Pierluigi Viale

Infections caused by multidrug-resistant Gram-negative (MDR-GN) bacteria, particularly carbapenem-resistant organisms (CROs), constitute a significant burden in critically ill patients (CIPs). A multidisciplinary, collaborative approach is essential for responsible antibiotic use in CIPs, balancing the necessity for effective treatment with mitigation of antimicrobial resistance (AMR). While the efficacy of existing antibiotics against CROs is increasingly limited due to resistance development and suboptimal pharmacokinetic/pharmacodynamic properties, several barriers impede the widespread adoption of new agents, including selective susceptibility testing, limited availability, high costs, and concerns regarding the fostering of resistance. Antimicrobial stewardship (AMS) strategies aim to optimize antibiotic use; however, there is an ongoing debate between restrictive and enabling approaches for new antibiotics in CIPs with CRO infections. While restrictive strategies focus on limiting antibiotic use to mitigate resistance, they may delay necessary treatment and negatively impact professional culture. Enablement strategies promote informed decision-making and accessibility when needed but require substantial workforce and expertise. In this narrative review and expert opinion, we propose an algorithm supporting a coordinated AMS approach in CIPs, emphasizing the importance of early diagnosis and appropriate therapy. We advocate for an enablement strategy for new antibiotics in CIPs with MDR-GN infections, aiming to reduce mortality and toxicity associated with older agents. This strategy should be integrated into local AMS programmes under the guidance of experienced clinicians.

Objectives: To assess whether attaining an aggressive pharmacokinetic/pharmacodynamic (PK/PD) target with continuous infusion (CI) cefiderocol could be an effective strategy for managing documented bloodstream infections (BSIs) and pneumonia caused by Stenotrophomonas maltophilia, and to identify independent predictors of microbiological and clinical failure. Methods: Patients receiving CI cefiderocol according to a real-time therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) program for managing documented BSIs and/or pneumonia caused by Stenotrophomonas maltophilia were retrospectively included. Free fractions of plasma cefiderocol steady-state concentrations (fC_ss) were calculated according to a protein binding of 58%, and aggressive PK/PD target was defined as the attainment of a fC_ss/MIC ratio > 4. Exploratory multivariate analysis was implemented for assessing potential independent predictors of microbiological and clinical failure. Results: Overall, 25 patients (14 BSIs, 10 pneumonia, and one bacteremic pneumonia) were included. Early and overall aggressive cefiderocol PK/PD target was attained in 100.0% of cases. Microbiological eradication rate was 75.0% (15/20) among patients having available follow-up cultures, whereas clinical cure rate was 60.0% (15/25). No case of resistance occurrence to cefiderocol emerged. Bacteremia emerged as the only potential predictor of reduced risk of microbiological failure (odds ratio [OR] 0.04; 95%CI 0.01–0.54; p = 0.016), whereas mechanical ventilation was potentially associated with higher risk of clinical failure (OR 15.17; 95%CI 2.03–111.35; p = 0.008). No significant differences between cefiderocol mono- or combination therapy in terms of microbiological and/clinical outcome were found. Conclusions: Our findings could suggest that CI cefiderocol could be a feasible way for attaining aggressive PK/PD target. This approach could represent a valuable strategy for favoring the microbiological eradication and/or clinical cure of documented Stenotrophomonas maltophilia infections with cefiderocol monotherapy in critical immunocompromised patients. Prospective comparative studies would be warranted for confirming our hypothesis.

Background: Appropriate antibiotic therapy is a key determinant of outcomes in Pseudomonas aeruginosa bloodstream infection (BSI), but the impact of adequate source control on prognosis has not been well defined in large cohorts. Methods: We conducted a retrospective multicenter study including hospitalized patients with P. aeruginosa BSI across 14 Italian hospitals between January 2021 and December 2022. Results: Overall, 639 BSI episodes were analyzed. The most frequent sources were an unknown source (31.8%), central venous catheter BSI (22.5%), hospital-acquired/ventilator-associated pneumonia (20.3%), urinary tract infections (11.4%), and intra-abdominal infections (6.9%). Source control was required in 34.0% of cases and was achieved early and adequately in 49.3% of these. The 30-day all-cause mortality rate was 23.9%. Mortality was significantly lower in patients who received early adequate source control (6.5%) compared with those without early adequate source control (23.6%) or in whom it was deemed unnecessary (28.4%) (P < .0001). In multivariable analysis, age, corticosteroid therapy, and septic shock were independently associated with increased mortality, whereas prior P. aeruginosa colonization, early adequate source control, and appropriate antibiotic therapy were protective. A propensity score–matched analysis confirmed the association between early adequate source control and reduced 30-day mortality (adjusted hazard ratio 0.15; P = .0024). Conclusions: Early adequate source control is a critical determinant of survival in P. aeruginosa BSI. Outcomes are optimized by a combined approach integrating timely source control with appropriate antibiotic therapy.

