibiotics when tested against Enterococcus spp. The clinical choice of linezolid in combination with other antibiotics should be guided by reasoned empiric therapy in the suspicion of a polymicrobial infection or targeted therapy on microbiological results, rather than on an intended synergistic effect of the linezolid-based combination.

Tailored treatment for tuberculosis in transgender individuals: a call for a patient-centered approach from a large Italian cohort.

Tuberculosis (TB) diagnosis and management in special populations remain challenging. Data about TB and transgender individuals is scarce, and strategies aimed at reducing the TB burden in this at-risk group are needed. We conducted an observational monocentric study from a national reference center for TB, including transgender individuals with active TB in a low-TB burden country (Italy), over 34 years (1990-2023). Sixty-six transgender males and two transgender females (median age 30 years, interquartile range 26-38 years, 65 migrants) were included. Most patients (38/66, 57.6%) lived in poor social conditions. 65.2% (43/66) of patients were people living with HIV. Multidrug- and rifampicin-resistant tuberculosis and isoniazid-resistant TB were diagnosed in five (7.6%) and three (4.5%) patients, respectively. The overall treatment success rate was 72.7% (48/66 patients), with differences observed according to social conditions. Our study highlights the need for a tailored approach to increase treatment success in this at-risk population.

Daptomycin synergistic properties from in vitro and in vivo studies: a systematic review.

INTRODUCTION: Daptomycin is a bactericidal lipopeptide antibiotic approved for the treatment of systemic infections (i.e. skin and soft tissue infections, bloodstream infections, infective endocarditis) caused by Gram-positive cocci. It is often prescribed in association with a partner drug to increase its bactericidal effect and to prevent the emergence of resistant strains during treatment; however, its synergistic properties are still under evaluation. METHODS: We performed a systematic review to offer clinicians an updated overview of daptomycin synergistic properties from in vitro and in vivo studies. Moreover, we reported all in vitro and in vivo data evaluating daptomycin in combination with other antibiotic agents, subdivided by antibiotic classes, and a summary graph presenting the most favourable combinations at a glance. RESULTS: A total of 92 studies and 1087 isolates (723 Staphylococcus aureus, 68 Staphylococcus epidermidis, 179 Enterococcus faecium, 105 Enterococcus faecalis, 12 Enterococcus durans) were included. Synergism accounted for 30.9% of total interactions, while indifferent effect was the most frequently observed interaction (41.9%). Antagonistic effect accounted for 0.7% of total interactions. The highest synergistic rates against S. aureus were observed with daptomycin in combination with fosfomycin (55.6%). For S. epidermidis and Enterococcus spp., the most effective combinations were daptomycin plus ceftobiprole (50%) and daptomycin plus fosfomycin (63.6%) or rifampicin (62.8%), respectively. FUTURE PERSPECTIVES: We believe this systematic review could be useful for the future updates of guidelines on systemic infections where daptomycin plays a key role.

An octopus gift: Mycobacterium marinum multiple skin lesions.

Mycobacterium marinum is a nontuberculous mycobacterium responsible of infections in humans, ranging from skin infection to disseminated infection in immunocompromised hosts. Clinical suspicion and prompt diagnosis are crucial to prescribe appropriate antimycobacterial treatment and avoid sequelae.

The challenge of infectious diseases consultations in the emergency department: an Italian nationwide survey.

Diagnosis and management of infectious diseases (ID) at the emergency department (ED) are challenging due to the peculiar setting and the available diagnostic tools. The involvement of an ID consultant has been described to improve clinical outcomes and antimicrobial stewardship (AMS) programs. An online survey was sent to 100 Italian Departments of Infectious Diseases affiliated with the Italian Society of Infectious Diseases and Tropical Medicine (SIMIT). The primary objective of our study was to describe the characteristics of ID services in Italian EDs to identify possible challenges and shortcomings and provide tips to improve the management of patients. Secondary objectives included the evaluation of diagnostic capability and the management of patients with suspected or confirmed ID. Seventy-six out of the 100 SIMIT centers, 32 (42.1%) of which were teaching hospitals, answered the survey. In 62 (82.7%) centers, consultations were performed by the IDs specialist on call. In 29 (38.2%) centers, there was a formal AMS program, and 32 (42.7%) had protocols for antibiotic use in the ED. Microbiological tests to be performed before starting antibiotic treatment in the ED were clearly defined in 44 (57.9%) hospitals. This survey highlighted several challenges in the current organization of ID consultations in Italian EDs.

