Proactive Therapeutic Drug MONiToring to Guide Suppressive Antibiotic Therapy with DALBAvaNcin (>12 weeks) in Osteoarticular Infections (MONTALBANO) Chiara Mariani, Matteo Passerini, Lucia Galli, Alice Covizzi, Marta Colaneri, et al. Journal of Bone and Joint Infection, 2025 Introduction: Long-term dalbavancin use is increasingly adopted off-label for osteoarticular infections (OAIs), but data on administration timing and long-term effects beyond 12 weeks are scarce. This study evaluated the pharmacological efficacy of proactive therapeutic drug monitoring (TDM) to optimize dalbavancin administration. Methods: This single-center, retrospective study included adult OAI patients treated with ≥4 doses of dalbavancin from July 2022 to October 2024. Initial doses were given on days 1, 8, and 43. From the third dose onward, Cmin and Cmax values informed dosing schedules via log-linear regression models, targeting Cmin≥8 mg L−1. The primary outcome was the pharmacological efficacy of dalbavancin, assessed by the proportion of patients with Cmin≥8 mg L−1 and ≥4 mg L−1 after the third dose. Clinical outcomes and safety data were collected as descriptive data. Results: A total of 33 patients provided 118 Cmin determinations. Pharmacological efficacy was achieved in 93/118 (78.8 %) and 114/118 (96.6 %) determinations for Cmin thresholds of ≥8 mg L−1 and ≥4 mg L−1, respectively. Efficacy improved when considering only determinations at the correct timing. A total of 18 (54.5 %) patients are still in treatment, while 11 (33.3 %) completed therapy with clinical success. Three patients experienced a relapse after the end of the treatment, while one patient experienced failure, and no adverse events were reported. Conclusions: Dalbavancin is a viable option for prolonged OAI management when other therapies are unavailable or high-risk. Proactive TDM effectively supports this approach by ensuring adequate drug exposure while preventing accumulation.
NAT2 Acetylation Status Predicts Hepatotoxicity During Antituberculosis Therapy: Cumulative Risk Analysis of a Multiethnic Cohort Marco Schiuma, Sofia Dinegro, Vera Battini, Alessandro Torre, Alice Covizzi, et al. International Journal of Molecular Sciences, 2025 Antituberculosis drug-induced hepatotoxicity (ATDH) is a common adverse drug reaction often requiring treatment interruption, complicating tuberculosis management. The slow acetylator phenotype, characterized by reduced N-acetyltransferase 2 (NAT2) enzyme activity, is associated with increased hepatotoxicity risk, while rapid acetylators are associated with a higher risk of therapeutic failure. This study investigates the association between the NAT2 acetylation phenotype and ATDH occurrence, with an emphasis on its predictive value in regard to a multiethnic population and its impact on the timing of ATDH onset. A retrospective observational study was conducted on tuberculosis patients treated at Luigi Sacco Hospital, Milan, Italy (July 2020–September 2023). The NAT2 genotyping identified slow and rapid/intermediate acetylators. Cumulative incidence analysis and Fine–Gray competing risks regression models were used to assess ATDH risk and onset timing. Among 102 patients, 21.6% developed ATDH, including 16.7% with slow and 4.9% with rapid/intermediate acetylators. ATDH onset was significantly earlier in regard to slow acetylators (median 0.5 vs. 2 months, interquartile range-IQR: 0.5–3 vs. 1.7–5.5). Slow acetylators were associated with a higher risk of developing ATDH (Sub-distribution hazard ratio, SHR = 3.05; 95% confidence interval-CI: 1.17–7.95; p = 0.02), even after adjusting for confounders. The NAT2 acetylation phenotype strongly influences ATDH risk and timing. Early acetylator status identification may enable dose adjustments, enhancing treatment safety. These findings highlight the role of pharmacogenetics in optimizing antituberculosis therapy by improving efficacy and minimizing toxicity.