Background: Empirical broad-spectrum antibiotic therapy is currently recommended for patients undergoing surgical treatment of prosthetic joint infections (PJIs), while awaiting intraoperative culture results. However, widespread use of Gram-negative coverage may lead to more adverse reactions, resistance selections and costs. Objectives: This study aimed to identify the factors associated with having a PJI caused by Gram-negative bacteria (GNB). Methods: This was an observational retrospective study of patients with hip and knee PJIs undergoing infection surgery between 2015 and 2019. PJI was defined according to 2018 Musculoskeletal Infection Society-International Consensus Meeting criteria. To assess risk factors for GNB-PJI, univariate and multivariate logistic regression analysis was carried out; statistical significance was considered for P values <0.05. Results: A total of 281 patients were included, 137/281 (49%) were males, median age was 68 years (IQR 55-75), and the hip was involved in 147/281 (52%) cases. The most frequent surgical approach was a two-stage revision, carried out in 171/281 (61%), and the overall treatment failure rate was 19% (54/281). A Gram-negative aetiology was found in 51/281 (18%) cases; in this group the most frequent aetiological agents were Enterobacterales (n = 36). After surgery, 192/281 (68%) patients received empirical broad-spectrum antibiotic therapy with GNB coverage. In the logistic regression analysis, hip PJI was an independent risk factor for GNB-PJI (OR 2.88, 95% CI 1.44–5.77, P = 0.003) while delayed infection was associated with lower risk (OR 0.45, 95% CI 0.21–0.94, P = 0.03). Conclusions: In our cohort, hip PJI was associated with a higher likelihood of GNB infection, whereas delayed-onset PJI was associated with a significantly lower likelihood.

Background: The study aim was to evaluate the effectiveness of anti–methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins in combination with daptomycin (anti-MRSA Ceph + DAP) compared to other antimicrobial regimens (OARs) as initial treatment of MRSA bloodstream infection (BSI). Methods: This retrospective observational study enrolled patients with MRSA-BSI from 1 January 2020 to 31 December 2024 at 4 large Italian hospitals. The primary endpoint was 90-day all-cause mortality. Cox regression was used for primary endpoint analysis; results were confirmed with inverse probability of treatment weighting (IPTW). Treatment efficacy was also assessed using the desirability of outcome ranking (DOOR) approach, assigning 1 additional point beyond recovery for 1 of the following negative outcomes: (i) persistent MRSA infection, (ii) persistent bacteremia (≥5 days), (iii) drug resistance, (iv) any adverse event, and (v) 90-day relapse. A score of 7 was assigned for death at any time point. Results: Overall, 465 patients were enrolled: Median age was 76 (IQR, 61–83) years, 59% male, with a Charlson Comorbidity Index score of 7 (IQR, 4–8). Of them, 50 (11%) and 116 (25%) patients had endocarditis and metastatic infection, respectively. Importantly, 90-day mortality occurred in 181 (39%) patients, while 260 (56%) experienced at least 1 negative outcome included in DOOR analysis. Overall, patients in the anti-MRSA Ceph + DAP arm had a 59.9% (95% CI, 52.4%–67.4%) probability of having a better outcome than those in the OAR arm. Particularly, anti-MRSA Ceph + DAP was associated with reduced mortality (aHR, 0.54 [95% CI, .34–.85]), confirmed after adjustment with IPTW analysis. Conclusions: Anti-MRSA Ceph + DAP could represent a valid initial therapy for MRSA-BSI, especially in patients with high risk of worse outcomes.