Anaerobic bloodstream infections in Italy (ITANAEROBY): A 5-year retrospective nationwide survey.

INTRODUCTION: A lack of updated data on the burden and profile of anaerobic bloodstream infections (ABIs) exists. We assessed the incidence of ABIs and trends in antimicrobial resistance in anaerobes isolated from blood in Italy. MATERIAL AND METHODS: We conducted a retrospective study on 17 Italian hospitals (2016-2020). Anaerobes isolated from blood culture and their in vitro susceptibility profiles (EUCAST-interpreted) were registered and analyzed. RESULTS: A total of 1960 ABIs were identified. The mean age of ABIs patients was 68.6 ± 18.5 years, 57.6% were males. The overall incidence rate of ABIs was 1.01 per 10.000 patient-days. Forty-seven% of ABIs occurred in medical wards, 17% in ICUs, 14% in surgical wards, 7% in hemato-oncology, 14% in outpatients. The three most common anti-anaerobic tested drugs were metronidazole (92%), clindamycin (89%) and amoxicillin/clavulanate (83%). The three most common isolated anaerobes were Bacteroides fragilis (n = 529), Cutibacterium acnes (n = 262) and Clostridium perfringens (n = 134). The lowest resistance rate (1.5%) was to carbapenems, whereas the highest rate (51%) was to penicillin. Clindamycin resistance was >20% for Bacteroides spp., Prevotella spp. and Clostridium spp. Metronidazole resistance was 9.2% after excluding C. acnes and Actinomyces spp. Bacteroides spp. showed an increased prevalence of clindamycin resistance through the study period: 19% in 2016, 33% in 2020 (p ≤ 0.001). CONCLUSIONS: Our data provide a comprehensive overview of the epidemiology of ABIs in Italy, filling a gap that has existed since 1995. Caution is needed when clindamycin is used as empirical anti-anaerobic drug.

Fosfomycin in continuous or prolonged infusion for systemic bacterial infections: a systematic review of its dosing regimen proposal from in vitro, in vivo and clinical studies.

Fosfomycin (FOS) administered intravenously has been recently rediscovered for the treatment of systemic infections due to multidrug-resistant bacteria. Its pharmacokinetic properties suggest a time-dependent dosing schedule with more clinical benefits from prolonged (PI) or continuous infusion (CI) than from intermittent infusion. We revised literature concerning PI and CI FOS to identify the best dosing regimen based on current evidence. We performed a MEDLINE/PubMed search. Ninety-one studies and their pertinent references were screened. Seventeen studies were included in the present review. The activity of FOS against Gram-negative and Gram-positive bacteria was evaluated in fourteen and five studies, respectively. Six studies evaluated FOS activity in combination with another antibiotic. Daily dosing of 12, 16, 18 or 24 g, administered with different schedules, were investigated. These regimens resulted active against the tested isolates in most cases. Emergence of resistant isolates has been shown to be preventable through the coadministration of another active antibiotic. FOS is a promising option to treat systemic infections caused by multidrug-resistant bacteria. Coadministration with another active molecule is required to prevent the emergence of resistant bacterial strains. The results of our review suggest that a therapeutic regimen including a loading dose of FOS 8 g followed by a daily dose of 16 g or 24 g CI could be the best therapeutic approach for patients with normal renal function. The dosing regimens in patients with renal insufficiency and CI or PI superiority compared with intermittent infusion in clinical settings should be further investigated.

Mycobacterium chimaera infections: An update.

Mycobacterium chimaera is a non-tuberculous mycobacterium belonging to the Mycobacterium avium complex, described for the first time in 2004. It acts as an opportunistic pathogen, with infections, usually respiratory illnesses, occurring more frequently in immunocompromised patients or in patients with underlying respiratory diseases. During the last decade Mycobacterium chimaera disseminated infections following cardiothoracic surgery, especially open-heart surgery, have been increasingly reported worldwide. From a pathogenic standpoint, Mycobacterium chimaera is acquired during cardiopulmonary bypass via bioaerosols emitted from contaminated heater-cooler units water systems. Due to non-specific symptoms and long latency, postoperative Mycobacterium chimaera infections may not be promptly diagnosed and treated, and may become life-threatening. The indication for revision surgery needs to be carefully evaluated on a case-by-case basis, and antibiotic therapy should be based on drug susceptibility testing results. Our review aims to provide an updated account of microbiological characteristics, clinical presentation, diagnosis, and management of Mycobacterium chimaera infections, with a special focus on those developing after cardiothoracic surgery.