SARS-CoV-2 infectivity can be modulated through bacterial grooming of the glycocalyx Cameron Martino, Benjamin P. Kellman, Daniel R. Sandoval, Thomas Mandel Clausen, Robert Cooper, et al. Mbio, 2025 The gastrointestinal (GI) tract is a site of replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and GI symptoms are often reported by patients. SARS-CoV-2 cell entry depends upon heparan sulfate (HS) proteoglycans, which commensal bacteria that bathe the human mucosa are known to modify. To explore human gut HS-modifying bacterial abundances and how their presence may impact SARS-CoV-2 infection, we developed a task-based analysis of proteoglycan degradation on large-scale shotgun metagenomic data. We observed that gut bacteria with high predicted catabolic capacity for HS differ by age and sex, factors associated with coronavirus disease 2019 (COVID-19) severity, and directly by disease severity during/after infection, but do not vary between subjects with COVID-19 comorbidities or by diet. Gut commensal bacterial HS-modifying enzymes reduce spike protein binding and infection of authentic SARS-CoV-2, suggesting that bacterial grooming of the GI mucosa may impact viral susceptibility. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019, can infect the gastrointestinal (GI) tract, and individuals who exhibit GI symptoms often have more severe disease. The GI tract’s glycocalyx, a component of the mucosa covering the large intestine, plays a key role in viral entry by binding SARS-CoV-2’s spike protein via heparan sulfate (HS). Here, using metabolic task analysis of multiple large microbiome sequencing data sets of the human gut microbiome, we identify a key commensal human intestinal bacteria capable of grooming glycocalyx HS and modulating SARS-CoV-2 infectivity in vitro . Moreover, we engineered the common probiotic Escherichia coli Nissle 1917 (EcN) to effectively block SARS-CoV-2 binding and infection of human cell cultures. Understanding these microbial interactions could lead to better risk assessments and novel therapies targeting viral entry mechanisms.
Understanding the burden of antibiotic resistance: a decade of carbapenem-resistant Gram-negative bacterial infections in Italian intensive care units Giovanni Scaglione, Matilde Perego, Marta Colaneri, Camilla Genovese, Fabio Brivio, et al. Frontiers in Microbiology, 2024 IntroductionIn patients admitted to intensive care units (ICUs), Gram-negative bacteria (GNB) infections pose significant challenges due to their contribution to morbidity, mortality, and healthcare costs. During the SARS-CoV-2 pandemic, Italy witnessed a rise in healthcare-associated infections (HAIs), with GNBs involved in a substantial proportion of cases. Concerningly, carbapenem-resistant GNBs (CR-GNBs) have increased worldwide, posing therapeutic challenges.MethodsRetrospective multicentre study analysing data from over 299,000 patients admitted to Italian ICUs from 2013 to 2022.ResultsThe study revealed an average of 1.5 infections per patient, with HAIs peaking during the pandemic years. Ventilator associated pneumonia (VAP) emerged as the most common HAI, with Klebsiella spp. and Pseudomonas aeruginosa predominating. Alarmingly, CR-GNBs accounted for a significant proportion of infections, particularly in VAP, bloodstream infections, and intra-abdominal infections.DiscussionOur findings underscore the pressing need for enhanced infection control measures, particularly in the ICU setting, to mitigate the rising prevalence of CR-GNBs and their impact on patient outcomes. The study provides valuable insights into the epidemiology of HAIs in Italian ICUs and highlights the challenges posed by CR-GNBs, especially in the context of the SARS-CoV-2 pandemic, which exacerbated the issue and may serve as a crucial example for the management of future viral pandemics.
Immunogenicity of two doses of BNT162b2 and mRNA-1273 vaccines for solid cancer patients on treatment with or without a previous SARS-CoV-2 infection Nicla La Verde, Agostino Riva, Maria Silvia Cona, Arianna Gabrieli, Monica Cattaneo, et al. International Journal of Cancer, 2023 Previous studies on the immunogenicity of SARS‐CoV‐2 mRNA vaccines showed a reduced seroconversion in cancer patients. The aim of our study is to evaluate the immunogenicity of two doses of mRNA vaccines in solid cancer patients with or without a previous exposure to the virus. This is a single‐institution, prospective, nonrandomized study. Patients in active treatment and a control cohort of healthy people received two doses of BNT162b2 (Comirnaty, BioNTech/Pfizer, The United States) or mRNA‐1273 (Spikevax, Moderna). Vaccine was administered before starting anticancer therapy or on the first day of the treatment cycle. SARS‐CoV‐2 antibody levels against S1, RBD (to evaluate vaccine response) and N proteins (to evaluate previous infection) were measured in plasma before the first dose and 30 days after the second one. From January to June 2021, 195 consecutive cancer patients and 20 healthy controls were enrolled. Thirty‐one cancer patients had a previous exposure to SARS‐CoV‐2. Cancer patients previously exposed to the virus had significantly higher median levels of anti‐S1 and anti‐RBD IgG, compared to healthy controls (P = .0349) and to cancer patients without a previous infection (P < .001). Vaccine type (anti‐S1: P < .0001; anti‐RBD: P = .0045), comorbidities (anti‐S1: P = .0274; anti‐RBD: P = .0048) and the use of G‐CSF (anti‐S1: P = .0151) negatively affected the antibody response. Conversely, previous exposure to SARS‐CoV‐2 significantly enhanced the response to vaccination (anti‐S1: P < .0001; anti‐RBD: P = .0026). Vaccine immunogenicity in cancer patients with a previous exposure to SARS‐CoV‐2 seems comparable to that of healthy subjects. On the other hand, clinical variables of immune frailty negatively affect humoral immune response to vaccination.