Onco-haematological patients with febrile neutropenia are at high risk of severe infections caused by multidrug-resistant pathogens. Continuous infusion (CI) of beta-lactams may improve pharmacokinetic/pharmacodynamic (PK/PD) target attainment, yet evidence in this population remains limited. To evaluate the likelihood of achieving an aggressive PK/PD target with CI beta-lactams during the first week of therapy in onco-haematological patients and to identify predictors of target non-attainment. This prospective observational study enrolled adult onco-haematological patients receiving CI beta-lactams for empirical or targeted treatment over a 1-year period. Steady-state plasma concentrations were measured between days 3 and 7. The aggressive PK/PD target was defined as a free steady-state concentration-to-MIC (or clinical breakpoint) ratio ≥4; for beta-lactam/beta-lactamase inhibitor combinations, a joint PK/PD target was applied. Multivariate logistic regression analysis identified factors associated with target attainment. A total of 256 patients were included, 82 of whom (32.1%) received targeted therapy. Aggressive PK/PD target attainment was achieved in 85.4% of patients undergoing targeted treatment, compared with 57.5% of those treated empirically. Target non-attainment occurred most frequently with piperacillin/tazobactam and ceftazidime/avibactam. Augmented renal clearance (OR 12.29, P < 0.001), male sex (OR 3.79, P < 0.001) and age P = 0.025) independently predicted target non-attainment, whereas targeted therapy and meropenem use were associated with a higher attainment. CI beta-lactams reliably achieve aggressive PK/PD targets during targeted therapy but not during empirical treatment in onco-haematological patients. Augmented renal clearance is a major determinant of underexposure, supporting the use of therapeutic drug monitoring to optimize dosing in this high-risk population.

Background: To assess the true prevalence and the risk factors of augmented renal clearance (ARC) in critical orthotopic liver transplant (OLT) recipients and its impact on early aggressive pharmacokinetic/pharmacodynamic (PK/PD) target non‐attainment of continuous infusion (CI) beta‐lactams. Methods: OLT recipients without renal dysfunction and undergoing one or more measured creatinine clearance (mCLCr) assessments in the first 30 days posttransplant were retrospectively included. Reliability of three different eGFR formulas (Cockcroft–Gault, 2021, CKD‐EPI, and MDRD) in estimating mCLCr was tested. Univariate analyses compared the clinical features of ARC versus non‐ARC patients and the severity of the clinical conditions during ARC versus non‐ARC episodes in the whole cohort. In patients receiving CI beta‐lactam therapy, risk factors for early aggressive PK/PD target non‐attainment were investigated. Results: Among 450 critical OLT recipients, 112 were included. The true prevalence of ARC was 23.2%. ARC versus non‐ARC patients were younger ( p = 0.003), had lower MELD score ( p = 0.001), received lower number of intraoperative blood transfusions ( p = 0.007), and had a lower need for venovenous bypass technique ( p = 0.024). ARC episodes occurred more frequently in patients having lower SOFA score ( p = 0.005) and lower median serum creatinine levels ( p < 0.001). None of the eGFR formulas properly estimated mCLCr. In the subset of 50 OLT recipients receiving 60 CI beta‐lactam treatment courses, ARC was the only factor associated with early aggressive PK/PD target non‐attainment ( p = 0.018). Conclusions: ARC is a quite prevalent condition among critical OLT recipients, which may hinder early aggressive PK/PD target attainment when using standard beta‐lactams dosing regimens, regardless of delivery by CI.

Background: Antimicrobial resistance poses a significant threat to global health, with Gram-negative pathogens contributing to morbidity, mortality and healthcare costs. While ceftolozane/tazobactam provides an effective treatment option against these pathogens, real-world data on healthcare resource use associated with ceftolozane/tazobactam, especially outside the USA, remain limited. Materials and methods: This retrospective, multinational observational study includes 617 adult inpatients from Australia, Austria, Germany, Italy, Mexico, Spain and the UK who received ≥48 hours of ceftolozane/tazobactam. The outcomes included 30-day all-cause and infection-related readmission rates, hospital length of stay and post-ceftolozane/tazobactam length of stay. Subgroup analyses were conducted by rank of ceftolozane/tazobactam initiation, ICU admission and cystic fibrosis status. Results: The overall 30-day all-cause readmission rate was 10.2%. The infection-related readmission rate was 4.9%. The median hospital length of stay was 42 days (IQR 22–71), and median post-ceftolozane/tazobactam length of stay was 6 days (IQR 1–25). Among ICU patients (n = 298), the 30-day all-cause readmission rate was 3.4% and median length of stay was 59 days. In cystic fibrosis patients (n = 64), the 30-day all-cause readmission rate was 10.9% and the median length of stay was 31.5 days (IQR 16–48.5). Conclusions: This is the largest multinational, real-world dataset on healthcare resource use associated with ceftolozane/tazobactam outside the USA. These descriptive findings show differences in readmission rates and length of stay across rank-of-initiation groups; however, no causal relationships can be inferred from these data. The results are hypothesis-generating for future adjusted and economic analyses. Further research is warranted for economic evaluations and to optimize the timing of ceftolozane/tazobactam initiation.