Management of abdominal aortic prosthetic graft and endograft infections. A multidisciplinary update.

Abdominal aortic graft infections (AGIs) occur in 1-5% of aortic prosthetic placements. It can result in limb amputation, pseudo-aneurysm formation, septic emboli, aorto-enteric fistulae, septic shock and death. The most frequently involved pathogens are methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, followed by Enterobacteriaceae and uncommon bacteria. In case of gut involvement the presence of fungi has to be considered. Computed tomography angiography is actually the gold standard diagnostic imaging but magnetic resonance is a valid alternative. Nuclear medicine imaging is commonly used to improve sensitivity and specificity. Signs and symptoms are often aspecific and blood cultures can be negative, requiring alternative ways to detect the microorganism responsible for infection, such as 16S rRNA gene sequencing and molecular rapid diagnostic tests. Curative surgical intervention is the first choice approach, with in-situ reconstruction providing by far the best outcome and xenopericardial bovine patch as a promising option. For patients unable to undergo major surgery, the outcome of conservative approach remains uncertain but usually provides for life-long suppressive therapy. However, in selected cases an attempt of stopping antibiotic treatment after 3-6 months can be done. Given the difficulty in their management, we performed a review of AGIs, in order to raise awareness on clinical presentation, current available diagnostic tools, prophylaxis, surgical and anti-infective treatment of AGIs.

Antiviral combination regimens as rescue therapy in immunocompromised hosts with persistent COVID-19.

The management of severe/prolonged SARS-CoV-2 infections in immunocompromised hosts is still challenging. We describe nine patients with hematologic malignancies with a history of unsuccessful SARS-CoV-2 treatment receiving antiviral combination treatment for persistent infection at a tertiary hospital in central Italy (University Hospital of Careggi, Florence). Combination treatments consisted of nirmatrelvir/ritonavir plus molnupiravir (n = 4), nirmatrelvir/ritonavir plus remdesivir (n = 4) or remdesivir plus molnupiravir (n = 1) for 10 days, in some cases associated with sotrovimab. Combinations were generally well tolerated. One patient obtained viral clearance but died due to the underlying disease. In eight cases, clinical and virological success was confirmed by radiological follow-up. Antivirals combination is likely to become a mainstay in the future management of COVID-19 among immunocompromised patients, but knowledge in this field is still very limited and prospective studies on larger cohorts are urgently warranted.

Tuberculosis in migrants: epidemiology, resistance and outcome in Milan, Italy.

BACKGROUND: Human migration and the ever-changing geopolitical scenarios are redefining the epidemiology and the management of tuberculosis (TB), especially in low-TB burden countries welcoming high rates of people from high-TB burden countries. METHODS: We conducted an observational retrospective mono-centric study in a Northern-Italy TB reference centre from 1 January 1990 to 31 December 2019, focusing on the differences in epidemiology, resistance patterns and treatment outcomes between Italians and migrants with active TB. Data were collected from medical records. RESULTS: A total of 10555 patients were included, 4614 Italians and 5941 migrants. Among migrants, higher rates of rifampin-resistant (RR) or multidrug-resistant (MDR) TB were reported, as well as higher rates of loss to follow-up. Among Italians, higher mortality rates and a higher number of extrapulmonary TB cases were found. CONCLUSION: Our study describes one of the largest cohorts of patients with active TB in Italy, highlighting the need for tailored approaches in native and migrant populations.

How We Treat Drug-Susceptible Pulmonary Tuberculosis: A Practical Guide for Clinicians.

Tuberculosis (TB) remains one of the leading causes of morbidity and mortality worldwide and pulmonary TB (PTB) is the main variant responsible for fueling transmission of the infection. Effective treatment of drug-susceptible (DS) TB is crucial to avoid the emergence of Mycobacterium tuberculosis-resistant strains. In this narrative review, through a fictional suggestive case of DS PTB, we guide the reader in a step-by-step commentary to provide an updated review of current evidence in the management of TB, from diagnosis to post-treatment follow-up. World Health Organization and Centre for Diseases Control (CDC) guidelines for TB, as well as the updated literature, were used to support this manuscript.

Combination regimen of nirmatrelvir/ritonavir and molnupiravir for the treatment of persistent SARS-CoV-2 infection: A case report and a scoping review of the literature.

Immunocompromised patients still experience unpredictable courses of COVID-19, despite that effective vaccines and drugs against SARS-CoV-2 are now available. Antiviral combination regimens may have a role in SARS-CoV-2 infection in immunocompromised hosts, but current knowledge is still limited. We describe the case of a 73-year-old Italian man affected by follicular lymphoma with persistent SARS-CoV-2 infection who was successfully treated with co-administration of oral antivirals (10-day molnupiravir and nirmatrelvir/ritonavir). The therapy was well tolerated both from a clinical and biochemical standpoint, with no signs of toxicity. We also performed a scoping review, to sum up available knowledge on combined antiviral regimens including remdesivir, molnupiravir, or nirmatrelvir/ritonavir. Pending further studies on larger cohorts of patients, our report is consistent with available pre-clinical and clinical data, supporting the possible use of combination therapy in selected difficult-to-treat COVID-19 cases.

Safety and Efficacy of Outpatient Treatments for COVID-19: Real-Life Data from a Regionwide Cohort of High-Risk Patients in Tuscany, Italy (the FEDERATE Cohort).

Early COVID-19 treatments can prevent progression to severe disease. However, real-life data are still limited, and studies are warranted to monitor the efficacy and tolerability of these drugs. We retrospectively enrolled outpatients receiving early treatment for COVID-19 in 11 infectious diseases units in the Tuscany region of Italy between 1 January and 31 March 2022, when Omicron sublineages BA.1 and BA.2 were circulating. Eligible COVID-19 patients were treated with sotrovimab (SOT), remdesivir (RMD), nirmatrelvir/ritonavir (NRM/r), or molnupiravir (MOL). We gathered demographic and clinical features, 28-day outcomes (hospitalization or death), and drugs tolerability. A total of 781 patients (median age 69.9, 66% boosted for SARS-CoV-2) met the inclusion criteria, of whom 314 were treated with SOT (40.2%), 205 with MOL (26.3%), 142 with RMD (18.2%), and 120 with NRM/r (15.4%). Overall, 28-day hospitalization and death occurred in 18/781 (2.3%) and 3/781 (0.3%), respectively. Multivariable Cox regression showed that patients receiving SOT had a reduced risk of meeting the composite outcome (28-day hospitalization and/or death) in comparison to the RMD cohort, while no significant differences were evidenced for the MOL and NRM/r groups in comparison to the RMD group. Other predictors of negative outcomes included cancer, chronic kidney disease, and a time between symptoms onset and treatment administration > 3 days. All treatments showed good safety and tolerability, with only eight patients (1%) whose treatment was interrupted due to intolerance. In the first Italian multicenter study presenting real-life data on COVID-19 early treatments, all regimens demonstrated good safety and efficacy. SOT showed a reduced risk of progression versus RMD. No significant differences of outcome were observed in preventing 28-day hospitalization and death among patients treated with RMD, MOL, and NRM/r.

How we deal with Staphylococcus aureus (MSSA, MRSA) central nervous system infections.

Among central nervous system (CNS) infections (e.g., meningitis, brain abscess, ventriculitis, transverse myelitis), those caused by Staphylococcus aureus (SA) are particularly challenging both in management and treatment, with poor clinical outcomes and long hospital stay. It has been estimated that SA is responsible for around 1%-7% of meningitis (up to 19% in healthcare-associated meningitis). Recent neurosurgical procedures and immunocompromisation are major risk factors for SA CNS infections. Hand hygiene, surveillance nasal swabs and perioperative prophylaxis are crucial points for effective SA infections prevention. In case of SA-CNS infections, pending microbiological results, anti-methicillin-resistant SA (MRSA) antibiotic, with good CNS penetration, should be included, with prompt de-escalation as soon as MRSA is ruled out. Consultation with an expert in antimicrobial therapy is recommended as well as prompt source control when feasible. In this narrative review, we reviewed current literature to provide practical suggestions on diagnosis, prevention, management, and treatment of SA CNS infections.

Mycobacterium marinum: A brief update for clinical purposes.