Introduction. Clinical trials and observational studies of co-formulated regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) and doravirine/lamivudine, tenofovir disoproxil fumarate (DOR/3TC/TDF) demonstrated potent efficacy in both antiretroviral therapy-naive and -experienced patients, but data on efficacy in naive people with high-level Human Immunodeficiency Virus (HIV) viraemia are still lacking. Hypothesis. BIC/F/TAF and DOR/3TC/TDF have comparable effectiveness in naive people with high-level viraemia. Aim. To compare the effectiveness of BIC/F/TAF and DOR/3TC/TDF in naive people with high-level viraemia. Methodology. We performed a retrospective cohort study of adult people living with HIV, who were naive to antiretroviral therapy, had baseline HIV-1 RNA > 500,000 copies ml ⁻¹ and initiated the co-formulated regimen BIC/F/TAF or DOR/3TC/TDF. Virological efficacy, changes in immunological parameters and safety profiles after 12 months of treatment were evaluated. Results. Inclusion criteria were met by 78 patients: 43 in the BIC/F/TAF group and 35 in the DOR/3TC/TDF group. Baseline characteristics were similar in both groups: median age was 45.2 years, median HIV RNA was 5.95 log ₁₀ , median CD4 T lymphocyte count was 383 cells mm ⁻³ and 22 patients (28%) had HIV RNA >10 ⁶ copies ml ⁻¹ . After 12 months, virological efficacy was comparable: HIV RNA −1 was obtained in 40 patients (93%) in the BIC/F/TAF group and in 31 (89 %) in the DOR/3TC/TDF group. The median increase in CD4 T lymphocyte count was comparable between groups (+139 and +117 cells mm ⁻³ , respectively), such as incidence of adverse events, while median increase in low-density lipoprotein cholesterol and weight gain was significantly greater in the BIC/F/TAF group (weight change, +1.64 kg vs. +0.85 kg; P =0.013). Conclusion. In this real-life cohort, BIC/F/TAF and DOR/3TC/TDF showed high and comparable virological efficacy in naive patients with baseline HIV RNA above 500,000 copies ml ⁻¹ .

Background: Staphylococcal bloodstream infections (BSIs) and infective endocarditis (IE) are associated with high morbidity and mortality. Among the different antimicrobial combination strategies proposed to enhance antibacterial activity, the association of daptomycin and ceftobiprole may be valuable. The aim of this study was to assess the PK/PD target attainment, safety, and clinical outcomes of such combination therapy for BSI and IE treatment. Methods: This retrospective monocentric study included adult patients with targeted treatment of staphylococcal BSI or IE with daptomycin plus continuous infusion (CI) ceftobiprole. Therapeutic drug monitoring (TDM) was performed for both agents, including Bayesian estimation of daptomycin 24 h area under the concentration–time curve (AUC_24h). PK/PD targets were defined as daptomycin AUC_24h/MIC ≥ 666 and ≥1081, and ceftobiprole steady-state concentration/MIC ≥ 4. Dose adjustments, safety, microbiological response, and clinical outcomes were assessed. Results: Twenty-three patients (11 BSI and 12 IE) were included. Methicillin-resistant Staphylococci were identified in 91.3% of cases. At first TDM assessment, daptomycin PK/PD targets were achieved in all patients, while ceftobiprole targets were achieved in 91.6% of BSI cases and in all IE cases. PK-/PD-guided dose de-escalation was frequently feasible. Clinical cure was observed in 77.8% of evaluable patients with BSI and in 91.7% with IE. Creatine phosphokinase elevations occurred in two patients, while hyper-eosinophilia was observed in 69.6% and was manageable with monitoring. Conclusions: Targeted therapy with daptomycin plus CI ceftobiprole achieved high PK/PD target attainment and favorable clinical outcomes in staphylococcal BSI and IE. TDM and model-informed precision dosing may enable dose optimization and may improve the balance between efficacy and safety. Multicenter studies are warranted.