Mycobacterium marinum (M. marinum) is a free-living, slow grower nontuberculous mycobacteria (NTM), strictly related to Mycobacterium tuberculosis, that causes disease in fresh and saltwater fish and it is one of the causes of extra-pulmonary mycobacterial infections, ranging in human from simple cutaneous lesions to disseminated forms in immunocompromised hosts. The first human cases of M. marinum infection were reported from skin lesions of swimmers in a contaminated pool, in 1951, in Sweden by Norden and Linell. Two conditions are required to develop M. marinum infection: (1) skin solution of continuity and (2) exposure to the contaminated water or direct contact with fish or shellfish. The so-called "fish-tank granuloma", the most frequent cutaneous manifestation of M. marinum infection, is characterized by a single papulonodular, verrucose and/or ulcerated granulomatous lesion in the inoculum site. Careful patient's history collection, high clinical suspicion and appropriate sample (e.g. cutaneous biopsy) for microbiological culture are crucial for a timely diagnosis. The treatment is not standardized yet and relies on administration of two active antimycobacterial agents, always guided by antimicrobial susceptibility test on culture, with macrolides and rifampin as pivotal drugs, as well as prompt surgery when feasible. In this narrative review, we provide to Clinicians an updated report of epidemiology, microbiological characteristics, clinical presentation, diagnosis, and management of M. marinum infection.

Meta-analysis on the Association Between Thyroid Hormone Disorders and Arterial Stiffness.

Context: Aortic stiffness is an emerging predictor of cardiovascular morbidity and mortality. Current data about the effect of subclinical and overt thyroid hormone disorders on aortic stiffness are often conflicting. Objective: Primary outcome was to investigate if subclinical and overt thyroid hormone disorders were associated with aortic stiffness. Secondary outcome was to identify disease effect modifiers. Methods: Data sources were PubMed, Google Scholar, SCOPUS, Web of Sciences, and the Cochrane Library. Eligible studies included reports of pulse wave velocity (PWV), which is the gold standard method for measuring aortic stiffness, in patients with subclinical and overt thyroid disorders. Two investigators independently identified eligible studies and extracted data. Pooled mean difference was the summary effect measure. Data were presented in forest plots with outlier and influential case diagnostics. Univariate meta-regression analysis was used to identify effect modifiers. Results: Eleven observational studies were selected, including 1239 patients with subclinical hypothyroidism, 81 patients with overt hypothyroidism, 338 patients with thyrotoxicosis, and 12 715 controls. PWV was significantly higher in subclinical (P < .001) and overt hypothyroidism (P < .001), as well as in patients with thyrotoxicosis (P = .027) compared with controls. Age was an effect modifier in hypothyroid patients. Conclusion: This study shows that both overt and subclinical hypothyroidism as well as thyrotoxicosis were associated with an increase of aortic stiffness. The impact of treatment of these conditions on aortic stiffness should be assessed in clinical trials.

Arterial Stiffness in Thyroid and Parathyroid Disease: A Review of Clinical Studies.

Growing evidence shows that arterial stiffness measurement provides important prognostic information and improves clinical stratification of cardiovascular risk. Thyroid and parathyroid diseases are endocrine diseases with a relevant cardiovascular burden. The objective of this review was to consider the relationship between arterial stiffness and thyroid and parathyroid diseases in human clinical studies. We performed a systematic literature review of articles published in PubMed/MEDLINE from inception to December 2021, restricted to English languages and to human adults. We selected relevant articles about the relationship between arterial stiffness and thyroid and parathyroid diseases. For each selected article, data on arterial stiffness were extracted and factors that may have an impact on arterial stiffness were identified. We considered 24 papers concerning hypothyroidism, 9 hyperthyroidism and 16 primary hyperparathyroidism and hypoparathyroidism. Most studies evidenced an increase in arterial stiffness biomarkers in hypothyroidism, hyperthyroidism and primary hyperparathyroidism, even in subclinical and mild forms, although heterogeneity of measurement methods and of study designs prevented a definitive conclusion, suggesting that the assessment of arterial stiffness may be considered in the clinical evaluation of cardiovascular risk in these diseases.

The Role of PCSK9 in Infectious Diseases.

BACKGROUND: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, in particular regarding its role in lipid metabolism, cardiovascular risk but also its role in innate immunity. Increasing evidence is available on the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, as well as in the regulation of host response to bacterial infections, mainly sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. OBJECTIVE: Aim of this paper is to review available published literature on the role of PCSK9 in a wide array of infectious diseases. CONCLUSION: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients for the treatment of HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Finally, a loss of function in the PCSK9-encoding gene has been reported to possibly reduce mortality in malaria infection.